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) COMMISSION OF THE EUROPEAN COMMUNITIES Brussels, 08. 09. 1999 COM( 1999) 213 final 99/0180 (COD) Proposal for a EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE on the Community code relating to veterinary medicinal products. (codified version) (presented by the Commission). EXPLANATORYMEMORANDUM 1. In the co~tcXt of a people's Europe, the Commission attaches great importance to simplifying and clarifying Community law so·as to make it clearer and more accessible to the ordinary citUcn, thus. giving him new opportunities and the chance to make use of the specific rights it gives him. · This aim cannot be achieved so long as numerous provisiQDS that have been amended several tilnes, often quite· substantially, remain scattered, so that they must be sought partly in the original instrument and partly in later amending ones. Considerable research work, comparing many different instruments, is thus needed to identify the current rules. · For this reason a codification of rules that have frequently been amended is also essential if Community law is to. be clear and transparent 2. On 1 April 1987 the Commission therefore decided to instruct its staff that all legislative measures should be ~ after no more than ten amendments, stressing that this was a minimum requirement and that departments should endeavour to condify at even sboncr intervals the texts for which they were responsible, to ensure that the Community rules were clear and readily understandable. 3. The Conclusions of the Presidency of the Edinburgh European Council (December 1992) confinned this, stressing the importance of legislative codification as it offers certainty as to the law applicable to a given matter at a given time. It must be undertaken in full compliance with the nonnal Community legislative procedure. Given that no changes of substance may be made to the instruments affected by legislatjve codification. Parliament, interinstitutional agreement dated 20 December 1994, that an accelerated procedure may be used ·for the fast-track adoption of codification instruments. the Commission have agreed, by an the Council and 4. The purpose of this proposalU> for legislative codification of Council Directives 81/8S 1/EEC of 28 September 1981 on the approximation of the laws of the Member States relating to veterinazy medicinal products; 81/8S2/EEC of 28 September 1981 on the approximation of the laws of the Member States relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect ofthe testing of veterinary medicinal products; 90/677/EEC of 13 December 1990 extending the scope of Directive Sf/851/EEC on the approximation of the laws of the Member States relating to veterinary medicinal products and laying down additional provisions for immunological veterinary medicinal products; 92/74/EEC of 22 September 1992. widening the scope of Directive 8118S 1/EEC on the approximation of provisions laid down by law, regulation or administrative action relating to veterinary medicinal products and laying down additional provisions on homeopathic veterinary medicinal products, is to undertake official codification of this type. The new directive will supersede the various directives incorporated in it(2), their content is fully preserve~ and they are brought together with onlv such fonnal amendments as are required b;. · the codification exercise itself. 4a In order to point out the satisfactory application of the codification of the Directive mentioned above, in order to take into account the fact that since the last Directive cited in point 4, the European Agency for the Evaluation of Medicinal Products has been established by Council Regulation (EEC) 2309/93 of22 July 1993. In the. same manner, in order to point out that this codification proposal concerning medicinal products for human use was created in parallel with the codification proposal for Directives relating to veterinary medicinal products. S. This legislative codification proposal was drawn up on the basis of a prelimina. rv consolidation. in all the official languages. The instruments amending it, carried out by the Office for Official Publications of the European Communities, by means of the data-processing SVstcm referred to in the conclusions of the European Council meeting at Edinburgh. Although the articles have been given new numbers, the old numbering has been retained in the margin for case of reference; the correlation between the old and new numbers is shown in a table set out in Annex lll of the consolidated Directive. · (1) Enta'Cd in the legislative programme for 1998. en Sec Annex n, Part A of this Proposal. 2 Proposal for a EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE of ••• oa tbe Coblbluility code relatiDg to. veterillary medicblal products , THE EUROPEAN PARLIAMENT AND THE CQUNC~ OF THE EUROPEAN UNION, Having regard to the Treaty establishing the European Community, and in particular Article 95 ·thereof: · Having regard to the proposal from the- Commission,· Having regard to the opinion of the Economic and Social Committee«n. Acting in accordance with the procedure laid down in Article 25 1 of the Treaty<l>, (1) Whereas Council Directive 81/851/EEC of 28 September 1981 on the approximation of the laws of the Member States relating to veterinary medicinal products0 l, Council Directive 81/852/EEC of 28 September 1981 on the approximation of the laws of the Member States relating· to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of veterinary medicinal products<•>, Council Directive 90/677/EEC of 13 December 1990 extending the scope of Directive 81/85 1/EEC on the approximation of the laws · of the Member States relating to veterinarY medicm. l products and laying down additional provisions for immunological veterinary medicinal prod~S). and Council Directive 92174/EEC of 22 September 1992 widening the. scope of Directive 81/851/EEC on the approximation of provisions laid down by law, regulation or administrative action relating to veterinary medicinal products and laying down additional provisions on homeopathic veterinary medicinal products(l) have been frequently and substantially amended; whereas, in the interests of clarity and rationality, the said Directives should therefore be codified by assembling them in a single text; U> OJ C (2) P> OJ L 317, 6. 11. 1981, p. 1. Din:ctive as last amended by Dilutive 93/40/EEC (OJ L 214, 24. 8. 1993, p. 31). <•> OJ L 317, 6. 11. 1981, p. 16. Directive as last amended by Directive 93/40/EEC. 5> OJ L 373, 31. 12. 990, p. 26. < <6> OJ L 297, 13. 10. 1992, p. 12. 3 (2) Whereas the primmy purpose of any rules for the production and distribution · of vetefin:uY medicinal products must be the ~guarding of public health; 1. 811851/. £EC (3) Whereas, however, this objective must be achieved bY means which will not hinder the development of indusby and trade in medicinal products within the Co~unity; 2. 81/851/EEC ( 4) Whereas, in so far as the Member States already have certain provisions laid down by law, regulation or administrative action governing veterinary medicinal products, such provisions differ in essential principles; whereas this results in the hindering of trade in medicinal-products within the Community, thereby directly affecting the fimctioning of the intemal market;· 3. 811851/EEC (adapted) 4. 81/851/EEC 3. 90/676/EEC 3. ' 93/40/EEC (adapted) (5) Whereas such hindrances must, accordingly, be removed; whereas this entails approximation of the ~Ievant provisions; ( 6) Whereas it is necessary from the ~int of view of pu_blic health and the free movement of veterinary medicinal products for the competent authorities to have at their disposal all useful information on authorized veterinary medicinal products in the form of approved summaries of the characteristics of products; (7) Whereas, with the exception of those medicinal products which are subject to the centralized Community authorization procedure established by Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a Emopean Agency for the ), a marketing authorization in one Member Evaluation of Medicinal Products«1 State ought to be recognized by the competent authority of the other Member States unless there are serious grounds for supposing that the authorization of the veterinary medicinal product concerned may present a risk to human or animal health, or to the environment; whereas, in the event of a disagreement between Member States about the quality, the safety or the efficacy of a medicinal product, a scientific evaluation of the matter should be undertaken according to a Community standard, lead to a single decision on the area of disagreement, binding on the Member States concerned; whereas this Decision should be adopted by a rapid procedure ensuring close cooperation between the Commission and the Member States; (8) Whereas, for this purpose, a Committee for Veterinary Medicinal Products should be set up in accordance with the EW'Opean Agency for the Evaluation of Medicinal Products laid down in the aforementioned Regulation (EEC) No 2309/93. 10. 81/851/EEC (adapted) U> OJ L 214, 24. 8. 1993. p. 1; Regulation as IIDCDded by Commission Regulation (EC) No 649198 (OJ L 81, 24. 3. 1998, p. 7). 4 -(9): Wheioas this Directive is only one stage in the achievement. of ihe ahn of freedom. of movement of vete,riDar)r medicinal products; wh~, however, for tbiS purj)ose, new. measures will prove necessary, in the light of experience · gained • especially within the CoiDD)ittee for ·veterinary Medicinal Products • · for the· removal of the remaining barriers ~ freedom of movement; 11. 811851/EEC. (adapted) (lO)Whereas medicated feedingstuffs do not come within the scope of this ·Directive; whereas, however, it is necessary~ for ~th public health· and. economic reasons, to prohibit the use of unauthorized medicinal. products in the manufacture of medicated feedingstuffs; 6. 81/851/EEC. (ll)Whereas the concepts of harmfulness and therapeutic efficacy can be examined only in relation to one another and have only a relative significance, · depending on the progress of scientific knowledge and the use for which the medicinal product is intended; whereas the partic:ulars and documents which must accompany an application for marketing authorization must demOilStrate that potential hazards are outweighed by the benefits due to efficacy; (12)Whereas marketing authorization should be refused where a medicinal product lacks therapeutic effect or where there is insufficient proof of such effect; whereas the concept of therapeutic effect must be understood as being the effect promised by the manufacturers; I (13)Wbereas such marketing authorization should cilso be refused where the withdrawal period indicated is not long enough to eHminate health hazards arising from residues; (14)Whereas, before an authorization to market an. immunological veterinary medicinal product can be granted, the manufacturer must demonstrate his ability to attain batch-to-batch consistency; (IS)Wbereas the competent authorities should also be empowered to prohibit the use of an the immunological responses of the treated animal will interfere with a national or Community programme for the diagnosis, eradication or control of animal disease; immunological veterinary medicinal· product when 7. 811852/EEC (adapted} 7. 8. 811851/EEC (adapted) 81/851/EEC {adapted) 5. 90/677/EEC ,. 6. 90/677/EEC ( 16) Whereas it is desirable in the first instance to provide users of homeopathic medicinal products with a very clear indication of their homeopathic character and with sufficient guarantees of their quality and saf~ty; 7. 92174/EEC (17)Whereas the rules relating to the manufiscture, control and inspection of homeopathic veterinaey medicinal. products must be harmonized to permit the circulation throughout the Community of medicinal products which are safe. and of good quality; 8. 92174/EEC s (li)Wbereas, having. regard to· the particill8r characteristics. ofthese·hm;neopadiic veterinary medicinal products, such as the very low level of active principles they comain·and the difficulty of applying to them the conventional statistical methods · relating to clinical trials, it is desirable to provide a special, simplified registratiOn procedure for those traditional homeopathic medicinal products which are placed on ·the market without ·therapeutic. indications in a phalmaceutical form and dosage which do not present a risk for the animal; ( 19)Whereas the usual· rules governing the authorization to market_ veteriDary ·. medicinal ·prOducts must be applied to homeopathi<;. veteriDary medicinal productS · marketed with therapeutic indications or in. a form which may. present risks which must be balanced against the desired therapeutic effect; whereas· Member States should ·be able to apply particular rules for· the evaluation of the results of tests and trials intended to establish the safety and efficacy of these medicinal products for pet animals and exotic species, · provided that they notify them to the Commission; (20)Whereas in order to better protect human and animal health and avoid any unnecessary duplication of effort during the examination of application for a marketiDg authorization, Member :States should systematically prepare assessment reports in respect of each veterinary medicinal product which is authorized by them, and exchange the reports upOn request; whereas, furthermore, a Member State should be able to suspend the examination of an. application for authorization to place a veterinary medicinal product on the market which is currently under active consideration in another Member State with a view to recognizing the decision reached by the latter Member State; 9. 92!14/EEC (adapted) 11. 92n4/EEC (adapted) 4. 93/40/EEC (adapted) (21 )Whereas, in order to facilitate the movement of veterinary medicinal products and to prevent the checks canied out in one Member· State from being repeated in another, harmonised requirements for manufacture and imports from third countries,. and the grant of corresponding authorization, should be applied to veterinary medicinal products, 12 811851/EEC (adapted) (22)Whereas the quality of veterinary medicinal products manufactured within the Community should be guaranteed by requiring compliance with the principles of good manufacturing practice for medicinal products irrespective of the final destination of the medicinal products; 7. 90/676/EEC (adapted) (23)Whereas measures should also be taken to ensure that distributors of veterinary medicinal products are authorized by MCJQber States and maintain adequate records; 10. 90/676/EEC 6 (24)Whereas standards and. protocols for. the perfouliance of tests on veterinary · medicioal. produds ·arc an e1fective meaos of control of these products and, hence, of protecting public health and can facilitate the moveme. ot of these productS by laying down WUform rules applicable to tests and the compilation of dossiers,·allowing the competent authorities to·anive. at their decisions on the basis of UDifom tests and by reference to uniform criteria, and therefore helping to obviate diff~ces in evaluatioD; 3. + 4. 811852/EEC (adapted) (2S)Whereas it is advisable to stipulate more precisely the cases in which the results pfpharmacological and toxicological tests or clinical trials do not have to. be provided with. a view to obtaining authorization for a. veterinary mediciDal product which is essentially similar to an innovative product, while ensuring that innovative forms are not placed at a disadvantage; whereas, however, there are reasons of public policy for not repeating tests carried out on aliimals without overiding cause; (26)Whereas following the establishment of the mtemal market, specific controls. to guarantee the quality of veterinary medicinal products imported from third countrieS can be waived only if appropriate arrangements have been made by the Community to ensure that the necessary controls are tarried out in th,e exporting COtmtry; (27)Whereas it is desirable to codify and improve ·the· cooperation and exchange of the information between Member States surveillance o( veterinary medicinal· products and in particular the monitoring of adverse reactions under practical conditious of use through the natio!W phannacovigilance systems; relating to (28)Whereas in order to improve the protection of public health,. it is necessary to specify that foodstuffs for human consumption may not be taken from animals which have been used in clinical trials of veterinary medicinal products unless a· maximum residue limit has b~ laid down for residues of the veterinary medicinal product concerned in accordance with the provisions of Cotmcil·. IU:gulation (EEC) No 2377/90. of 26 June 1990 laying down a Community prOcedme for the establishment of maximum residue limits of veterinary medicinal products in foodstuffs of animal originU);; (29) Whereas the Commission the necessary changes laid down in Annex I in order to adapt to scientific and technical progress;. should be empowered to adopt · 6. 90/676/EEC s. 93/40/EEC 6. 93/40/EEC 7. 93/40/EEC 7. 90/677/EEC (adapted) (30) Whereas, this Directive is without prejudice to the obligations of the Member States concerning the deadlines for transposition set out in Annex Il, PartB; · HAVE ADOPTED THIS DIRECTIVE: (I) OJ L 224, 18. 1. 1990, p. · 1; RCgu1alioa u·llst acadcd by Cm~mission Rcpllticm (EC) No 1958198 (OJ L 2S4, 16. 9. 1998, p. 7). 7. tTI'i. J:'I DEFINITIONS Article 1 For the pm-poses of this Directive, the following terms sbaU bear the following meanings: 65/65/EEC Art. 1 (1) and (2) (adapted) 81/851/EEC Art. 1 (1) (adapted) 81/851/EEC Art. 1 (2), 2nd indent 65/65/EEC Art. 1 (3) 81/851/EEC Art. 1 (1) (adapted) 1. Propriet'al'y medicinal product: Any ready-prepared medicinal product placed on the market under a special name ·and m a special pack. 2. Veterinluy medicinlll product: Ally substance or combination of substances _presented for treating or preventing. disease in animals. Ally substance or combination of substances which may be administered to animals with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in animals is likewise considered a veterinary medicinal product. 3. Ready-made veterinary medicina~ product shall mean any veterinary medicinal product prepared· in advance which does not comply with the definition of proprietary medicinal products and which is marketed in a pharmaceutical form which may be used without further processing. · 4. Substance: Any matter iiTespective of origin which may be:. human, e. g. human blood and human blood products; - animal,. e. g. micro-organisms, whole animals, parts of organs, animal secretions,· toxins, extracts, blood products; 8 • vegetable~ e. g. micro-orpnisms, plants, ·parts of plams, vegetable secretions, ~;. • chemical, e. g. elements, naturally occurring chemical materials and chemiall. products. obtained by chemical change or synthesis. 5. Pr. ,mi% for medicatedftedingstuffs 65165/EEC, Art. 1 (3) 81/85 1/EEC. Art. 1 (1) (adapted) 81185 1/EEC Art. 1 (2), 3rd and Any veterinary medicinal product pRpared in advance with a view to the subsequent 4th indents manufacture of medicated feedingstuffs, 6. Medicatedfeedinptuffs. Any mixture of a veterinary medicinal product or products and feed or feeds which is ready prepared ·for marketing and intended to be fed to animals without further processing. because of its curative or preventive properti~s or other properties as a medicinal product covered by point 2. 7. Immunological veteri1U11')' medicinal product A veterinary medicinal product administered to animals in order to produce active or passive immunity or to diagnose the ~ of immunity. 8. J!omeopathic veterinary medicinal product 90/677/EEC Art. I (2) 92n4/EEC Art. I Any veterinary medicinal product prepared from products, substances or compositions called homeopathic stocks in accordance with a homeopathic manufacturing procedure described by the EW'Opean Pharmacopoeia or, in the absence in the Member States. the pharmacopoeias CUil'ently used officially thereof: by A homeopathic veterinary · medicinal product may also contain a number of principles. 9. Withdrawal period Period between the last administration of the veterinary medicinal product to animals under normal conditions of use and the production of foodstuffs from such animals, 90/676/EEC Art. 1 (5)) in order to ensure that such foodstuffs do not contain residues in quantities in excess of the maximum limits laid down in applying Regulation (EEC) No 2377/90. (adapted). 81/851/EEC Art. 5, 3rd paragraph, (8) (as amended by 9 ·1 0. Adverse l'eaction · 81/SS 1/EEC · Art. 42b (as amended by A reaction which is harmfUl and uninteJided and which occurs at doses normally used in animals for the prophylaxis, diagnosis or. 1J'eatment of disease or the modification 93/40/EEC Art 1 (12)) of physiological function. 11. Serious adverse reaction An adverse reaction which is fatal, life-threatening lesion-producing, disabling, incapacitating, or which results in permanent or prolonged symptoms in the animals treated. 12. Unexpected adverse reaction An adverse reaction which is not mentioned in the summary of the product characteristics. 13. Serious unexpected aiherse reaction An adverse reaction which is both serious and unexpected. 14. Wholesale dealing in veterinary medicinal products Any activity which includes the purchase, sale, import, export, or any other commerCial transaction in veterinary medicinal products, whether or not for profit, exceptfor. · - - the supply by a manufacturer of veterinary medicinal products manufactured by himself, retail supplies of veterinary medicinal products by persons entitled to caiTY out such supplies in accordance with Article 66. 15. Agency EW'opean Agency for the evaluation of medicinal products set up by Regulation (EEC) No 2309/93. 16. Risk to human or animal health or the environment Any risk referring to the quality, safety and efficacy of the veterinary medicinal product. 811851/EEC Art. SOa (1 ), 2nd subparagraph (as amended by 90/676/EEC Art. 1 (27)) (adapted) 811851/EEC Art. 16 (1), (as amended by 93/40/EEC Art. 1 (10)) (adapted) 811851/EEC Art. 18 ( 1 ), footnote (as (lmended by 93/~0/EEC Art. 1 ( 1 0)) (adapted) 10 The provisions of this Directive shall·apply to veterinacy medicinal products. I ,Artiele2 · Artiele3 This Directive sball not apply to:. 1. Medicated feedingstuffs set out in Council Directive 90/167/EECO,; 811851/EEC Art. 2. (1) (adapted) 81/851/EEC Art 2 (2), 1st indent · (adapted) However, ·medicated feedingstuffs may. be prepared only from pre-mixes which have 81/851/EEC been authorized Under this Directive; Art. 2 (3) (adapted) 2. inactivated immunological veterinary medicinal products which are manufactured 90/677/EEC from pathogens obtained from an animal or aDimals from a hc;>lding and used for the Art 1 (3) treatment oftbat animal or the animals of that holding in the same locality; (adapted) 3. Any medicinal product prepared in a pharmacy in accordince with a prescription for an individual animal (commonly known as the magistral formula); 65/65/EEC Art. 1, points 4 and S (as amended by 89/341/EEC Art. 1 (2)) (adapted) 4. Any medicinal product· prepared in a pharmacy prescriptions of a pbannacopoeia and is intended to be supplied directly to the. Art. 1 (1) (adapted) end-user (commonly known as the official formula); in accordance with the 81/851/EC · 5. Veterinary medicinal products based on radio-active isotopes; 811851/EEC Art. 2 (2), 3rd inden~ 1 6. Any additives covered by Council Directive 70/524/EEC'l•, where they are 8 1/851/EEC incoiP. Orated in animal feedingstuffs and supplementary animal feedingstuffs in accordance with that Directive. Art. 1 ( 4) (adapted) (I) OJ L 92. 7. 4. 1990, p. 42. C:Z) OJ L 270, 14. 12. 1970, p. 1~ DileciM as 1. st IIDCDdcd by CommissiaD DiJective 98119/EC (OJ L 96,28. 3. 1998, p. 39). 11 Artide4 1. Member States ~Y. provicSe that t;his Directive shall not apply to non-ictivated 90/677/EEC immunological veteJjnarymedicinal products manufactured from. pathogens obtained· Art. 1· (4) from an animal or animals from a holdhlg and used for ·tbe treatment of that animal (adapted) of that holdiDg in the same IQCality. 2. Member States may permit exemptions on their tenitory in respect of. veterinaJy 81/85 1/EEC. medicinal products intended solely for aquarilDD ·fish, cage birds, hommg pigeons, An. 3 terrarilDD animals and small rodents, from tbe provisions in Articles 5, 7 and · 8, provided that such producEs do not' contain substances the use of which requires veterinary control and that all possible measures have been taken to prevent unauthorized use of the product$ for ~ther animals. TITLE m MARKETIN'G Chapter 1 · Marketing ·authorization Article 5 No veterinary medicinal product may be placed on the market of a Member State unless a marketing authorization has been issued by the competent authorities of that Member State in accordailce with this Directive or a marketing authorization has been granted in accordance with Regulation (EEC) No 2309/93. ·. Article 6. In order that a veterinary medicinal product may be the subject of a marketing authorization for the pU;fpOse of administering it to food-producing animals, the active substances which it contains must be shown in Annexes I, ll or m of Regulation (EEC) No2377/90. Article 7 Where the health situation so requires, a Member State may authorize the marketing or administration to animals of veterinary medicinal products which have been authorized by another Member State in accordance with this Directive. 12 811851/EEC An. 4 (1), 1st sub paragraph (as amended by 93/40/EEC Art. 1 (1 l' (adapted) 81/851/EEC Art. 4 (2), 1st subparagraph (as 'amended by 90/676/EEC Art. 1 (4)) (adapted) 81/851/EEC· Art. 4 (1 ), 2nd sub paragraph (as amended by 90/676/EEC Art. 1 (4)) (adapted) Article 8 In. the· event. of serious disease epidemic, Member States may provisionally allow the use · 811851/EEC of immunological veterinary mediciDal products without the authorization for placing on Art. 4 (1), 3rd the market, in ·the. absence of ·a suitable mediciDal product and after informing the subparagraph (as amended by Commission of the detailed conditions of use. 90/676/EEC Art. 1 (4)) (adapted) · · 81/SS I !EEC. Art. 4 (3), 1st subparagraph (as amended by 90/676/EEC Art. 1 (4)) _(adapted) 81/851/EEC An. 4 (4), 1st and 2nd subparagraphs (as amended by 90/676/EEC Art. 1 (4)) (adapted) Article 9 No veterinary medicinal product may be administered to animals unless the marketing authorization has been issued, except for the tests of veterinary medicinal products referred to in Article 12 (3) (j) which bave been accepted by the competent national authorities, following notification or authorization, in accordance with the national rules in force. Article 10 1. Where there is no authorized medicinal product for a condition, Member States may exceptionally, in particular in order to avoid causing unacceptable suffering to the animals concerned, pemut the administration by a veterinarian or under his/her direct personal responsibility to an animal·or to a small number of animals on a particular holding: (a) of a veterinaty medicinal product authorized in the Member State cOncerned under this Directive or under Regulation (EEC) No 2309/93 for use in another animal species, or f~r another condition in the same species; or (b) if there is no product as referred to in point (a), of a medicinal product authorized for use in the Member State concerned in human beings in accordance with Directive [65/65/EEC] or under Regulation (EEC) No 2309!93; or (c) if there is no product as referred to in point (b) and within the limits of the law of the ·veterinary. medicinal product prepared Member State concern~ of a extemporaneously by a person authorized to do so under national legislation in accordance with the terms of a veterinary prescription. For the purposes of this paragraph, the phrase 'an animal or a small number of animals on a particular holding' also covers pets, and shall be interpreted more flexibly for minor or exotic animal species which do not produce food. 13 2. The Provisions of paragraph 1 shall apply provided tbat the inediciDal product, where _administ. ered to food-producing animals, contains only substances to be found in a veterinary medicinal product· authorized for such animals in the Member State concerned and that in the case of food·produ~ing animals the veterinarian responsible ·specifies an appropriate withdrawal period- to eDS1U'e that food produced from the treated animals does not contain residues harmfUl to consumers. 811851/EEC. Art. 4 (4), 1st and 2nd subparagraphs (as amended by 90/676/EEC Art. I_ (4)) (adapted) Unless the medicinal. product used indicates -a withdrawal period for the species concerned, the specified withdrawal period sball not be less than: · 7. days 7days 28 days 500 degree· days eggs, milk, meat fr'Qm'poultry and mammals including fat and oftal, meat from fish. With· regard to homeopathic veterinary medicinal products -in which the level· of 92174/EEC ·active principles is equal to or less than one part per million, the withdrawal period Art. 2 (1), 2nd referred to in the first and second subparagraphs is reduced to zero. subparagraph (adapted) Artiele 11 The veterinarian shall keep adequate records of the date of examination of the animals, · details of the owner, the number of animals treated, the diagnosis, the medicinal products prescrib~ the dosages administered, the duration of treatment and the withdrawal periods recommended, and make these records available for inspection by the competent authorities for a period of at least three years. This requirement may be extended by the Member States to food-producing animals. 811851/EEC Art. 4 (4), 3rd subparagraph (as amended by 90/676EEC Art I ( 4)) (adapted) Artiele 12 1. For the pmposes of obtaining an authorization for placing on the market irrespective ofthe procedure established by Regulation (EEC) No 2309/93, an application shall be lodged by the competent authority of the Member State concerned. 2. A marketing authorization may only be granted to an applicant established in -the Community. 81/851/EEC Art. 5, 1st subparagraph, (as amended by 90/676/EEC Art. I (5)) (adapted) 81/851/EEC Art. 5, 2nd subparagraph (as amended by · 93/4~/EEC Art. 1 (3)) (adapted) 14 · 3. 