2001L0082 — EN — 30.04.2004 — 001.001 — 1
This document is meant purely as a documentation tool and the institutions do not assume any liability for its contents
►B DIRECTIVE 2001/82/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
of 6 November 2001
on the Community code relating to veterinary medicinal products
(OJ L 311, 28.11.2001, p. 1)
Amended by:
Official Journal
No page date
►M1 Directive 2004/28/EC of the European Parliament and of the Council of
31 March 2004L 136 58 30.4.2004
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DIRECTIVE 2001/82/EC OF THE EUROPEAN PARLIAMENT
AND OF THE COUNCIL
of 6 November 2001
on the Community code relating to veterinary medicinal products
THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE
EUROPEAN UNION,
Having regard to the Treaty establishing the European Community, and
in particular Article 95 thereof,
Having regard to the proposal from the Commission,
Having regard to the opinion of the Economic and Social
Committee (1),
Acting in accordance with the procedure laid down in Article 251 of
the Treaty (2),
Whereas:
(1) Council Directive 81/851/EEC of 28 September 1981 on the
approximation of the laws of the Member States relating toveterinary medicinal products (
3), 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 ofveterinary medicinal products (
4), Council Directive 90/677/EEC
of 13 December 1990 extending the scope of Directive 81/851/EEC on the approximation of the laws of the Member Statesrelating to veterinary medicinal products and laying down addi-
tional provisions for immunological veterinary medicinal
products (
5), and Council Directive 92/74/EEC of 22 September
1992 widening the scope of Directive 81/851/EEC on theapproximation of provisions laid down by law, regulation oradministrative action relating to veterinary medicinal products
and laying down additional provisions on homeopathic veter-
inary medicinal products (
6) have been frequently and
substantially amended; in the interests of clarity and rationality,the said Directives should therefore be codified by assemblingthem in a single text.
(2) The primary purpose of any rules for the production and distri-bution of veterinary medicinal products must be the safeguardingof public health.
(3) However, this objective must be achieved by means which willnot hinder the development of industry and trade in medicinal
products within the Community.
(4) In so far as the Member States already have certain provisions
laid down by law, regulation or administrative action governingveterinary medicinal products, such provisions differ in essentialprinciples. This results in the hindering of trade in medicinalproducts within the Community, thereby directly affecting thefunctioning of the internal market.
(5) Such hindrances must, accordingly, be removed; whereas thisentails approximation of the relevant provisions.
(6) It is necessary from the point of view of public health and thefree movement of veterinary medicinal products for the compe-2001L0082 — EN — 30.04.2004 — 001.001 — 2
(1) OJ C 75, 15.3.2000, p. 11.
(2) Opinion of the European Parliament of 3 July 2001 (not yet published in the
Official Journal) and Council Decision of 27 September 2001.
(3) OJ L 317, 6.11.1981, p. 1. Directive as last amended by Commission Direc-
tive 2000/37/EC (OJ L 139, 10.6.2000, p. 25).
(4) OJ L 317, 6.11.1981, p. 16. Directive as last amended by Commission
Directive 1999/104/EC (OJ L 3, 6.1.2000, p. 18).
(5) OJ L 373, 31.12.1990, p. 26.
(6) OJ L 297, 13.10.1992, p. 12.
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tent authorities to have at their disposal all useful information on
authorized veterinary medicinal products in the form of approvedsummaries of the characteristics of products.
(7) With the exception of those medicinal products which aresubject to the centralised Community authorization procedureestablished by Council Regulation (EEC) No 2309/93 of 22July 1993 laying down Community procedures for the authoriza-tion and supervision of medicinal products for human and
veterinary use and establishing a European Agency for the
Evaluation of Medicinal Products (
1), a marketing authorization
in one Member State ought to be recognized by the competentauthority of the other Member States unless there are seriousgrounds for supposing that the authorization of the veterinary
medicinal product concerned may present a risk to human or
animal health, or to the environment; in the event of a disagree-ment between Member States about the quality, the safety or theefficacy of a medicinal product, a scientific evaluation of thematter should be undertaken at a Community level, lead to asingle decision on the area of disagreement, binding on the
Member States concerned. This Decision should be adopted by
a rapid procedure ensuring close cooperation between theCommission and the Member States.
(8) For this purpose, a Committee for Veterinary Medicinal Productsshould be set up in accordance with the European Agency for
the Evaluation of Medicinal Products laid down in the aforemen-
tioned Regulation (EEC) No 2309/93.
(9) This Directive is only one stage in the achievement of the aim offreedom of movement of veterinary medicinal products.However, for this purpose, new measures will prove necessary,in the light of experience gained — especially within the
Committee for Veterinary Medicinal Products — for the removal
of the remaining barriers to freedom of movement.
(10) Medicated feedingstuffs do not come within the scope of thisDirective. However, it is necessary, for both public health andeconomic reasons, to prohibit the use of unauthorized medicinal
products in the manufacture of medicated feedingstuffs.
(11) The concepts of harmfulness and therapeutic efficacy can be
examined only in relation to one another and have only a rela-tive significance, depending on the progress of scientificknowledge and the use for which the medicinal product is
intended. The particulars and documents which must accompany
an application for marketing authorization must demonstrate thatpotential hazards are outweighed by the benefits due to efficacy.Failing such demonstration, the application must be rejected.
(12) Marketing authorization should be refused where a medicinalproduct lacks therapeutic effect or where there is insufficient
proof of such effect. The concept of therapeutic effect must be
understood as being the effect promised by the manufacturers.
(13) Such marketing authorization should also be refused where thewithdrawal period indicated is not long enough to eliminatehealth hazards arising from residues.
(14) Before an authorization to market an immunological veterinarymedicinal product can be granted, the manufacturer must demon-strate his ability to attain batch-to-batch consistency.
(15) The competent authorities should also be empowered to prohibitthe use of an immunological veterinary medicinal product when
the immunological responses of the treated animal will interfere
with a national or Community programme for the diagnosis,eradication or control of animal disease.2001L0082 — EN — 30.04.2004 — 001.001 — 3
(1) OJ L 214, 24.8.1993, p. 1. Regulation as amended by Commission Regula-
tion (EC) No 649/98 (OJ L 88, 24.3.1998, p. 7).
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(16) It is desirable in the first instance to provide users of homeo-
pathic medicinal products with a very clear indication of their
homeopathic character and with sufficient guarantees of theirquality and safety.
(17) The rules relating to the manufacture, control and inspection ofhomeopathic veterinary medicinal products must be harmonisedto permit the circulation throughout the Community of medicinalproducts which are safe and of good quality.
(18) Having regard to the particular characteristics of these homeo-pathic veterinary medicinal products, such as the very low levelof active principles they contain and the difficulty of applying to
them the conventional statistical methods relating to clinical
trials, it is desirable to provide a special, simplified registrationprocedure for those traditional homeopathic medicinal productswhich are placed on the market without therapeutic indicationsin a pharmaceutical form and dosage which do not present a
risk for the animal.
(19) The usual rules governing the authorization to market veterinarymedicinal products must be applied to homeopathic veterinary
medicinal products marketed with therapeutic indications or ina form which may present risks which must be balanced againstthe desired therapeutic effect. Member States should be able toapply particular rules for the evaluation of the results of testsand 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) In order to better protect human and animal health and avoid anyunnecessary duplication of effort during the examination ofapplication for a marketing authorization, Member States shouldsystematically prepare assessment reports in respect of eachveterinary medicinal product which is authorized by them, andexchange the reports upon request. Furthermore, a Member State
should be able to suspend the examination of an application for
authorization to place a veterinary medicinal product on themarket which is currently under active consideration in anotherMember State with a view to recognizing the decision reachedby the latter Member State.
(21) In order to facilitate the movement of veterinary medicinalproducts and to prevent the checks carried out in one Member
State from being repeated in another, minimum requirements
for manufacture and imports from third countries, and the grantof corresponding authorizations, should be applied to veterinarymedicinal products.
(22) The quality of veterinary medicinal products manufacturedwithin the Community should be guaranteed by requiringcompliance with the principles of good manufacturing practicefor medicinal products irrespective of the final destination of
the medicinal products.
(23) Measures should also be taken to ensure that distributors ofveterinary medicinal products are authorized by Member States
and maintain adequate records.
(24) Standards and protocols for the performance of tests and trialson veterinary medicinal products are an effective means ofcontrol of these products and, hence, of protecting public healthand can facilitate the movement of these products by layingdown uniform rules applicable to tests and the compilation of
dossiers, allowing the competent authorities to arrive at their
decisions on the basis of uniform tests and by reference touniform criteria, and therefore helping to obviate differences inevaluation.
(25) It is advisable to stipulate more precisely the cases in which theresults of pharmacological and toxicological tests or clinicaltrials do not have to be provided with a view to obtainingauthorization for a veterinary medicinal product which is essen-2001L0082 — EN — 30.04.2004 — 001.001 — 4
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tially similar to an innovative product, while ensuring that inno-
vative forms are not placed at a disadvantage. However, thereare reasons of public policy for not repeating tests carried out
on animals without overriding cause.
(26) Following the establishment of the internal 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 thatthe necessary controls are carried out in the exporting country.
(27) In order to ensure the continued safety of veterinary medicinal
products in use, it is necessary to ensure that pharmacovigilance
systems in the Community are continually adapted to takeaccount of scientific and technical progress.
(28) For public health protection, relevant data on adverse effects in
humans related to the use of veterinary medicines should be
collected and evaluated.
(29) The pharmacovigilance systems should consider the availabledata on lack of efficacy.
(30) In addition, collection of information on adverse reactions due tooff-label use, investigations of the validity of the withdrawalperiod and on potential environmental problems may contributeto improve regular monitoring of good usage of veterinary medi-
cines.
(31) It is necessary to take account of changes arising as a result of
international harmonisation of definitions, terminology and tech-nological developments in the field of pharmacovigilance.
(32) The increasing use of electronic means of communication ofinformation on adverse reactions to veterinary medicinalproducts marketed in the Community is intended to allow asingle reporting point for adverse reactions, at the same time
ensuring that this information is shared with the competent
authorities in all Member States.
(33) It is the interest of the Community to ensure that the veterinarypharmacovigilance systems for centrally authorised medicinal
products and those authorised by other procedures are consistent.
(34) Holders of marketing authorisations should be proactively
responsible for ongoing pharmacovigilance of the veterinarymedicinal products they place on the market.
(35) The measures necessary for the implementation of this Directiveshould be adopted in accordance with Council Decision 1999/468/EC of 28 June 1999 laying down the procedures for theexercise of implementing powers conferred on the Commis-
sion (
1).
(36) In order to improve the protection of public health, it is neces-
sary to specify that foodstuffs for human consumption may notbe taken from animals which have been used in clinical trials
of veterinary medicinal products unless a maximum residue limit
has been laid down for residues of the veterinary medicinalproduct concerned in accordance with the provisions of CouncilRegulation (EEC) No 2377/90 of 26 June 1990 laying down aCommunity procedure for the establishment of maximum residuelimits of veterinary medicinal products in foodstuffs of animal
origin (
2).
(37) The Commission should be empowered to adopt the changes
necessary in order to adapt Annex I to scientific and technicalprogress.2001L0082 — EN — 30.04.2004 — 001.001 — 5
(1) OJ L 184, 17.7.1999, p. 23.
(2) OJ L 224, 18.8.1990, p. 1. Regulation as last amended by Commission
Regulation (EC) No 1274/2001 (OJ L 175, 28.6.2001, p. 14).