1be following partiCulars ·and documents shall be appeDded tO the;application· in ~e with Almu 1:. - (a) name or business name and permanent a&tress or registered place of business of the ~. responsible for placiDg. the product on the market and, if different,. of the IDID1Ificturer or manufacturers ·involved and of the sites ofmanufilculre; '81/851/E2C. Art. s, 3rd subparagraph, points 1 to 9 (as amended by 99/676/EEC Art. 1 (5)) (adapted) · (b) name of the veterinary medicinal prodUct (brand name, non-proprietary ~e;· with + or without a trademark, or· name of the II1IIWfacturer or scientific name or formula, with or without a tradeirwk, or the name of the manufacturer); · · · 81/852/EEC Art. 1 t 1st paragraph (adapted) (c) qualitative and quantitative particulars of all the constituents of the veterinary medicinal product, using the ·usua1 terminology, but not empirical chemical formulae. · lnd giving the intemational non-proprietary name recommended by the World Health OrpnilJltiozi. where such a name exists; (d) description of the method of~;. ·(e) therapeutic indications, contra-indications and adverse reactions;. (f) clOsaae for the various species of animal for which the veterinary medicinal product. is intended, its pharmaceutical form, method and route of administration and proP,sed shelf life; · (g) if applicable, explanations of the precautiomuy and safety measures to be taken when the product is stored, when it is administered to animals and when waste therefrom is disposed of, together with an indication of any potential risks the medicinai product might pose to tbe environment and the health of humans, animals or plants;. (h) indication of the withdrawal period. Where necessary, the applicant shall propose ind justify a tolerance level for residues which may be accepted in foodstuffs without risk for the conslimer, together with routine analysis methods which could be used by the cOmpetent authorities to trace residues; (i) description of the control testing methods employed by the manufacturer (qualitative and quantitative analysis of the co~tuents and the finished product, specific tests e. g. sterility tests, test for the presence of pyrogens, for the presence of heavy metals, stability tests, biological and toxicity tests, tests on intermediate products); IS (j) results of. - • physico-chemical, biological or microbioiogical tests, toxicological and pharmacological tests, cliJrlcal trials. (k) a summary in accordance with Article 14 of the product characteristics, one or more specimens or mock-ups of the sales presentation of the veterinary medicinal product together with the package insert; 0) a document showing that the manufacturer is authorized in his own country to ~uce veterinary medicinal products;. (m) copies of any marketing authorization obtained in another Member State or in a third. country for the relevant veterinary medicinal product, together with a list of:those Member States in which an application for authorization submitted in accordance with this Directive is under examination. Copies of the summary of the product characteristics proposed by the applicant in accordance with Article 14 -or approved by the competent authority of the Member. State in accordance with Article 25 and copies of the package insert proposed, details of any decision to refuse authorization, whether in the Community or a third country and the reasons for that deeision. This information shall be updated on a regular basis; (n) in the case ·of medicinal products containing new active substances which are not mentioned in Annex I, D or m to Regulation (EEC) No 2377/90, a copy of the documents submitted to the Commission in accordance with Annex V to that Regulation. 81/SSl/EEC. Art. s, ~rd paragraph, point 10, 1st. subparagraph (as amended by. 90/61~<?Art. 1 (5)) 81/851/EEC Art. · 5, 3rd paragraph, points 11 and 12 (as amended by 90/676/EEC Art. 1 (S)) (adapted) 81/851/EEC Art. 5, 3rd paragraph, point 13 (as amended. by 93/40/EEC Art. 1 (4)) (adapted) 81/851/EEC Art. 5, 3rd paragraph, point 14 (as amended by 90/676/EEC Art. l (5)) (adapted) 16 Artldell 1. By way. of derogation from point 0) of Article 12 (3), and without prejudice to ·the law relating to the protection of industrial and commercial property: (a) the applicant sball not· be required to provide the results of toxicological and pharmaco!ogical tests and clinical trials if he can demonstrate: (i) either that the v~terinaly medicinal product is essentially similar to a medicinal product authorized in the Member State concerned by the application and that ~e mark~ting authorization · holder · has agreed toxicological, pharmacological and clinical ~ferences contained in :the file on the original veterinary ·medicinal product may be used for the purpose of examining the 'application·in question; that the 81/851/EEC Art. S, 3rd paragraph, point 10, 2nd. subparagraph. (as amended by 90/676/EEC Art. 1 (S)) (adapted) (ii) or that the constituent or constituents of the veterinary medicinal product have a well-established medicinal use, with recognized efficacy'· and also an acceptable level of safety, with detailed references to the scientific literature; (iii) or that the veterinary medicinal product is essentially similar to a medicinal product which has been authorized. within the Community, in accordance with Community provisions in force; for not less than six years and is marketed in the Member State for which the application is made; this period shall be extended to 10 years in the case of high-technology having been authorized in pursuance of the procedwe established by Article 2 (5) of Council Directive 87122/EE01 • • Furthermore, a Member State may also. extend this period to 10 years by a single Decision covering all the medicinal products marketed in its territory where it considers this necessary in the interest of public health. Member States are at liberty not to apply the six-year period beyond the date of expiry of a patent · protecting the origibal medicinal product. (b) in the. case of new veterinary medicinal products containing known constituents not hitherto used in combination for therapeutic purposes, the results of toxicological and pharmacological tests and of clinical trials relating to that combination must be provided, but it shall not be necessary to provide the relevant documentation for each individual constituent. 2. Annex I shall apply in like manner where, pursuant to point (aXii) of paragraph. I, 81/852/EEC references to published data are submitted. Art. 1, 2nd paragraph (adapted) U> OJ LIS, 17. 1. 1987, p. 38, DiRctivc repealed by Direclive 93/41/EEC (OJ L 214, 24. 8. 1993, p. 40). 17 Article 14. · The summary of the product characteristics shall contain the following information: 1. Name of the veterinary medicinal products; 2. Qualitative and ciwmtitative composition in terms of the active substances and constituents of the excipient, knowledge of which is essential ·for. proper ~on of the medicinal product; the inter. nltional non-proprietary names recommended bY the World Health Organi~tion shall be used, where such names exist, or failing this, the usual non-proprietary name o~ chez;nical ~ption; 81/851/EEC Art. Sa · {as amended by~ 90/676/EEC Art. 1 (6)) (adapted) 3. Pharmaceutical form; 4. Pharmacological properties and, in so far as this information. is useful for the therapeutic purposes, pharmacokirietic particulars; ·5. · clinical particulars; 5. 1 target species, 5. 2 indications for use, specifying the target species, 5. 3 contra-indications, S. 4 undesirable e~ects (frequency and seriousness), 5. 5 special precautions for use, 5. 6 use during pregnancy and lactation, 5. 7 interaction with other medicaments and other forms of interaction, S. 8 posology Jnd method of administration, S. 9 overdose (symptoms, emergency procedures, antidotes) (if necessary), S. I 0 special warnings for each target species, 5. 11 withdrawal periods, S. I2 special precautions to be taken by the per59n administering the medicinal product to animals; 18 6. · Pharmaceutical particulars: 6. 1 major in~mpatibllities, 6. 2 shelf life; when neceSSII'Y- after reconstitution of the medicinal product or when · the container is opened for the first time, · 6. 3 special precautions for storage, 6. 4 na11u'e and contents of container, 81/851/EEC Art Sa (as amended by 90/676/EEC Art 1 (6)) (adapted) 6. 5 special precautions for the disposal of unused medicinal product or waste · materials if any· · ' ' t. • 7. Name or corporate name and address or registered place of business of the. authoriZation holder. · Article 15 1. Member States shall make all necessary arrangements to eDSW'e ~ the documents 81/85 1/EEC an~ particulars listed in Article 12 (3) {h), (i), 0) and Article 13 (1) are drafted by Art. 6 experts with the requisite technical or professional qualifications before being submitted to the competent authorities. These documents and particulars shall be signed by the experts in question. 2. According to their particular qualifications, the role ofthe experts shall be: (a) to carry out such work as falls within their particular discipline (analysis, pharmacology and similar experimental sciences,. clinical trials)- and to describe objectively the results obtained in both quantitative and qualitative terms; (b) to describe their findings in accordance with Annex I and in particular to state: (i) in the case of analysts, whether the medicinal product conforms with the stated composition, providing any reasons for the control testing methods which the manufacturer is·to use; 811851/EEC An. 7 (1), (2) and (3), 1st subparagraph (adapted) 19 (ii) in the ease of pharmacologists and appropriately qualified specialists: 81/85 1/EEC · Art. ,. (1), (2) and (3), 1st • the toxicity of the medicinal product and the pharmacological pro~ subparagraph observed, (adapted) · - whether, after administration of the veterinary medicinal product under normal conditions of use and observance Qf ~e recommended withdrawal. period, foodstuffs obtained from the treated animals contain residues wliich might constitute a health hazard to the consumer; ·. (iii) in the case of clinicians, whether they have. found in animals treated with the medicinal product effects corresponding to the information furnished by the manufacturer pursuant to Articles 12 and. 13 (1 ), whether the medicinal product is well tolerated,. what dosage they recommend and what are the contra indications and adverse reactions, if any; (c) to give reasons for the use of the references to published data referred to in point (a) (ii) of Article 13(1). 3. The experts' detailed reports shall form part of the documentation which the applicant shall lodge with the competent authorities. A brief curriculum vitae of the expert shall be appended to each report. 81/851/EEC Art. 7 (3), 2nd subparagraph (as amended by 90/676/EEC An. I (8)) 20 ·· Chapter2 · Particular provisions applicable to · homeopathic veterin81)' medi~al pro~ucts Artiele 16 1. Member States · shall eDSW'e that homeopathic veterinary ·medicinal products 92f14/EEC manufactured· and marketed Within the ·Community are registered or authorized ~ Art. 6 ·accordance with the provisions of Articles 17 (1) and (2), 18 ~d ·J9. Each Member State shall take due account of registrations and ·authorizations previously granted by another Member State. (adapted) · · · 2. A• Member State may refrain from establishing a special, simplified registration procedure for the homeopathic veterinary mediciDal products referred to in Article 17 ( 1) and (2). A Member State applying this provision shall inform the Commission accordingly. The Member State concerned shall, by 31 December 1995 at the latest, allow. use in its tenitory of homeopathic veterinary medicinal products registered. by other Member States in accordance with Article 17 (I) and (2) and Article 18. Artielel7 "1. Only homeopathic veterinary medicinal products which satisfy all of the following 92174/EEC conditions may be subject to a special, simplified registration procedure: Art. 7 ( 1) (adapted) they are. intended for administration to pet animals or exotic species which are. non food-producing, they are administered by a route described in the European Pharmacopoeia or, in absence thereot by the pharmacopoeias cwrently used officially in the Member States, no specific therapeutic indication appears on the labelling of the ·veterinary medicinal product or in any information relating thereto, there is a sufficient degree of dilution to guarantee the safety of the medicinal product; in p~icular, the medicinal product may not contain either more than one part per 10 000 of the mother tincture or more than 1/1 OOth of the smallest dose used in allopathy with regard to active principles whose presence in an allopathic medicinal product results in the obligation to submit a veterinary prescription. At the time of registration, Member States shall determine the classification for the dispensing of the medicinal product. 2. The criteria and rules of procedure provided for in Chapter 3 shall apply by analogy 92174/EEC to the special, simplified registration procedure for homeopthaic veterinary medicinal Art. 7 (3) products laid down in paragraph 1, with the exception of the proof of therapeutic (adapted) effect. 21 3. The proof of therapeutic effect · sb8u not. be require. d for homeopathic. veteriDary J92fl. 4/EEC. medicinal products registered in accordance with paragraph 1. of this Article or,. Art. 4, 2nd subparagraph where appropriate, admitted in accordance~ ~cle 16 (2). (adapted) · Article 18 ~ special, simplified application for registration may cover a series of medicinal products 92174/EEC · derived from the same homeopathic stock or stocks. The following document sbal1 be Art. 8 included with the application in order to demonsttate, in particular, the pharmaceutical quality and the batch-to-batch homogeneity of the products concerned: (adapted) · scientific name or. other name given in a pharmacopoeia of the homeopathic stock or stocks, tOgether with a statement of the various routes. of administration, pharmaceutical forms and degree of dilution to be registered, dossier describing ·how the homeopathic stock or stocks is/are obtained and controlled, and justifying its/their homeopathic nature, on the basis of an adequate bibliography; in the case of homeopathic veterinary m~cinal products containing biological substances, a description of the measures taken to ensure the abSence of pathogens; manufacturing and control file for each pharmaceutical form and a description of the method of dilution and ~tentiation, manufacturing authorization for the medicinal products concerned, -· copies of any registrations or authorizations obtained for the same medicinal products in other Member States, one or more specimens or mock-ups of the sales presentation of the medicinial products to be registered, · data concerning the stability of the medicinal product 22 Artiele 19 1. 'Homeopathic veteriDary products other than those referred to in Article 17 (1) shin 92174/EEC be authorized in KCOrdance with the provisions of Articles 12 and 13 and Chapter 3. Art. 9 (adapted) 2~ A Member State may introduce or retain in itS territoty specific rules for the phartnatological and toxicological tests and clinical trials of homeopathic veterinary medicinal products intended. for pet animals and exotic species which are non foocJ. producing other tban those referred to in Article 17 (1), in accordance with the principles and characteristics of homeopathy as practised· in that Member State. In this case, the Member State concerned sball notify the Commission of the specific ~esinf~. · - This Chapter shall not apply to immunological veterinary medicinal products. Ardele20 92174/EEC Art. 2 (3) (adapted) 23 Chapter~ · Procedure for marketing authorization·. Artide21 1. Member States shall take all appropriate measures to ·ensure that the procedure for granting an authorizatiOn to place a veterinary medicinal product on the market· is completed within 210 days of the submis~ion of a valid. application. · 2. Where a Member State notes that an application for authorization submitted is already under active examination in another Member State in respect of that ·veterinary medicin81 prod~ the Member State concerned may decide to. suspend. the detailed examination of the application in order to await the assessment report prepared by the other Member State in accordance with Article 25 (4). 81/851/EEC Art. 8 (as amended by 93140/EEC Art. 1 (6)) (adapted). The Member State concerned shall inform the other Member State and the applicant ·. of. its decision to suspend detailed examination of the application in question. As soon as it has completed the examination of the application and reached a decision, · the other Member State shall forward a copy of its assessment report to the Member State concerned. · Artide22 Where a Member State is informed in accordance with Article 12 (3) (m), that another Member State has authorized a veterinary medicinal product which is the subject of an application for authorization in the Member State con~ed, that Member State shall forthwith request the authorities of the Member State which has granted the authorization to forward to it the assessment report referred to in Article 25 (4). 81/851/EEC Art. 8a (as amended by 93/40/EEC Art. 1 (7)) (adapted) Within 90 days of receipt of the assessment report, the Member State concerned shall either recognize the decision of the first Member State and the summary of the product characteristics as approved by it or, if it considers that there are groun~ for supposing that the authorization of the veterinary medicinal product concerned may present a risk to human or animal health or the environment, it shall apply the procedures set out in Articles 19 and 33 to 38. 24 Article 23 In order to examine the application submitted pursuant to Articles 12 and 13 (l), the 81/85. 1/EEC competent authority of the Member States: · Art. 9 (I) (adapted) 1. sball check that the documentation submitted m support of the appliCation' complies with Articles 12 and 13 (l) and, on the basis :of the reports drawn up by the experts puisuant to Article 15. (2) and (3), ascertain whether the conditions for the issue of the marketing authorizatiC?n have been fulfilled; · 2. may· submit the medicinal product, its raw materials and if necessary intermediate products or other constituent materials. for testing by a State laboratory or by a· laboratory designated for that pmpose, in order to ensure that the testing methodS employed by the manufacturer and described in the application documents, in accordance with Article 12 (3) (i), are satisfactory; · · 811851/EEC Art. 9 (2) (as amended by 90/676/EEC Art. ' 1 (9)) (adapted) 3. may, where appropriate, require the applicant to provide further information as regards the items listed in Articles 12 ~ 13 (1). Where the competent' authorities take this course of action, the time-limits specified in -Article 21 shall be suspended until the further data required have been provided. Similarly, these time-limits shall be suspended for any period which the applicant may be given to provide oral or written explanatioas; 81/851/EEC Art. 9 {3) (adapted) 4. may require the applicant to submit substances in the quantities necessary to verify the analytical detection method proposed by the applicant in accordance with Article 12 (3) (h) and to put it into effect as part of routine checks to reveal the presence of residues of the veterinary ·medicinal products concerned. 81/851/EEC Art. 9 (4) (as amended by 90/676/EEC An. I (10)) (adapted) 811851/EEC Art. 10 Member States shall take all appropriate measures to ensure that:. Article%4 (a) the _competent authorities ascertain that the manufacturers and importers of veterinary medicinal products from third countries are able tO manufacture them in compliance. with the details. supplied pursuant to Article ·12 (3) (d), and/or· to carry out control tests· in accordance with the methods described in the application docwnents under Article 12 (3) (i); (b) the competent authorities may authorize manufacturers and importers of veterinary medicinal-products from third countries, where cin:umstances so justify, to ·have certain stages of manufacture and/or certain of the control tests,. referred to in (a) carried out by third parties; in such cases, checks by the competent authorities shall also be carried out in the establishments concerned. Article-25 1. Wh~ the marketing authorization is issued, the holder shall be informed by the competent authorities of the Member State concerned, of the summary of the product characteristics as approved by it 2. The competent authorities shall take all necessary measures to ensure tbat the information given· in the summary is in conformity with that accepted when the marketing authorization is issued or subsequently. 811851/EEC Art. Sb (as amended by 93/40/EEC Art. 1 (5)) (adapted) 3. The competent authorities shall forward to the Agency a copy of the authorization together with the summary of the product characteristics. 4. The competent authorities Shall draw up an assessment report and comments on the dossier as regards the results of the analytical and pharmacotoxicological tests and the clinical trials of the veterinary medicinal product concerned. The assessment report shall be updated whenever new information becomes available which is of importance for the evaluation of the quality, safety or efficacy of the veterinary medicinal product concerned. 26 Articlel6 1. The ·marketing authorization may require the holder to indicate on the container 81/85 1/EEC and/or the outer wrapping ~ the package insert, where the Jauer iS required, other Art. 12 particulars essential for safety or health protection, including any special prCcautions from the clinical and relating pharmacological trials prescnDed in Articles 12 (3) (j) and 13 (1) or from experience gained during the use of the veterinary medicinal product once it has been marketed. to use and any other Warnings. resultiDg (adapted) 2. The authorization may also require the inclusion of a tracer substance in the veterinary medicinal product. 3. In exceptional circumstances,. an4 following consultation with the applicant, an 81/851/EEC authorization may be granted subject to certain specific obligations, and subject to Art. 15 (2) annual review, including: {as amended by 93/40/EEC Art. 1 (9)) - - the carrying out of tbrther ~es following the granting of authorization, the notification of adverse ·rea~ons to the veterinary medicinal product. These exceptional decisions may only be adopted for objective and verifiable reasons. Article 27 1. After a marketing authorization has been issued, the holder must, in respect of the manufacturing methods and control methods provided for in Article 12 (3) (d) and (i), take account of scientific and technical progress and intrOduce any changes that may be required to enable tbat veterinary medicinal product to be manufactured and checked by means of generally accepted scientific methods. These changes shall be subject to the approval of the competent. authority of the Member State concerned. 2. Upon request from the competent authority, the marketing authorization holder shall also review the analytical detection methods provided for in Article 12 (3) (h) and propose any changes w~ch may be necessary ·to take account of scientific and technical progress. 3. The marketing authorization holder shall ford. twith inform the competent authority of any new. information which might entail the amendment of the particulars and documents referred to in Articles 12 and 13 (I) or of the approved summary of the product characteristics. ID particular, he shall forthwith inform the competent authority of any prohibition or restriction imposed by the competent authority of any country in which the veterinary medicinal product is marketed and of any. serious unexpected adverse effect occurring in the animals concerned or hlUilaD beings. 811851/EEC Art. 14 (1), 1st sub paragraph (as amended by 93/40/EEC Art. 1 (8)) (adapted) 81/851/EEC Art. 14 (1), 2nd subparagraph and (2) (as amended by 90/676/EEC Art. I (11)) (adapted) 27 4. The~ authorization ~der ~. be~ tO maintain records of all ,81/851/EEC. adverse reictions observed in animals or human beings. The records ·so estabisbed Art. 14 (3) and ( 4} sbal1 be kept at least five 'years and shall be made available_ to the competent (u amended by authorities upon request. · 90/676/EEC Art. 1 (11)} (adapted) S. The marketing. authorization holder sball immediately infonn the conlpetent authoriti~, with a view to ~orization, of any alteration he proposes to make to the particulars and documents refemd to. ~ Articles 12 and 13 (1). · Article 28 · Authorization shall be valid for five years and shall be renewable for five-year periods, 81185 1/EEC on application by the holder at. least three months before the expiry date and after An. 15 (1) consideration. of a dossier updating ~e infonDation previously submitted. (as amended by 93/40/EEC Art. 1 (9)) Article 29 The granting of authorization shall not diminish the general legal liability of the 81185 1/EEC manufacturer and, where appropriate, of the authorization holder. Art. 13 (adapted) Article 30 The marketing authorization shall be withheld if examination. of the documents and. 81185 1/EEC particulars listed in Articles 12 and 13 (1) establishes that: Art. 11 (adapted) (a) the veterinary medical product is harmfUl under the conditions of use stated. at the time of application for authorization; or (b) has no therapeutic effect or the applicant has not provided sufficient proof of such effect as regards the species of animal which is to be tr~d; or (c) its qualitative or quantitative composition is not as stated; or (d) the withdrawal period recommended by the applicant is not long enough to ensure that foodstuffs obtained from the treated animal do not contain residues which might constitute a health hazard to the consumer, or is insufficiently substantiated; or (e) the veterinary medicinal product is offered for sale for a use prohibited under other community provisions; or · · (f) a veterinary medicinal product presents a risk for the protection of public health, consumer or animal·health. Authorization shall also be withheld. if the application documents submitted to· the competent authorities do not comply with Articles 12, 13 (1) and 15. Chapter4 ·Mutual reeopition of authorizations Artlcl~31' 1. In order to facilitate the adoption of common decisions by Member States on the authorization. ofveterinary·medicinal products on the basis of the scientific criteria of quality, safety and efficacy, and to achieve thereby the free. movement of veterinary medicinal products. within the Community, a Committee for Veteriiwy Medicinal Products, hereinafter referred to as "the Committee", is hereby set up. The Committee shall be part oftb. e Agency. 81/851/EEC Art. 16 (1) (as amended by 93/40/EEC Art. i (l 0)) (adapted) 2~ In addition to the other responsibilities conferred upon it by Community law, the Committee shall examine -. ny question relating to the granting, variation, suspension or withdrawal of marketing authorization which is submitted to it in accordance with the provisions of this Directive. It shall also examine any question relating to tests of veterinary medicinal products. · 3. The Committee shall adopt its own rules of procedure. Artide32 81/851/EEC Art. 16. (2) (as amended by 93/40/EEC Art. 1 (10)) + 81/852/EEC Art. 2 (adapted) 81/851/EEC Art. 16 (3) (as amended by 93/40/EEC Art. I (lO)J 1. Before submitting an application for mutual recognition of marketing authorizations, 81/851/EEC the holder of the authorization shall inform the Member State which granted Art. 17 (3) the authorization on which the application is based (hereinafter: the referential Member State) that an application is to be made in accordance with this Directive 93/40/EEC Art. I (10)) and shall notify it of any additions to the original dossier; that Member State may require the applicant to provide it with all the particulars and documents necessary to enable it to check that the dossiers filed are identical. (as amended by (adapted) In addition, the holder of the authorization shall request the referential Member State which granted the initial authorization to prepare an assessment report in respect of the veterinary medicinal product concerned, or, if necessary, to update it. That Member State shall prepare it within 90 days of receipt of the request " At the same time as the application is submitted in accordance with paragraph 2 the referential Member Sate which granted the initial authorization shall forward the assessment report to the Member State or Member States concerned by the application. 29 2. In order to obtain the recognition according to the procedure laid· down in this 81/85 1/EEC Chapter in one or·more of the Member StateS of a marketing authorization issued by. Art. 17 (0 and (2) (as amended by. · ·. a Member State, the holder. of_ the authorization sbal1 submit an application to the competent authority. of the Member State. or Member States concerned, together with 93/40/EEC Art. 1 (1 0)) the information- and pani~ refemd to in Articles 12, 13 (1) and 14. He sball testify tbat the dossier is identical to that accepted by the referential Member State,. or. sball identify any ~ons or amendments it may ·contain. In the latter case, he shall certify that the summary of the product characteristics proposed by him in accordance with Article · 14 is identical to that accepted by the referential Member State. Moreover, he shall certify that all the dossiers tiled as part o. f this procedure are identical. (adapted) · · 3; The holder of the marketing authorization shall transmit the application to the. Agency, inform it ofthe Member States concerned and of the dates of submission of the application and send it a copy of the authorization granted by the referential Member State. He shall ~ send the Agency copies of any such authorization which may have been granted by the other Member States in respect of the veterinary medicinal product concerned, and shall · ~dicate whether any application for authorization is currently under consideration in any Member State. 4. Save in the exceptional case provided for in Article 33 (1), each Member State shall recognize the marketing authorization granted by ·the referential Member State within 90 days of receipt of the application and the assessment report. It shall inform the referential Member State, the other Member States concerned by the application, the Agency, and the authorization bolder for placing the product on the market 811851/EEC Art. 17 (4) (as amended by 93/40/EEC Art. 1 (1 0)) (adapted) Article33 1. Where a Member State considers that there are grounds for supposing that the 811851/EEC. marketing authorization of the veterinary medicinal product concerned may present a Art. 18 risk to human or animal health or the environment, it sb8n forthwith inform the applicant, the referential Member State, any other Member States concerned py the 93/40/EEC Art. 1 (1 0)) application and the Agency. The Member State shall state its reason in detail and shall indicate what action may be necessary to correct any defect in the application. (as amended by (adapted) 2. All the Member States concerned shall use their best endeavoms to reach agreement on ·the action to be taken in respect of the application. They shall ptovide the applicant with the opportunity. to make his point of view known orally or in writing. However, if the Member States have not reached agreement within the time-limit referred tQ in Article 32 (4) they shall forthwith refer the matter to the Agency, according to the reference to the Committee, for the application of the procedure laid down in Article 36. , 3·. Wif:hin the time-limit referred to in Article 32 ( 4 ), the Member States concerned shall provide the Committee with a detailed statement of the matters on which they have been unable to reach agreement and the reasons for their disagreement The applicant shall be provided with a copy of this information. 4. As soon as he is informed that the matter has been referred to the Committee, the applicant shall forthwith forward to the Committee a copy of the information and particulars referred to in Article 32 (2). 30 Article34 If several applications submitted in accordance with Articles 12, ·13 (1 ). and 14 have been 81/85 1/EEC made for marketing authonz. tion for a particular veterinary medicinal. product and Art. 19 Member States have adopted divergent ~isious concerning the authorization of that veterinary medicinal prod~ or suspension or withc;trawar· of that authorimtion, a 93/40/EEC Art 1 (10)) Member· State, or the Commissi~ or the marketing authorization holder may refer the matter to the Committee for application ofthe p~ wd down in Article 36. (as amended by (adapted). The Member State concerned, the marketing authorization holder or the Commission shall clearly identify the question which is referred to the Committee for. consideration and, if appropriate, shall inform the aforemention~d holder thereof. The Member States and the marketing authorization holder shall forward to the Committee all available information relating to the matter in question. Article35 The Member States or the Commission or the applicant or holder of the marketing 81/851/EEC authorization may, in specific cases where the interests of the Community are involved, Art 20 refer the matter to the Committee for the application of the procedure laid down in. (as amended by Article 36 before reaching &·decision on a request for a marketing authorization or on the 93/40/EEC Art. 1 (10)) suspension or withdrawal of an authorization, or on any other variations to the terms of a· marketing authorization which appears necessary, in particular to take account of the information collected in accordance with Title vn. (adapted) The Member State concerned or the Commission shall clearly identify the question which is referred to the Committee for consideration and shall inform the marketing authorization holder. The Member States. and the holder shall forward to the Committee all available information relating to the matter in question. 31 Artiele36 1. When ~ference is pwie to the procedure described in this Article, the Committee sbal1 consider the matter concerned. and issue a reasoned· opinion within. 90 days of the date on which the matter was referred to it However, in cases submitted to the Committee in accofdance with Articles 34 and 35, this period may be extended l>Y 90. days. 81/851/EEC Art. 21 (as amended by 93/40/EEC Art. 1 (10)) (adapted) In case of urgency, on a proposal from its Chairman, the Committee may agree to a. shorter deadline. · · 2. 3. In order to consider the matter, ·the Committee may appoint one of its members to. ad as rapporteur. The Committee may also appoint individual experts to advise it on specific questions. When appointing experts, the Committee shall define their tasks and specify the time-limit for the completion of these tasks. In the cases ·referred to in Articles 33 and 34, before issuing its opinion, the Committee shall provide the· marketing authorization holder with an opportunity to present written or oral explanations. In the case referred to in Article 35, the marketing authorization holder may be asked to explain himself orally or. in writing. If it considers it appropriate, the Committe. e may invite any other person to provide infonnation relating to the matter before it. The Committee may suspend the time-limit referred to in paragraph 1 in order to allow the marketing authorization holder to prepare explanations. 32 811851/EEC Art. 21. (as amended·by 93/40/EBC Art. 1 ( 1 0)) {adapted). 4. , ·The ApDty sball forlhwith inform the marketiDg authorization holder where the · opinion oflhe Committee is that: the ippUcation does not ~fy the criteria for authorization, or. the summary of the product characteristics· proposed by the applicant in iccordance with Article 14 should be amended, or the authorization should be granted subject to conditions, with regard to conditions considered essential for the safe and effective use of the ·veterinary medicinal product including pharmBcovigilance, or · a marketing authorimtion should be suspended, ~ed or withdrawn. Within 15 days of the receipt of the opinion, the holder may notify the Agency in writing of his intention to appeal. In that case, he sball forward the detailed grounds for appeal to the Agency within 60 days of receipt of the opinion. Within 60 days of. receipt of the grounds for appeal, the Committee shall consider whether its opinion should be revised, and the conclusions reached on the appeal shall be annexed to the · assessment report referred to in paragraph 5. S. Within 30 days of its adoption, the Agency shall forward the final opinion of the Committee to the Member States, the Commission and the marketing authorization holder together with a report describing th~ assessment of the veterinary medicinal product and the reasons for its conclusions. In the event of an opinion in favo\D" of granting or maintaining an authorization to place the veterinary medicinal product concerned on the market, the following documents shall be annexed to the opinion: (a) a draft summary of the product characteristics, as referred to in Article 14; where necessary this will reflect differences in the veterinary conditions pertaining in the Member States. · (b) any conditions affecting the authorization within the meaning of paragraph 4. · 33 Artlcle3'7 Within 30 days of receipt of the opinion, the Commission shall prepare a ~ of the · 811851/EEC decision to be~ in respect ofth~ application, taldng into ·account Community law. Art. 22 (1) (as amended by ·In the event of a draft decision which enVisages the granting of marketing authorization,. 93/~0/EEC Art 1 (1 0)) the documents referred to in Article 36 (5), 2nd mbparagraph, (a) and (b) shall be annexed. Where, exceptionally, the draft decision is not in accordance with the opinion of the Agency, the Conimission sball· also apnex a detailed explanation of the reasons for the differences. · The draft decision sbal1 be foovard~ to. the Member States and the applicant. Artiele38 1. A final decision on the application sball bf: adopted in accordance with the procedure laid down in Article 91. 2. The rules of procedure of the Standing Committee set up by Article 88 shall be adjusted to take account of the tasks incumbent upon it in accordance with thiS Chapter. 81/851/EEC Art. 22 (2), (3) and (4) (as amended by 93/40/EEC Art 1 (1 0)) ·(adapted) These adjustments shall involve the following: except in cases referred to in the third paragraph of Article 37, the opinion of the Standing Committee shall be obtained in. writing, · each Member State is allowed at least 28 days to forward written observations on the draft decision of the Commission, each Member State is able to require in writing that the draft decision be discussed by the Standing Committee, giving its reasons in detail. in the opinion of the Commission, Where, the written observations of a Member State raise important new questions of a scientific or technical nature which have not been addressed in the opinion of the Agency, the Chairman sball suspend the procedure and refer the application back to the Agency for further consideration. The provisions necessary for the implementation of this paragraph shall be adopted by the Commission in accordance with the procedure laid down in Article 90. 3. A decision as referred to in paragraph 1 shall be addressed to the Member States concerned by the matter and communicated to the marketing authorization holder. The Member States shall either grant or withdraw marketing authorization, or vary the terms of a marketing authorization as necessary to comply With the decision within 30 days of its notification. They shall inform the Commission and the Agency thereof. 34 Artide39. 1. ' Any application. · by' the. marketing authorization holdei to varY a malteting autborization Which bas been granted in accordance with the provisions of this Chapter shall be submitted to all thf. ' Member States which have previously authorized the veterinary medicinal product concerned. 81/851/EEC Art. 2~ (as amended by 93/40/EEC Art. 1 ( 1 0)) (adapted) The · Commission shall, in consultation with. the Agency, adopt appropriate. arrangements for the examination of ·variations to the terms of a marketing authorization. These arrangements shall include a notification. system or administration 'procedures concerning minor variations and define precisely the concept of "a minor variation". These arrangements shall be adopted by the Commission in the form of an implementing regulation in ~ce with the-procedure laid down in Article 89. · 2. The procedure laid down in Articles 36, 37 and 38 shall apply by analogy to · variations made to marketing authorizations for products. Article 40 1. Where a Member State. considers that the variation of the terms of a marketing 81/851/EEC authorization which has been granted in accordance with the provisions of this Art. 23a Chapter or its suspension or withdrawal is necessary for the protection of human or aitimai health or the environment, the Member State concerned shall forthwith 93/40/EEC Art. 1 (10)) refer the matter to the Agency for the application of the procedures laid down in Articles 36, 37 and 38. (as amended by (adapted) 2. Without prejudice to the provisions of Article 35, in exceptional cases, where mgent action is essential to protect human or animal health or the environment, until a definitive decision is adopted, a Member State may suspend the marketing and the use of the veterinary medicinal product concerned on its territory. It shall inform the Commission and the other Member States no later than the following working day of the reasons for its action. · 3S Artide41 Articles 39 and 40 shall apply by analogy tO veteriiwy medicinal productS authorized by 81/851/BEC Member States following an opinion of the Committee given in accordance with Article 4 Art. 23b of Directive 87f22/EEC before 1 January·t995. · · (as amended by 93/40/EEC Art. 1 (1 0)) Artide4l 1. The Agency shall publish. an annual repOrt on the operation of the procedures laid· 81/85 1/EEC doWn in this Chapter and sba1l forward it to the European P. -liament and the Art. 23c Council for information. · (as amended by 93/40/EEC Art. 1 (1 0)) 2. By 1 January 2001, the Commission shall. publish a detailed review of the operation of the procedures laid down in this Chapter and shall propose any amendments which may be necessary to improve these procedures. The Council shall decide, under the conditions provided for in the Treaty, on the Commission proposal within one year of its submission. The provisions of Articles 31 to 38 shall not apply to homeopathic veterinary medicinal products referred to in Article 19 (2). ·Artiele43 81/851/EEC Art. 22 {5) {as amended by 93/40/EEC Art. 1 (10)) (adapted) 36 TITLE IV MANUFACTURE AND IMPORTS Article 44 1. · Member Swes shall take all appropriate measures. to ensure that the manufacture of veteJinary medicinal products in their tenitory is subject. to the holding of an authorization. This manufacturing authorization shall likewise be required for veterinary medicinal products intended for export. ·811851/EEC Art. 24 (1) (as amended by 90/676/EEC Art. l (14)) (adapted). ' 2. The authorizatiOn refened to in paragraph 1 sball·be requirCd both for total and 81/851/EEC partial manufacture _and for the various ·processes of dividing up, packaging or· Art. 24 (2) and (3), 1st · presentation. subparagraph (adapted) However, sueh authorization shall not be rCqu. ired for preparation, dividing up, changes in packaging or presentation where these processes are ~ed out solely for the dispensing of retail supply by pharmacists ·in dispensing pharmacies or by persons legally authorized in the Member States to c:any out such processes. 3. The authorization referred to in paragraph l shall also be required for imports from third countries into a Member State; this Title and Article 83 shall apply to such impons in the same way as to manufacture. ' Member States shall take all appropriate measures to ensure that veterinary medicinal products brought. into their territory from a third country and destined for another Member State are accompanied by a copy of the authorization refemd to in paragraph 1. 811851/EEC Art. 24 (3), 2nd subparagraph (as amended by 90/676/EEC Art. 1 (15)) Article45 In order to obtain the manufacturing authorization, the applicant shall meet at least the 81/85 1/EEC following requirements: Art. 25 (adapted) (a) he shall specify the veterinary medicinal products and pharmaceutical forms which are to be manufactured or imported and also the place where they are to be manufactured and/or controlled; (b) he shall have at his disposal, for the manufacture or impon of the above, suitable and sufficient premises, technical equipment and control. facilities. complying with the legal requirements which the Member State concerned lays down· as regards both manufacture and control and the storage of products, in accordance with Article 24; (c) he shall have at his disposal the services of at least one qualified person within the meaning of Article 52. The applicant shall provide particulars in his application to establish his compliance with the above requirements. 37 Article46 1. The compdent authority 9f the Member ·State sbalf not issue the manufaCuuing 81/85 llEEC authorization until. it ~ established the accuracy of the particulars supplied pursuant · Art. 26 to Article 45 by means of an inquiry carried out by its representatives. (adapted) 2. In order to ensure that the requirements referred tO in Article 45 ·are complied with, authorization may be made ·conditional on the ful1ilment ~f certain obligations imposed either when authorizatio~ is granted or at a later date. 3. The authorization shall apply only to the premises specified in the application and to the veterinary medicinal products and pharmaceutical forms Specified in that application. · · Article 47 The Member States shall take all appropriate measures to ensure that the time taken for 81185 1/EEC the procedure for granting the manufacturing authorization does not exceed 90 days from An. 28 (1) (adapted) the day on which the competent authority receives the application. ArticleU If th~ holder of the manufacturing authorization requests a change in any of the 81/85 1/EEC particulars referred to in Article 45 (1) (a) and (b), the time taken for the procedure An. 28 (2) relating to this request shall not exceed 30 days. In exceptional cases, this period of time (adapted) may be extended to 90 days. Article 49 The competent authority of the Member States may require from the applicant further 81/851/EEC information concerning both the particulars supplied pursuant· to Article 45 and the Art. 28 (3) qualified person referred to in Article 52; where the competent authority concerned (adapted) exercises this right, application of the time-limits referred to in Articles 47 and 48 shall be suspended until the additional data required have been supplied. 38 Artlde50. · The ~~of a m""nfacturing aUthorization shall at least be obliged to:. (a) -have at his disposal the services of Staff complying with the legal requireDients existing in the Member State concerned as iegards ~th manufacture and controls; · (b) dispOse of tbe. authorized veterinary medicinal products only in accordance with the legislation of the Member States conceme!i; 81/85 1/BEC· Art. 27 (a) to (e) (adapted) (c) give prior notice to the competent authority of any changes which he may wish to make to any of the particulars supplied pursuant to Article 45; the competent' ·authority shall, in any event, be immediately informed if the qualified person referred to m Article 52 is replaced unexpectedly; (d). allow the representatives of the competent authority of the Member State concerned access to his premises at any time; · (e) enable ·the qualified person referred to in Article 52 to carry out hiS duties, particularly by placing at. bis disposal all the necessary facilities. (t) comply with the principles and the guidelines of good manufacturing practice for 811851/EEC medicinal products laid down by Community law; Art. 27 (t) ~d (g) (as amended by (g) keep detailed records of all veterinary medicinal products supplied by him, including 90/676/EEC An. 1 (17)) samples, in accordance ·with the laws of the countries of destination. The following information at least sbaU be recorded in respect of each transaction, whether or not it i$ made for payment: - - date, name of the veterinary medicinal product, quantity supplied, • name and address of the recipient, batch number. These records shall be available for inspection by the competent authorities for a period of. at least three years. Article 51 The principles and guidelines. of good manufacturing practice for veterinary meqicinal products referred to in Article SO (f) shall be adopted in the form of a Directive addr~sed to the Member States in accordance with the procechu'e laid down in Article 90. Detailed guidelines shall be published by the Commission and revised as appropriate to take account of scientific and teclmical progress. 811851/EEC Art. 27a (as amended by 90/676/EEC An. 1 {18)) (adapted) 39 Artlde52 1. Member States sbal1 take all appropriate measures to ensure tbat. the holder of the 81/851/EEC manufacturing authorization has permanently and continuo~ly at his disposal the Art. 29 services of·at least one qualiDed person who 1Wfils the conditions laid down in (adapted) Article 53 and is responsible, in particular, for carrying out· the duties specified in Article SS. · 2. If he personally fulfils the conditions laid down in· Article 53, the holder of the authorization may himself assume the responsibility referred to in paragraph 1. Article 53 1. Member States shall ensme tbat the qualified person referred to in Article 52 fulfils 81/851/EEC the minimum conditions of qualification set oUt in paragraphs 2 and 3. Art. 31 · (adapted) 2. The qualified person shall be. in possession of a diploma, certificate or other evidence· of formal qualifications awarded on completion of a university course of study, or a course recognized as equivalent by the· Member 'State concerned, extending over a period of at least four years of theoretical and practical study in one of the following scientific disciplines: pharmacy, medicine, veterinary science, chemistry, pharmaceutical chemistry and technology, biology. However, the minimum duration of the university course may be three and a half years where the coW'Se is followed by a period of theoretical and practical training of at least one year and includes a training period of at least six months in a pharmacy open to the public, corroborated by an examination at university level, Where two university or recognized equivalent courses co-exist in a. Member State and where one of these extends over four ,years and the other over three years, the diploma, certificate or, other evidence of formal qualifications awarded on completion of the three-year university course or its recognized equivalent shall be -considered to fulfil the condition ·of duration referred to in the first subparagraph. in so far as the diplomas, certificates or other evidence of formal qualifications awarded on completion of both courses are recognized as equivalent by the State in question. 40 The course shall include theoretic81 and practical tuition bearing upon at least the 8118SliEEC foubwing basic subjects:. · · Art. 31 (adapted) - experim. emal physics, general andjnorpaic chemistry, organic chemistry, "analytical chemistry, pbannaceutical chemistry, including analysis of medicinal products, general and applied biochemistry (medical) , physiology, microbiology, pharmacology, phar. maceutical technology, toxicology, pharmacognosy (study of the composition and effects of the active principles of natural substances of plant and animal origin). Tuition in these subjects should be so balanced as to enable the person concerned to fulfil the obligations specified in Article SS. In so far as certain diplomas, certificates or other evidence of formal qualifications mentioned in this paragraph do not fulfil the criteria laid down above, the competent authority of the Member State shall ensure that the person concerned provides evidence that he has, in the subjects involved, the knowledge required for the man~ and control of veterinary medicinal Products. 3. The qualified person shall have acquired practical experience over~ least two years, in one or more undertakings which are authorized manufacturers, in the activities of. qualitative analysis of medicinal products, of quantitative analysis of active substances and of the testing and checking necessary to ensure the quality of veterinary medicinal products. The duration of practical experience may be reduced by one year where a university course lasts for at least five years and by a year and a half where the course lasts for at least six years. 41 Artide54 1. A person engaging m the activities of the person referred to in Article 52 from the 81185 1/EEC time of the application of Directive 81/85 1/EEC, but not complyiDg with the. · An. 32 provisions of Article 53 shall·})e eligJ. ole to continue to engage in those activities in (~ted) the State concerned. · 2. The · bolder of a diploma, certificate or other evidence of formal qualifications · awarded on completion of a university course • or a course recognized as equi~ent by the Member State concerned • in a scientific discipline allowing him to engage. in ,. · the. activities of the person referred tO in Article 52. in accordance with the laws of that State may - if be began his course prior to 9 October _1981 • be conSidered as qualified to cany out in that State. the duties of the person referred to in Article· 52, provided that be has previouSly engaged in the following activities for· at least two years before before 9 October 1991. in ·one or more 1mdertakings authorized ·to manufactlue: production supervision. and/or qualitative and quantitative analysis of active substances, and the neceSS81)' testing and checking under the direct authority of a person as refemd to in Article 52 to ensure the quality of veterinary medicinal' products. If the person concerned has acquired the practical experience referred to in the first subparagraph before 9 October 1971, a further one year's practical experience in accordance with the Conditions referred to. in the first subparagraph shall · be completed by him immediately before be engages in such activities. 42 ArtltleSS l. · Member States shall take all appropriate measures to ensure that the qualified ~n 81/85 1/EEC ·referred to in Article 52 is, without prejudice to his relati~ with the holder of Art. 30 (1), 1st and 2nd the manufacturing authorizatiOD,. ~ible, in the context of the. procedures subparagraphs. referred to in Article 56, for ·ensuring that: · (adapted). (a) in the case of veterinary medicinal products manufactured within the Member State concerned, each batch of veterinary medicinal ·products has been manufactured and checked in·compliance with the laws in force in that Member State and in accordance with the requirements of the marketing. authorization; (b) in the case of veterinary medicinal prOducts coming from third countries, each production batch imported has undergone in the importing Member State a full qualitative 8D8lys~, a quantitative analysis. of at least all. the active substances and all the other tests or checks necessary to ensure the quality of veterinary medicinal products in accordance \\ith the ~ments of the marketing authorization. Batches of veterinary medicinal products which have undergone such controls in a Member State shall be exempt from the above controls if they are marketed in another Member State, accompanied by the control reports signed by the qualified person. 2. 3. In the case of veterinary medicinal products imported from a third country, where 81/851/EEC appropriate arrangements have been made by the Community with the exporting Art. 30 (I), 3rd country to ensure that the manufacturer of the veterinary medicinal product applies standards of good manufacturing practice at least. equivalent to those laid down by the Community and to ensure that the controls referred to under point (b) of the first 93/40/EEC Art. 1 (11)) subparagraph of paragraph 1 have been carried out in the exporting country, the qualified person may be relieved of responsibilil:}' for carrying out those controls. subparagraph (as amended by In all cases, and particularly where the veterinary medicinal products are released for 81/851/EEC sale, the qualified person shall certify, in a register or equivalent document provided Art. 30 (2) for the purpose, that each production batch satisfies the provisions of this Article; the said register or equivalent document shall be kept up to date as operations are. carried out and shall remain at the disposal of the representatives of the competent authority for the period specified in the provisions of the Member State concerned an~ in any event, for at least five years. Article 56 Member States shall ensure that the obligations of qualified persons referred to in Article 81/85 1/EEC 52 are fulfilled, either by means of appropriate administrative measures or by making Art. 33 such persons subject to a professional code of conduct. Member States may provide for the temporary suspension of such a person upon the commencement of administrative or disciplinary proceedings against him for failure to fulfil his obligations. - The provisions of this Title shall apply to homeopathic veterinary medicinal products. ·Article 57 92n4/EEC Art. 3· (adapted) 43 TITLEV. LABELLING AND PACKAGE INSERT Artiele58 l. The following information, which shall conform with the particulars and documents 81/85 1/EEC provided pursuant to Articles 12 and 13 (1) and be. approved by the competent Art. 43 (1) · authorities, shall · appear in legible characters on containers and outer packages of medicinal products: · (a) Name of the veterinary medicinal product, which may be a brand name or a non proprietary name accompanied by a trade mark or the name of the manufacturer, or a scientific name or foimula, with or without , a trade mark, or the name of the manu1Dcturer. 81/851/EEC Art. 43 (1), points 1 and 2 (as amended by 90/676/EEC Arl1 (23)). (adapted) Where the special name of a medicinal product· containing only one active substance is a brand name, this name must be. accompanied in legible characters by the international non·propriety name recommended by the World Health Organization, where such name exists or, where no such name exists, by the usual non-proprietary name. (b) A statement of the active substances expressed qualitatively and quantitatively per dosage unit or according to the form of administration for a particular volume or weight, using the international non-proprietary names recommended by the World Health Organization, where such names exist or, where no such names exist, the usual non-proprietary names. (c) Manufacturer's batch number; (d) Marketing authorization number; 81/851/EEC Art. 43 (1 ), points 3 to 6 (adapted) (e) Name or corporate name and permanent address or registered place of business of the marketing authorization holder and of the manufacturer, if different; (f) The species of animal for which the veterinary medicinal pro9uct is intended; the method and route of administration; (g) The withdrawal period, even if nil, in the case of veterinary medicinal products administered to food-producing animals; (b) Expiry date, in plain language; (i) Special storage precautions, if any; 81/851/EEC Art. 43 (1), points 7 and8 (as amended by 90/676/EEC Art. 1 (23)) (adapted) 81/851/EEC Art. 43 (1), point 9 811851/EEC (j) Special precautions for disposal of unused medicinal products or waste material from Art. 43 (1 ), point 9a medicinal products, if any; (as amended by 90/676/EEC Art. 1 (23)) (adapted) ·44 (k) Particulars ~to be indicated pursuant to Article 26_ {1), if ~y; (I) The wOrds "For animal ~ent only". 2. lbe. pharmaceutical·form and the contents by weight, volume or num~ of dose-. units need only be shown on the outer package. 81/8$1/BEC Art. 43 {1), points 10 andll 81/851/EEC Art. 42 (2) and (3) (adapted) 3. The provisions of Pan 1, A of Almex I, in so far as they concern the qualitative and quantitative composition of veteriruuy medicinal prpducts in respeCt of active. substances, shall apply to the particulars provided for in paragraph 1 (b). 4. · The pam_'culars mentioned in paragraph 1 (f) to (1) shall appear on the outer package 181/851/EEC and on the container of:the medicinal products in the language or languages of the Art. 47 country in which they. are placed on the market (adapted) Article 59 1. As regards ampoules, the paniculars listed in the first paragraph of Article SS (1) 81/851/EEC shall be given on the outer package. · On the containers,. however, only the following Art. 44 particulars shall be necessary: (adapted) · ·. • name of veterinary medicinal product, quantity of the. active substances, - routeof~o~. manufacturer's batch number, - date of expiry, • the words 'For aniinal treatment only'. 2. As regards small single-dose containers, other than ampoules, on which it is 811851/EEC impossible to give the particulars mentioned in paragraph 1, the requirements of Art. 45 Article 58 (1),·(~) and (3}, shall apply only to the outer package. 3. The particulars mentioned in the third and sixth indents of paragraph I shall appear 81/85 1/EEC on the outer package and on the container of the medicinal products in the language Art. 47 or languages of the country in which they are placed on the market Article 60 Where there is no outer package, all the particulars which Should feature on such a 81/85 1/EEC package pursuant to the Articles 58 and 59 shall be shown on the container. Art. 46 (adapted) Artide61. 1. ·The inclusion of a package insert in. the packaging of veterinary medicinal prOducts 81/85 1/EEC shall be obligatory unless all the information required by this Article can be Art 48 (1) conveyed. on the CODtainer and the eXtemal packaging M~ States shall take all appropriate measures to ensure that the insert relates solely to the veterinary 90/676/EEC An. 1 (24)) mediciDal product with which it is included. The. insen shall be in the· official langUage or languages of the fdember State in. which the medicinal product is marketed. (as amended by 2. The package insert shall contain at least the following information, which· shall 81185 1/EEC conform to the particulars and documents provided pursuant to Art;icles. 12 and Art. 48 (2) (a) to (d) · 13 (1) and be approved by the competent authorities: (adapted) · · {a) name or corporate name and permanent address or registered place of business of the marketing authorization holder and ofthe·manufacturer, if different; (b) name of the veterinary. medicinal product and a statement of its active substances expressed qualitatively and quantitatively; The international non-proprietary names recommended by the World Trade Organization shall be used wherever they exist; · (c) the therapeutic indications; (d) contra-indications and adverse reactions in so far as these particulars are necessary for the use of the veterinary medicinal product; (e) the species of animal for which the veterinary medicinal product is intended, the dosage for each species, the method and route of administration and advice on correct administration, if necessary; (f) the withdrawal period, even if this is nil, in the case of veterinary medicinal · products administered to food-producing animals; (g) special storage precautions, if any; (h) particulars required to be indicated pW'Suant to Article 26 (1), if any. (i) special precB:Utions for the disposal of unused medicinal products or waste materials from medicinal products, if any; 81/851/EEC Art. 48 (2) (e) (as amended by 90/676/EEC An. 1 (25) (a)) 81/851/EEC Art. 48 (2) (t) and (g) 81/851/EEC Art- 48 {2) (h) (as amended by 90/676/EEC An. 1 (25) (b)). 