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(38) This Directive should be without prejudice to the obligations of
the Member States concerning the time-limits for transposition
of the Directives set out in Annex II, Part B,
HAVE ADOPTED THIS DIRECTIVE:
TITLE I
DEFINITIONS
Article 1
For the purposes of this Directive, the following terms shall bear the
following meanings:
2.Veterinary medicinal product:
(a) any substance or combination of substances presented as having
properties for treating or preventing disease in animals; or
(b) any substance or combination of substances which may be used in
or administered to animals with a view either to restoring,correcting or modifying physiological functions by exerting a phar-macological, immunological or metabolic action, or to making amedical diagnosis.
4.Substance:
Any matter irrespective of origin which may be:
— human, e.g.
human blood and human blood products;
— animal, e.g.
micro-organisms, whole animals, parts of organs, animal secretions,
toxins, extracts, blood products;
— vegetable, e.g.
micro-organisms, plants, parts of plants, vegetable secretions,
extracts;
— chemical, e.g.
elements, naturally occurring chemical materials and chemical
products obtained by chemical change or synthesis.
5.Pre-mix for medicated feedingstuffs:
Any veterinary medicinal product prepared in advance with a view to
the subsequent manufacture of medicated feedingstuffs.
6.Medicated feedingstuffs:
Any mixture of a veterinary medicinal product or products and feed or
feeds which is ready prepared for marketing and intended to be fed toanimals without further processing, because of its curative or preven-tive properties or other properties as a medicinal product covered bypoint 2.
7.Immunological veterinary medicinal product:
A veterinary medicinal product administered to animals in order to
produce active or passive immunity or to diagnose the state of immu-
nity.
8.Homeopathic veterinary medicinal product:
Any veterinary medicinal product prepared from substances called
homeopathic stocks in accordance with a homeopathic manufacturingprocedure described by the European Pharmacopoeia or, in the absence2001L0082 — EN — 30.04.2004 — 001.001 — 6
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thereof, by the pharmacopoeias currently used officially in Member
States. A homeopathic veterinary medicinal product may contain anumber of principles.
9.Withdrawal period:
The period necessary between the last administration of the veterinary
medicinal product to animals, under normal conditions of use and in
accordance with the provisions of this Directive, and the production of
foodstuffs from such animals, in order to protect public health byensuring that such foodstuffs do not contain residues in quantities inexcess of the maximum residue limits for active substances laid downpursuant to Regulation (EEC) No 2377/90.
10. Adverse reaction:
A reaction to a veterinary medicinal product which is harmful and
unintended and which occurs at doses normally used in animals forthe prophylaxis, diagnosis or treatment of disease or to restore, correct
or modify a physiological function.
11. Human adverse reaction:
A reaction which is noxious and unintended and which occurs in a
human being following exposure to a veterinary medicine.
12. Serious adverse reaction:
An adverse reaction which results in death, is life-threatening, results in
significant disability or incapacity, is a congenital anomaly/birth defect,or which results in permanent or prolonged signs in the animals treated.
13. Unexpected adverse reaction:
An adverse reaction, the nature, severity or outcome of which is not
consistent with the summary of the product characteristics.
14. Periodic safety update reports:
The periodical reports containing the records referred to in Article 75.
15. Post-marketing surveillance studies:
Pharmacoepidemiological study or a clinical trial carried out in accor-
dance with the terms of the marketing authorization, conducted with
the aim of identifying and investigating a safety hazard relating to an
authorized veterinary medicinal product.
16. Off-label use:
The use of a veterinary medicinal product that is not in accordance
with the summary of the product characteristics, including the misuseand serious abuse of the product.
17. Wholesale dealing in veterinary medicinal products:
Any activity which includes the purchase, sale, import, export, or any
other commercial transaction in veterinary medicinal products, whetheror not for profit, except for:
— the supply by a manufacturer of veterinary medicinal products
manufactured by himself,
— retail supplies of veterinary medicinal products by persons entitled
to carry out such supplies in accordance with Article 66.
17a. Representative of the marketing authorisation holder:
The person, commonly known as local representative, designated by
the marketing authorisation holder to represent him in the MemberState concerned.2001L0082 — EN — 30.04.2004 — 001.001 — 7
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18. Agency:
The European Medicines Agency established by Regulation (EC)
No 726/2004 (1).
19. Risks relating to use of the product:
— any risk relating to the quality, safety and efficacy of the veterinary
medicinal products as regards animal or human health;
— any risk of undesirable effects on the environment.
20. Risk/benefit balance:
An evaluation of the positive therapeutic effects of the veterinary
medicinal product in relation to the risks as defined above.
21. Veterinary prescription:
Any prescription for a veterinary medicinal product issued by a profes-
sional person qualified to do so in accordance with applicable nationallaw.
22. Name of veterinary medicinal product:
The name, which may be either an invented name not liable to confu-
sion with the common name, or a common or scientific name
accompanied by a trademark or the name of the marketing authorisa-tion holder.
23. Common name:
The international non-proprietary name recommended by the World
Health Organisation, or, if one does not exist, the usual common name.
24. Strength:
The content of active substances, expressed quantitatively per dosage
unit, per unit of volume or weight according to the dosage form.
25. Immediate packaging:
The container or any other form of packaging that is in direct contact
with the medicinal product.
26. Outer packaging:
The packaging into which is placed the immediate packaging.
27. Labelling:
Information on the immediate or outer packaging.
28. Package leaflet:
The leaflet containing information for the user that accompanies the
medicinal product.
TITLE II
SCOPE
Article 2
1. This Directive shall apply to veterinary medicinal products,
including pre-mixes for medicated feedingstuffs, intended to be placedon the market in Member States and prepared industrially or by amethod involving an industrial process.2001L0082 — EN — 30.04.2004 — 001.001 — 8
(1) OJ L 136, 30.4.2004, p. 1.▼B
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2. In cases of doubt, where, taking into account all its characteris-
tics, a product may fall within the definition of a ‘veterinarymedicinal product’ and within the definition of a product covered by
other Community legislation, the provisions of this Directive shall
apply.
3. Notwithstanding paragraph 1, this Directive shall also apply to
active substances used as starting materials to the extent set out in Arti-cles 50, 50a, 51 and 80 and additionally to certain substances that may
be used as veterinary medicinal products that have anabolic, anti-infec-
tious, anti-parasitic, anti-inflammatory, hormonal or psychotropicproperties to the extent set out in Article 68.
Article 3
1. This Directive shall not apply to:
(a) medicated feedingstuffs as defined in Council Directive 90/167/
EEC of 26 March 1990 laying down the conditions governing the
preparation, placing on the market and use of medicated feeding-
stuffs in the Community (
1);
(b) inactivated immunological veterinary medicinal products which are
manufactured from pathogens and antigens obtained from an
animal or animals from a holding and used for the treatment ofthat animal or the animals of that holding in the same locality;
(c) veterinary medicinal products based on radio-active isotopes;
(d) any additives covered by Council Directive 70/524/EEC of
23 November 1970 concerning additives in feedingstuffs (
2) where
they are incorporated in animal feedingstuffs and supplementary
animal feedingstuffs in accordance with that Directive; and
(e) without prejudice to Article 95, medicinal products for veterinary
use intended for research and development trials.
However, medicated feedingstuffs referred to in subparagraph (a) may
be prepared only from pre-mixes that have been authorised under this
Directive.
2. Except for the provisions on the possession, prescription, dispen-
sing and administration of veterinary medicinal products, this Directiveshall not apply to:
(a) any medicinal product prepared in a pharmacy in accordance with a
veterinary prescription for an individual animal or a small group of
animals, commonly known as the magistral formula; and
(b) any medicinal product prepared in a pharmacy in accordance with
the prescriptions of a pharmacopoeia and intended to be supplied
directly to the end-user, commonly known as the officinal formula.
Article 4
1. Member States may provide that this Directive shall not apply to
non-inactivated immunological veterinary medicinal products which are
manufactured from pathogens and antigens obtained from an animal or
animals from a holding and used for the treatment of that animal or theanimals of that holding in the same locality.
2. In the case of veterinary medicinal products intended solely for
aquarium fish, cage birds, homing pigeons, terrarium animals, small
rodents, and ferrets and rabbits kept exclusively as pets, Member Statesmay permit exemptions, in their territory, from the provisions in Arti-cles 5 to 8, provided that such products do not contain substances theuse of which requires veterinary control and that all possible measuresare taken to prevent unauthorised use of the products for other animals.2001L0082 — EN — 30.04.2004 — 001.001 — 9
(1) OJ L 92, 7.4.1990, p. 42.
(2) OJ L 270, 14.12.1970, p. 1. Directive as last amended by Regulation (EC)
No 1756/2002 (OJ L 265, 3.10.2002, p. 1).▼B
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TITLE III
MARKETING
CHAPTER 1
Marketing authorization
Article 5
1. No veterinary medicinal product may be placed on the market of
a Member State unless a marketing authorisation has been granted bythe competent authorities of that Member State in accordance with thisDirective or a marketing authorisation has been granted in accordance
with Regulation (EC) No 726/2004.
When a veterinary medicinal product has been granted an initial
authorisation in accordance with the first subparagraph, any additional
species, strengths, pharmaceutical forms, administration routes, presen-
tations, as well as any variations and extensions, shall also be grantedan authorisation in accordance with the first subparagraph or beincluded in the initial marketing authorisation. All these marketingauthorisations shall be considered as belonging to the same globalmarketing authorisation, in particular for the purpose of the application
of Article 13(1).
2. The marketing authorisation holder shall be responsible for the
marketing of the medicinal product. The designation of a representative
shall not relieve the marketing authorisation holder of his legal respon-
sibility.
Article 6
1. A veterinary medicinal product may not be the subject of a
marketing authorisation for the purpose of administering it to one ormore food-producing species unless the pharmacologically active
substances which it contains appear in Annexes I, II or III to Regula-
tion (EEC) No 2377/90.
2. If an amendment to the Annexes to Regulation (EEC) No 2377/90
so warrants, the marketing authorisation holder or, where appropriate,
the competent authorities shall take all necessary measures to amendor revoke the marketing authorisation within 60 days of the date onwhich the amendment to the Annexes to that Regulation was publishedin the Official Journal of the European Union .
3. By way of derogation from paragraph 1, a veterinary medicinal
product containing pharmacologically active substances not includedin Annexes I, II or III to Regulation (EEC) No 2377/90 may beauthorised for particular animals of the equidae family that have been
declared, in accordance with Commission Decision 93/623/EEC of
20 October 1993 establishing the identification document (passport)accompanying registered equidae (
1) and Commission Decision 2000/
68/EC of 22 December 1999 amending Decision 93/623/EEC andestablishing the identification of equidae for breeding and produc-
tion (
2), as not being intended for slaughter for human consumption.
Such veterinary medicinal products shall neither include activesubstances that appear in Annex IV to Regulation (EEC) No 2377/90nor be intended for use in the treatment of conditions, as detailed inthe authorised Summary of Product Characteristics, for which a veter-inary medicinal product is authorised for animals of the equidae family.2001L0082 — EN — 30.04.2004 — 001.001 — 10
(1) OJ L 298, 3.12.1993, p. 45. Decision as amended by Commission Decision
2000/68/EC (OJ L 23, 28.1.2000, p. 72).
(2) OJ L 23, 28.1.2000, p. 72.▼M1
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Article 7
Where the health situation so requires, a Member State may authorise
the marketing or administration to animals of veterinary medicinalproducts which have been authorized by another Member State in
accordance with this Directive.
Article 8
In the event of serious epizootic diseases, Member States may provi-
sionally allow the use of immunological veterinary medicinal products
without a marketing authorisation, in the absence of a suitable medic-
inal product and after informing the Commission of the detailedconditions of use.
The Commission may avail itself of the option set out in the first para-
graph when explicit provision is made for that option underCommunity rules concerning certain serious epizootic diseases.
If an animal is being imported from, or exported to, a third country and
is thereby subject to specific binding health rules, a Member State maypermit the use, for the animal in question, of an immunological veter-
inary medicinal product that is not covered by a marketing
authorisation in the Member State in question but is authorised underthe legislation of the third country. Member States shall take all appro-priate measures concerning the supervision of the importation and theuse of such immunological products.
Article 9
No veterinary medicinal product may be administered to animals unless
the marketing authorization has been issued, except for the tests ofveterinary medicinal products referred to in Article 12(3)(j) which
have been accepted by the competent national authorities, following
notification or authorization, in accordance with the national rules inforce.
Article 10
1. Member States shall take the necessary measures to ensure that, if
there is no authorised veterinary medicinal product in a Member Statefor a condition affecting a non food-producing species, by way ofexception, the veterinarian responsible may, under his/her directpersonal responsibility and in particular to avoid causing unacceptablesuffering, treat the animal concerned with:
(a) a veterinary medicinal product authorised in the Member State
concerned under this Directive or under Regulation (EC) No 726/
2004 for use with another animal species, or for another conditionin the same species; or
(b) if there is no product as referred to in point (a), either:
(i) a medicinal product authorised for human use in the Member
State concerned in accordance with Directive 2001/83/EC of
the European Parliament and of the Council or under Regula-tion (EC) No 726/2004, or
(ii) in accordance with specific national measures, a veterinary
medicinal product authorised in another Member State inaccordance with this Directive for use in the same species orin another species for the condition in question or for anothercondition; or
(c) if there is no product as referred to in subparagraph (b), and within
the limits of the law of the Member State concerned, a veterinarymedicinal product prepared extemporaneously by a personauthorised to do so under national legislation in accordance withthe terms of a veterinary prescription.2001L0082 — EN — 30.04.2004 — 001.001 — 11
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The veterinarian may administer the medicinal product personally or
allow another person to do so under the veterinarian's responsibility.
2. By way of derogation from Article 11, the provisions of para-
graph 1 of this Article shall also apply to the treatment by aveterinarian of an animal belonging to the equidae family provided
that it has been declared, in accordance with Commission Decisions
93/623/EEC and 2000/68/EC, as not being intended for slaughter forhuman consumption.
3. By way of derogation from Article 11, and in accordance with the
procedure referred to in Article 89(2), the Commission shall establish alist of substances essential for the treatment of equidae and for whichthe withdrawal period shall be not less than six months according tothe control mechanisms laid down in Commission Decisions 93/623/EEC and 2000/68/EC.
Article 11
1. Member States shall take the necessary measures to ensure that, if
there is no authorised veterinary medicinal product in a Member Statefor a condition affecting a food-producing species, by way of excep-tion, the veterinarian responsible may, under his direct personalresponsibility and in particular to avoid causing unacceptable suffering,treat the animals concerned on a particular holding with:
(a) a veterinary medicinal product authorised in the Member State
concerned under this Directive or under Regulation (EC) No 726/2004 for use with another animal species, or for another condition
in the same species; or
(b) if there is no product as referred to in point (a), either:
(i) a medicinal product for human use authorised in the Member
State concerned in accordance with Directive 2001/83/EC orunder Regulation (EC) No 726/2004, or
(ii) a veterinary medicinal product authorised in another Member
State in accordance with this Directive for use in the samespecies or in another food-producing species for the conditionin question or for another condition; or
(c) if there is no product as referred to in subparagraph (b), and within
the limits of the law of the Member State concerned, a veterinarymedicinal product prepared extemporaneously by a person
authorised to do so under national legislation in accordance with
the terms of a veterinary prescription.
The veterinarian may administer the medicinal product personally or
allow another person to do so under the veterinarian's responsibility.
2. Paragraph 1 shall apply provided that pharmacologically active
substances included in the medicinal product are listed in Annex I, II
or III to Regulation (EEC) No 2377/90, and that the veterinarian speci-fies an appropriate withdrawal period.
Unless the medicinal product used indicates a withdrawal period for the
species concerned, the specified withdrawal period shall not be lessthan:
— 7 days for eggs,
— 7 days for milk,
— 28 days for meat from poultry and mammals including fat and
offal,
— 500 degree-days for fish meat.
However, these specific withdrawal periods may be modified in accor-
dance with the procedure referred to in Article 89(2).
3. With regard to homeopathic veterinary medicinal products in
which active principles figure in Annex II to Regulation (EEC)No 2377/90, the withdrawal period referred to in the second subpara-graph of paragraph 2 shall be reduced to zero.2001L0082 — EN — 30.04.2004 — 001.001 — 12
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4. When a veterinarian has recourse to the provisions of paragraphs
1 and 2 of this Article, he shall keep adequate records of the date ofexamination of the animals, details of the owner, the number of
animals treated, the diagnosis, the medicinal products prescribed, the
doses administered, the duration of treatment and the withdrawalperiods recommended, and shall make these records available forinspection by the competent authorities for a period of at least fiveyears.
5. Without prejudice to the other provisions of this Directive,
Member States shall take all necessary measures concerning the import,distribution, dispensing of and information on the medicinal productswhich they permit for administration to food-producing animals inaccordance with paragraph 1(b)(ii).
Article 12
1. For the purposes of obtaining a marketing authorisation in respect
of a veterinary medicinal product, otherwise than under the procedureestablished by Regulation (EC) No 726/2004, an application shall be
lodged with the competent authority of the Member State concerned.
In the case of veterinary medicinal products which are intended for one
or more food-producing species but whose pharmacologically activesubstances have not yet been included, for the species in question, in
Annexes I, II or III to Regulation (EEC) No 2377/90, a marketing
authorisation may not be applied for until after a valid application hasbeen made for the establishment of maximum residue limits in accor-dance with that Regulation. At least six months shall elapse between avalid application for the establishment of maximum residue limits andan application for a marketing authorisation.
However, in the case of veterinary medicinal products referred to in
Article 6(3), a marketing authorisation may be applied for without avalid application in accordance with Regulation (EEC) No 2377/90.All the scientific documentation necessary for the demonstration of
the quality, safety and efficacy of the veterinary medicinal product, as
provided for in paragraph 3, shall be submitted.
2. A marketing authorisation may only be granted to an applicant
established in the Community.
3. The application for marketing authorisation shall include all the
administrative information and scientific documentation necessary fordemonstrating the quality, safety and efficacy of the veterinary medic-inal product in question. The file shall be submitted in accordance withAnnex I and shall contain, in particular, the following information:
(a) name or business name and permanent address or registered place
of business of the person responsible for placing the product onthe market and, if different, of the manufacturer or manufacturersinvolved and of the sites of manufacture;
(b) name of veterinary medicinal product;
(c) qualitative and quantitative particulars of all the constituents of the
veterinary medicinal product, including its international non-proprietary name (INN) recommended by the WHO, where anINN exists, or its chemical name;
(d) description of the method of manufacture;
(e) therapeutic indications, contra-indications and adverse reactions;
(f) dosage for the various species of animal for which the veterinary
medicinal product is intended, its pharmaceutical form, methodand route of administration and proposed shelf life;
(g) reasons for any precautionary and safety measures to be taken
when storing the veterinary medicinal product, administering it toanimals and disposing of waste, together with an indication ofpotential risks that the veterinary medicinal product might pose tothe environment, to human and animal health and to plants;
(h) indication of the withdrawal period in the case of medicinal
products intended for food-producing species;2001L0082 — EN — 30.04.2004 — 001.001 — 13
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(i) description of the testing methods employed by the manufacturer;
(j) results of:
— pharmaceutical (physico-chemical, biological or microbiolo-
gical) tests,
— safety tests and residue tests,
— pre-clinical and clinical trials;
— tests assessing the potential risks posed by the medicinal
product for the environment. This impact shall be studied andconsideration shall be given on a case-by-case basis to specificprovisions seeking to limit it.
(k) a detailed description of the pharmacovigilance system and, where
appropriate, the risk management system that the applicant will putin place;
(l) a summary in accordance with Article 14 of the product character-
istics, a mock-up of the immediate packaging and the outerpackaging of the veterinary medicinal product, together with thepackage leaflet, in accordance with Articles 58 to 61;
(m) a document showing that the manufacturer is authorised in his own
country to produce veterinary medicinal products;
(n) copies of any marketing authorisation 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 authorisation submitted in accordance with thisDirective is under examination. Copies of the summary of theproduct characteristics proposed by the applicant in accordancewith 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 authori-sation, whether in the Community or a third country and thereasons for that decision. All this information shall be updated ona regular basis;
(o) proof that the applicant has the services of a qualified person
responsible for pharmacovigilance and has the necessary means
for the notification of any adverse reaction suspected of occurring
either in the Community or in a third country;
(p) in the case of veterinary medicinal products intended for one or
more food-producing species and containing one or more pharma-cologically active substances not yet included, for the species inquestion, in Annexes I, II or III to Regulation (EEC) No 2377/90,
a document certifying that a valid application for the establishment
of maximum residue limits has been submitted to the Agency inaccordance with the aforementioned Regulation.
The documents and particulars relating to the results of the tests
referred to in point (j) of the first subparagraph shall be accompaniedby detailed and critical summaries, drawn up as specified in Article 15.
Article 13
1. By way of derogation from point (j) of the first subparagraph of
Article 12(3), and without prejudice to the law relating to the protec-tion of industrial and commercial property, the applicant shall not be
required to provide the results of the safety and residue tests or of the
pre-clinical and clinical trials if he can demonstrate that the medicinalproduct is a generic of a reference medicinal product which is or hasbeen authorised under Article 5 for not less than eight years in aMember State or the Community.
A generic veterinary medicinal product authorised pursuant to this
provision shall not be placed on the market until ten years have elapsedfrom the initial authorisation of the reference product.
The first subparagraph shall also apply when the reference medicinal
product was not authorised in the Member State in which the applica-tion for the generic medicinal product is submitted. In this case, theapplicant shall indicate in the application the Member State in which2001L0082 — EN — 30.04.2004 — 001.001 — 14
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the reference medicinal product is or has been authorised. At the
request of the competent authority of the Member State in which theapplication is submitted, the competent authority of the other Member
State shall transmit, within a period of one month, confirmation that
the reference medicinal product is or has been authorised togetherwith the full composition of the reference product and if necessaryother relevant documentation.
However, the ten-year period provided for in the second subparagraph
shall be extended to 13 years in the case of veterinary medicinal
products for fish or bees or other species designated in accordance
with the procedure referred to in Article 89(2).
2. For the purposes of this Article:
(a) ‘reference medicinal product’ shall mean a product authorised
within the meaning of Article 5 in accordance with the provisionsof Article 12;
(b) ‘generic medicinal product’ shall mean a medicinal product which
has the same qualitative and quantitative composition in activesubstances and the same pharmaceutical form as the referencemedicinal product, and whose bioequivalence with the reference
medicinal product has been demonstrated by appropriate bioavail-
ability studies. The different salts, esters, ethers, isomers, mixturesof isomers, complexes or derivatives of an active substance shall beconsidered to be the same active substance, unless they differsignificantly in properties with regard to safety and/or efficacy. Insuch cases, additional information intended to provide proof of the
safety and/or efficacy of the various salts, esters or derivatives of
an authorised active substance must be supplied by the applicant.The various immediate-release oral pharmaceutical forms shall beconsidered to be one and the same pharmaceutical form. Bioavail-ability studies need not be required of the applicant if he candemonstrate that the generic medicinal product meets the relevant
criteria as defined in the appropriate detailed guidelines.