3. The particulars referred to in paragraph 2 shall appear in the language or languages 81185 1/EEC of the counny in which the produa is marketed. The other infonnation shall be Art. 48 (3) (adapted) clearly separate from such particulars. 46 Article 62 Where tbe ps:ovisiollS of this Title are not observed and a formal notice addressed to the person conceriaed bas been ineffectual, tbe competent authorities of the Member States Art. 49, 1st paraaraph may suspend or withdraw lll81'ketinl authorization. 81/IS li£EC Artide63 The requirements of Member states· concerning conditions of supply to the public, the 81/851/EEC marldQg of prices on medicinal products for veterinary use and industrial property rights Art. SO. shall not be affe~ by the provisions of this Title. Artlcle. 64 1. Without prejudice. to paralraph 2, the homeopathic veterinary products shall be 92174/EEC identified by the inclusion on their labels, in clearly legible form, of the words Art. 2 (2) 'homeopathic m. ediciDal· product for veterinary use'. (adapted) 2. In addition to the clear mention of the words 'homeopathic veterinary medicinal 92174/EEC product without approved therapeutic indications', the labelling and, where Art 7 (2) appropriate, package insert for the homeopathic veterinary medicinal products (adapted) referred to in Article 17 (1) ·shall bear the following information and no other information: • - the scientific name of the stock or stocks followed by the degree of dilution, using the symbols of the pharmacopoeia used in accordance with point 8 of Article 1, name and address of the marketing authorization holder and, where appropriate, of the manufacturer, method of administration and, if necessary, route, expiry date, in clear terms (month, year), pharmaceutical ~orm, contents of the sales presentation, special storage precautions, if any, - target species, a. special warning if necessary for the medicinal product, ·- manufacturer's batch number, - registration number. 47 TITLE VI POSSESSION~ WHOLESALE DISTRIBUTION AND DISPENSIN'G OF VETERINARY MEDICIN'AL PRODUCTS Article 65 1. Member States shall take all appropriate measures to ensure that wholesale distribution of ·veterinary medicinal products is subject to the holding of an authorization. and to ensme that the time taken for the procedure for granting this authorization does not exceed 90 days from the date on which the competent authority receives the application. · Member States may also exclude supplies of small q~tities of veterinary medicinal products from one retailer to another. 2. · In order to obtain the authorization for· distribution, the applicant shall have at his disposal technically competent staff and suitable and sufficient premises comp}ying with the requirements laid down in the Member State concerned as regards the storage and handling of veterinary medicinal products. 3. The holder of the authorization for distribution shall be required to keep detailed records. The following minimum· information shall be recorded in respect of each incoming or outgoing transaction: · 81/851/EEC Art. 50a (1), 1st subparagraph· (as amended by 90/676/EEC Art. 1 (27)) (adapted) 81/851/EEC Art. 50a (1), 3rd subparagraph and {2), {3) and{4) · (as amended by 90/676/BEC Art. 1 (27)) ·(adapted) (a) date; (b) precise identity of the veterinary medicinal prod~ct; (c) manufacturer's batch number,; (d) quantity received or supplied; (e) name and address ofthe supplier or recipient. At least once a year a detailed audit shall be carried out to compare incoming and outgoing medicinal supplies with supplies currently held in stock, any discrepancies being recorded. These records shall be available for inspection by the competem authorities for· a period of at least three years. 4. Member States shall take all appropriate measures to ensure that wholesalers supply veterinary medicinal products only to persons permitted to carry out retail activities in accordance with Article 66, or to other persons who are lawfully permitted to receive veterinary medicinal products from wholesalers. 48 Article 66 1. Member States shall take all appropriate measures to ensure that the retail supply of veterinary medicinal products is conducted only by persons who are permitted to c1rry out such operations by the legislation of the Member State concerned. 2. Any· person permitted under paragraph 1 to sell veterinary medicinal products shall be required to keep detailed records. The following information shall be recorded in ~. of each incoming or outgoing transaction: · 81/851/EEC Art. SOb (as amended by 90/676/EEC Art. 1 (27)) (adapted) (a) date; · (b) precise identity of the veterinary medicinal product; (c) manufacturer's batch number; (d) quantity received or supplied; (e) name and address of the supplier or recipient; (f) where relevant, name and address of the prescribing veterinarian and a copy of the prescription. At least once a year a detailed audit shall be carried out, and incoming and outgoing veterinary medicinal products shall be reconciled with products currently held in stock, any discrepancies Qc:ing recorded. These records shall be available for inspection by the competent authorities for a period of three years. 3. Member States may limit the number of detailed documenting requirements referred to in paragraph 2. However, these requirements shall always be applied in case of veterinary medicinal products which are intended for administration to food producing animals and which are available only on veterinary prescription or in respect of which a withdrawal period must be observed. 4. Not later that I January 1992, Member States shall communicate to the Commission a list of the veterinary medicinal products which are available without prescription. After having taken note of the communication from the Member States, the Commission shall examine whether suitable measures should be proposed for drawing up a Community list of such medlcinal products. 49 811851/EEC Art. 4 (3), 3rd subparagraph (as amen~ by 90/676/EEC Art. I (4)) (adapted) Artide67 Without prejudice· to stricter Community or national rules relating to dispensing veterinary medicinal products and to protect human and animal health,. a prescription shall be required' for dispensing to the public the following veterinary medicinal products; (a) those'products subject to official restrictions on supply or use, s~ch as:. the restrictions resulting from the implementation of the relevant United Nations conventions on narcotic and psychotropic sub~ces, · the restrictions on the use of veterinary medicmai products resulting from Community law; (b) those products in respect of which special precautions must be taken by the veterinarian in order to avoid any unnecessary risk to: the target species, the person administering the products to the animal, the consumer of foodstuffs obtained from the treated animal, the environment; (c) those products intended for treatments or pathological processes which require a precise prior diagnosis or the use of which may cause effects which impede or interfere with subsequent diagnostic or therape~c measures; (d) magistral fonnulae intended for animals. In addition, a prescription shall be required for new veterinary medicinal products containing an active substance which has been authorized for use in a veterinary medicinal product for less than five years unless, having regard to the· information and particulars provided by the applicant, or experience acquired. in the practical use of the veterinary medicinal product, the competent authorities are satisfied that none of the criteria referred to in (a) to (d) of the first paragraph apply. so Article 68 :1. -··Member. · States shaii · take ail measures necessazy · to ensure· that only pei-sons empowered UJider their national legislation ·in for~· possess or have under their control v~. medicina1 products or substances which may be. used as veterinary. medicinal products inflammatoty, honnoJ. ial ~r psychotropic properties~ that have anabolic, anti-infectious, anti-parasitic; anti 81/851/EEC Art. 1 (5) (as amended by 90/676/EEC An. I (1 )) (adapted): 2. Member States. shall main~ a register. of manufacturers and dealers permitted· to be· in possession. Of· active. substances ·which may be used in the manufacture of - veterinary ·medicinal products having the ·properties referred ·to in ·paragraph 1. Such persons must jnaintain detailed records of all deaHn~ in subStances which may be used in the manufacture. of veterinary medicinal products and keep these records ' available for inspection by the competent authorities for a period of at least three years. 3. Any amendments to be made to the list of substances referred to in paragraph 1 shall be adopted in accordance with the procedure refetred to in Article 90. Article 69 Member States shall ensure that the owners or keepers of food-producing animals can provide proof of purchase, possession and administration of veterinary medicinal products containing the substances set out in Article 68; Member States may extend the scope of this obligation to other veterinary medicinal products. In particular, Member States may require the maintenance of a record giving at least the following information: 811851/EEC Art. 50c (as amended by 90/676/EEC Art. 1 (27)) (adapted) (a) date; · (b) name of the veterinary medicinal product; (c) quantity; (d) name and address of the supplier of the medicinal product; (e) identification of the animals treated. Sl Artide70 · Nothwithstand. ing Articles 9 and 67, Member States shall ensure that veterinarians 81/851/EEC providing services in another Member State can take with them and adm. inister to animals Art. 4 (S) ~ quantities of ready-made veterinary medicinal products not exceeding daily requirements. other than im. nlunological veterinary medicinal products which are not 90/676/EEC Art. I (4)) authorized for use in the M~ber State in which the ser;vlces are provided (hereinafter: (~pted) host Member State), providing that the ·foll9wing conditions ~ satisfied: (as. amended by · · · (a) the authorization to place the product on the market provided for in. Articles S, 7 and 8 has been issued by the competent authorities of th~ Member State in which the veterinarian is established; · (b) the veterinary medicinal products are transported by the veterinarian in the Original manufacturer's packaging; · (c) the veterinary medicinal products intended for administration to food-producing animals have the same qualitative and quantitative composition in terms of active substances as the medicinal products authorized in accordance with Articles s, 7 and 8 in the host Member State; (d) the veterinarian providing services in another Member Stite acquaiiJ. ts himself with the good veterinary practices applied in that Member State and ensures that the. Withdrawal period specified on the labelling of the veterinary medicinal product concerned is complied with, unless he could reasonably be expected to know that a longer withdrawal period should be specified to comply with these good veterinary practices; (e) the veterinarian shall not furnish any veterinary medicinal product to the owner or keeper of the animals treated in the host Member State unless this is permissible on the basis of the rules of the host Member State; in this case he shall, however, supply only in relation to animals under his care and only the minimmn quantities of · veterinary medicinal product necessary to complete the treatment of animals concerned on that occasion; (f) the veterinarian shall be required to keep detailed records of the animals treated, the diagnosis, the veterinary medicinal products administered, the dosage arlminist~ the dmation of treatment and the withdrawal period applied. These records shall be available for inspection by the competent authorities of the host Member State for a period of at least three years; (g) the overall range and quantity of veterinary medicinal products canied by the veterinarian shall not exceed that generally. required for the daily needs of good veterinary practice. 52 Artiele71 1. · In th~ absence· of ·speCific CommunitY legislation concerning · the use of 90/677/EEC iliunuoologicai veteimary mediciDal products for the eradication or cOntrOl of animal Art. 4· disease, a Members-. ·may, in ~rdance with its national legislation, prohlbit the ·man~, import, ·posstsion, sale, supply and/or use of immunological veterinary medicinal Proctucts on the whole or part of its territorY if it is established tbat: (a) the administration of the product. to axUmalS Will ·interfere ·With ihe. (adapted) ··. implementation of a uationai programme for the ciiaSnosis, control or eradiction of: aniJDal· ·disease,. or will cause difficulties in certifying the ·absence · of. Contamination in. live animals or in foodstuffs or other products obtaip. ed from treated anjfnals; (b) the disease to ·which the product is intended to confer immunity is largely absent from the territoty in question. 2. The competerit authorities of the Member States shall inform the Commission of all instances in which the provisions of paragraph 1 are applied. S3 TITLE VU PHARMACOVIGILANCE. Article 72 Member States ·shall take aii apprQpriate measures ·to ·encourage the reporting to the c~ authorities of Suspected. adverse reactions to the veterinmy mediciDal products. Si/851/EEC. Art. 42e (as amended by 93/40/EEC Art. l {12)) (idapted) Artie~73 in order to ensure the adoption of appropriate regulatory decisions concerning the 81/85 1/EEC veterinary medicinal products authorized· withiD the Commui'lity, having regard to Art. 42a · information obtained ab9ut suspected adverse. · r:eacuons to medicinal products under normal conditions of use, the Mem~ States ·shall establish a pharmacovigilance system. 93/40/EEC J_\rt. 1 (12)) This system shall be used to collect information useful in the surveillance of veterinmy. medicinal products, with particular reference to adverse reactions in animals, and to evaluate such information scientifically. '(as amended by · Such information shall be collated with data on consumption of veterinary medicinal products. This system shall also collate information on frequently observed misuse and serious abuse of veterinmy medicinal products. Article 74 The marketing authorization· holder shall have permanently and continuously at his disposal an appropriately qualified person responsible for pharmacovigilance. That qualified person shall be responsible for the follo~g: (a) the establishment and maintenance of a system which ensures that information about all suspected adverse reactions which are reported to the personnel of the company, including its representatives, is collected and collated at a single point; (b) the preparation for the competent authorities of the reports referred to in Article 75, in such form as may be laid down by those authorities,. in accordance with the relevant national or Community guidelines; (c) ensuring that lilY request from the competent authorities for the provision of additional information necessary for the evaluation of the benefits and risks afforded by a veterinary medicinal product is answered fully and promptly, including the provision of information about the volume of sales or prescriptions of the veterinary medicinal product concerned 81/851/EEC Art. 42c (as amended by 93/40/EEC Art. I (12)) (adapted) Articl~ 75 · 1. The marketing aUthorization holder sball be required to record and to report all · suspected. serious. ad~ ·. reactions which are· brought ~ his. attention _to ·the competent authoritieS immediately,. and in any case~ 15 days. of~eir·i'eceipt at. the~. 2. The marketing aluthorization holder. shall be Rquired to maintain detailed records of : all other suspected adverse reactions which are reported to him. · Unless _other requirements·· have been laid down as a condition of the granting of authorizatioli. ~ese records. shall be subuiitted to the competeat authorities immec:Uare~ upon request or at· least every six months during the fiist' two years following authorization, and once a year for ·the following three years. Thereafter, the records· sball be· submitted at five-yearly intervals together with the application for renewal of the authorization, or ~ediateJY upon request. These records shall be accompanied by a scientific evaluation. · Article 76 Member States shall ensure that reports of suspected serious adverse reactions are immediately brought to the attention of the Agency and the marketing authorization holder, and in any case within 15 days of their notification, at the latest. 8~/851/EEC. Art. 42d {is amended by 93/40/EEC Art. 1 (12)) (adapted). 811851/EEC Art. 42f (as amended by 93/40/EEC Art. 1 (12)) (adapted) Article 77 In order to facilitate the exchange of information about pharmacovigilancc; within the 81/851/EEC Community, the Commission, in consultation with the Agency, Member States and An. 42g interested parties, shall draw up guidance on the collection, verification and presentation of adverse reaction reports. (as amended by 93/40/EEC Art. 1 (12)) This guidance shall take account of international harmonization work carried out with regard to terminology and classification in the field of pharmacovigilance when use of such worlc can be made in the field of the vet&mnaly medicinal product concerned. ss Article 78 ·. 1 ~ WbCre as~a reSUlt. ·of the evaluation Qf adverse reaction Je. Potts a c:Ompetem authority m a ··Member State. cousiders. that a ID8Iketii1g. authorization should be Wrled, suspended ,br withdra~ · it shall -forthwith infOrm the. Agency and the ~ authOrization holder. ·si!Bsi!EEc. Arl42h (as amended by ·. · 93/40/EEC Art. 1 (12)) (adapted). 2. In case of urgency,. the toulpetcnt authority ·of a M* State concerned may suspend the ID8Iketii1g of. a. veterinary medicinal product,. provided the Agency is informed no later than on the first following working day. · Article 79 Any amendments which may be necessary to update the provisions of Articles 72 to 78 to 81/85 I !EEC take account of scientific and technical progress shall be· adopted in accordance witb. the An. 42i · · procedure laid down in Article 90. (as amended by 93/40/EEC Art. 1 (12)) (adapted) S6 TITLEVlll SUPERVISION AND SANCTIONS Article 80 L The _co. tDpetent authority ~f the Member State concerned shall ensure by means of 81/851/EEC repeated inspection that the legal requirements relating to veterinary medicinal M 34, 1st subparagraph products are complied:with. · · (as amended by 90/676/EEC Art. 1 {19)) SuCh inspections sball'be cmied out by authorized representatives of the competent 81185 1/EEC Art 34, 2nd authoritywho·sballbe empowered to: subparagrapb (adapted) (a) inspect manufacturing or trading estabbsbments and any laboratories entrusted by the holder of the manufacturing authorization,. with the task of carrying out control tests pursuant to Article 24; (b) take samples; (c) examine any documents relating to the object of the inspection, subject to current provisions in the Member States from 9 October 1981 which place restrictions on these powers with regard to the description of the manufacturing method. 2. Member States shall take all appropriate measures to ensure that the manufacturing 90/677/EEC processess used in the manufacture of immunologi~ veterinary medicinal products Art 3 (1) (adapted) are completely validated and batch-to-batch consistency ·is ensured. 3. The officials representing the competent authority shall report after each of the inspections mentioned in the first paragraph on whether the manufacturer complies with !he principles and guidelines of good manufacturing practice referred to in Article 5 I. The inspected manufacturer shall be informed of the content of such reports. 811851/EEC Art. 34, 3rd subparagrapb (as amended by 90/676/EEC Art. 1 (19)) Article 81 1. Member States shall take all appropriate measures to ensure that the marketing 81185 I !EEC authorization holder and, where appropriate, the holder of the manufacturing Art. 35 authorization fwnish proof of the control tests carried out on the veterinary medicaf product and/or on the constituents and intermediate products of the manufacturing process, in accordance with the methods laid down for the purposes cf marketing authorization. (adapted) ,, 2. ·For the puqJOses of_implementing paragraph 1,. Membrer States ·may reqUire the. 90/671tEEC marketing authorization holder for mmiunologiCal veterlnary medicinal· products to Art. 3 (2). sobmit to. the competeilt authorities copies of ·all the control reports signed by the. (adapted). "qualified person m accOrdance with Article 55. The·~etiug ~rizatioil holder for immlDlological veterinary medicinal proaucts _ shall ensure that an ad~ ·number _of representative samples. of eaA;h batch of veterimuy medical products is held in stock. at least up to the expiry date, and provide samples promptly to the competent authorities on request Article 82 1; Where it considers it necessary,. a Metn:ber State may require the marketing 90/677/EEC authorization holder for immunological products to submit samples from the batches Art. 3 (3) of tbe bulk and/or medical product for examination by a State laboratory or. an (adapted) approved laboratory before entry into circulation. In the case of a batch manufactured in another Member State, examined by ·the competent authority of another Member State and declared to be in conformity with national specifications, such a control may be canied out only after the control reports of the batch in question have been examined, after the Commission has been informed, and where the difference in veterinary conditions between the two Member States concerned justifies it. 2. Except where the Commission has been informed that a long period is necessary to complete the analyses, Member States sball ensure that any such examination is completed within 60 days of receipt of the samples. The marketing authorization holder shall be notified of the results of the examination within the same time-limit. 3. Before 1 January 1992, the Member States shall notify the Commission of the immunological veterinary medicinal products subject to compulsory· official control before being placed on the market. ss. ·. ~~83··. -The Competem auth~rities of the Member States shall suspend or ~draw marketing ~orization wh~ 1i is clea;r tbat: · · · · ' '81/85 1/EEC Art. 36 (adapted). · (a) 1he ~·medicinal product proves to. be harmful. pnder the -conditions of use stated at the time of appli~on for authorization or ~bsequently; (b) the veteriDaJy medicinal product does not have any therapeutic effect on the specieS of animal for which the. treatment ~ intended; (e) its qualitative and quantitative eomposition is not as stated; (d) the recommended withdrawal period is inadequate to ensure that foodstuffS obtained from the treated animal do not contain residues which might constitute a health · · hazard to the consumer; (e) the veterinary medicinal product is offered for sale for a use which is prohibited by other community provisions. However, pending Community rules, the competent authorities may refuse to grant authorization for a veterinary medicinal product where such action is necessary for tbe protection of public, consumer or animal health; (f) the information given in the application documents pursuant to Article 12, 13 (1) and 27 is incomct; ' (g) the control tests referred to in Article 81 (I) have ~ot been carried out; (h) the obligation referred to in Article 26 (2) has not been twfilled. Authorization may also be suspended, or withdrawn where it is established that: (a) the particulars supporting the aPPlication, as provided for in Articles 12 and 13 (1), have not been amended in accordance with Article 27 (I),. (b) any new information as referred to in paragraph 3 of Article 27 has not been (adapted) communicated to the competent authorities. S9 Artide~ 1. Witholl_t prejudice. to. Article 83,. Member States ·shall take. all necessary measures to 811851/EEC. ensure tbat supply of a veterinary medicinal product is prohibited: and ·that die Art. ·37 {1) tnediciDal ~ ~ed is withdrawn form the market, where: (a) it is clear that the veteiiQary medicinal product is harmful under the conditions of 1ase stated ait the time of the application for authorization or subsequently, ·. pursumit to Article 27 (5); · · · {b) the. veterinary medicinal product has DO therapeutic effect. OD the species of animal for which the treatment was intended; (c). the qualitative and quantitative composition of the veterinaJy medicinal product is not as stated; · (d) the rKOmmended withdrawal ·period is· inadequate to ensure that 'foodstuffs obtained from the treated animal do not contain residues which might constitute a health hazard to the consumer; (e) the control tests referred to in Article 81 (1) have not been canied out, or any other requirement or obligation relating to the grant of the manufacturing authorization referred to in Article 44 (I) has not been complied with. (adapted) 2. The competent authority may. confine the prohibition on supply and withdrawal from the market solely to the contested production batches. Article 85 I. The competent authority of a Member State shall suspend or withdraw the 81/851/EEC manufacturing authorization for a category of preparations or for all preparations if Art. 38 any of the requirements laid down in Article 45 are no longer met. (adapted) 2. The competent authority of a Member State may, -in addition to the measures provided for in Article 84, either suspend manufacture or im~ of veterinary medicinal products from third countries or suspend or withdraw the manufacturing authorization for a category of preparations or for all preparations in the event of non-compliance with the provisions regarding manufacture or imports from third countries. The provisions of this Title shall apply to homeopathic veterinary medicinal products. Article 86 92n4/EEC Art. 4 (1) (adapted) Artide 87 Member States shall. take appropriate measures to encourage veterinarians and other professionals concerned to report to the competent authorities any adverse reaction of veterinary medicinal products. · 81/851/EEC Art. 38a (as amended by 90/676/EEC Art. 1 (20)). (adapted) 60. TITLE IX STANDING. coMMITrEE Ai1ide88 1. A Standing Committee on Veterinary Medicinal Pl-oducts for the Adaptation to Technical Progress of the Directives on the Removal of Technical Baniers to Trade in ·the Veterinary Medicinal Products. Sector, hereinafter called "the Standing Committee", is hereby set up; it sba1l consist of representatives of the Member States with a ~tative of the Commission a. S· Chairman. 811852/EEC Art. 2b. (as amended by. 87/20/EEC Art. 1 (1)) (as amended by 93/40/EEC Art. 2) 2. The Standing Committee shall. adopt its own rules of procedure. (adapted) Article 89 Any changes which are necessary in order to adapt Annex I to take account of scientific ·and technical progress sball be adopted in accordance with the procedure laid down in Article 90. 81/852/EEC Art. 2a (as amended 87/20/EEC Art. 1 (1)) (adapted) 61 sv~silEEc Art. 42j (as· amelided by 93/40/EEC Art. 1 {13)) (adapted) 81/851/EEC Art. 42k (as amended by 93/40/EEC Art. 1 (13)) (adapted) Article9. 0 Where the procedure laid down in thiS Article. is ~. be followed the Commission shall be ·. assisted by _the Standing ~mmi~. · the rePresentative -of the·. Commissio~ shall submit to the Standing Committee a draft of. the IPeasures to be taken. The StandiJig Committee sbal~ deliver its opinion on the draft within a time-limit which the 'Chairman may lay down _according ~-the· urgency of the matter. The opinion shall be delivered by the majority laid do~ in Article 205 (2) of the Treaty in the case of decisions which the Council is required to adopt on. a proposal froiJl the Conu:nission. The votes of the representatives. of the Member States. within the Standing Committee: shall be ·weighted in the manner set out in that Anicle. The Chairman shall not vote. The Commission shall adopt the measures envisaged if they are in accordance with the opinion of the Standing Committee. If the measures envisaged are not in accordance with the. opinion of the Standing Committee, or if no opinion is delivered, the Commission shall, without delay, submit to the Council a proposal ~lating to the measures to be taken. The Council shall. act by a qualified majority. If on the expiry of a period of three months from the date of referral to the Council, the Council has not acted, the proposed measures shall be adopted by the Commission. Article 91 Where the procedure laid down in this Article is to be followed the Commission shall be assisted by the Standing Committee. The representative of the Commission shall submit to the Standing Committee a draft of the measures to be taken. The Standing Committee shall deliver its opinion on the draft within a time-limit which the Chairman may lay down according to the urgency of the matter. The opinion shall be delivered by the majority laid down in Article 205 (2) of the Treaty in the case of decisions which the Council is required to adopt on a proposal from the Commission. The votes of the representatives of the Member States within the Standing Committee shall be weighted in the manner set out in that Article. The Chairman shall not vote. The Commission shall adopt the measures envisaged if they are in accordance with the opinion of the Standing Committee. · If the measures envisaged are not in accordance with the opinion of the Standing Committee, or if no opinion is delivered, the Commission shall, without delay, submit to the Council a proposal relating to the measures to be taken. The Council shall act by a qualified majority. If on the expiry of a period of three months from the date of referral to the Council, the Council has not acted, the proposed measures shall be adopted by the Commission, save where the Council has decided against the said measures by a simple majority. 