3. In cases where the veterinary medicinal product does not fall
under the definition of a generic medicinal product set out in paragraph2(b) or where bio-equivalence cannot be demonstrated through bioa-vailability studies or in the case of changes to the active substance(s),therapeutic indications, strength, pharmaceutical form or route of
administration vis-à-vis the reference medicinal product, the results of
the appropriate safety and residue tests and pre-clinical tests or clinicaltrials shall be provided.
4. Where a biological veterinary medicinal product which is similar
to a reference biological veterinary medicinal product does not meetthe conditions in the definition of generic medicinal products, owing
to, in particular, differences relating to raw materials or in manufac-
turing processes of the biological veterinary medicinal product and thereference biological veterinary medicinal product, the results of appro-priate pre-clinical tests or clinical trials relating to these conditionsmust be provided. The type and quantity of supplementary data to be
provided must comply with the relevant criteria stated in Annex I and
the related detailed guidelines. The results of other tests and trials fromthe reference medicinal product's dossier shall not be provided.
5. In the case of veterinary medicinal products intended for one or
more food-producing species and containing a new active substancethat has not been authorised in the Community by 30 April 2004 theten-year period provided for in the second subparagraph of paragraph
1 shall be extended by one year for each extension of the marketing
authorisation to another food-producing species, if it is authorisedwithin the five years following the granting of the initial marketingauthorisation.
This period shall not, however, exceed a total of 13 years, for a
marketing authorisation for four or more food-producing species.2001L0082 — EN — 30.04.2004 — 001.001 — 15
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The extension of the ten-year period to 11, 12, or 13 years for a veter-
inary medicinal product intended for food-producing species shall begranted only if the marketing authorisation holder also originally
applied for determination of the maximum residue limits established
for the species covered by the authorisation.
6. Conducting the necessary studies, tests and trials with a view to
the application of paragraphs 1 to 5 and the consequential practicalrequirements shall not be regarded as contrary to patent-related rights
or to supplementary-protection certificates for medicinal products.
Article 13a
1. By way of derogation from point (j) of the first subparagraph of
Article 12(3), and without prejudice to the law on the protection ofindustrial and commercial property, the applicant shall not be requiredto provide the results of safety and residue tests or of pre-clinical tests
or clinical trials if he can demonstrate that the active substances of the
veterinary medicinal product have been in well-established veterinaryuse within the Community for at least ten years, with recognised effi-cacy and an acceptable level of safety in terms of the conditions set outin Annex I. In that event, the applicant shall provide appropriate scien-tific literature.
2. The assessment report published by the Agency following the
evaluation of an application for the establishment of maximum residuelimits in accordance with Regulation (EEC) No 2377/90 may be usedin an appropriate manner as literature, particularly for the safety tests.
3. If an applicant makes use of scientific literature to obtain author-
isation for a food-producing species, and submits, in respect of the
same medicinal product and with a view to obtaining authorisation for
another food-producing species, new residue studies in accordance withRegulation (EEC) No 2377/90, together with further clinical trials, itshall not be permissible for a third party to use such studies or suchtrials pursuant to Article 13, for a period of three years from the grant
of the authorisation for which they were carried out.
Article 13b
In the case of veterinary medicinal products containing active
substances used in the composition of authorised veterinary medicinalproducts but not hitherto used in combination for therapeutic purposes,the results of safety and residue tests, if necessary, and new pre-clinical
tests or new clinical trials relating to that combination shall be
provided in accordance with point (j) of the first subparagraph ofArticle 12(3), but it shall not be necessary to provide scientific refer-ences relating to each individual active substance.
Article 13c
After the marketing authorisation has been granted, the marketing
authorisation holder may allow use to be made of the pharmaceutical,
safety and residues, pre-clinical and clinical documentation contained
in the file for the veterinary medicinal product with a view to exam-ining a subsequent application for a veterinary medicinal producthaving the same qualitative and quantitative composition in activesubstances and the same pharmaceutical form.
Article 13d
By way of derogation from point (j) of the first subparagraph of Article
12(3), and in exceptional circumstances with respect to immunologicalveterinary medicinal products, the applicant shall not be required toprovide the results of certain field trials on the target species if thesetrials cannot be carried out for duly substantiated reasons, in particularon account of other Community provisions.2001L0082 — EN — 30.04.2004 — 001.001 — 16
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Article 14
The summary of the product characteristics shall contain, in the order
indicated below, the following information:
1) name of the veterinary medicinal product followed by the strength
and the pharmaceutical form;
2) qualitative and quantitative composition in terms of the active
substances and constituents of the excipient, knowledge of which
is essential for proper administration of the medicinal product.The usual common name or chemical description shall be used;
3) pharmaceutical form;
4) clinical particulars:
4.1. target species,
4.2. indications for use, specifying the target species,4.3. contra-indications,
4.4. special warnings for each target species,
4.5. special precautions for use, including special precautions to
be taken by the person administering the medicinal productto the animals,
4.6. adverse reactions (frequency and seriousness),
4.7. use during pregnancy, lactation or lay,
4.8. interaction with other medicinal products and other forms of
interaction,
4.9. amounts to be administered and administration route,
4.10. overdose (symptoms, emergency procedures, antidotes), if
necessary,
4.11. withdrawal periods for the various foodstuffs, including
those for which the withdrawal period is zero;
5) pharmacological properties:
5.1. pharmacodynamic properties,
5.2. pharmacokinetic particulars;
6) pharmaceutical particulars:
6.1. list of excipients,
6.2. major incompatibilities,
6.3. shelf life, when necessary after reconstitution of the medicinal
product or when the immediate packaging is opened for the
first time,
6.4. special precautions for storage,
6.5. nature and composition of immediate packaging,
6.6. special precautions for the disposal of unused veterinary
medicinal products or waste materials derived from the use
of such products, if appropriate;
7) marketing authorisation holder;
8) marketing authorisation number(s);9) date of the first authorisation or date of renewal of the authorisa-
tion;
10) date of revision of the text.
For authorisation under Article 13, those parts of the summary of
product characteristics of the reference medicinal product referring to
indications or dosage forms which were still covered by patent law atthe time when a generic medicine was marketed need not be included.
Article 15
1. Applicants shall ensure that the detailed and critical summaries
referred to in the second subparagraph of Article 12(3) are drafted and2001L0082 — EN — 30.04.2004 — 001.001 — 17
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signed by persons with the requisite technical or professional qualifica-
tions, set out in a brief curriculum vitae, before being submitted to thecompetent authorities.
2. Persons with the technical or professional qualifications referred
to in paragraph 1 shall justify any use made of the scientific literaturereferred to in Article 13a(1) in accordance with the conditions set outin Annex I.
3. A brief curriculum vitae of the persons referred to in paragraph 1
shall be appended to the detailed critical summaries.
CHAPTER 2
Particular provisions applicable to homeopathic veterinary medic-
inal products
Article 16
1. Member States shall ensure that homeopathic veterinary medic-
inal products manufactured and placed on the market within theCommunity are registered or authorised in accordance with Articles17, 18 and 19, except where such veterinary medicinal products are
covered by a registration or authorisation granted in accordance with
national legislation on or before 31 December 1993. In the case ofhomeopathic medicinal products registered in accordance with Article17, Article 32 and Article 33(1) to (3) shall apply.
2. Member States shall establish a simplified registration procedure
for the homeopathic veterinary medicinal products referred to in Article
17.
3. By way of derogation from Article 10, homeopathic veterinary
medicinal products may be administered to non-food producing animalsunder the responsibility of a veterinarian.
4. By way of derogation from Article 11(1) and (2), Member States
shall permit the administration of homeopathic veterinary medicinalproducts intended for food-producing species the active constituents ofwhich appear in Annex II to Regulation (EEC) No 2377/90 under theresponsibility of a veterinarian. Member States shall take appropriate
measures to control the use of veterinary homeopathic medicinal
products registered or authorised in another Member State in accor-dance with this Directive for use in the same species.
Article 17
1. Without prejudice to the provisions of Regulation (EEC) No
2377/90 on the establishment of maximum residue limits of pharmaco-
logically active substances intended for food-producing animals, only
homeopathic veterinary medicinal products which satisfy all of thefollowing conditions may be subject to a special, simplified registrationprocedure:
(a) they are administered by a route described in the European Phar-
macopoeia or, in the absence thereof, by the pharmacopoeiascurrently used officially in Member States;
(b) no specific therapeutic indication appears on the labelling of the
veterinary medicinal product or in any information relating thereto;
(c) there is a sufficient degree of dilution to guarantee the safety of the
medicinal product. In particular, the medicinal product shall not
contain more than one part per 10 000 of the mother tincture.
If it appears justified in the light of new scientific evidence, points (b)
and (c) of the first subparagraph may be adapted in accordance withthe procedure referred to in Article 89(2).2001L0082 — EN — 30.04.2004 — 001.001 — 18
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At the time of registration, Member States shall determine the classifi-
cation for the dispensing of the medicinal product.
2. The criteria and rules of procedure provided for in Chapter 3,
with the exception of Article 25, shall apply by analogy to the special,
simplified registration procedure for homeopathic veterinary medicinalproducts referred to in paragraph 1, with the exception of the proof oftherapeutic effect.
Article 18
A special, simplified application for registration may cover a series of
medicinal products derived from the same homeopathic stock or stocks.The following documents shall be included with the application inorder to demonstrate, in particular, the pharmaceutical quality and thebatch-to-batch homogeneity of the products concerned:
— scientific name or other name given in a pharmacopoeia of the
homeopathic stock or stocks, together with a statement of the
various routes of administration, pharmaceutical forms and degree
of dilution to be registered,
— dossier describing how the homeopathic stock or stocks is/are
obtained and controlled, and justifying its/their homeopathic nature,on the basis of an adequate bibliography; in the case of homeo-pathic veterinary medicinal 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 potentisation,
— 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 mock-ups of the outer packaging and immediate
packaging of the medicinal products to be registered,
— data concerning the stability of the medicinal product,— proposed withdrawal period together with all requisite justification.
Article 19
1. Homeopathic veterinary medicinal products other than those
referred to in Article 17(1) shall be authorised in accordance with Arti-
cles 12, 13a, 13b, 13c, 13d and 14.
2. A Member State may introduce or retain on its territory specific
rules for the safety tests and pre-clinical and clinical trials of homeo-
pathic veterinary medicinal products intended for pet species and non-
food-producing exotic species other than those referred to in Article17(1), in accordance with the principles and characteristics of homeop-athy as practised in that Member State. In this case, the Member Stateconcerned shall notify the Commission of the specific rules in force.
Article 20
This Chapter shall not apply to immunological homeopathic veterinary
medicinal products.
The provisions of titles VI and VII shall apply to homeopathic veter-
inary medicinal products.2001L0082 — EN — 30.04.2004 — 001.001 — 19
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CHAPTER 3
Procedure for marketing authorization
Article 21
1. Member States shall take all appropriate measures to ensure that
the procedure for granting a marketing authorisation for a veterinarymedicinal product is completed within a maximum of 210 days afterthe submission of a valid application.
Applications for marketing authorisations for the same veterinary
medicinal product in two or more Member States, shall be submitted
in accordance with Articles 31 to 43.
2. Where a Member State notes that another marketing authorisation
application for the same medicinal product is being examined inanother Member State, the Member State concerned shall decline toassess the application and shall advise the applicant that Articles 31 to43 apply.
Article 22
Where a Member State is informed, in accordance with point (n) of
Article 12(3), that another Member State has authorised a veterinarymedicinal product which is the subject of an application for authorisa-
tion in the Member State concerned, that Member State shall reject the
application unless it was submitted in compliance with Articles 31 to43.
Article 23
In order to examine the application submitted pursuant to Articles 12 to
13d, Member States' competent authorities:
1) shall check that the documentation submitted in support of the
application complies with Articles 12 to 13d and ascertain whetherthe conditions for the issue of the marketing authorisation have beenfulfilled;
2) may submit the medicinal product, its starting materials and if
necessary intermediate products or other constituent materials fortesting by an Official Medicines Control Laboratory or a laboratorythat a Member State has designated for that purpose, in order toensure that the testing methods employed by the manufacturer anddescribed in the application documents, in accordance with point
(i) of the first subparagraph of Article 12(3), are satisfactory;
3) may similarly check, in particular through consultation of a national
or Community reference laboratory, that the analytical method usedfor detecting residues presented by the applicant for the purposes ofArticle 12(3)(j), second indent is satisfactory;
4) may, where appropriate, require the applicant to provide further
information as regards the items listed in Articles 12, 13a, 13b,13c and 13d. Where the competent authorities take this course ofaction, 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 applicantmay be given to provide oral or written explanations.
Article 24
Member States shall take all appropriate measures to ensure that:
(a) the competent authorities ascertain that the manufacturers and
importers of veterinary medicinal products from third countries areable to manufacture them in compliance with the details suppliedpursuant to Article 12(3)(d), and/or to carry out control tests inaccordance with the methods described in the application docu-ments under Article 12(3)(i);2001L0082 — EN — 30.04.2004 — 001.001 — 20
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(b) the competent authorities may authorize manufacturers and impor-
ters of veterinary medicinal products from third countries, wherecircumstances 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 authoritiesshall also be carried out in the establishments concerned.
Article 25
1. When granting a marketing authorisation, the competent authority
shall inform the holder of the summary of product characteristics that it
has approved.
2. The competent authority shall take all necessary measures to
ensure that information concerning the veterinary medicinal product,
and in particular the labelling and package leaflet, is in conformitywith the summary of product characteristics approved when themarketing authorisation was granted or subsequently.
3. The competent authority shall make the marketing authorisation
publicly available without delay, together with the summary of productcharacteristics for each veterinary medicinal product that it hasauthorised.
4. The competent authority shall draw up an assessment report and
comments on the file as regards the results of the pharmaceutical,safety and residue tests and the pre-clinical and clinical trials of the
veterinary medicinal product concerned. The assessment report shall
be updated whenever new information becomes available which is ofimportance for the evaluation of the quality, safety or efficacy of theveterinary medicinal product concerned.
The competent authority shall make the assessment report and its
reasons for the opinion publicly available without delay, after deletingany information of a commercially confidential nature.
Article 26
1. The marketing authorisation may require the holder to indicate on
the immediate packaging and/or the outer wrapping and the package
leaflet, where the latter is required, other particulars essential for safetyor health protection, including any special precautions relating to useand any other warnings resulting from the clinical and pharmacologicaltrials prescribed in Article 12(3)(j) and in Articles 13 to 13d or fromexperience gained during the use of the veterinary medicinal product
once it has been marketed.
3. In exceptional circumstances, and following consultation with the
applicant, the authorisation may be granted subject to a requirement forthe applicant to introduce specific procedures, in particular concerning
the safety of the veterinary medicinal product, notification to the
competent authorities of any incident relating to its use, and action tobe taken. Such authorisations may be granted only for objective, verifi-able reasons. Continuation of the authorisation shall be linked to theannual reassessment of these conditions.
Article 27
1. After a marketing authorization has been issued, the holder must,
in respect of the manufacturing methods and control methods providedfor in Article 12(3)(d) and (i), take account of scientific and technicalprogress and introduce any changes that may be required to enable thatveterinary medicinal product to be manufactured and checked bymeans of generally accepted scientific methods.2001L0082 — EN — 30.04.2004 — 001.001 — 21
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These changes shall be subject to the approval of the competent autho-
rities of the Member State concerned.
2. The competent authority may require the applicant or the
marketing authorisation holder to provide sufficient quantities of thesubstances to enable controls to be made on the identification of thepresence of residues of the veterinary medicinal products in question.
At the competent authority's request, the marketing authorisation holder
shall provide his technical expertise to facilitate the implementation of
the analytical method for detecting residues of the veterinary medicinalproducts in the national reference laboratory designated under CouncilDirective 96/23/EC of 29 April 1996 on measures to monitor certainsubstances and residues thereof in live animals and animal products (
1).
3. The authorisation holder shall immediately supply the competent
authority with any new information that might entail the amendment ofthe particulars or documents referred to in Articles 12(3), 13, 13a, 13band 14 or Annex I.
In particular, he shall immediately inform the competent authority of
any prohibition or restriction imposed by the competent authorities of
any country in which the veterinary medicinal product is placed on
the market and of any other new information which might influencethe assessment of the benefits and risks of the veterinary medicinalproduct concerned.
In order to permit continuous assessment of the risk-benefit balance,
the competent authority may at any time ask the marketing authorisa-
tion holder to forward data demonstrating that the risk-benefit balance
remains favourable.
5. The marketing authorisation holder shall immediately inform thecompetent authorities, with a view to authorisation, of any alteration
which he proposes to make to the particulars or documents referred to
in Articles 12 to 13d.
Article 27a
After a marketing authorisation has been granted, the holder of the
authorisation shall inform the competent authority of the authorisingMember State of the date of the actual placing on the market of theveterinary medicinal product in that Member State, taking into account
the various presentations authorised.
The holder shall also notify the competent authority if the product
ceases to be placed on the market of the Member State, either tempora-rily or permanently. Such notification shall, otherwise than inexceptional circumstances, be made no less than two months beforethe interruption in the placing on the market of the product.
Upon request by the competent authority, particularly in the context of
pharmacovigilance, the marketing authorisation holder shall provide thecompetent authority with all data relating to the volume of sales of theveterinary medicinal product, and any data in his possession relating tothe volume of prescriptions.
Article 28
1. Without prejudice to paragraphs 4 and 5, a marketing authorisa-
tion shall be valid for five years.
2. The authorisation may be renewed after five years on the basis of
a re-evaluation of the risk-benefit balance.2001L0082 — EN — 30.04.2004 — 001.001 — 22
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To this end, the marketing authorisation holder shall submit a consoli-
dated list of all documents submitted in respect of quality, safety andefficacy, including all variations introduced since the marketing author-
isation was granted, at least six months before the marketing
authorisation ceases to be valid in accordance with paragraph 1. Thecompetent authority may require the applicant to submit the listeddocuments at any time.
3. Once renewed, the marketing authorisation shall be valid for an
unlimited period, unless the competent authority decides, on justifiedgrounds relating to pharmacovigilance, to proceed with one additionalfive-year renewal in accordance with paragraph 2.
4. Any authorisation that is not followed within three years of its
granting by the actual placing on the market of the authorised veter-inary medicinal product in the authorising Member State shall cease
to be valid.
5. When an authorised veterinary medicinal product previously
placed on the market in the authorising Member State is no longer
actually present on the market in that Member State for a period of
three consecutive years, the authorisation granted for that veterinarymedicinal product shall cease to be valid.
6. The competent authority may, in exceptional circumstances, and
on human or animal health grounds, grant exemptions from paragraphs4 and 5. Such exemptions shall be duly justified.
Article 29
The granting of authorization shall not diminish the general legal liabi-
lity of the manufacturer and, where appropriate, of the authorizationholder.
Article 30
The marketing authorisation shall be refused if the file submitted to the
competent authorities does not comply with Articles 12 to 13d andArticle 15.
The authorisation shall also be refused if, after examination of the
documents and particulars listed in Articles 12 and 13(1), it is clearthat:
(a) the risk-benefit balance of the veterinary medicinal product is,
under the authorised conditions of use, unfavourable; when theapplication concerns a veterinary medicinal product for zootech-
nical use, particular regard shall be had to the benefits for animal
health and welfare and to consumer safety; or
(b) the product has no therapeutic effect or the applicant has not
provided sufficient proof of such effect as regards the species ofanimal which is to be treated; 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 labelling or the package leaflet proposed by the applicant does
not comply with this Directive; or
(f) the veterinary medicinal product is offered for sale for a use
prohibited under other Community provisions.
However, when a Community legislative framework is in the course of
being adopted, the competent authority may refuse authorisation for aveterinary medicinal product where such action is necessary for theprotection of public health, consumer or animal health.2001L0082 — EN — 30.04.2004 — 001.001 — 23
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The applicant or marketing authorisation holder shall be responsible for
the accuracy of documents and data submitted.
CHAPTER 4
Mutual recognition procedure and decentralised procedure
Article 31
1. A coordination group shall be set up for the examination of any
question relating to marketing authorisation of a veterinary medicinalproduct in two or more Member States in accordance with the proce-
dures laid down in this Chapter. The Agency shall provide the
secretariat of this coordination group.
2. The coordination group shall be composed of one representative
per Member State appointed for a renewable period of three years.Members of the group may arrange to be accompanied by experts.
3. The coordination group shall draw up its own rules of procedure,
which shall enter into force after a favourable opinion has been givenby the Commission. These rules of procedure shall be made public.
Article 32
1. With a view to the granting of a marketing authorisation for a
veterinary medicinal product in more than one Member State, the
applicant shall submit an application based on an identical dossier inthose Member States. The dossier shall contain all the administrativeinformation and scientific and technical documentation described inArticles 12 to 14. The documents submitted shall include a list of
Member States concerned by the application.
The applicant shall request one Member State to act as reference
Member State and to prepare an assessment report in respect of theveterinary medicinal product in accordance with paragraphs 2 or 3.
Where appropriate, the assessment report shall contain an evaluation
for the purposes of Article 13(5) or Article 13a(3).
2. If the veterinary medicinal product has already received a
marketing authorisation at the time of application, the concernedMember States shall recognise the marketing authorisation granted bythe reference Member State. To this end, the marketing authorisation
holder shall request the reference Member State either to prepare an
assessment report in respect of the veterinary medicinal product or, ifnecessary, to update any existing assessment report. The referenceMember State shall prepare or update the assessment report within 90days of receipt of a valid application. The assessment report together
with the approved summary of product characteristics, labelling and
package leaflet shall be forwarded to the concerned Member Statesand the applicant.
3. If the veterinary medicinal product has not received authorisation
by the time of application, the applicant shall request the reference
Member State to prepare a draft assessment report and drafts of the
summary of product characteristics, labelling and package leaflet. Thereference Member State shall prepare these drafts within 120 days ofthe receipt of a valid application and shall send them to the concernedMember States and the applicant.
4. Within 90 days after receipt of the documents referred to in para-
graphs 2 and 3, the Member States concerned shall approve theassessment report, the summary of product characteristics, the labellingand the package leaflet and inform the reference Member State accord-ingly. The reference Member State shall record the agreement of allparties, close the procedure and inform the applicant accordingly.
5. Each Member State in which an application following paragraph
1 has been submitted shall adopt a decision in conformity with theapproved assessment report, summary of product characteristics, label-ling and package leaflet within 30 days after acknowledgement of theagreement.2001L0082 — EN — 30.04.2004 — 001.001 — 24
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Article 33
1. If a Member State cannot, within the period allowed in Article
32(4), agree with the assessment report, summary of product character-istics, labelling and package leaflet on grounds of a potential seriousrisk to human or animal health or to the environment, a detailed state-
ment of the reasons shall be provided to the reference Member State,
the other Member States concerned and the applicant. The points ofdisagreement shall be referred without delay to the coordination group.