62 TITLEX. ·. G~ PROy. ISIONS Article9l Member States ·shall take all measures necessary. to ensure that the competent authorities 81/85 I !EEC COii~ communicate. the appropriate· information to each other, in particular regarding. Art. 39 complian~· with the rCquin:uients adopted for manufacturing authorization,. or for. authorization to place J)roducts on·the mlrket. · · (as amended by 90/676/EEC Art: 1 (21)) (adapted) ·' Upon reasoned request, Member States ·shall forthwith communicate the reports referred to iD the third ~h of Article 80 (3) to the competent authorities of another Member State. If; after. CODSideriDg. the ~ the Member State receiving the repons considers that it caDDot acc:ept the conclusions reached by the competent authority of the Member State. in which the report was established, it sball inform the competent authorities concemed of i1s reasons ·and may request further information. The Member States - concerned shall attempt to reach agreement If necessary, in the event of serious differences of opinion, one of the M~bcr States concerned shall inform the Commission. Artiele 93 I. Each Member State shall take all appropriate measW'eS to ensure that the Agency is 81/85 1/EEC informed immediately of. decisions granting marketing authorization. and of all Art. 42 decisions refusing or withdrawing marketing authorization, cancelling a decision refusing or withdrawing marketing authorization, prohibiting supply or withdrawing 90/676/EEC Art. 1 (22)) a product from the market, together with the reasons on which such decisions are based. (as amended by (adapted) 2. The marketing authorization holder shall be obliged to notify the Member States forthwith of any action taken by him to suspend the marketing of a veterinary medicinal prOduct or to withdraw a product from the market, together with the reasons for such action if it concerns the effectiveness of the veterinary medicinal product or the protection of public health. Member States shall ensure that this information is brought to the attention of the Agency. 3. Member States shall ensure that appropriate information about actions tiken pursuant to paragraphs 1 and 2 which may affect the protection of health in third countries is forthwith brought to the attention of the relevant international organizations, with a copy to the Agency. · Artiele 94 Member States shall communicate to eaeh other. all the information necessary to 92!74/EEC guarantee the quality and safety· of homeopathic veterinary medicinal products Art. 5 manufactured and marketed within the Community, and in particular the information referred to in Articles 92 and 93. 63. 81/851/EEC Art. 24a (as amended by 90/676/EEC Art. 1 (16)) {adapted) ~de95 1. · At the mp. aest of rhe DlallU&cturer or exporteJ: of veterinarY blediciDBI produ~ or the ~orities of an Importing third country, Member. States shall certify ·that such marDJfacturer is in possession of the manUfacturing authOrization. When issuing such. certificates, ~einber States shall comp~ with the _following conditio~~$: (a) ·they shall have regard to the prevailing administrative arrangements of the World Health Organization; · (b) for veterinary m~cin81 products intended for export which. are already · authorized in their territory. they shall supply the summary ot the. product characteristics as approved in accordance with Article 25 or, m the absence · thereof: an equivalent document 2. Where the manufilcturer is not in possession· of an authorization to place the product on the market, be shall provide the authorities responsible for. establishing the certificate referred to in the first plflgr8ph with a declaration explaining why. such authorization is not available. Article 96 Any decision set out in this Directive, taken by the competent authorities of the Member 81185 1/EEC · States, shall state the reasons on which it is based. Art. 41 and 40 (adapted) Such a decision shall be notified to the party concerned who shall at the same time be informed of the remedies available to him under cwrent legislation and the time allowed for. seeking such remedies. · Marketing authorizations and revocations of such authorizations shall be published by each Member State in its o~cial gazette. Article 97 The Member States shall not permit foodstuffs. for human consumption to'be taken from test animals unless maximum residue limits· have been established by the Community in accordance with the provisions of Regulation (EEC) No 2377/90 and an appropriate withdrawal period has been established to ensure that this maximum limit will not be exceeded in the foodstuffs. 811851/EEC Art. 4 (2), 2nd subparagraph (as amended by 93/40/EEC Art. 1 (2)) (adapted) 64. 1TILEXI FINAL MEAsURES Article 98 Directives 81/851/EEC,'. 81/852/EEC, 90/677/EEC and 92f74/EEC referred to in. Annex n, Part A are repealed, without ptej~ce to the obligations of the Member · ·Smtes in respect. of the~~ for transposition laid down_ in Annex n, Pan B. The reference made to the said Repealed Directives shall be construe,d as references to this Directive and should be read in accordan~ with the correlation table set out in Annex m. This Directive enters into force on I January 2000. Article 99 Article 100 This Directive is addressed to the Member States. · Done at Bussels, For the European Parliament For the Council The President The President 65 ~I· ·lmQi1iR:EMENTS AND ANALYTICAL PROTOCOL, SAFETY TESTS, PRE-cLINICAL. AND CLINICAL. · FOR TESTS OF VETERINARY MEDICINAL PRODUCTS INTRODUCTION The particulars and documents accompanying an application for marketing authorization. pmsuant to Articles 12 and 13 (1) shall be presented in accordance with the requirements 92118/EEC Art 1) set out in this Annex and taking account of the guidance contained in the 'Notice to applicants for marketing authorizations for ·veterinary medicinal prochicts in the Member States of the European Community', published by the Commission in The rules governing medicinal products in the Eur_opean Community, volume V: Veterinllry Medicinal Products. (adapted) 81/852/EEC. ·Annex (as amend~ by In assembling the dossier for application for marketing authorization, applicants shall take into account the Community guidelines relating to the quality, safety and efficacy of veterinary medicinal products published by the Commission in The rules govermng · medicinal products in the European Community. All information which is relevant to the evaluation of the medicinal product concerned shall be included in the application, whether favourable or unfavourable to the product. In particular,. all relevant details shall be given of any incomplete or abandoned test or ·trial relating the veterinary medicinal product. Moreover, after marketing ·authorization, any information not in the original application, pertinent to the benefit/risk assessment, shall be submitted forthwith to the competent authority. to Member States ensure that all experiments on animals are conducted in accordance with Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws, regulations and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes(l). · The provisions of Title I of this Annex shall apply to veterinary medicinal products other than immunological veterinary medicinal products. The provisions of Title 11 of this Annex shall apply to immunological veterinary medicinal products. UJ OJL3S8,18. 2. 1986,p. l. 66 TITLE I REQUIREMENTS FOR VETERINARY MEDICiNAL PRODUCTS OTHER THAN. IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS 81/852ffiEC Annex (as amended by. 92/18/EEC Art. 1} (adapted} PARTl SUMMARY OF THE DOSSIER A. ADMINISTRATIVE DATA The veterinary medicinal product which is the sUbject of the application shall be identified by name and by name of the active substance(s}, together with the strength and phannaceutical form, the method and route of administration and a description of the · final saies presentation of the product. · The name and address of the applicant shall be given, together with the name and address of the manufacturers and the sites involved in the different stages of the manufilCture (including_the manufacturer of the finished product and the manufacturer(s) of the active substance(s)), and where relevant the name and address of the importer. The applicant shall identify the number and titles of volumes of documentation submitted in support of the application and indicate what samples, if any, are also provided. Annexed to the administrative data shall be a document showing that the manufacturer is authorized to produce the veterinary medicinal products concerned, as defined in Article 42, together with a list of countries in which authorization has been granted, copies of all the summaries of product characteristics in accordance with Article. 14 as approved by Member States and a list of countries in which an application has been submitted. B. SUMMARY OF PRODUCT CHARACTERISTICS The applicant shall propose a summary of the product characteristics, in accordance with Article 14 of this Directive. · In addition the applicant shall provide one or more specimens or mock-ups of the sales presentation of the veterinary medicinal prod. uct, together with a package insert where one is required. 67 C. EXPERT REPORTS. In acco~ with Article 15 · (2) and (3), ·expert reports must be provided oli the analytical doauilen1atioo,. doculnetitation and th~ clinical ~on. · the · ptwmacotoxict>logical documentation, · the residues 92/18/EEC Art:. l) "(adapted). 81/8S21EEC· •, AmleX (as amended by Each expert report shall consist of a critical evaluation of the various tests and/or trials which have been carried out in accord8nce with this Directive, and bring OUt. U the data relevant for. evaluation. 1be expert shall give ·his opinion as to whether sufficient gUarantees. have been provi~ as to the· quality, safety and efficacy of the product concerned. A ·fadual summary is not sufficient · All importairt data shall be summarized in -an appendix to the expert report, whenever possible in tabular or graphic form. The expert report and the summaries shall contain precise cross references to the inf~rmation contained in the main documentation. Each expert report shall be prepared by a suitably qualified and experienced person. It shall be signed and ·dated by the expert, and attached to the report shall be brief information about the educational background, training and occupational experience of the expert. The professional relationship of the expert to the applicant shall be declared. 68 ANALYTi~ ~BYSIC(). CBEMIC~ BIOLOGIC~ OR. MICRQBIOLOGICAL) TESTS OF VETERINARY MEDICINAL PRODUCfS 92/18/EEC Art. 1) OTHER THAN IMMUNOLOGICAL VETERINARY MEDiCINAL PRODUCTS (adapted). ·. · · stts52iEEC. Annex (as amended by ·PART~. All test ~ ~· comspond to the state of scientific progress ~ the time and. shall be wlidated procedures; results·ofthe validatiQn studieS shall be provided. All the test procedure(s) sbaU be described in sufficiently precise. ~ so as to be · reprodUcible in control ~ canied out at the request of the competent authority; any special apparatus and equipment whicp maY be used shall be descnDed in adequate detail, possibly accompanied by a diagram. The formulae of the laboratory reagents shall be supplemented, if necessary,. by the method of preparation. ·In the case of test procedures included in tbe European Pharmacopoeia or the pharmacopoeia of a Member State, this description may be replaced by a detailed reference to the pharmacopoeia in question. A. QUALITATIVE AND QUANTITATIVE PARTICULARS OF THE CONSTITUENTS The particulars and documents which must accompany applications for marketing authorization, pursuant to Article 12 (3) (c), shall be SlJbmitted in accordance with the following requirements. 1. Qualitative particulars 'Qualitative particulars' of all the constituents of the medicinal product shall mean the designation or description of: - the active substance(s), the constituent(s) of the excipients, whatever their· nature or the quantity used, including colouring matter, preservatives, adjuvants, stabilizers, thickeners, emulsifiers, flavouring and aromatic substances, etc, the constituents, intended to be ingested or otherwise administered to animals, of the outer covering of the medicinal products-capsules, gelatine capsules, etc. These particulars shall be supplemented by any relevant data concerning the container and, where appropriate, its manner of closure, together with details of devices with which the mediciDal product will be used or administered and which will be delivered with the medicinal produc:t. 69. 2. · The·~- termbiolOiY', to ·be ·used in describing the ·constitueilts. of i:Dedicinai. · a·l/852/EEC · products,. -Shall mCan. Dotwithstanding the application of the other provisicms of Annex Article. l2 (3) (c): · (as amended by •. -. · · ·. in reSpect of substances whim appear in tbe -E~opean Phannacop()eio ·ar,. · failing this, in the national pbannacopc>eia of one of the Member States, the main ·title at the head ·_of the monograph in _question. with reference to the pharmaco~ia concerned, 92/18/EECArt. 1) (adapted) ·. international non-proprietary name in respect 9f. otb. ef substances, the · recommended by the World _Health Oipnization (WHO), which may be accompanied by another non-proprietary. name, or, failing these, the ·exact scientific designation; substances not having an intemational non-proprietary ~ or an ·exact scientific designation shall be descnDed by a statement of how and from wbat they were prepared, supplemented, wb~ appropriate, by any other relevant details, in respect of colouring matter, designation by the 'E' code assigned to them in Council Directive 78/25/EEC of 12 December 1977 on the approximation of the rules of the Member States concerning the colouring matters authorized for use in medici;nal productsu,. 3. Quantitative particulan 3. 1. In order to give 'quantitative particulars' of all the active substances of the medicinal products; it is necessary, depending on the pharmaceutical form concerned, to specify the mass, or the number of units of biological activity, either per dosage-~t or per unit of mass or volume, of each active substance. Units of biological activity shall be used for substances which cannot be defined chemically. Where an International Unit of biological activity has been defined by the World Health Organization, this shall be used Where no International Unit has been defined, the units of biological activity shall be expressed in such a way as to provide UJWilbiguous information on the activity of the substances. · Whenever possible, biological activity per units of mass or volume shall be indicated · This information shall be supplemented: · in respect of injectable preparations, by the mass or units of biological activity of each active substance in the unit container, taking into account the usable volume of th~ product, after reconstitution, where appropriate, · in respect of medicinal products to be administered by drops, by the mass or units of biological activity of each active substance contained in the number of drops corresponding to 1 ml or 1 g of the prep~tion, in respect of syrups, emulsions, granular preparations and other pharmaceutical forms to be administered in measured quantities, by the mass or units of biological activity of each active substance per measured quantity. · CIJ OJ L 11, 14. 1. 1978, p. 11; Din:ctivc IS liSt IIDCDded by tbe ~-of Accession of Aus1iia, FiDIIDciiDd S'WCdcn. 70 3. 2. Active'. subst8nees ~-m the'fonn of CO~Unds' or derivatives sball be described quimtitadvely by their total ~' and if necessmy ·or rel~vant, by the mass of the active ~or entities of the mo~ecule. 3. 3. For IDCcliciDal pl\lducts containing an active substance which is the ·subject of an. application for ID8I'lcetiDg authorization. in ,any Member State· for the first time, the ·qusmtitarive statement of an active substance which is a salt or hydrate shall bC Systematically expressed m terms of the mass of the acti~ entity or entities in the molecule. All subsequently iuthorized medicinal products in the Member States shall have their quantitative composition stated in the same way for the same active substance. 81/852/EEC. Annex (as. amended by 92/18/EEC Art. 1) (adapted) 4. ' Development pharmaceuties An explanation shall be provided with regard to the choice of composition, constituents and comainer and the intended function of the excipients in. the finished product. This explanation shall be supported by scientific data on development pharmaceutics. The ov~e, with justification thereo( shall be ~ B. DESCRIPTION OF THE MANUFACTURING METHOD The description of the manufacturing method accompanying the application for marketing authorization pursuant to Article 12 (3) (d), shall be drafted in such a way as to give_ an adequate synopsis of the nature of the operations employed. For this pUrpose it shall include at least: mention of the various stages of manufacture, so that an assessment can be made of whether the processes employed in producing the pharmaceutical form might have produced an adverse change in the constituents, • · in the case of continuous manufacture, full details concerning precautions taken to ensure the homogeneity of the finished product, the actual manufactUring formula, with the quantitative particulars of all the substances used, the quantities of excipients, however, being given in approximate terms in so far as the pharmaceutical form makes this necessary; mention shall be made of any substances that may disappear in the course of manufacture; any overage ~ be indicated and justified, a statement of the stages of manufacture at which sampling is carried out for in process control tests, where other data in the documents supporting the application show such tests to be necessary for the quality control of the finished product, experimental studies validating the manufactwing process, where a non-standard method of manufacture is used or where it is critical for the product, for sterile products, details of the sterilization processes and/or aseptic procedures used. 71 C. CONTROL OF STARTING MATERIALS 1. For the purposes of this· paragraph, 'starting -materials' sballmean all the constituents of the medicinal product and, if necessary, of its container, as refemd to in Section ~ point 1, ·above. 811852/EEC Aimex (as amended bY. 92/18/EEC Art. 1) (adapted) In the case of an active substance Qot described in the Elll"opean Pharmacopoeia or in the pharmacopoeia of a Member State, or an active substance described in the Elll"opean ·Pharmacopoeia or in the pharmacopoeia of a Member State when prepared by a method liable to leave. impurities not mentioned in the pharmacopoeia! monograph· and for which the monograph is inappropriate to adequately control its quality, which is manufactured by a person different from the applicant, the latter may arrange for the detailed description· of the manufactwing method, quality coD1rOl during manufacture and process validation to be supplied directly to the competent authorities by the manufacturer of the active substance. In this case, the manufacturer shall however provide the applicant with all the data which may be necessary for the latter to take responsibility for the medicinal product. The manufacturer shall confirm· in writing to the applicant that he shall ensure batch to batch. consistency and not modify the manufacturing process or specifications without informing 'the applicant DoCuments and particulars supporting the application for such a change shall be supplied to the competent authorities. The particulars and documents accompanying the application for marketing authorization pursuant to Article 12 (3) (i) and G) and Article 13 (1), shall include the results of the tests, including batch analyses particularly for active substances, relating to quality control of all the constituents used. These shall be submitted in accordance with the following provisions. 1. 1. Starting materials listed in phannacopoeias The monographs of the European Pharmacopoeia shall be applicable to all substances appearing in it. In respect of other substances, each Member State may require observance of its own national pharmacopoeia with regard to products manufactured in its tenitory. Constituents fulfilling the requirements of the European Pharmacopoeia or the pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with Article 12 (3) (i). In this case the description of the analytical methods may be replaced by a detailed reference to the pharmacopoeia in question. 72 Howeva;:; where a Startmg IWiterial. in the Eliropean 'Pharmacopoeia or. in the pharmacopoeia of a Melnber State· has been prepared by a method liable to leave impurities not ~ntroUed in the pharmacopoeia monograph,. these impmities and their maximum tolerance limits must be declared and a suitable test procedure must be described. 81/852/EEC Annex (as amended by 92/. 18/EEC Art. 1) (adapted) Colouring matter ~ in all cases, ~fy the requirements of Council Directive 78125/EEC. The routine tests cani~ out on each batch of starting materials must be as stated in the application for marketing. authorization. If tests other than those mentioned in the pharmacopoeia are used, proof must be supplied that the starting materials ·meet the quality requirements of that pharmacopoeia. in a monograph of the ·European In cases where a specmcation contained Pharmacopoeia or in the national pharmacopoeia of a Member State might be insufficient to en. sWe the quality of the substance, the competent authorities may request more appropriate specifications from the marketing authorization holder. The competent authorities shall inform the authorities responsible for the pharmacopoeia in question. The marketing authorization holder shall provide the authorities of that pharmacopoeia with· the details of the alleged insufficiency and the additional specifications applied. In cases where a starting material is described neither in the European Pharmacopoeia nor in the pharmacopoeia of a Member State, compliance with the monograph of a third country pharmacopoeia can be accepted; in such cases, the applicant shall submit a copy of the monograph accompanied where necessary by the validation of the test procedures · contained· in the monograph and by a translation where appropriate. 1. 2. Starting materials not in a pharmacopoeia Constituents which are not given in any pharmacopoeia shall be described in the form of a monograph under the following headings: (a) the name of the substance, meeting the requirements of Section A point 2, shall be · suppleme~ted by any trade or scientific synonyms; (b) the definition of the substance, set down ·in a form similar to that used in the European Pharmacopoeia,. shall be accompanied by any necessary explanatory evidence, especially concerning the molecular structure where appropriate; it must be accompanied by an appropriate description of the method of synthesis. Where substances can only be described by their manufacturing method, the description shall be sufficiently detailed to characterize a substance which is constant both on its composition and in its effects; (c) methods of identification may be described in the form of complete techniques as used for production of the substance, and in the form of tests which ought to be canied out as a routine matter; 73 (cQ purity tests shall be described· iD relation to the sum total of predictable impurities, 81/852/EEC. especially. those whi~ ·may have a harmful effect, and,. if necessary, those whi~ Annex having regard to the combination of substances to which the application refers, might adversely affect the stability of the medicinal product or aistort analytical results; · (as imended by- · 92/18/EEC Art. 1) (adapted) (e) with regard to complex substances of plint or. animal origin, a distinction must be made between the case· where multiple pharmacological efrects render chemical, physical or biological control of the principal components necessary, and the case of substances containing one or inore groups of principles having similar activity, in respect of which an overall method of assay may be accepted; (f) when t:naterials of animal origin are used, measures to ensure freedom -from· potentially pathogenic agents shall ~ described; (g) any special precautions that may be necessazy during storage of the starting material and, if nec:essary, the maximum period of storage before retesting shall be given. 1. 3. Physico-chemical characteristics liable to affect bioavailability The following items of information concerning active subswices, whether or not listed in the pharmacopoeias, shall be provided as part of the general description of the active substances if the ·bio-availability of the medicinal product depends on them: crystalline form and solubility coefficients, particle size, where appropriate after pulverization, state of solvation, oiVwater coefficient of partition'1 ). The first three indents are not applicable to substances used solely in solution. 2. Where source materials such as micro-organisms, tissues of either plant or animal origin, cells or fluids (including blood) of human or animal origin or biotechnological cell constructs are used in the manufacture of veterinary medicinal products, the origin and history of starting materials shall be descnbed and documented. The description of the starting material shall include the manufacturing strategy, purification/inactivation procedures with ·their validation and all in-process control procedures designed to ensure. the quality, safety and batch to batch consistency of the finished product " 2. 1. When cell blnks are used, the cell characteristics shall be shown to have remained unchanged at the passage level used for the production and beyond U> lbe competent authorities may also n:qucst the pK/pH values if they tbiDic that this information is essential. 74 2. 2~ Seed malmials; cell banks, ·pOols of serum ·am~ other materials of biological-origin 811852/EEC ~ Whenever. possible, tbe source materials from which ·they are derived sb8ll be tested Annex for ~ous agents. (as amended by 92/18/EEC Art. 1) (adapted) If the presalee:· of potentiauy pathogenic· adventitious agents is inevitable, the material. sball be used Only when fUrther processing eDSlRS their elimination and/or inactivation, and this shin be validated · D. CONTROL TESTS CARRIED OUT AT INTERMEDIATE STAGES OF 1liE MANUFAcnJRING PROCESS The particulars and documents accompanying an application for marketing authorization, pursuant to Article 12 (3) (i) and 0) and also Article 13 ( 1 }, shall include particulars relating to the product control tests that may be carried out at an intermediate stage of the manufacturing process, with a view to enswing the consistency of the technical characteristics and the production process. · These tests are essential for checking the conformity of the medicinal product with the formula when, exceptionally, an applicant proposes an analytical method for testing the finished product which does not include the assay of all the active substances (or of all the excipient components subject to the same requirements as the active substances). The same applies where the quality control of the finished product depends on in-process control tests, panicularly if the substance is_ essentially defined by its manufacturing m~. E. TESTS ON THE FINISHED PRODUCT 1. For the control of the finished product, a batch of a finished product comprises all the units of a pharmaceutical form which are made from the same initial quantity of material and have undergone the same series of manufacturing and/or sterilization. operations or, in the case of a contiJ;luous production process, all the units manufactured in a given period of time. The application for marketing authorization shall ~ those tests which are carried out routinely on each batch of finished product. The frequency of the tests which are not carried out routinely shall be stated. Release limits sball be indicated. The particulars and documents accompanying the application for marketing authorization pW'SUIIlt to Article 12 (3) (i) and (j) and also Article 13 (1), shall include particulars relating to conttol tests on the finished product at release. They shall be submitted in accordance with the following requirements. The provisions of the general monographs of the European. Pharmacopoeia, or failing that, of a Member State, sball be applicable to all products defined therein. If test procedures and limits other than those mentioned in the general monographs of the European Pharmacopoeia, or failing this, in the national pharmacopoeia of a Member State, are used, proof shall be supplied that the finished product would, if tested in accordance with those monographs, meet the quality requirements of that pharmacopoeia for the pharmaceutical form concerned. 1S &11852/EEC. Almex (as amended by 92/18/EEC Art. 1) (adapted). 1. 1. G,;_;al ~cteristics ~/f!le. /inisluui produc! Certain tests of the general. chatacteristics of a product shall always be included among the tests On the finistwf product. These tests shall, wherever applicable, relate to the control of average masses and maxirmun deviations, to mechanical, physical or ~crobiological · tests, otganoleptic characteristics, physical characteristics such as density, pH, refractive index, etc. For each of these characteristics,· standards and tolerance limits sball be specified by the applicant in each particular case. · The· conditions of the tests, where appropriate, the equipment/apparatus employed and the standards shall be described. in precise details whenever they are not given in the European Pharmacopoeia or the pharmacopoeia of the Member States; the same sball apply in cases where the methods preScribed by such pharmacopoeias are not applicable. Furthermore, solid ph. armacCutical forms having to be administered orally shall be ~bjec:ted to in vitro studies on the hOeration and dissolution rate of the active substance or substances; these studies shall also be carried out where administration is by another means if the competent authorities of the Member State. concerned consider this necessary. 1. 2. Identification and as~ay of active svbstance(s) · Identification and assay of the ·active substance(s) shall be canied out either in a representative sample from the production batch or in a number of dosage-units analysed individually. Unless there is appropriate justification, the maxim'LIQl acceptable deviation in the active substance content of the finished product shall not exceed :t S% at the time of manufacture. On the basis of the stability tests, the manufacturer must propose and justify maximum acceptable tolerance limits in the active substance content of the finished product up to the end of the proposed $elf-life. In certain exceptional cases of particularly complex mixtures, where assay of active substances which are very numerous or present in very low amounts would ~ecessitate an intricate investigation difficult to carry out in respect of each production b~h, the assay of one or more active substances in the finished product may be omitted, on the express condition that such assays are made at intermediate stages in the production process. This relaxation may not be extended to the characterization of the substances concerned. This simplified ~hnique ~ be supplemented by a meth~ of quantitative evaluation, enablin'g the competent authority to have the conformity of the medicinal product with its specification verified after it has been placed on the market An in vivo or in vitro biological assay shall. ~ obligatory when physico-chemical methods cannot ·provide adequate information on the quality of the product. Such an assay shall, whenever possible, include reference materials and statistical analysis allowing calculation of confidence limits. Where these tests cannot be carried out on the finished product, they may be performed at an intermediate stage, as late as possible in the manufacturing process. 76 · Wh• the. particu]ats given in section B ·show tbat a significant overage. of an active 81/852/EEC sabstaace js. employed in tJ:ae man~ ·of the medicinal product, the description of Annex the coDtrol tests on·the finish~ produCt sball include, where ~propriate, the· chemical ancl, ·if n~, the :toxico-pharmacological investigation of the changes that this 92/18/EEC Art. 1) substance has undergone, and possibly the characterization and/or assay of the degradation products~ (as ~ended by (ad8pted) · 1. 3. Ic/eimficalion and asstk)l ofacipient components In so far as is necessary, the excipient components shall. be subject at least to identification tests. · · · The test procedure proposed for identifying colouring matters must enable a verification to be made that such matters·appear in the· list annexed to Directive 78125/EEC~ An upper and lower limit test shall be obligatory in respect of preserving agents and an upper limit test for any other excipient component liable to affect adv~ely physiological functions; an upper and lower limit test shall be obligatory in reSpect of the excipient if it is liable to affect the bio-availability of an active substance, unless bio-availability is guaranteed by other appropriate tests. 1. 4. Safety tests Apart from the toxico-pharmacological tests submitted with the application for marketing authorization, particulars of safety tests, such as sterility, bacterial endotoxin, pyrogenicity and local tolerance in animals shall be included in the analytical particulars wherever such tests must be undertaken as a matter of routine in order to verify the quality of the product. F. STABILITYTEST The particulars and documents accompanying the application for marketing authorization pursuant to Article 12 (3) (t) and (i) shall be submitted in accordance with the following requirements. A description shall be given of the investigations by which the shelf life, the recommended storage conditions and the specifications at the end of the shelf life proposed by the applicant have been determined. · In the case of pre-mixes for medicated feedingstuffs, information shall also be given as necessary on the shelf life of the medicated feedingstuffs. manufactured from these pre mixes in accordance with the recommended instructions for use. Where a finished product requires reconstitution ·prior to administration, details of the proposed shelf life for the reconstituted product are require~ supported by relevant stability data. In the case of multi-dose vials, stability data ~ be presented to justify a shelf life for the vial after it has been pun~ for the first time. 77. Where ·a finished product is ~le to give rise to ·degrldanon' products,. the applicant must 81/852/EEC dechR these and indicate characterization methods and test procedureS. · The conclusibus sball contain the results of analyses, justifying the proposed shelf life 92/18/EEC Art. 1) · \Dlder the recommended storage conditiOJlS and the specifications of the finished product at the end of the shelf ~ of the finished product under these recommended storage conditions. 'Annex (as;amendecfby. (adapted) · ·· · ·. · The maximum acceptabl~ level of degradation products at the end of shelf life shall be indicated. A study of the interaction between product and container shall be submitted wherever the risk of such interaction is regarded as possible~ especially where injectable preparations ·or aerosols for internal use are concerned PART3 SAFETY AND RESIDUES TESTING The particularS and documents which shall accompany the application for marketing authorization pursuant to Articles 12 (3) G) and 13 (1) shall be submitted in accordance with the requirements below. Member States shall ensUre that the tests are canied out in accordance with the provisions relating to good laboratory practice laid. down by Council Directives 87118/EEC0 ) and 88/320/EE<:<I). A. Safety testing CHAPTER I PERFORMANCE OF TESTS 1 ~ Introduction The safety documentation shall show: · 1. 2. 3. 4. the potential toxicity of the medicinal product and any dangerous or undesirable effects which may occur under the proposed conditions of use in animals; these should be evaluated in relation to the severity of' the pathological condition concerned; the potential harmful effects to man of residues of the veterinary medicinal product or substance in foodstuffs obtained from treated animals and what difficulties these residues may create in the industrial processing ~f foodstuffs; the potential risks which may result from the exposure of human beings 'to the medicinal product, for example during its administration to the animal; the potential risks for the environment resulting from the use ·of the medicinal product. (I) OJ L 15, 17. 1. 1987, p. 29. <l) OJ L 145, 11. 6. 1988, p. 3S, Directive u IIIIICDded by Commissioo Directive 90/11/EEC (OJ L·11, 13. 1. 1990, p. 37). 78 All JeSUits shall~be reliable aod valid generally. : Whenever appropriate, mathaiaatical and 81/852/EEC statisdc:al ~ sbaJl be used in desigrdng the experimemal. methods and· in A. Dnex eva1uatiDg :the·· results. AdditioD81ly, clinicians shall be giVen information about the thapeutic potential oftbe product and about the hazards connected with its use. · (as amended by 92/18/EEC Art. 1) (adapted). In some cases. it may be neceSsaty to test the. metabolites of the parent compound where these represeot tbe residues of concern. AD excipient used in the ·pharmacCutical field for the first time shall be treated like an active substance. · 2. Pba. ,. ~ology the mediciDal product produces Pharmacological studies are of fun~ental importance in·clarifying the mechanisms by which therefore pharmacological studies conducted· in experimental and target species· of animal should be included in Part 4. therapeutic eff~ and its · However, pharmacological studies may also ·assist in the understanding of toxicological phenomena. Moreover; where a medicinal product produces pharmacological effects in the absence of a toxic response, or at doses lower than those requ. ired to elicit toxicity, these pharmacological effects shall be taken into account during the· evaluation of the safety of ~e medicinal product. · the safety documentation shall always be preceded by details of Therefore pharmacological investigations undertaken in laboratory animals and all relevant information observed during clinical studies in the target animal. 3. Toxicology 3. 1. Single-dose toxicity Single-dose toxicity studies can be used to predict: the possible effects of acute overdosage in the target species, · the possible effects of accidental administration to humans, the doses which may usefUlly be employed in the repeat dose studies. Single dose toxicity studies should reveal the acute toxic effects of the substance and the time course for their onset and remission. 19 theSe studies shouid normally ~ carried out in at least two mammalian species. One 81/852/EEC manunalian species may ·be rep~· if appropriate, by an animal species for which the Annex medicinal product is intended. At least ~o different routes of administtation should ·normally be studied. One of these may be the same as, or similar to, that proposed for the 92/18/EEC Art. 1) target species. If substantial exposure of the user of the medicinal product is anticipated, for example by inhalation or dermal contact, these routes should be studied. (as amended by (adapted) In order to reduce the number and suffering of the animals involved, new protocols for single dose toxicity testing are contiriually being developed. Studies carried out in accordance with these new p~dures when properly· validated will be accepted, as well as ·studies ·carried out in accordance. with established internationally recognized guidelines. 3. 2. Repeated-dose toxicity Repeated-dose toxicity tests are intended to reveal any physiological and/or pathological changes induced by repeated administration of the active substance or combination of active substances under examination, and to determine how these changes are related to dosage. In the case of substances or medicinal products intended solely for use in non food· pl'Qd~cing animals, a repeated dose toxicity study in one species of experimental animal wiU normally be sufficient. This study may be rep!Ked by a studY conducted in the target animal. The frequency and route of administration, and the duration of the study should be chosen having regard to the proposed conditions of clinical use. The investigator shall giv~ his reasons for the extent and duration of the trials and the dosages chosen. In the case ·of substances or medicinal products intended for use in food producing animals, the study should be conducted in at least two species, one of which should be a non-rodent. The investigator shall give his reasons for the choice of species, having regard to the available knowledge ofthe metabolism_ of the prodqct in animals and man. The test substance shall be administered orally. The duration of the test shall be at least 90 days. The investigator shall clearly state and give his reasons for the method and frequency of administration and the length of the trials. The maximum dose should normally be selected so as to bring harmful effects to light. The lowest dose level should not produce any evidence of toxicity. Evaluation of the toxic effects shall be based on observation of behaviour, growth, haematology and physiological tests, especially those relating to the excretory organs, and also on autopsy reports and accompanying histological data. The choice and range of each group of tests depends on the species of animal used and the state of scientific knowledge at the time. · 80 (6) li1 the case' of new combinations of mown substanceS which have been investigBted in &CCQrdance with the provisions of this Directive, the repeated-dose tests may, except where toxicity tests have demonstrated potel;ltiation or novel toxic effects, be. suitably modified by tbe investigator, ~o sbali submit his reasons for such modifications. 81/852/EEC. Ann~ (as amended by 92/18/EEC An. I) (adapted) 3. 3 •. Tolerance in the target species Details should· be provided of any signs of intolerance which have been observed dwing · studies conducted in the target species in accordance with the requirements of Part 4, Chapter I, Section B. The studies conceined, ·the dosages at which the intolerance occurred and the species and breeds concerned should be identified. Details ·of any unexpected physiological changes should also be provided. 3. 4. Reproductive toxicity including teratogenicily 3. 4. 1. Study of the effects on reproduction The purpose of this study is to identify possible impairment of male or female reproductive function or harmful effects on progeny resulting from the administration of the medicinal products or substance under investigation. In the case of substances or medicinal products intended for use in food-prC>Qucing animals, the study ofthe effects on ~roduction shall be carried out in the form of a two generation study on at least one species, usually a rodent The substance or pr~duct under investigation shall be administered to males and females at an appropriate time prior to mating. Administration should continue until the. weaning of the. f2 generation. At least three dose levels shall be used. The maximum dose should be selected so as to bring harmful effects to light The lowest dose level should not produce any evidence of toxicity. Evaluation of the effects on reproduction shall -be based upon fertility, pregnancy and maternal behaviour; the suckling, growth and development of the Fl offspring from conception to maturity; the development of the F2 offspring to weaning. · 3. 4. 2. Study of embryotoxic/fetotoxic effects including teratogenecity In the case of substances or medicinal products intended for use in food producing animals, studies of embryotoxic/fetotoxic effects, including teratogelii. city, shall be carried out These studies shall be carried out in at least two mammalian species, usually a rodent and the rabbit. The details of the test (number of animals, doses, time at which administered. and criteria for the evaluation of results) Shall depend on the state of scientific. knowledge at the time the application is lodged and the level of statistical significance which the results should attain. The rodent study may be combined with the study of effects on reproductive functioa In the case of substances or medicinal products which are not intended for use in food producing animalst a study of embryotoxic/fetotoxic effects, including teratogenicity, shall be required in at least one species, which may be the target species, if the product is intended for use in animals which might be used for breeding. 81 3. S. _Mutagenicity : Mutagenicity ·tests an; inteoded to ·assess the _potential of substances to , cause. ttansmissible changes in the genetic material of cells. -. Any new substance intended for. use in veteriDary ~cinal-products must be as~sed for tnutagenic properties. 81~852/EEC Ann~. (as amended by 92/18/EEC Art. 1) (adapted). The number and types of tests and the criteria for the evaluation of tbe results shall depend on the state of scientific knowledge when the application is submitted. 3. 6. Carcinogenicity Long term aDimal carcinogenicity studies will usually be required for substances to which human beings will be exposed which have a close chemical analogy with kno:wn carcinogens, which during mutagenicity testing produced results indicating a ~ssibility of carcinogenic effects, which have given rise to suspect signs during toxicity testing. The state of scientific knowledge at the time the application is submitted shall be taken into account when designing ~arcinogenicity studies and evaluating their results. 3. 7. Exceptions Where a medicinal product IS intended for topical use, systemic absorption shall be investigated in the target species of animal. If it is proved that systemic absorption is negligible, the repeated dose toxicity tests, the tests for reproductive toxicity and the carcinogenicity tests may be omitted, unless: under the conditions of use laid down, oral ingestion of the medicinal product by the animal is to be expected, or the medicinal particular may enter foodstuffs obtained from the treated animal (intramammary preparations). &2 81/852/EEC 'Annex (as amended by , 92/18/EEC Art 1) (adapted) 4. Otlaer reqairellleats 4. 1. Jmmunotoxicity ~ere the ~ffects observed. during repeated dose studi~ in anjmals. include specific changes in lylllphoid ·organ weights and/or histology and changes ·in the cellularity of lymphoid tissues, bone marrow or peripheral leukocytes, ·the investigator shall consider· the need for additioual studies of the effec:ts of the product on the immune system. The state of scientific knowledge at the time the application is· submitted shall be taken into account when designing such studies and evaluating their results. 4. 2. Microbiological properties ofresidues 4. 2. 1. Potential effects on the human gut flora The microbiological risk presented by residucs of anti-microbial compounds for the human intestinal flora shall be investigated in accordance with the state of scientific knowledge at the time the application is submitted · 4. 2. 2. Potential effects on the microorganisms used for industrial food processing In certain cases, it may be necessary to carry out tests to· determine whether residues cause difficulties affecting technological processes in industrial foodstuff processing. 4. 3. Observations in humans. Information shall be provided showing whether the constituents of the veterinary medicinal product are used as medicinal products in human therapy; if this is so, a report should be· made on all the effects observed (including adverse reactions) in humans and on their cause, to the extent that. they may be important for the assessment of the veterinary medicinal product, where appropriate in the light of trial results of bibliographical documents; where constituents of-the veterinary medicinal products are themselves not used or are no longer used as medicinal products in human therapy, the reaso~ should be stated. S. Ecotoxidty S. l. The purpose of the study of the ecotoxicity of a veterinary medicinal product is to assess the potential harmful effects which the use of the product may cause to the environment and to identify iny precautionary measures which may be necessmy to reduce such risks. 5. 2. An assessment of ecotoxicity shall be Compulsory for any application for marketing authorization for a veterinary medicinal product other than applications submitted in accordance with Articles 12 (3) G) and 13 (1). 83 5. 3. ·This assessment shali nOrmally be conducted in two phases. , In the first phase, the investigator shall assess the potential extent of exposure to ~ environment of the product, its active substances or releVant metabolites, taking into accotmt: Bi/8S2/EEC Annex (as ·amended by 92/18/EEC Art. 1) (adapted) the target species, and the proposed pattern of use (for example, mass-medication or individual animal medication), the method of administration; in particular the likely extent to which the product will enter directly into environmental systems, · the possible excretion of the product, its active substances or rel~vant metabolites into the environment by treated animals; persistence in such excretia, the disposal of unused or waste product 5. 4. In a second phase, having regard to the extent of exposme of the product to the environment, and the available information about the physical/ch~c:al, pharmacological and/or toxicological properties of the compound which has beeli obtained during the conduct of the other tests and trials required by this Directive, the investigator shall then consider whether further specific investigation of the effects of the product on particular eco-systems is necessary. S. S. As appropriate, further investigation may be required of: fate and behaviour in soil, fate and behaviour in water and air, effects on aquatic organisms, effects on other non-target organisms. These further investigations shall be carried out in accordance with the test protocols laid , or where an end point is not. down in Annex V of Council Directive 671548/EEC'1 adequately covered by these protocols, in accordance with other internationally recognized protocols. The number and types of tests and the criteria for their evaluation shall depend upon the state of scientific knowledge at the time the application is subnriued. · m OJ L 196, 16. 8. 1967, p. 1; Direc:tive u last amended by Commission DiRd:ive 98173/EC (OJ L 305, 16. U. 1998, p. 1). 84 CHAPTER:n PRISENTArJON OF PARTICULARs AND DOCUMENTS As in any scientific work, the dossier of safety tests sball include the following: (a) an. iiltroduction defining the subject, accompanied by any useful ·bibliographical references; 811852/EEG Annex (as amended by 92/18/EEC Art. I) (adapted). (b) the detailed identU]cation of the substance under review, including: international non-proprietary name ~, International Union of Pure and Applied Chemistry Name (IUP AC), Chemical Abstrac:t Service (CAS) number, therapeutical and pharmacological classification, synonyms and abb~viations, sttuctural formula, · ~olecular formula, molecular weight, degree of impurity, qualitative and quantitative composition of impwities, descrip~on of physical properties, melting point, boiling point, vapour pressure, solubility in water and organic solvents exp~ in g/1, with indication of temperature, · density,. spectra of refraction, rotation, etc; {c) a detailed experimental protocol giving the reasons for any omission of certain tests 'listed above, a description of the methods, apparatus and materials used, details of the species, breed or strain of animals, where they were obtained, their number and the conditions under which they were housed and fed, stating inter alia whether they were free from specific pathogens (SPF);. 8S. ~ (d) all the results obtained, whether favourable or unfavourable. Th~ original data should 81/852/EEC be described in sufficient detail to allow the reSults to be · ciitically evaluated independently of their interpretation by the author. By way of explanation, the results may be accompanied by illustrations; · ·Annex (as amended by 92/18/EEC (adapted) (e) a statistical analysis of the results, where such is Called for by the test programme, and variance within the data; · (f) ·an objective discussion of the results obtained, leading to conclusions on the safety · of the substance, on its safety margin in· the test animal and the target animal and its possible side-effects, on its fields of application, on its active dose levels anq any possible incompatibilities; (g) a deiailed description and a thorough discussion of the results of the study of the safety of residues in food, and its relevance for the evaluation of potential risks presented by residues to humans. This discussion shall be followed by proposals to ensure that any danger to man is eliminated by applying internationally recognized assessment criteria, for example: no observed effect level in animals, proposals for a choice of safety factor and for acceptable daily intake (AD I); (h) a thorough discussion of any risks for persons preparing the medicinal product or administering it to animals, followed by ,proposals for appropriate measures to reduce such risks; (i) a thorough discussion of the risks which use of the veterinary medicinal product under the practical conditions proposed may represent for the environment followed by appropriate proposals to reduce such risks; G) all information necessary to acquaint the clinician ~ fully ~ possible with the utility of the proposed product. The discussion will be supplemented by suggestions as to side-effects and possible treannent for acute toxic reactions in animals to which the product is to be administ~red; (k) a concluding expert report which provides a detailed critical analysis of the information referred to above in the light of the state of scientific knowledge at the time the application is submitted together with a detailed summary of all the results of the relevant safety tests and precise bibliographical references. 86 a. Residue testiaa CHAPTER I PERFORMANCE OF TESTS 1. lati'oduetion ·8l/8S21EEC Annex. (as amended by 92/18/EEC Art. 1) (adapted) For the pmposes of this Directive, 'residues' means all active substances or metabolitcs thereof which remam in meat or other foodstuffs produced from the animal to which the medicinal product in question has been administered. The purpose of studying residues is to determine whether, and if so under what conditions and to wbat extent, residues persist in foodstuffs produced from treated animals and to ascertain the withdrawal periods to be adhered to in order to obviate any hazard to human health and/or difficulties in the industrial processing of foodstuffs. Assessment of the hazard due to residues entails establishing whether residues are present in the animals treated under recommended conditions of use and investigating the effects of those residues. · In ~e case of veterinary medicinal products intended for use in food-producing animals, the residue documentation shall show: 1. 2. to what exten~ and how long, do residues of the veterinary medicinal product or its metabolitcs persist in the tissues of the treated animal. or ·foodstuffs obtained' therefrom; that in order to prevent any risk to the health of the consumer of foodstuffs of treated animals, or difficulties in the indus1rial processing of foodstuffs, it is possible to establish realistic withdrawal periods which can be observed under practical farming conditions; 3. that practical analytical methods suitable for routine use are available to verify compliance with th~. withdrawal period. 2. Metabolism and rtsidue kinetics 2. 1. "Phanna~oldnetics (absorption, distribution, biotransformation, excretion) The pUrpose of pharmacokinetic studies with respect to residue~ of veterinary medicinal products is to evaluale the absorption, distribution, biotransformation and excretion of the product in the target species. lbe final product, or a formulation which is bioequivalent, shall be administered to the target species at the maximum recommended dose. Having regard. to the method of administration, the extent of absorption of the medicinal !)I'Oduct shall be fully described. If it is demonstrated that systemic absorption of produc~ for topical application is negligible, further residue studies will not be required. 87 The distribution of the bledicinal product in the target lliDDal shall be · de5cribed; the possibility of plasma protein binding, or passage · h1to. milk or eggs and· of the · accumWati~ of lipophilic compoun~ sball be· cousidered. The pathways for the excretion of the product from the target animal shall be described. The maj~ metabo~ sball be iden~ed and characterized. 81/852/EEC Annex (as amended by '92/l~C Art. 1) (adapted) 2. 2. Depletion of residues The purposes of these· studies, which measure the rate at which residues deplete in the target animal after the last administration of the medicinal product, is to permit the determination of withdrawal periods. · At varying times after the test animal has received the final dose of the medicinal product, the quantities of residues present shall be determined by appropriate physical, chemical or biological methods; the· technical procedures and the reliability and sensitivity of the methods employed shall be spcc:ified. 3. Routine analytical method for the detection or residues Analytical ·procedures shall be proposed which can be carried out in the course of a routine examination and which bave a level of sensitivity such as to enable violations of legally 'permitted maximum residue limits to be detected with certainty. The analytical method proposed shall be described in detail. It shall be validated and shall be sufficiently rugged for use under normal conditions of routine monitoring. for residues. The following characteristics shall be described: specificlty, •· accuracy, including sensitivity,·. precision, limit of detection, limit of quantitation, - practicability and applicability under normal laboratory conditions, susceptibility to interference. The suitability of the analytical method proposed shall be evaluated in the light of the state of scientific and technical knowledge at the time the application is submitted 88 CHAPT. ERU PRESENT AnON OF PARnCULARS AND DOCUMENTS. As in any ·scientific work, the dossier of residue tests sbal1 include the following: (a) an iiltroduction defining the subject, accompanied by any useful bibliographical references; (b) a detailed identification of the medicinal, including: 811852/EEC Annex (as amended by 92/18/EEC Art. 1) (adapted) · composition, purity, batch identification,. relationship to the final product, specific activity and radio-purity of labelled substances, position of labelled atoms in the molecule;· (c) a detailed experimental protocol giving the reasons for any omission of certain tests listed above, a description of the methods, apparatus and materials used, details of the species, breed or strain of animals, where they were obtained, their number and the conditions under which they were housed and fed; (d) all the results obtained, whether favourable or unfavourable. The original data should be described in sufficient detail to allow the results to be critically evaluated independently of their interpretation by the author. The results may be accompanied by illustrations; (e) a statistical analysiS of the results, where such is called for by the test programme, and variance within the data; (f) an objective discussion of the results obtained, followed by proposals for maximum residue limits for the active substances contained in the product, specifying the marker residue and target tissues concerned, and proposals concerning the withdrawal periods necessary to ensure that no residues which might constitute a hazard for consumers are present ·in foodstuffs obtained from treated animals; (g) a concluding expert report which provides a detailed critical analysis of the information referred to above in the light of the state of scientific knowledge at the · time the application is submitted together with a detailed· summary of the results of the residue tests and precise bibliographical references. 89 PART4 PRE-CLINICAL AND CLINICAL TESTING The ·particulars and documents which shall accompany applications for marketing authorizations pursuant to Articles 12 (3) (j) and 13 (1) shall be submitted in accordance with. the. provisions of this Part. 81/852/EEC Annex (as amended by 92/18/. EEC Art. 1) (adapted) CHAPTER I PRE-CLINICAL REQUIREMENTS Pre-clinical studies are required to· establish the pharmacological activity and· the tolerance of the product. A. Pharmacology A. 1. PHARMACODYNAMICS The study of pharmacodynamics shall follow two distinct lines of approach: First, the mechanism of action and the pharmacological effects on which the recommended application in practice is based shall be adequately described. The results shall be expressed in quantitative terms (using, for example, dose-effect curves, time effect curves, etc. ) and, wherever possible, in comparison with a substance the activity of which is well known. Where a higher efficacy is being claimed for an active substance, the difference shall be demonstrated and shown to be statistically significant. Secondly, the investigator shall give an overall pharmacological assessment of the. active substance, with special reference to the possibility of side-effects. In general, the main functions shall be investigated. The investigator shall identify the effect of the route of adm. inistiation, formulation, etc, on the pharmacological activity of the active substance. The investigations shall be intensified where the recommended dose approaches that liable to produce adverse reactions. The experimenia. l techniques, unless they are standard procedures, shall be described in such detail as to allow them to be reproduced, and the investigator shall establish their validity. The experimental results shall· be set out clearly and, for cenain types of tests, their statistical significance quoted. · Unless good reasons are given tO the contrary, any quantitative modification of responses resulting from repeated administration of the substance shall also be investigated. \ Medicinal combinations may be prompted either on pharmacological grounds or by clinical indications. In the first case, the pharmacodynamic and/or pharmacokinetic studies shall demonstrate those interactions which might make the combination itself of value in clinical use. In the second case, where scientific justification fcir the medicinal combination is sought through clinical experimentation, the investigation shall determine. whether the effects expected from the combination can be demonstrated in animals and, at least, the importance of any adverse reactions shall be checked. If a combination. includes a· novel active substance, the latter shall have been previously studied in depth. 90 Basic pharmacoldnetic information concerning a new active substance is generally useful in the·clinical context. ·. 