If a Member State to which an application has been submitted invokes
the reasons referred to in Article 71(1), it shall no longer be regardedas a Member State concerned by this Chapter.
2. The Commission shall adopt guidelines defining a potential
serious risk for human or animal health or for the environment.
3. Within the coordination group, all Member States referred to in
paragraph 1 shall use their best endeavours to reach agreement on theaction to be taken. They shall provide the applicant with the opportu-nity to make his point of view known orally or in writing. If, within 60days of the communication of the reasons for disagreement to the coor-
dination group the Member States reach an agreement, the reference
Member State shall record the agreement, close the procedure andinform the applicant accordingly. Article 32(5) shall apply.
4. If within the period of 60 days the Member States fail to reach an
agreement, the Agency shall be immediately informed with a view toapplication of the procedure laid down in Articles 36, 37 and 38. TheAgency shall be provided with a detailed description of the matters onwhich agreement could not be reached and the reasons for the disagree-
ment. The applicant shall be provided with a copy of this information.
5. As soon as the applicant has been informed that the matter has
been referred to the Agency, he shall forthwith forward to the Agency
a copy of the information and documents referred to in the first subpar-agraph of Article 32(1).
6. In the case referred to in paragraph 4, the Member States that
have approved the assessment report, summary of product characteris-tics, labelling and package leaflet of the reference Member State may,on request by the applicant, grant a marketing authorisation for theveterinary medicinal product without waiting for the outcome of the
procedure laid down in Article 36. In that case, the authorisation
granted shall be without prejudice to the outcome of that procedure.
Article 34
1. If two or more applications submitted in accordance with Articles
12 to 14 have been made for marketing authorisation for a particularveterinary medicinal product and Member States have adopted diver-
gent decisions concerning the authorisation of that veterinary
medicinal product, or suspension or revocation of authorisation, aMember State, or the Commission, or the marketing-authorisationholder may refer the matter to the Committee for Medicinal Productsfor Veterinary Use, hereinafter referred to as ‘the Committee’, for the
application of the procedure laid down in Articles 36, 37 and 38.
2. With a view to promoting the harmonisation of veterinary medic-
inal products authorised in the Community, and to strengthening the
efficiency of the provisions of Articles 10 and 11, Member States shall
send to the coordination group, no later than 30 April 2005, a list ofveterinary medicinal products for which a harmonised summary ofproduct characteristics should be prepared.
The coordination group shall agree on a list of medicinal products, on
the basis of proposals sent by Member States, and shall forward the listto the Commission.
The medicinal products on the list shall be subject to the provisions in
paragraph 1 in accordance with a timetable established in cooperationwith the Agency.2001L0082 — EN — 30.04.2004 — 001.001 — 25
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The Commission, acting in collaboration with the Agency, and taking
into consideration the views of the interested parties, shall agree thefinal list and timetable.
Article 35
1. Member States or the Commission or the applicant or marketing
authorisation holder shall, in specific cases where the interests of theCommunity are involved, refer the matter to the Committee for theapplication of the procedure laid down in Articles 36, 37 and 38 beforea decision is reached on a request for a marketing authorisation or on
the suspension or withdrawal of an authorisation, or on any other varia-
tions to the terms of a marketing authorisation which appear necessary,so as to take account in particular of the information collected in accor-dance with Title VII.
The Member State concerned or the Commission shall clearly identify
the question which is referred to the Committee for consideration andshall inform the applicant or the marketing authorisation holder.
The Member State and the applicant or the marketing authorisation
holder shall forward to the Committee all available information relatingto the matter in question.
2. Where the referral to the Committee concerns a range of medic-
inal products or a therapeutic class, the Agency may limit theprocedure to specific parts of the authorisation.
In that case, Article 39 shall apply to those medicinal products only if
they are covered by the marketing authorisation procedure referred toin this Chapter.
Article 36
1. When reference is made to the procedure laid down in this
Article, the Committee shall consider the matter concerned and shall
issue a reasoned opinion within 60 days of the date on which thematter was referred to it.
However, in cases submitted to the Committee in accordance with Arti-
cles 34 and 35, this period may be extended by the Committee for afurther period of up to 90 days, taking into account the views of themarketing authorisation holders concerned.
In an emergency, and on a proposal from its Chairman, the Committee
may agree to a shorter deadline.
2. In order to consider the matter, the Committee shall appoint one
of its members to act as rapporteur. The Committee may also appointindependent experts to advise it on specific questions. When appointingsuch experts, the Committee shall define their tasks and specify thetime limit for the completion of these tasks.
3. Before issuing its opinion, the Committee shall provide the appli-
cant or the marketing authorisation holder with an opportunity topresent written or oral explanations within a time limit that it will
specify.
The opinion of the Committee shall include the draft summary of
product characteristics and the drafts of the labelling and package
leaflet.
If it considers appropriate, the Committee may invite any other person
to provide information relating to the matter before it.
The Committee may suspend the time limit referred to in paragraph 1
to allow the applicant or the marketing authorisation holder to prepare
the explanations.
4. The Agency shall forthwith inform the applicant or the marketing
authorisation holder when the opinion of the Committee is that:
— the application does not satisfy the criteria for authorisation, or2001L0082 — EN — 30.04.2004 — 001.001 — 26
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— the summary of product characteristics proposed by the applicant or
the marketing authorisation holder in accordance with Article 14should be amended, or
— the authorisation should be granted subject to conditions, with
regard to conditions considered essential for the safe and effectiveuse of the veterinary medicinal product including pharmacovigi-lance, or
— a marketing authorisation should be suspended, varied or revoked.
Within 15 days after receipt of the opinion, the applicant or the
marketing authorisation holder may notify the Agency in writing ofhis intention to request a re-examination of the opinion. In that case,he shall forward to the Agency the detailed grounds for the requestwithin 60 days after receipt of the opinion.
Within 60 days following receipt of the grounds for the request, the
Committee shall re-examine its opinion in accordance with the fourthsubparagraph of Article 62(1) of Regulation (EC) No 726/2004. The
reasons for the conclusion reached shall be annexed to the assessment
report referred to in paragraph 5 of this Article.
5. Within 15 days after its adoption, the Agency shall forward the
final opinion of the Committee to Member States, the Commission
and the applicant or the marketing authorisation holder, together witha report describing the assessment of the veterinary medicinal productand the reasons for its conclusions.
In the event of an opinion in favour of granting or maintaining a
marketing authorisation, the following documents shall be annexed tothe opinion:
(a) a draft summary of the product characteristics, as referred to in
Article 14; where necessary this will reflect the differences in theveterinary conditions in Member States;
(b) any conditions affecting the authorisation within the meaning of
paragraph 4;
(c) details of any recommended conditions or restrictions with regard
to the safe and effective use of the veterinary medicinal product;
and
(d) drafts of the labelling and package leaflet.
Article 37
Within 15 days after receipt of the opinion, the Commission shall
prepare a draft of the decision to be taken in respect of the application,taking into account Community law.
In the event of a draft decision that envisages the granting of a
marketing authorisation, the documents referred to in the secondsubparagraph of Article 36(5) shall be annexed.
If, exceptionally, the draft decision is not in accordance with the
opinion of the Agency, the Commission shall also annex a detailedexplanation of the reasons for the differences.
The draft decision shall be forwarded to Member States and the appli-
cant or marketing authorisation holder.
Article 38
1. The Commission shall take a final decision in accordance with,
and within 15 days after the end of, the procedure referred to in Article
89(3).
2. The rules of procedure of the Standing Committee set up by
Article 89(1) shall be adjusted to take account of the tasks incumbentupon it in accordance with this Chapter.2001L0082 — EN — 30.04.2004 — 001.001 — 27
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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,
— Member States shall have 22 days to forward their written observa-
tions on the draft decision to the Commission. However, if a
decision has to be taken urgently, a shorter time-limit may be set
by the Chairman according to the degree of urgency involved.This time-limit shall not, otherwise than in exceptional circum-stances, be shorter than 5 days,
— Member States shall have the option of submitting a written request
that the draft decision be discussed in a plenary meeting of theStanding Committee.
Where, in the opinion of the Commission, the written observations of a
Member State raise important new questions of a scientific or technicalnature which have not been addressed in the opinion of the Agency, theChairman shall suspend the procedure and refer the application back tothe Agency for further consideration.
The provisions necessary for the implementation of this paragraph shall
be adopted by the Commission in accordance with the procedurereferred to in Article 89(2).
3. A decision as referred to in paragraph 1 shall be addressed to all
Member States and communicated to the marketing authorisation
holder or the applicant for information. The concerned Member Statesand the reference Member State shall either grant or withdrawmarketing authorisation, or vary the terms of a marketing authorisationas necessary to comply with the decision within 30 days of its notifica-
tion and shall refer to it. They shall inform the Commission and the
Agency accordingly.
Article 39
1. Any application by the marketing authorization holder to vary a
marketing authorization which has been granted in accordance with
the provisions of this Chapter shall be submitted to all the Member
States which have previously authorized the veterinary medicinalproduct concerned.
The Commission shall, in consultation with the Agency, adopt appro-
priate arrangements for the examination of variations to the terms of a
marketing authorization.
These arrangements shall be adopted by the Commission in the form of
an implementing regulation in accordance with the procedure referredto in Article 89(2).
2. In case of arbitration submitted to the Commission, the procedure
laid down in Articles 36, 37 and 38 shall apply by analogy to variations
made to marketing authorizations.
Article 40
1. Where a Member State considers that the variation of the terms of
a marketing authorization which has been granted in accordance withthe provisions of this Chapter or its suspension or withdrawal is neces-
sary for the protection of human or animal health or the environment,
the Member State concerned shall forthwith refer the matter to theAgency for the application of the procedures laid down in Articles 36,37 and 38.
2. Without prejudice to the provisions of Article 35, in exceptional
cases, where urgent action is essential to protect human or animal2001L0082 — EN — 30.04.2004 — 001.001 — 28
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health or the environment, until a definitive decision is adopted, a
Member State may suspend the marketing and the use of the veterinarymedicinal 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.
Article 41
Articles 39 and 40 shall apply by analogy to veterinary medicinal
products authorized by Member States following an opinion of theCommittee given in accordance with Article 4 of Directive 87/22/EEC
before 1 January 1995.
Article 42
1. The Agency shall publish an annual report on the operation of the
procedures laid down in this Chapter and shall forward it to theEuropean Parliament and the Council for information.
2. At least every ten years the Commission shall publish a report on
experience gained on the basis of the procedures provided for in thischapter and shall propose any amendments necessary to improve theprocedures. The Commission shall submit this report to the EuropeanParliament and the Council.
Article 43
Articles 33(4), (5) and (6) and 34 to 38 shall not apply to the homeo-
pathic veterinary medicinal products referred to in Article 17.
Articles 32 to 38 shall not apply to the homeopathic veterinary medic-
inal products referred to in Article 19(2).
TITLE IV
MANUFACTURE AND IMPORTS
Article 44
1. Member States shall take all appropriate measures to ensure that
the manufacture of veterinary medicinal products in their territory issubject to the holding of an authorization. This manufacturing authori-zation shall likewise be required for veterinary medicinal products
intended for export.
2. The authorization referred to in paragraph 1 shall be required
both for total and partial manufacture and for the various processes of
dividing up, packaging or presentation.
However, such authorization shall not be required for preparation,
dividing up, changes in packaging or presentation where these
processes are carried out solely for retail supply by pharmacists in
dispensing pharmacies or by persons legally authorized in the MemberStates to carry out such processes.
3. The authorization referred to in paragraph 1 shall also be required
for imports from third countries into a Member State; this Title andArticle 83 shall apply to such imports in the same way as to manufac-ture.
Member States shall take all appropriate measures to ensure that veter-
inary medicinal products brought into their territory from a thirdcountry and destined for another Member State are accompanied by acopy of the authorization referred to in paragraph 1.
4. The Member State shall forward to the Agency a copy of the
manufacturing authorisations referred to in paragraph 1. The Agencyshall enter that information in the Community database referred to inArticle 80(6).2001L0082 — EN — 30.04.2004 — 001.001 — 29
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Article 45
In order to obtain the manufacturing authorization, the applicant shall
meet at least the following requirements:
(a) he shall specify the veterinary medicinal products and pharmaceu-
tical 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 import 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 manufactureand control and the storage of products, in accordance with Article24;
(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.
Article 46
1. The competent authority of the Member State shall not issue the
manufacturing authorization until it has established the accuracy of theparticulars supplied pursuant to Article 45 by means of an inquirycarried out by its representatives.
2. In order to ensure that the requirements referred to in Article 45
are complied with, authorization may be made conditional on the fulfil-
ment of certain obligations imposed either when authorization isgranted 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 pharmaceu-tical forms specified in that application.
Article 47
The Member States shall take all appropriate measures to ensure that
the time taken for the procedure for granting the manufacturing author-
ization does not exceed 90 days from the day on which the competentauthority receives the application.
Article 48
If the holder of the manufacturing authorization requests a change in
any of the particulars referred to in Article 45, first paragraph, (a) and(b), the time taken for the procedure relating to this request shall notexceed 30 days. In exceptional cases, this period of time may be
extended to 90 days.
Article 49
The competent authority of the Member States may require from the
applicant further information concerning both the particulars supplied
pursuant to Article 45 and the qualified person referred to in Article52; where the competent authority concerned exercises this right, appli-cation of the time-limits referred to in Articles 47 and 48 shall besuspended until the additional data required have been supplied.
Article 50
The holder of a manufacturing authorization shall at least be obliged
to:
(a) have at his disposal the services of staff complying with the legal
requirements existing in the Member State concerned as regards
both manufacture and controls;
(b) dispose of the authorized veterinary medicinal products only in
accordance with the legislation of the Member States concerned;2001L0082 — EN — 30.04.2004 — 001.001 — 30
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(c) give prior notice to the competent authority of any changes which
he may wish to make to any of the particulars supplied pursuant toArticle 45; the competent authority shall, in any event, be immedi-
ately informed if the qualified person referred to in 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 his disposal all the necessary facil-ities;
(f) comply with the principles and the guidelines on good manufac-
turing practice for medicinal products and use as starting materials
only active substances which have been manufactured in accor-
dance with the detailed guidelines on good manufacturing practicefor starting materials;
(g) keep detailed records of all veterinary medicinal products supplied
by him, including samples, in accordance with the laws of thecountries of destination. The following information at least shallbe recorded in respect of each transaction, whether or not it ismade 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 autho-
rities for a period of at least three years.
Article 50a
1. For the purposes of this Directive, manufacturing active
substances for use as starting materials shall include the complete or
partial manufacture or the import of an active substance used as a
starting material, as defined in Part 2, Section C of Annex I, and thevarious processes of dividing up, packaging or presentation prior to itsincorporation in a veterinary medicinal product, including repackagingor re-labelling, such as carried out by a starting material distributor.
2. Any amendments which may be necessary to adapt the provisions
of this Article to scientific and technical progress shall be adopted in
accordance with the procedure referred to in Article 89(2).
Article 51
The principles and guidelines of good manufacturing practice for veter-
inary medicinal products referred to in Article 50(f) shall be adopted inthe form of a Directive addressed to the Member States in accordance
with the procedure referred to in Article 89(2).
Detailed guidelines shall be published by the Commission and revised
as appropriate to take account of scientific and technical progress.
The principles of good manufacturing practice as regards the manufac-
turing of active substances for use as starting materials as referred to in
Article 50(f) shall be adopted in the form of detailed guidelines.
The Commission shall also publish guidelines on the form and content
of the authorisation referred to in Article 44(1), the reports referred toin Article 80(3) and the form and content of the certificate of goodmanufacturing practice referred to in Article 80(5).2001L0082 — EN — 30.04.2004 — 001.001 — 31
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Article 52
1. Member States shall take all appropriate measures to ensure that
the holder of the manufacturing authorization has permanently and
continuously at his disposal the services of at least one qualified person
who fulfils the conditions laid down in Article 53 and is responsible, inparticular, for carrying out the duties specified in Article 55.
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 ensure that the qualified person referred to in
Article 52(1) fulfils the conditions of qualification referred to in para-graphs 2 and 3.
2. The qualified person shall be in possession of a diploma, certifi-
cate or other evidence of formal qualifications awarded on completionof a university course of study, or a course recognized as equivalent bythe Member State concerned, extending over a period of at least four
years of theoretical and practical study in one of the following scien-
tific 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 course 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, corroboratedby an examination at university level.
Where two university or recognized equivalent courses coexist in a
Member State and where one of these extends over four years and theother over three years, the diploma, certificate or other evidence of
formal qualifications awarded on completion of the three-year univer-
sity course or its recognized equivalent shall be considered to fulfilthe condition of duration referred to in the first subparagraph in so faras the diplomas, certificates or other evidence of formal qualificationsawarded on completion of both courses are recognized as equivalent by
the State in question.
The course shall include theoretical and practical tuition bearing upon
at least the following basic subjects:
— experimental physics,
— general and inorganic chemistry,— organic chemistry,— analytical chemistry,— pharmaceutical chemistry, including analysis of medicinal products,— general and applied biochemistry (medical),— physiology,— microbiology,— pharmacology,— pharmaceutical 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 55.
In so far as certain diplomas, certificates or other evidence of formal
qualifications mentioned in this paragraph do not fulfil the criterialaid down above, the competent authority of the Member State shallensure that the person concerned provides evidence that he has, in thesubjects involved, the knowledge required for the manufacture andcontrol of veterinary medicinal products.2001L0082 — EN — 30.04.2004 — 001.001 — 32
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3. The qualified person shall have acquired practical experience over
at least two years, in one or more undertakings which are authorizedmanufacturers, 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 medicinalproducts.
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.
Article 54
1. A person engaging, in a Member State, in the activities of the
person referred to in Article 52(1) on the date on which Directive 81/
851/EEC became applicable, without complying with the provisions ofArticle 53, shall be eligible to continue to engage in those activitieswithin the Community.
2. The holder of a diploma, certificate or other evidence of formal
qualifications awarded on completion of a university course — or acourse recognized as equivalent by the Member State concerned — ina 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 he began his course prior to 9 October 1981 — beconsidered as qualified to carry out in that State the duties of theperson referred to in Article 52, provided that he has previouslyengaged in the following activities for at least two years before 9
October 1991 in one or more undertakings with a manufacturing
authorization; production supervision and/or qualitative and quantita-tive analysis of active substances, and the necessary testing andchecking under the direct authority of a person as referred to in Article52 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'spractical experience in accordance with the conditions referred to in thefirst subparagraph shall be completed by him immediately before heengages in such activities.
Article 55
1. Member States shall take all appropriate measures to ensure that
the qualified person referred to in Article 52 is, without prejudice to hisrelationship with the holder of the manufacturing authorization, respon-sible, in the context of the procedures referred to in Article 56, forensuring that:
(a) in the case of veterinary medicinal products manufactured within
the Member State concerned, each batch of veterinary medicinalproducts has been manufactured and checked in compliance withthe laws in force in that Member State and in accordance with therequirements of the marketing authorization;
(b) in the case of veterinary medicinal products coming from third
countries, even if manufactured in the Community, each production
batch imported has undergone in a Member State a full qualitativeanalysis, a quantitative analysis of at least all the active substances,and all the other tests or controls necessary to ensure the quality ofveterinary medicinal products in accordance with the requirements
of the marketing authorisation.
Batches of veterinary medicinal products which have undergone such
controls in a Member State shall be exempt from the above controls ifthey are placed on the market in another Member State, accompaniedby the control reports signed by the qualified person.2001L0082 — EN — 30.04.2004 — 001.001 — 33
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2. In the case of veterinary medicinal products imported from a third
country, where appropriate arrangements have been made by theCommunity with the exporting country to ensure that the manufacturer
of the veterinary medicinal product applies standards of good manufac-
turing practice at least equivalent to those laid down by the Communityand to ensure that the controls referred to under point (b) of the firstsubparagraph of paragraph 1 have been carried out in the exportingcountry, the qualified person may be relieved of responsibility for
carrying out those controls.
3. In all cases, and particularly where the veterinary medicinal
products are released for sale, the qualified person shall certify, in aregister or equivalent document provided 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 operationsare carried out and shall remain at the disposal of the representatives ofthe competent authority for the period specified in the provisions of theMember State concerned and, in any event, for at least five years.
Article 56
Member States shall ensure that the obligations of qualified persons
referred to in Article 52 are fulfilled, either by means of appropriateadministrative measures or by making such persons subject to a profes-
sional code of conduct.
Member States may provide for the temporary suspension of such a
person upon the commencement of administrative or disciplinaryproceedings against him for failure to fulfil his obligations.
Article 57
The provisions of this Title shall apply to homeopathic veterinary
medicinal products.
TITLE V
LABELLING AND PACKAGE INSERT
Article 58
1.►M1 Except in the case of the medicinal products referred to in
Article 17(1), the competent authority shall approve the immediatepackaging and outer packaging of veterinary medicinal products.
Packaging shall bear the following information, which shall conform
with the particulars and documents provided pursuant to Articles 12 to13d and the summary of product characteristics, and shall appear inlegible characters: ◄
(a) The name of the medicinal product, followed by its strength and
pharmaceutical form. The common name shall appear if the medic-
inal product contains only one active substance and its name is an
invented name;
(b) A statement of the active substances expressed qualitatively and
quantitatively per unit or according to the form of administrationfor a particular volume or weight, using the common names;
(c) Manufacturer's batch number;
(d) Marketing authorization number;
(e) Name or corporate name and permanent address or registered place
of business of the marketing authorisation holder and, where appro-priate, of the representative designated by the marketingauthorisation holder;
(f) The species of animal for which the veterinary medicinal product is
intended; the method and, if necessary, the route of administration.Space shall be provided for the prescribed dose to be indicated;2001L0082 — EN — 30.04.2004 — 001.001 — 34
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(g) The withdrawal period for veterinary medicinal products to be
administered to food-producing species, for all the speciesconcerned and for the various foodstuffs concerned (meat and offal,
eggs, milk, honey), including those for which the withdrawal
period is zero;
(h) Expiry date, in plain language;
(i) Special storage precautions, if any;
(j) Specific precautions relating to the disposal of unused medicinal
products or waste derived from veterinary medicinal products,where appropriate, as well as a reference to any appropriate collec-tion system in place;
(k) Particulars required to be indicated pursuant to Article 26(1), if
any;
(l) The words ‘For animal treatment only’ or, in the case of the medic-
inal products referred to in Article 67, the words ‘For animal
treatment only — to be supplied only on veterinary prescription’.
2. The pharmaceutical form and the contents by weight, volume or
number of dose-units need only be shown on the outer package.
3. The provisions of Part 1, A of Annex I, in so far as they concern
the qualitative and quantitative composition of veterinary medicinal
products in respect of active substances, shall apply to the particulars
provided for in paragraph 1(b).