81/852/EEC Annex (as amended by · 92/18/EEC Art. 1) {adapted) Pharmacokinetic objectives can be divided into two main areas: (i) descriptive pharmacokinetics leading to. the evaluation of basic parameters such as body clearance, volume(s) of distribution, mean residence time, etc; (ii) use or' these parameters to investigate the relationships between dosage regimen, ·. plasma and tissue concentration and pharmacologic, therapeutic or toxic effects. In target species, pharmacoldnetic studies are, as a rule, necessary in order to employ drugs with the greateSt possible efficacy and safety. Such studies arc especially useful to assist the clinician in establishing dosage regimens (route and site of administration, dose, dosing interval, number of administrations, etc. ) and to adopt dosage regimens according to certain population variables (e. g. age, disease). Such studies can be more efficient in number of animals and generally provide more ·information than classical dose titration studies. · In the case of new combinations of known substances which have been investigated in accordance with the provisions of this Directive, pharmacokinetic studies. of the fixed combination are not required if it can be justified tbat the administration of the active substances as a fixed combination does not change their pharmacokinetic properties. A. 2. 1. Bioavailability/bioequivalence Appropriate bioavailability studies ·shall be undertaken to establish bioequivalence: when comparing a reformulated medicinal product with the existing one, · when comparing a new method or route of administration with an established one, in all cases referred to in Article 13 (1 ). 91 · 81/852/EEC. AJmex (as. amended by. 92/18/EEC Art. 1). (adapted) B. · Toleraa~. iD the tarcet s~ of uim. The pmpose of thiS stUdy, which sball be Carried out with all animal $JleCies for ~eh the. medicinal product is iDteDded, is to carry out in all such aDimal. species local and geo. eral tOlerance triaJs· designed to ~lish a tolerated ~e wide enough to allow an adequate safety ~ and the ·clinical symptomS of intolerance UsiDg the recommended route -or routes, m ·so far as this may be ~eved by increasing the therapeutic dose and/or the duration Of treatment The report OD the trials shall comain U many deiaiJs · 8S possible of the expeded pharmacological effects and the adverse reactions; the latter shall be assessed with due regard to the fact~ the Mjmals used may be ~f very high value. The medicinal product shall·be administered at least via the recommended route of administration. · C. Resistaace Data OD the emergence of resistant organiSms are necessary. in the case of medicinal. products used for the prevention or trealment of iilfectious diseases ·or parasitic infestations in animals. · CHAPTERll CLINICAL REQUIREMENTS 1. Geaeral principles The pwposes of clinical trials are to demonstrate or substantiate the effect of the veterinary medicinal product after administration of the recommended dosage, to specify its indications and contra-indications according to species, age, breed and sex, its directions for use, any adverse reactions which it may have and its safety and tolerance under normal conditions of use. Unless justified, clinicai trials shall be carried out with control animals (controlled clinical trials). The effect obtained should be compared with a placebo or with absence of trealment and/or with the effect of an a~oriz. ed mediciDal product known to be of therapeutic value. All the results obtained, whether positive or negauve, shall be reponed. The methods used to make the diagnosis shall be specified. The results shall be set out by making use of quantitative or conventional clinical criteria. Adequate statistical methods shall be used and justified. 92 ID the case of a VeteriDary medicinal ploduct intended primarily for ~-as. a performance Jl/852/EBC. , ~cert particadar. ~~n sball be given tO: · ·. Annex. (as imlend~ by 92/18/EEC Art 1) (adapted) • the yield of animal produce, ' the quality of animal produce (organoleptic, nutritional, hygienic and technological qualities),. • · ·nutiitional. efficienq and growth of animal, the general status ofhealth of the animal. Experimental data shall be confinned by data obtained under ~cal field conditions. Where, in respect of particular therapeutic indications, the applicant can show tbat he is unable to provide comprehensive data on therapeutic etfect because: (a)' the indications for which the medicinal _product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence; (b) in _the present state of scientific knowledge, comprehensive information cannot be provided; the marketing authorization may only be granted subject to the following conditions: (a) the medicinal product in question is to be supplied on veteriuary prescription only and may, in certain cases, be administered only under strict veterinary supervision; (b) the package insert and any other information must draw the attention of the veterinary practitioner to the fact that, in certain specified respects, the particulars. available concerning the medicinal product in question are as yet incomplete. · 2. Performance of trials All veterinary clinical trials shall be conducted in accordance with a fully considered detailed trial protocol which shall be recorded in writing prior to commencement of the trial. The welfare of the trial animals sball be subject to veterinary supervision and shall be taken fully into consideration during the elaboration· of any trial protocol and throughout the conduct of the trial. Pre-established systematic written procedures for the organization, conduct, data collection, documentation and verification of clinical trials shall be required. 93 Before tbe·ccmuDena:mentof any. trial, the info~ consent of the oWner bfthe ;,Jma1s ·: &1/852/EEC· to be ·used m the triai slwlbe obu. med and documeiite~ In particular,. the anima(o\vner Annex (as amended. by. shall be informed "in Writing of the ccmsequences· of participation in the ,. tri8J for the sUbsequeDt. dispOsai of treated. animals or fot tbe taldn8 of foodstuffs: from ·treated 92/18/EECArt>1) ariimaJs •. A. aJPY of this notification, countersigned and dated by the animal owner, shall be included in the lrial documentation. ·Unless the trial is conducted with,a blind design, the provisions. ofArticics ss. S6 and S7 concerning· the labelling of veterinary medicinal products shall apply by analogy to the labelling of formulations intended for use in veterinary clinical trials. In· all cases, the. words 'for veterinary clinical trial use only' siWI appear prominently ~d indehbly upon the labelling. (idapted) · · · CHAPTER ill PARTICULARS AND DOCUMENTS As in any scientific wo~ the dossier on efficacy shall include. an introduction defining. the subject accompanied by any usetw bibliographical documentation. All pre-clinical and clinical documentation must be sufficiently detailed to enable an objective judgement to be made. All studies and trials must be reported, whether favourable or unfavourable to the applicant i. Records of pre-cliDical observations Wherever possible, particulars shall be given of the results of: (a) tests demonstrating pharmacological actions; (b) tests demonstrating the pharmacological mechanisms underlying the therapeutic ·effect; (c) tests demonstrating the main pharmacokinetic processes. Should unexpected results occur during the course of the tests, these should be detailed. 94 8. 1/852/EEC Am:iex. : -. (as amended by. 92/18/EEC Art. 1) (adapted) (a) aslunmary; (b) a detiiiCd. experim~ protocol giving a description of the methods, apparatus and 'materials used, details such as ·species, age, weight,. sex, number, breed or straiD of · animals, identification of animals, dose,. route and schedule of administration; (c) a staJ:istical analysis· of the results where relev,ant; ·-· (d) an objective discussion of the results obtained, leading to conclusions on the safety. ~ efficacy. of the product. Total or partial omission of these data must be explained 2. 1. Records of clinictll observations All the· particulars shall be supplied by each of the investigators on individual record sheets in the case. of individual treatment and collective record-sheets in the case of collective treatment The particulars supplied shall take the following form: (a) name, address, function and qualifications of investigator in charge; I (b) place and date. of treatment; name and address of owner of the animals; (c) details of the trial protocol giving a description of the methods used, including methods of randomization and blinding, details such as the route of administration, schedule of administration, the dose, identification of trial animals, ~ies, breeds or strains, age, weight, sex, physiological status; · (d) method of rearing and feeding, stating the composition of the feed and the nature and quantity of any additives contained in the feed; (e) case history (as full as possible), occurrence and coW'Se of any inter-current diseases; {f) diagnosis and means used to make it;. (g) Symptoms and severity of the disease, if possible accor~g to conventional criteria; (h) the precise identification of the clinical trial formulation Used in the trial; 95 (i) dosage of the medic~ product, method, route'. and hquency of adminisiration and 81/852/EEc· , ~oos, ·i:f any, taken~ administration (duration of ~jection, etc~);. AnneX. (as amended ,by· 92/18/. EEC Art. 1) (adapted) (j) ~ tJftteatuient and period of subsequent obsemition; ,. (k) all. delailS concerning medicinal products (other thaD that·under study) which have. been ~ during the period of examination, either prior to or concmently with the teSt_product and, in th~ latter·case, details of the interactions observed; 0) all results of the clinical~ (including unfavourable oi negative results) with a full statement of the. clinical observations and the results of the objective tests of actiVity {laboratory analyses, physiological te$),· required to evaluate the application; the techniques used must be specified, and the significance of any variations in the results explained (for example, variance in method, variance between individuals or · the effects of the medication); demonstration of the pharmacodynamic effect in animals shall not in itself suffice to justify conclusions concerning any therapeutic effect;. (m) all particulars of any unintended effects, whether harmful or not, and of any measures taken in consequence; the cause-and-effect relationship sball be investigated if possible; (n) effect of animals' performance (for example: egg-laying, milk production and reproductive function); ( o) effects on the quality of foodstuffs obtained from treated animals, particularly in the case of medicinal products intended for use as performance enhancers; · (p) a conclusion on each individual case or, where collective treatment is concerned, on each collective case. · Omission of one or more items (a) to {p) shall be justified. The marketing authorization holder shall make all necessary arrangements to ensure that the original documents, which formed the basis of the data supplied, are kept for at least five years after the veterinary-medicinal product is no longer authorized. 96 2. 2:. SUiflit:iary. and conclusions of cliliica! observations In iespect of eacJi ~linical trial, the clinical observations shall ]?e suminarized in a synopsiS ~~the trials and the results thereof: indicating in ~cular:. · (a)· the. nwnber of coJ11:rOis, the number of animals treated either individually or · collectively, with a breakdown according to species, b~ or strain, age and sex; (b) the number of anjmals withdrawn prematurelY from the trials and the reasons for· such wi~drawal; 81/852/EEC Annex · (as amended by 92/18/EEC. Ait. I) (adapted)' {c) in the. case of control animals, whether they have: received no treatment; received a placebo; received another authorized medicinal product of known effect; ~ received the active substance. under investigation in a different formulation or by a differeJ)t route; (d) the frequency of observed adverse reactions; (e) observations as to the effect on perfon;ance (for example, egg-laying, milk production, reprOductive function and food quality); (f) details concerning test animals which may be at increased risk owing to their age, their mode of ~ or feeding, or. the pmpose for which they are intended, or animals the physiological or pathological condition of which requires special consideration; (g) a statistical evaluation of the results, when this is called for by the test programme. Finally, the investigator shall·draw general conclusions from the experimental evidence, expressing his opinion. on the harmlessness of the medicinal product under the proposed conditions of use, its therapeutic effect and any useful information relating to indications and contra-indications, dosage and average duration of treatment and where appropriate, any interactions observed with other medicinal products or feed additives as well as anY, special precautions to be taken during treatment and the clinical symptoms of overdosage. In the case of fixed combination products, the investigator shall also draw conclusions concerniJlg the safety and the efficacy of the product when compared with the separate administration of the active substances involved. 3. Concludin~ expert report The concluding expert report shall provide a. detailed critical analysis of all the pre clinical and. clinical documentation in the light of the state of scientific knowledge at the time the application is subJ;nitted together with a detailed ·summary of the results of the tests and trials submitted ~d precise bibliographic references. 97 TITLED REQ~ FORIMMUNOLOGI~ VElERINARY MEPtCINAL PRODUCTS · 81/852/EEC. Aimex (as amcilded by 92/18/EEC Art. 1) ( adapteci). WithoUt prejudice to the specific reqUirements ·iaid doWn by Community legislation tor the contrQI and eradication of animal desease; tbefolk>wing ~enf:S sball BJ)ply tb immunological veterinary medicinal products. PARTS SlJMMARY OF 'l'lm·DOSSIER A. ADMINISTRATIVE DATA The immunological veterinary medicinal product which is the subject of the application shall be ·identified by name and by name. of the active substances, together with the strength and pharmaceutical form, the method and route of administration, and a· description of the final sales presentation of the product. The name and address of the applicant shall be given, together with the name and address of the manufacturer and· the sites involved in the different ·scages of manufacture (including the manufacturer of the finished product and the manufacturer(s) of the active substance(s)) and where relevant the name and address. of the importer. The applicant sball identify the number and tides of volumes of documentation submitted in support of the application and indicate what samples, if any, are also provided. Annexed to the administrative data shall be copies of a document showing that the manufacturer is authorized to produce immunological veterinary medicinal products, as defined in Article 44 (with a brie( description of the production site). Moreover, the list of organisms bandied at the production site shall be given. I The applicant shall submit a list of countries in which authorization has been granted,. copies of all the summaries of product characteristics in accordance with Article 14 as approved by Member States and a list of countries in which an application has been · submitted. · B. SUMMARY OF PRODUcr CBARACI'ERISTICS The applicant shall propose a summary of the product characteristics, in accordance with Article 14. In addition the applicant shall provide one or more specimens or mock-ups of the sales presentation of the immunological veterinary medicinal product,. together· with a package insert, where one is required. 98. All important data shall be summarised in an appendix to the expert report, whenever possible in tabular or graphic form. The expert report and the summaries. shall contain prec~ cross references to the information containc;d in the main documentation. Each expert report sball be prepared by ·a suitably qualified and experienced ·person. It shall be signed and dated by tbe expert, ,and attached to the report shall be brief information about the ed~onal background, training and occupational experience of the expert. The professional relationship of the expert to the applicant shall be declared. PART6 ANALYTICAL (PHYSICo-cHEMICAL, BIOLOGICAL OR MICROBIOLOGICAL) TESTS OF IMMUNOLOGICAL MEDICINAL PRODUCfS. VETERINARY All test procedures used shall correspond to the state of scientific progress at the time and shall be validated procedures; results of the validation studies shall be proVided. All the test procedure(s) shall be described in sufficiently precise detail so as to be reproducible in control tests, carried out at the request of the competent authority; any special apparatus and equipment which may be used shall be described in adequate detail, possibly accompanied by a diagram. The formulae of the laboratory reagents shall be supplemente~ if necessary, by the manufacturing method. In the case of test procedures included in the European Pharlnllcopoeia or the pharmacopoeia of a Member State, this description may be replaced by a detailed reference to the pharmacopoeia in question. 99 A. QUALITATIVE· AND · QUANTITATIVE PARTI~. OF THE 81/852/EEC CONSTITUENTS The Particulars and. documents which. must accOmpany applications for marketing 92/18/EEC Art. I) authorization, pursuant to. Article 12 (3) {c), shall be submitted in accordance· with the following requirements. (adapted) · Annex (as amended by 1. Qualitative partieulan '·Qualitative particulars' of all the constituents of the· immunological veterinary medicinal · product shall mean the designation or description of: the active substance(s), the constituents of the adjuvants, the constituent(s) of the excipients, whatever their nat\U'e or the quantity used, including preservatives, stabilizers, emulsifiers, colouring matter, flavouring, aromatic substances, markers, etc. , the constituents of the phannaceutical form administered to animals. These particulars shall be supplemented by any relevant data concerning ~e container · and, where appropriate, its manner of cloSW'e, together with details of devices with which the immunological veterinary medicinal product will be used or administered and which will be delivered with the medicinal product. 2. The 'usual terminology', to be used in describing the constituents of immunological veterinary medicinal products, shall mean, notwithstanding the application of the other provisions of Article 12 (3) (c): in respect of substances which appear in the European Pharmacopoeia or, failing this, in the national pharmacopoeia of one of the Member States, the main title of the monograph in question, which will be obligatory for all such substances, with reference to the phannacopoeia concerned, in respect of other substances, the international non-proprietary name recommended by the World Health Organization, which may be accompanied· by another non proprietary name or, failing these, the exact scientific designation; substances not having an international non-proprietary name or an exact scientific designation shall be described. by a statement of how and from ·what they were prepared, supplemented, where cq)propriate, by any other relevant details, in respect of colouring matter, designation by the 'E' code assigned to them in Directive 78/25/EEC. 100 3. · Qaatitative particulars. ·. ID older. to give. · dle 'quantitative particUlars• of the activ~ subS. ces of· an immunological veterinary medicinal product, it is necessary to specify whenever possible the number. of organisms, the specific proteiD content, the mass, the number of lntemational Units ·(IU) or units· of biological activity,· either per ~sage-unit or volume, and with regard to the adjuvant and to the constituents of the eicipients,. the mass or the volume of each of them, with due allowance for the details provided in section B. · Where an International Unit of biological activity has been· defined, this sbaU be used. 811852/EEC. Annex (as amended by 92/1. 81EEC Art. 1) (adapted) The units of biological activity for which no pUblished data exist shaD ·be expressed in such a way as io provide unambiguous information on the activity of the ingredients, e. g. by :StatiJig the immunological ·effect on which the method of determining the dose is based. ,. 4. Development pharmaceutics An explanation · sbaU be provided with regard to t"Qe composition, components and containers, supported by scientific data on development pharmaceutics. ~ overage, with justification thereof: sball be stated. The efli:cacy of any preservative system shall be dem9nstrated. B. DESCRIPTION OF MANUFACI'URING MEmOD OF THE FINISHED PRODUCf The description of the manufacturing method accompanying the application for marketm. g authorization pursuant to Article 12 (3) (d), shall be drafted in such a way as to give an adequate description of the nature of the operations employed. For this purpose the description shall include at least: the various stages of manufacture (including ·purification procedures) so that an assessment can be made of the reproducibility of the manufacturing procedure and of the risks of adverse effects on the finished prod~cts, such as microbiological contamination, in the case of continuous manufacture, full details concerning precautions taken to ensure the homogeneity and consistency of each batch ~f the finished product, mention of substances which cannot be recovered in the course of manufacture, the details of the blending, with the quantitative particulars of all ~e substances used, a statement of the stage of manufacture at which sampling is carried out for in- process control tests. · 101 C. PRODUCTION AND CONTROL OF STARTJNG. Ml\TERIALS. For ·the purposes of this paragraph 'stBrting materials' means all components Used. in the production of the immunological veterinary medicinal prodilCt. Culture media-used for 92/18/EEC Art. I) the production of the active substance. are considered as one single s1artiJlg material. (adapted). ·. :. 811852/EEC. Annex (as -. nended by ln~eca5eof ~ active. · substance not · describCd in the European Pharmacopoeia or in the pharmacopoeia of a Member State, or. - in the European Pharmacopoeia or in the an active substance described pharmacopoeia of a Member State when prepared_ by a method liable to leave impurities not mentioned in the pharmacopoeial monograph. and for which the monograph is inappropnate to adequately control its quality, which is manu&ctured by a person different from the applicant, the latter may mange for the detailed description of the manufacturing method, quality control during manufacture and process validation to be supplied directly to· the ~mpetent authorities by the manufacturer of t11e active substance. In this case, the manufacturer · shall however provide the applicant with all the data which may be necessary for the latter to take responsibility for the medicinal product. The manufacturer shall confirm in writing to the applicant. that he slW1 ensure batch-to-batch. consistency and not modify the manufacturing process or specifications without informing the applicant Documents and particulars supporting. the application for such a change shall be supplied to the competent authorities. · The particulars and documents accompanying the application for marketing authorization pursuant to·Article 12 (3) (i) and 0) and Article 13 (1) shall include the results of the tests relating to quality control of all the components "USed and shall be submitted in accordanc~ with the following provisions. 1. Starting materials listed in pharmacopoeias The monographs of the European Pharmacopoeia shall be applicable to all substances. appearing in it In respect of other substances, each Member State may require observance of its own national pharmacopoeia with regard to products manufactured in jts territory. Components ful. tilling the requim;nents of the European Pharmacopoeia or the pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with Article 12 (3) (i). In this case the description of the analytical methods may be replaced by a detailed reference to the pharmacopoeia in question. · 102 Reference ·to pharmacopoeia~. of third ~untries may be permitted in cases ~ere the substan~ is described neither m the··Eurapean ·Pharmacopoeia. nor in the national p~ia concerned; in. that ~ the monograph shall be sUbmitted, acconipanied where·necessary by a tranSlation for whi~h the applicant Win be responsibl~. 81/852/EEC Annex, (as amended ~Y 92/18/EEC Art. 1) (adapted). Colouring matter shall, in all· cases, satisfy the requirements· of Council Directive 78/25/EEC. The routine tests caniea out on each batch of starting materials must be as stated in the ·application for mirketing author. izaiion. If tests o~ than those mentioned in the pharmacopoeia are used, proof must be. supplied that the starting materials meet. the quality requirements oftbat pharmacopoeia. · · In cases Wtiere a specification or other provisions contained in a monograph of the' European Pharmacopoeia or in the national pharmacopoeia of a Member State might be insufficient to ensure the quality of the substance, th~ competent authorities may request more appropriate specifications from the marketing authorization holder. The competent authorities shall inform the authoriti~ reSponsible for the pharmacopoeia in question. · The marekting auth9rization holder shall provide the authorities of that pharmacopoeia With the details of the alleged insutliciency and the additional specifications applied. In cases where a starting material is described neither in the. European Pharmacopoeia nor in the pharmacopoeia of a Member State, compliance with the monograph of a third country pharmac:opoeia can be accepted; in such ~s, the applicant shall submit a copy of the monograph accompanied where necessary by the validation of the test procedures contained in the monograph and by a translation ·where appropriate. For active ingredients, demonstration of the ability of the monograph adequately to control their quality shall be presented. l. Starting materials not listed in a pharmacopoeia 2. 1. Starting materials of biological origin The description shall be given in the form of a monograph. · Whenever possible, Vaccine production shall be based on a seed lot system and on established cell banks. For the production of immunological veterinary medicinal products consisting of serums, the origin, general health and immunological status of the producing animals shall be indicated; defined pools of source materials shall be used. The origin and history of starting materials shall be described. and documented. For genetically engineered starting materials this information shall include details such as the description of the starting cells or strains, the construction ·of the expression vector (name, origin, function of the replicon, promoter enhancer and other regulator elements), control ofthe,sequence of DNA or RNA effectively inserted, oligonucleotid. ic sequences of plasmid vector in cells, plasmid used. for cotransfection, added or deleted genes, biological properties of the final construct and the genes expressed, copy number and gen~c stability. 103 Jl/852/EEC Annex (as amended by 92/18/EEC Art. 1) {adapted) Seed. materials, mcluding, Cell binks and raw serum for anti~serum production shall be tested f~ identity ~d adventitious agents. · Information sball be provided OD all substances of biologiCal origin used at any stage in the manufacturing procedure. The information shall include:. - details. ofthe source of the materials, details of any processing,· purifi~on and inactivation applied, With data on the validation of these process and in-process controls, · details of any tests for contamination canicd out. on each batch of the sUbstance. If the presence of adventitious agents is detected or suspected, tb:e corresponding material shall be discarded ·or. used in very exceptional circumstances only when further processing of the produCt ensilres their elimination and/or inactivation; elimination and/or inactivation of such adventitious agents shall be demonstrated When cell banks are used, the cell characteristics shall be shown to have remained unchanged up to the highest passage level used for the production. For live attenuated vaccines, proof of the stability of the attenuation characteristics of the seed has to be given. When required, samples of the biological starting material or reagents used in the testing procedures shall be provided to enable the competent authority to arrange for check tests to be carried out. 2. 2. Starting materials of non-biological or. igin The description shall be given in th~ form of a rqonograph under the following headings: the name of the starting material meeting the requirements of point 2 of Section A · shall be supplement~ by any trade or scientific synonyms, the description of the starting material, set down in a form similar to that used in a descriptive item m the European Pharmacopoeia, the function of the starting material, methods of identification, purity shall be described in relation to the sum total of predictable impurities, especially those which may have a harmful effect and, if necessary, those which, having regard to the. combination of substances to which the application ref~ may adversely effect the stability of the medicinal product or distort analytical. results. A brief description shall be provided of the tests undertaken to establish the pmity of each batch of the starting material, 104 any· special Precautious ·which may ~ necessary. during storage· of the SWting S·118S21EEC ~ and,. if necessary, its storQe life shall be given. · Annex (is amended by 92/18/EEC Art. 1) (adapted) D. CONTRO~. TESTS DURING ~RODUCI'ION 1. The particulars' and documents accompanying · an application for marketing authorization, ·pursuant to Article 12 (3) (i) and (j) and Article 13. (1 ), shall include particulars ~lating to the controJ tests which are. canied out on intermediate products with a view ta verifying the consistency of the production process and the final. ~ ' 2. For inactivated or detoxified vaccines, inactivation or detoxification shall be tested during each production run. immediately~ after the inactivation or detoxification process. E. CONTROL TESTS ON THE FINISHED PRODUCI' The particulars and documents acCompanying the application for marketing authorization pursuant to Article 12 (3) (i) and (j) and Article 13 (1), shall include particulars relating to control tests on the finished product. Where appropriate monographs. exist, if test procedures and limits other than those mentioned in the monographs of the Emopean PharmaCopoeia, or failing this, in the national pharmacopoeia of a Member State, are used, proof must be supplied that the finished product would, if tested in accordance with those monographs, meet the quality requirements of that pharmacopoeia for the pharmaceutical form concerned. The application for marketing authorization shall list those tests which are. carried out on representative samples of each batch of finished produ~ The frequency of the teSts which are not carried out on each batch shall be stated. Release limits shall be indicated. 1. General characteristics of the finished product Certain tests of the gene~ characteristics of a product shall be included among the tests on the finished product, even if they have been carried out in the course of the manufacturing process. These tests shall, wherever applicable, relate to the control of average masses and maximum deviations, to mechanical, physical, chemical or microbiological tests, physical characteristics such· as density, pH, refractive index, etc. For each of these characteristics, specifications, with appropriate confidence limits, shall be established by the applicant in each particular case. 2. Identification and assay of active substance(s) For all tests, the description of the techniques for analyzing the finished product shall be set out in s~ciently precise detail, so that they can be reprodu~d readily. The assay of biological activity of the active substance(s) shall be carried out either in a representative sample from the production batch or in a number of dosage-units analysed individually. 10S Wh~:nccessacy, a specific test for identification sliall also be ·canied o~ ~ certain exCCJrti:onal cases where assay of active· substances which are very numerous or present in very low. ampunts would necessitate an. ~cate investigation difficult to cany. _. out in respect of each pociuctioh batch, the assay of one or more active substances· in. the finished product may ·be omitied, OQ the express condition tb8t SUCh assays are made at intermediate stages as late as possible in the production process. This relaxation may not be extended to the chara:cterization of the. substanCes concerned. This simplified technique shall be supplemented by a method of quantitative ~evaluation,· enabling the com~t. authority to verify that the immunological veterinary medicinal product iS in accordance with ~ts formula after it has been placed on the market 81/852/EEC Annex (as amended by 92/18/EEC Art. 1). (adapted) 3. ldentifieation and assay of adjuvaats ~. In so far as testing Pr-ocedures are available, the quantity and natw:e of the adjuvant and its components shall be verified on the finished product. 4: Identification and assay of excipient components In so far as is necessary, the excipient(s) shall be subject at least to identification tests. The test procedure proposed for identifying coloming matters must enable a verification to be made that such matters are permitted under Directive 78/25/EEC. An upper and lower limit. test shall be obligatory in respect of preserving agents; an upper limit test for any other excipient components liable to give rise to an adverse reaction shall be obligatory. 5. Safety tests Apart from the results of tests submitted in accordance with Part 7 of this Annex, ·particulars of safety tests shall be submitted. These tests shall preferably be overdosage studies carried out in at least ·one of the most sensitivcr target species and by at least the recommended route of administration posing the· greatest risk. 6. Sterility and purity test Appropriate tests to demonstrate the absence of contamination by adventitious agents or other substances shall be carried out according to the nature- of the immunological veterinary medicinal product, the method and the conditions of manufacture. 106 -7. IDactivaUOD Where ·. ppncable~ a test to verify iDadivation sball ~ carried_ out on the product in the final ~er. · :81/852/EEC Annex (as amended by ' 9Z/. t81£EC An. 1) (adapted) ~ Residual hllllli~ Each batch of lyophilized ~et sball-~ tested for residual hilmi~ _. · 9. Bateh-•bateh. eoaslsteney In order to eusure that efficacy of the product is reproduCible from batch to batch and to demonstrate conformity with specifications, potency tests based upon in vitro or in vivo ~~;~ethods, including appropriate. reference materials whenever available, shall be carried out on ead1 final bulk or each batch of finished product, with apprOpriate confidence limits; in. exCeptional circumstances, · potency testing may be carried out at an intermediate stage, as late as possible in the production process. · F. STABD. JTY TESTS The particulars and documents accompanying the application for marketing authorization pursuant to Article 12 (3) (f) and (i) shall be submitted in accordance with the following requirements. A description shall be given of the tests uodertaken to supJ)ort the shelf life proposed by the applicant. These tests shall always be real-time studies; they shall be carried out on a sufficient number of batches prl?duced according to the described production process and on products stored in the final container(s); these. tests include biological and physico chemical stability tests. The conclusions shall contain the results of analyses, justifying the proposed shelf-life under all proposed storage conditions. ' In the case of products administered in the feed, information shall also be given as necessary on the shelf-life of the product, at the different stages of mixing, when mixed in accordance with the recommended instructions. Where a finished product requires reconstitution prior to administration, details of the proposed shelf-life are reqWrec:l for the prodUct reconstituted as recommended. Data in support of the proposed shelf-life for the reconstituted product shall be submitted. ' ' 107 PAR. T7 SAFETY TESTING · , • I A. INTRODUCI10N 81/852/EEC ·. Annex (as amended by 92/18/EEC Art. 1) (adapted). 1. The safety ~ shall show the po•tial risks from the immunol~gical veterinaly ·medicinal prOdw:t which may occur under the proposed conditions of use in animals: these sbal1 be ·evaluated in relation to-the potentiaJ benefits of the product. · Where immunologic81 · veteriiwy· medicinal. products consist of live. organisms, especially those which could be shed by vaccinated animals; the potential risk to unvaccinated animals of the same or of any other potentially exposed species shall be evaluated. 2. nie particulars and documents which shall aceompany the application for marketing authorization purSuant to Article 12 (3j (j) and 13 (1) shall be submitted in accordance with the requirements of section B. 3. Member States shall ensure that the laboratory tests are cmied out in conformity with the ·principles of good laboratory practice laid down in Council Directives 87118/EEC and 88/320/EEC. B. GENERAL REQ~MENTS 1. The safety tests shall be carped out in the target species. 2. The dose to be used shall be that quantity of the product to be recommended for use and containing the maximum titre or potency for which the application is submitted. 3. The sample used for safety testing shall be taken from a batch or batches produced according to the manufacturing process descnDed in the application for marketing authorization. 108 81/852/. EEC :. Annex· (as· imended by 92/18/EEC Art. 1) · (adapted) C •. LABORATORY~ 1. ··Safety of the admiDJstration of. one dose The immunologi'*. veterinary' medicinal product ~ be administered at the ~ended. dose and by each recommended route ~fadu;linistration to animals of each. species and category. in which it is intended for use, including anjmals of the minimum age of administration. The animaJs sbal1 be obserVed and examined for signs of systemic m,d local reactions. Where appropriate, these studies shall· include detailed post-mortem macroscopic and microscopic examinations of tbe. injection site. Other objective criteria shall be~ such as-~ temperat1D'e and performance ineasurements. The anjmals sball be o~served and examined until reactions may no "longer be expected, but in all cases, the observation and examination period shall be at least 14 days after administration. 2. Safety of o~e admi. Distration of an overdose An overdose of the immunological veterinary medicinal product shall be administered by each recommended route of administration to animals of the most sensitive categories of the target species. The animals shall be observed and examined for signs of systemic and local reactions. Other objective criteria shall be recorded, such as rectal temperature and performance measurements. The animals shall be observed and examined for at least 14 days after administration. 3. Safety of the repeated administration of one dose Repeated administration of one dose may be required to reveal any adverse effeets induced by such administration. These tests shall be carried out on the most sensitive categories of the target species, using the recommended route of administration. The animals shall be observed and examined for at least 14 days after the last administration for signs of systemic and local reactions. Other objective criteria shall be recorded, such as rectal temperature and performance measurements. 4. Examination of reproductive performance Examination of reproductive performance shall be considered when data suggest that the starting material from which the product is derived may be a potential risk factor. Reproductive performance of males and non-pregnant. and pregnant females shall be investigated with the recommended dose and by each of the recommended routes of administration. In addition, harmful effects on the progeny, as well as teratogenic and abortifacient effects, shall be investigated. These studies may form part of the safety. studies described in paragraph I. 109 5. · Eumiaatlon of lmmuaoJopcal fDDctioDJ Where the imDiunologic8l veterinary medicinil. produCt· might adv~IY 8tfect the immune respouse. of the vaccinated animal or· of. its oroRenv. suitable tests on the immunological f_unctiQDS sblll be cmied out ll/IS21EEC Annex (as amended by 92/18/EEC Art. 1) (adapted) ~· S~l require10ents for live vaeeines: 6. 1. Spread of the vaccine strain Spread of the vaccine strain from vacc~ to unvaccinated target animals sball be investigated, using the recommended route of administration most likely to result in the spread. Moreover, it may be necessary to investigate the spread to non target species which could be highly susceptible to a live vaccine strain. · 6. 2. Dissemination in the vaccinated animal Faeces, urine, milk, eggs, oral, nasal and other secretions shall be tested for the presence of the organism. Moreover, studies may be required of the dissemination of the vaccine strain in the body, with particulir attention being paid to the j,redilection sites for replication of the organism. In the case of live vaccines for well established zoonotic diseases for food producing animals, these studies must be undertaken. 6. 3. Reversion to virulence of attenuatedvaccines Reversion to virulence shall be investigated with material from the passage level which is least attenuated between the master seed and the final product. The initial vaccination shall be carried out using the recommended route of administration most. likely to lead to. reversion to virulence. At least five serial passages through animals of the target species shall be undertaken. Where ~ is not technically possible due to fiilure of the organism io replicate adequately, as many passages as possible shall be carried out in the target species. If necessary, in vitro propagation of the organism may be carried out between passages in vivo. The passages shall be undertaken by 1;he route of administration most likely to lead to revers~on to virulence. 6. 4. Biological properties of the vaccine strain Other tests may be necessary to determine as precisely as possible the intrinsic biological properties of the vaccine strain (e. g. neurotropism). 6. 5. Recombination or genomic reassortmenl of strains The probability of recombination or genomic reassortment with field or other strains shall be discussed 110 7. Study of fesidues For imDlunological veterinary medicinal products, it will normally not be ·necessary to undertake a study ofresidues. However, where adjuvants and/or preservimves are used in 92/18/EEC M 1) the manufacture of immuiaological veterinary medicinal prod~, consideration shall be given. to ·the possibility of any ·residue remaining. in. the foodstuffs~. If necessary, the effects of such residues shaD be investigated. Moreover, in the case ofli~e, vaccines for zoonotJc diselses, the· determinat:ion. of residues at the injection site may be required in ~on to the-studies described m· paragraph 6. 2. (adapted). 811$52/EEC Annex. (as amended by A proposal f~ ·a withdrawal period shall be made and its adequacy shall be_ discussed in relation to any·resid_ue studies which have· been undertaken. 8. lateractioas Any known interactions with other products shall be. indicated. D. FIELD STUDIES Unless justified, results from laboratory studies shall be supplemented with supportive data from field studies. E. ECOTOXICITY The purpose of the study of the ecotoxicity of an immunological veterinary medicinal. product is to assess the potential harmful effects which the use of the product may cause to the environment and to identify any precautionary measures which may be necessary to reduce such risks. An assessment of ecotoxicity shall be compUlsory for any application for marketing authorization for an immunological veterinary medicinal product other than applications submitted in accordance with Article 12 (3}0) and 13 (I). 111 ·This assessment shall ~o~ be~~ in two p~. 811852/EEC Annex The first phase of the assessment shall always be carried out the inv~gator shall assess · (u amended by the. potential extent of exposure of the environment to the prOduct, its ~ve substances, ·. 92/1. 8/EEC Art. 1) or relevant metabolites, taking into accouD. ~ (adapted) · the target species and the proposed pattern of use (for example, mass medication or individual animal medi~on),. · · the method of ~on, in particular th~ llkely extent to which the prOduC:t will enter directly into environmental system, · the possible excretion of the product, its active substances or relevant metabolites · into the environment by treated animals, persistence in such excretia, the disposal of unused or waste product Where the conclusions of the first phase indicate potential exposure of the environment to the. product, the applicant shall proceed to the second phase and evaluate the potential ecotoxicity of the product. For this purpose, he shall consider the extent and duration of exposure of the environment to information about the physical/chemical, pharmacological and/or toxicological properties of the compound obtained during the conduct of the other tests and trials required by this Directive. Where necessary, further investigations on the impact of the product (soil, w~r, air, aquatic systems, non-target organisms) shall be carried out. the product, and. the These further investigations shall be carried out in accordance with the te~ protocols laid down in Annex V to Council Directive 67/548/EEC or where an end point is not adequately covered by these protocols, in accordance with other internationally recognised protocols on the immunological veterinary medicinal product and/or the active substances and/or the excreted metabolites as appropriate. The number and types of tests and the criteria for their evaluation shall depend upon the state of scientific knowledge at the time the application is submitted. 112 (8) PAllTI ·· EmCACY TRIALS. A. INTRODUCTION. 81/852/EEC -Annex. (as amend~ by 92/18/EEC Art. 1) ·(adapted) 1. The purpose of. the trials described in this Part· ·is to demonstrate or to confirm the efficacy of the immunological veterinary. m~cinal product. All claims made· by the. appliCant with regard to the properties, effects and use of the product, shall be fully supported by· results of ~itic trials contained in the application for· marketing authorization. · · · 2. The particulars and· documents which ~ accompany -applications for rilarketing authorizations pursuant ·to Article 12. (3) (j) and 13 (1) sball be submitted· in accordance~ -the provisions below. · , 3. All veterinary clinical tri8ls shall be condu~~ in accordance with a. fully considered detailed trial protocol which shall be recorded in w. ritlng prior to commencement of the trial. The welfare of the trial animals shall be subject· to veterinary supervision and shall be taken fully into consideration during the elaboration of any trial protocol and throughout the conduct of the trial. Pre-established systematic written procedures for the organization, conduct, data c~llection, docmnentation and verification of clinical trials shall be required. 4. Before the commencement of any trial, the informed ·consent of the owner of the animals to be used in the trial shall be obtained and documented. In particular, the animal owner shall be informed in writins of the COJl. Sequences of participation in the trial for the subsequent disposal of treated animals or for the taking of foodstuffs from treated animals. A copy of this notification, countersigned and dated by the animal owner, shall be included in the trial documentation. 5. Unless the trial is conducted with a blind design, the provisions of Articles 55, 56 and 57 shall apply by analogy to the labelling of formulations intended for use in veterinary clinical trials. In all cases, the words 'for veterinary clinical trial use only' shall appear prominently and indelibly upon the labelling. B. GENERAL REQUIRE~ 1. The choice of vaccine strains shall be justified on the ba:sis of epizoological data. 2. Efficacy trials carried out in the laboratory shall be controlled trials, including untreated control animals. 113 In general, these 1rai1s shaD be supported by trials canied out hi. field. conditions, including untreated control animals •. All trials Shall be described in sufficiently precise details so as to be reproducible in control trials, carried out at the request of the competent authorities. The investigator ·shall demonStrate the validity. of all the techniques involved. All results shall be plesented as p~isely as possible. · 81/852/EEC · AnneX. (as amtmded by 92/18/EECM 1) (~) All Rsults obtained,. whether favoUrable or unfavourable, shall be reported. 3. The efficacy. of an immunological veterin8ry. memcinal product shall be deDtonstrated for each category of each species recommended for vaccinatio~ by each recommended route of administration and using the proposed schedule of administration. The influence of passively acquired -and maternally derived antibodies on the efficacy of a vaccb:ie shall be adequately evaluated. Any claims ·regarding the onset and duration of protection shall be supported by data froi:n trials. 4. The efficacy of e8ch of the components of multivalent and combined immunological veterinary medicinal products shall be demonstrated. If the product is recommended for administration in combination with or at the Sam. e time as another veterinary medicinal product, they shall be shown to be eompatible. S. Whenever a product forms part of a vaccination scheme recommended by the applicant, the priming or booster effect or the contribution of the p~duct to the efficacy of the scheme as a whole shall be demo~. 6. The dose to be used shall ~ that quantity of the product to be recommended for use and containing the minimum titre or potency for which the ~plication is submitted. 7. The samples used for efficacy trials shall be taken from a batch or batches produced according to the manufacturing process described in the application for marketing authorization. 8. For diagnostic immunological veterinary medicinal products administered to animals, the applicant shall indicate how -reactions to the product are to be interpreted. 1. In principle, demonstration of efficacy shall be undertaken under well controlled laboratory conditions by challenge after administration of the immunological veterinary medicinal product to the species animal under the recommended conditions of use. In so far as possible, the conditions under which the challenge is carried out shall mimic the natural conditions for infection, for example with regard to the_ amount of cllallenge organism and the route of ~on of the cllallenge. 2. If possible, the immune mechanism (cell-mediated/humoral, locaJ/general classes of immunoglobulin) which is initiated after the administration of the immunological veterinary medicinal product to target -inimals by the rccon;unend~ roUte of administration shall be specified -and documented. · 114 81/852/EEC · Annex (as amended by · 92/18/EEC Art. 1) (adapted). D. F1ELD TRIALs · · 1. - Unlessjustified, resuits ftopl Jaboratoey trials shall· be supplemented with data from. field 1rials. · 2. ·Where laboratory trials cannot be supportive of efficacy, the peiforinance of field · trials ·alone may be acCeptable. PAR. T9' PARTICULARS·AND DOCUMENTS CONcERNING SAFETY TESTING AND EmCACY. TRIALS ·OF IMMUNOLOGIC~ VETERINARY MEDICINAL PRODUCfS· A. INTRODUCI'ION As in any scientific work, the dossier of safety and efficacy studies shall include an · introduction defining the subject and in~cating the tests ~hich have been carried out in compliance with Parts 7 and 8, as well as a summary, with references to the published literature. Omission of any tests or trials listed in Parts 7 and 8 shall be indicated and discussed. B. LABORATORY STUDIES The following shall be. provided for all studies: 2. the niune of the body having carried out the studies; 3. a detailed experimental protocol giving a description of the methods, apparatus and materials used, details such as species, breed or strain of animals, categories of animals~ where they were. obtained, their identification and number, the conditions under which they were housed and fed (stating inter. alia whether they were free from any specified pathogens and/or specified antibodies, the nature and quantity of any additives contained in the feed), dose, route, schedule and dates of administration, a description of the statistical methods used; 4. in the case of control animals, whether they received a placebo or no treatment; I llS • •t. ·S. ·all geoeral. and individual obserVations and results obtained (wbh averages and· 811852/EEC. staDdard. deviations), whether favOmable or unfavourable. · ·ne datA sball· be Annex· described in. Jumcient detail to· allow the resUlts to be critically evaluatei:l · independently of their~ by the author •. ne raw data Sball be presented in · 92/li!EEC ~ 1) tabuJar:form. By way of explanltion and illus1ration, the results ~Y be acccmipai;iied by reproductions of reccmtings, photomicrographs, etc. ; · · (as amended. by (adapted) 6. · the nature, frequency and duration of obser:ved sido-e1fects~. 7. the number of animals ~wn prematurely ftom the studies and reasons for sUch withdrawal;. 8. a· statistical milYsis of the ~, where such is called ·for by the test· programme, · · mdwrlm~~~the~ 9. OCCWTence and course of any intercuri'ent disease; 10. all details concerning medicinal products (other than the product under study), the administration ofwhi~h was n~cessaey during the course of the study; 11. an objective discussion of the results obtained, 1Qdmg. to conclusions on the. safety ·. and efficacy of the product. C. · FIELD STUDIES Particulars concerning field studies shall be sufficiently detailed to enable an objective judgement to be made. ·They shall include the following: I. a summary; 2. name, address, function and qualifications of the investigator in charge; 3. place and date of administration, name and address of the owner of the animal(s); 4. details of the trial protocol, giving a description of the methods, apparatus and materials. used, details such as the route of administration, the schedule of administration, the dose, the categories of animals, the duration of observation, the serological response and other investigations carried out on the animals after administration; · ·. S. in the case of control animals, whether they received a placebo or no treatment; 6. identification of the treated and control animals (collective or individual, as · appro~ }, such as species, breeds or strains, age, weight, sex, physiological status;. 7. •· brief clesclipion of the. ·mel;hod of rearing. and feeding, ~ the nature and quantity of any additives ccmtained in the feed;. ·a. all· the. particulars on observations,. performances· and results-(~ av«ages and ·. stiodard deviation); individual da1a shall be. ilidicated When tests and measurements. 81/852/EEC. Annex (as amended by · 92/18/EEC Art. 1) (adapted). OD in~ have been CIJried out; · · 9. all obserVations and results of the studies, whether filvo~le or unfavourable~ With a tWl statement of the observati~ and the results of the objective tests of activity required to evaluate the product; the techniques -used must be specified and the significance of any variations in the results explained; 10. effect on the animals' performances· (e. g. egg laying. milk production,· reproductive · performance); · 11. the number of animals withdrawn prematurely from the studies and reasons for ~eh withdrawal; 12. the nature, frequency and duration of ob~ed adverse reactions; 13. oecurrence and course of any intercmrent disease; 14. all details concerning medicinal products (other than the product 1mder study) which have been administered either prior to or concmrently with the test prOduct or during the observation period; details of any interactions observed; IS. an objective discussion of the results obtained, leading to conclusions on the safety and efficacy of th~ product. D. GENERAL CONCLUSIONS General conclusions on all results of tests and trials canied out in compliance with Pans 7 and 8 shall be given. They shall contain an objective discussion of all the results obtained and lead to a· conclusion on the safety and efficacy of the immunological veterinary medicinil product. E. BmLIOGRAPHICAL REFERENCES The bibliographical references cited in the summary mentioned under Section A shall be ~inde~. 117 ·ANNEXn Pan A Repealed DireetiVes (referred to by 1\rti~le 98) Council Directive 81/851/EEC (OJNo L 3i7, 6. 11. 1981~ p. l) Council Directive 90/676/EEC (OJ L 373,31. 12. 1990, p. 15). Council Directive 90/677/EEC (OJ L 373, 31. 12. 1990, p. 26) Council Directive 92f74/EEC (OJ L 297, 13. 10. 1992, p. 12) Council Directive 93/40/EEC (OJ L 214,24. 8. 1993, p. 31) Council ~irective 81/852/EEC (OJ L 317, 6. 11. 1981, p. 16) Council Directive 87/20/EEC (OJ L 15, 17. 1. 1987, p. 34) Council. Directive 92/18/EEC (OJ L 97, 10. 4. 1992, ·p. 1) Council Directive 93/40/EEC (OJ L 214,24. 8. 1993, p. 31) 118 ~art B. ~~·_for tnmspositioo into oatioullaw '. (referred to by Article 94) Directive Directive 81/851/EEC · Directive 81/852/EEC. · Directive· 87/20/EEC Directive 90/676/EEC Directive 90/677/EEC Directive 92/18/EEC. Directive 92174/EEC Directive 93/40/EEC '. 9 October 1983 9 October 1983 l July 1987 1J~1992· 1 January 1992 1 Aprill993 31 December 1993 1 January 1995 1 January 1998 (An. I. 7) 119 This Directive Dir. 6S/6SIEEC Dir. 81/85 I !EEC Dir. 81/852/EEC Dir. 90/677/EEC Dii:. ANNEX Ill CORRELATION TABLE Art. I (I) and (2) ) · Art. I. point 3 Art. I (I) Art. 1. 1 2). - 2nd indent Art. 11 IT- Art. I I 2). 3rd and 4th indents , Art. S. 3rd suboara21'8Ph. point 8 Art. 42b Art. SOa (If 2nd SUL Art. l6 (I). Art. 18 (I), footnote Art. 2 I) Art. 2 (2), 1st indent h Art. 2 (3) Art. I (1) and {2) Art. I ~ 3) Art. I~ 4) Art. I I S)and(6) Art. I~ 7) Art. I~ 8) Art. I~ 9) Art. I (10) to (13) Art. I (14) Art. I (IS) Art. I (16) Art. 2 Art. 3 (I), 1st h sub Art. 3 (I}, 2nd sub h Art. Art. 3 (2) ; 92174/EEC. •. Art. I (2} · Art. I ' I I I I l I. Art. I (3) ·. 120 This Directive Art. 3 (3) and (4) Art. 3 (5) Art. 3 ~ 6) Art. 4 ~ I) Art. 4 ~ 2) Art. 5 Art. 6 Art. 7 Art. 8 Art. 9 Art. 10 (I) and (2), lstand 2nd. subparagraphs Art. 10 (2), 3rd subparagraph Art. 11 Art. 12 (I) Art. 12 {2) Art. 12 {3) {a) to {i) Art. 12 (3) (j) Art, 12 {3) (k) to (n) Art. 13 (I) · Dir. 65/65/EEC. Dir. 81/85 I !EEC Art. I ( 4}_ and 1SJ Art. I (I) - Art. 2 (2), 3rd indent Art. 1 (4) Dir. 81/852/EEC Dir. 90/677/BEC Dir. 92174/BEC Art. 3 Art. 4_(1 ), 1st sub_parag. raph Art. 4 (2), 1st subparagraph Art. 4 ( 1 ), 2nd subparagraph Art. 4 (I),_ 3rd sub_paragraph Art. 4 (3)f. 1st subparagraph Art. 4 (4), 1st and 2nd subparagraphs "'. Art. 4 (4), 3rd subparagraph Art. S, 1st subparagraph Art. s, 2rid subparagraph Art. S, 3rd subpargraph, points I to 9 Art. S, 3rd subpargraph, points 10, Jst subparagt¥h Art. S, 3rd subpargraph, poirits 11 to 14 Art. S, 3rd subpargraph, points I 0, 2nd subparagraph Art. 1, 1st subparagral)h Art. I (4) -·. - - Art. 2 ·(I), 2nd. subparagraph. I I. I I 1 ~ 121 Dir. 90/677/EEC Dir. 92174/EEC 'h. ,. ,. -Art. 6. M 7(1) Art. 7 (3) Art. ~. 2rid -. h sub. Art. 8 Art. 9 Art. 2 (3). I ! - - - - - - • - I This Directive Art. 13 (2) Art. 14 Art. IS (I) Art. IS (2) and (3). Art. 16 Art. 17 (1) Art. 17 (2) Art. 17 (3). Art. 18 Art. 19 Art. 20 Art. 21 Art. 22 Art. 23 Art. 24 Art. 2S Art. 26 (I) and (2) Art. 26 (3) Dir. 6S/6SIEEC Dir. 81/8S I /EEC Dir. 81/8S2/EEC Art. I, 2nd sub Art. Sa Art. 6 Art. 7 Art. 8 Art. 8a Art. 9 Art. 10 Art. Sb Art. "12 Art. IS {2) 122 Dir. 65/65/EEC This Directive Art. 27 (I) Art. 27 (2) Art. 27 (3) Art. 27 (4) and (S) Art. 28 Art. 29 Art. 30 Art. 31 (1) Art. 31 (2) Art. 31 (3) Art. 32 (I) Art. 32 {2) Art. 32(3) Art. 32 (4 Art. 33 )U1. 34 Art. 3S Art. 36 Art. 37 Art. 38 Art. 39. Dir. 811851/EEC Art 14 (I), I st subparagraph · Art. 14 ( 1). 2nd subparagraph Art. 14 (2) Art. 14 (j) and (4) Art. IS (I) Art. 13 Art. 11 Art. 16(1) Art. 16 (il Art. 16 (3) Art. 17 (3) Art. 17 (I) ~. 17-(2) Art. 17 (4) Art. 18 Art. 19 Art. 20 Art, 21 I Art. 2fln Art. 22 {2). {3) and {4) Art. 23 · Dir. 81/852/EEC Dir. 90/677/EBC Dir. 92174/EBC. - _. 123 Dir. 65/65/EEC -. This Directive Art. 40 Art. 41 Art. 42 Art. 43 Art. 44 Ait. 45 Art. 46. Art. 47 Art. 48 Art. 49 Art. so Art. 51 Art. 52 Art. 53 Art. 54 Art. ss (I) Art. ss (2) Art. ss (3) Art. 56 Art. 57 Art. 58 (I) to (3) Dir. 81/851/EEC Art. 23a Art. 23b Art. 23c Art. 22 (5) Art. 24 Art. 25 Art. 26 Art. 28{1) Art. 28 (2) Art. 28(3)- Art. 27 Art. 27a Art. 29. Art. 31 Art. 32 M·. ~0 (1 ), 1st and 2nd hs su" Art. 30 (1). 3rd subpara~h Art. 30 (2). Art. 33 Art. 43 Dir. 81/852/EEC Dir. 90/677/EEC · ' Dir. 92174/EBC. : • 0 ·-. : '. Art. 3. '. ~ : 124 Dir. 65/65/EEC This Directive Art. 58 (4) Art. 59 I) Art. 59 2) Art. 59 3) Art. 60 Art. 61 (I) Art. 61 (2)' Art. 61 3) Art. 62 Art. 63 Art. 64 I) Art. 64 ~2). Art. 65 ~ I) Art. 65 ~ 2). (3) and (4) Art. 66 Art. 67 Art. 68 Art. 69 Art. 70 Art. 71 Art. 72 Art. 73 - Dir. 81/851/EEC Art. 47 Art. 44 Art. 45 Art. 47 Art. 46 Art. 48(1) Art. 48 (2) Art. 48 (3) Art. 49. 1st paragraph Art. 50 , Art. SOa(l~ 1st and 3rd subparagraphs Art. SOa (2), (3) and ( 4}_ Art. SOb Art. 4· (3 ), 3rd subparagraph Art. I (5) Art. SOc Art. 4 (S) Art. 42e Art. 42a Dir. 81/852/EEC Dir. 90/677/EEC. Dir. 92!14/BEC ~ \. Art. 2 (2} Art. 7(2)- Art. 4 - L______ 12S. This Directive Art. 74 Art. 15 Art. 76 Art. 77 Art. 78 Art. 79 Art. 80 (I) Art. 80 (2) Art. 80 {3) Art. 81 {1) Art. 81 (2) Art. 82. Art. 83 Art. 84 Art. 8S Art. 86 Art. 87 Art. 88 Art. 89 Art. 90 Art. 91·. Art. 92 Dir. 65/65/EEC. Dir. 81/851/EEC Art. 42c Art. 42d Art. 42f Art. 422 Art. 42h Art. 42i Art. 34, 1st and 2nd subparagraphs · Art. 34, 3rd subparagraph Art. 35. Art. 36 Art. 37 Art. 38 Art. 38a Art. 42_i Art. 42k Art. 39. Dir. 81/852/EEC Dir. 90/677/EEC Dir. 92r/4/EBC '. Art. 3 (I). Art. 3 (2) Art. 3 (3) ' I ~ ~ r. I Art. 4, lst. sub paragraph Art. 2b Art. 2a '. 126 Art. 5. - -. - ~ - , - •· ~- Dir. 65/65/EEC I Dir. 81/85 I !EEC Art. 42 Dir. 81/852/EEC · Dir. 90/677/EEC. Dir. 92!74/EBC. 'Ibis Directive Art. 93 Art. 94. Art. 95 Art. 96 Art. 91 Art. 98 Art. 99 'Art. lOO Annex I Annexll Annex Ill - - - - - Art. 24a Art. 40 and 41 Art. 4 (2), 2nd subparagraph - - - - - - - - Annex - - - - - - - 127