4. The particulars mentioned in paragraph 1(f) to (l) shall appear on
the outer package and on the container of the medicinal products in thelanguage or languages of the country in which they are placed on themarket.
5. In the case of medicinal products that have been granted a
marketing authorisation under Regulation (EC) No 726/2004, MemberStates may permit or require that the outer packaging bear additional
information concerning distribution, possession, sale or any necessary
precautions, provided that such information is not in infringement ofCommunity law or the terms of the marketing authorisation, and isnot promotional.
This additional information shall appear in a box with a blue border to
separate it clearly from the information referred to in paragraph 1.
Article 59
1. As regards ampoules, the particulars listed in the first paragraph
of Article 58(1) shall be given on the outer package. On the immediatepackaging, however, only the following particulars shall be necessary:
— name of veterinary medicinal product,
— quantity of the active substances,
— route of administration,— manufacturer's batch number,
— date of expiry,
— the words ‘For animal treatment only’.
2. As regards small immediate packaging containing a single dose,
other than ampoules, on which it is impossible to give the particularsmentioned in paragraph 1, the requirements of Article 58(1), (2) and(3) shall apply only to the outer package.2001L0082 — EN — 30.04.2004 — 001.001 — 35
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3. The particulars mentioned in the third and sixth indents of para-
graph 1 shall appear on the outer package and on the immediatepackaging of the medicinal products in the language 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 package pursuant to Articles 58 and 59 shall beshown on the immediate packaging.
Article 61
1. The inclusion of a package leaflet in the packaging of veterinary
medicinal products shall be obligatory unless all the informationrequired by this Article can be conveyed on the immediate packagingand the outer packaging. Member States shall take all appropriatemeasures to ensure that the package leaflet relates solely to the veter-inary medicinal product with which it is included. The package leaflet
shall be written in terms that are comprehensible to the general public
and in the official language or languages of the Member State in whichthe medicinal product is marketed.
The first subparagraph shall not prevent the package leaflet from being
written in several languages, provided that the information given isidentical in all the languages.
Competent authorities may exempt labels and package leaflets for
specific veterinary medicinal products from the obligation for certain
particulars to appear and for the leaflet to be in the official languageor languages of the Member State in which the product is placed onthe market, when the product is intended to be administered only by aveterinarian.
2. The competent authorities shall approve package leaflets. Leaflets
shall contain at least the following information, in the order indicated,which shall conform to the particulars and documents providedpursuant to Articles 12 to 13d and the approved summary of product
characteristics:
(a) name or corporate name and permanent address or registered place
of business of the marketing authorisation holder and of the manu-
facturer and, where appropriate, of the representative of the
marketing authorisation holder;
(b) name of the veterinary medicinal product followed by its strength
and pharmaceutical form. The common name shall appear if theproduct contains only one active substance and its name is aninvented name. Where the medicinal product is authorisedaccording to the procedure provided for in Articles 31 to 43 under
different names in the Member States concerned, a list of the
names authorised in each Member State;
(c) the therapeutic indications;
(d) contra-indications and adverse reactions in so far as these particu-
lars 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 ofadministration 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 pursuant to Article 26(1), if
any;
(i) special precautions for the disposal of unused medicinal products or
waste materials from medicinal products, if any.2001L0082 — EN — 30.04.2004 — 001.001 — 36
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Article 62
Where the provisions of this Title are not observed and a formal notice
addressed to the person concerned has been ineffectual, Member States'competent authorities may suspend or revoke the marketing authorisa-tion.
Article 63
The requirements of Member States concerning conditions of supply to
the public, the marking of prices on medicinal products for veterinary
use and industrial property rights shall not be affected by the provisionsof this Title.
Article 64
1. Without prejudice to paragraph 2, homeopathic veterinary medic-
inal products shall be labelled in accordance with the provisions of this
title and identified by the inclusion on their labels, in clearly legible
form, of the words ‘homeopathic medicinal product for veterinary use’.
2. In addition to the clear mention of the words ‘homeopathic veter-
inary medicinal product without approved therapeutic indications’, the
labelling and, where appropriate, package leaflet for the homeopathicveterinary medicinal products referred to in Article 17(1) shall bearthe 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 accor-
dance with point (8) of Article 1. If the homeopathic veterinary
medicinal product is composed of more than one stock, the label-ling may mention an invented name in addition to the scientificnames of the stocks,
— 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 form,
— 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.
TITLE VI
POSSESSION, DISTRIBUTION AND DISPENSING OF VETER-
INARY MEDICINAL 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 ensure that the time taken for theprocedure for granting this authorization does not exceed 90 daysfrom the date on which the competent authority receives the applica-tion.
Member States may exclude supplies of small quantities of veterinary
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2. In order to obtain the authorization for distribution, the applicant
shall have at his disposal technically competent staff and suitable andsufficient premises complying with the requirements laid down in the
Member State concerned as regards the storage and handling of veter-
inary medicinal products.
3. The holder of the authorization for distribution shall be required
to keep detailed records. The following minimum information shall be
recorded in respect of each incoming or outgoing transaction:
(a) date;
(b) precise identity of the veterinary medicinal product;
(c) manufacturer's batch number, expiry date;
(d) quantity received or supplied;
(e) name and address of the 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 heldin stock, any discrepancies being recorded.
These records shall be available for inspection by the competent autho-
rities for a period of at least three years.
3a. The holder of a distribution authorisation shall have an emer-
gency plan guaranteeing the effective implementation of any recall
operation ordered by the competent authorities or undertaken in coop-eration with the manufacturer of the medicinal product in question orthe holder of the marketing authorisation.
4. Member States shall take all appropriate measures to ensure that
wholesalers supply veterinary medicinal products only to personspermitted 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.
5. Any distributor, not being the marketing authorisation holder,
who imports a product from another Member State shall notify themarketing authorisation holder and the competent authority in theMember State to which the product will be imported of his intentionto import it. In the case of products which have not been granted an
authorisation pursuant to Regulation (EC) No 726/2004, the notifica-
tion to the competent authority shall be without prejudice toadditional procedures provided for in the legislation of that MemberState.
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 carry out such operations by the legisla-tion of the Member State concerned.
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inary medicinal products shall be required to keep detailed records for
veterinary medicinal products that may be supplied only on prescrip-
tion, the following information being recorded in respect of eachincoming or outgoing transaction: ◄
(a) date;
(b) precise identity of the veterinary medicinal product;
(c) manufacturer's batch number;
(d) quantity received or supplied;
(e) name and address of the supplier or recipient;
(f) where relevant, name and address of the prescribing veterinarian
and a copy of the prescription.2001L0082 — EN — 30.04.2004 — 001.001 — 38
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At least once a year a detailed audit shall be carried out, and incoming
and outgoing veterinary medicinal products shall be reconciled withproducts currently held in stock, any discrepancies being recorded.
These records shall be available for inspection by the competent autho-
rities for a period of five years.
3. Member States may permit the supply on their territory of veter-
inary medicinal products for food-producing animals for which aveterinary prescription is required by or under the supervision of aperson registered for this purpose who provides guarantees with respectto qualifications, record-keeping and reporting in accordance withnational law. Member States shall notify the Commission of relevant
provisions of national law. This provision shall not apply to the supply
of veterinary medicinal products for the oral or parenteral treatment ofbacterial infections.
Article 67
Without prejudice to stricter Community or national rules relating to
dispensing veterinary medicinal products and serving to protect humanand animal health, a veterinary prescription shall be required fordispensing to the public the following veterinary medicinal products:
(a) those products subject to official restrictions on supply or use,
such as:
— the restrictions resulting from the implementation of the rele-
vant United Nations conventions on narcotic and psychotropicsubstances,
— the restrictions on the use of veterinary medicinal products
resulting from Community law;
(aa) veterinary medicinal products for food-producing animals.
However, Member States may grant exemptions from this require-
ment according to criteria established in accordance with theprocedure referred to in Article 89(2).
Member States may continue to apply national provisions until
either:
(i) the date of application of the decision adopted in accordance
with the first subparagraph; or
(ii) 1 January 2007, if no such decision has been adopted by
31 December 2006;
(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 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 diagnosticor therapeutic measures;
(d) official formula, within the meaning of Article 3(2)(b), intended
for food-producing animals.
Member States shall take all necessary measures to ensure that, in the
case of medicinal products supplied only on prescription, the quantity2001L0082 — EN — 30.04.2004 — 001.001 — 39
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prescribed and supplied shall be restricted to the minimum amount
required for the treatment or therapy concerned.
In addition, a prescription shall be required for new veterinary medic-
inal products containing an active substance that has been authorisedfor use in a veterinary medicinal product for fewer than five years.
Article 68
1. Member States shall take all measures necessary to ensure that
only persons empowered under their national legislation in forcepossess or have under their control veterinary medicinal products orsubstances which may be used as veterinary medicinal products thathave anabolic, anti-infectious, anti-parasitic, anti-inflammatory,
hormonal or psychotropic properties.
2. Member States shall maintain 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 havingthe properties referred to in paragraph 1. Such persons must maintaindetailed records of all dealings in substances which may be used inthe 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
referred to in Article 89(2).
Article 69
Member States shall ensure that the owners or keepers of food-produ-
cing animals can provide proof of purchase, possession andadministration of veterinary medicinal products to such animals for
five years after their administration, including when the animal is
slaughtered during the five-year period.
In particular, Member States may require the maintenance of a record
giving at least the following information:
(a) date;
(b) name of the veterinary medicinal product;
(c) quantity;
(d) name and address of the supplier of the medicinal product;
(e) identification of the animals treated.
Article 70
By way of derogation from Article 9 and without prejudice to Article
67, Member States shall ensure that veterinarians providing services in
another Member State can take with them and administer to animalssmall quantities of veterinary medicinal products not exceeding dailyrequirements other than immunological veterinary medicinal productswhich are not authorised for use in the Member State in which the
services are provided (hereinafter: ‘host Member State’), provided that
the following conditions are satisfied:
(a) the authorization to place the product on the market provided for in
Articles 5, 7 and 8 has been issued by the competent authorities of
the Member State in which the veterinarian is established;
(b) the veterinary medicinal products are transported by the veteri-
narian in the original manufacturer's packaging;
(c) the veterinary medicinal products intended for administration to
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composition in terms of active substances as the medicinal products
authorized in accordance with Articles 5, 7 and 8 in the hostMember State;
(d) the veterinarian providing services in another Member State
acquaints himself with the good veterinary practices applied inthat 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 knowthat a longer withdrawal period should be specified to complywith 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 MemberState unless this is permissible on the basis of the rules of the hostMember State; in this case he shall, however, supply only in rela-tion to animals under his care and only the minimum quantities ofveterinary 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 productsadministered, the dosage administered, the duration of treatment
and the withdrawal period applied. These records shall be available
for inspection by the competent authorities of the host MemberState for a period of at least three years;
(g) the overall range and quantity of veterinary medicinal products
carried by the veterinarian shall not exceed that generally requiredfor the daily needs of good veterinary practice.
Article 71
1. In the absence of specific Community legislation concerning the
use of immunological veterinary medicinal products for the eradicationor control of animal disease, a Member State may, in accordance withits national legislation, prohibit the manufacture, import, possession,
sale, supply and/or use of immunological veterinary medicinal products
on the whole or part of its territory if it is established that:
(a) the administration of the product to animals will interfere with the
implementation of a national programme for the diagnosis, controlor eradication of animal disease, or will cause difficulties in certi-fying the absence of contamination in live animals or in foodstuffs
or other products obtained from treated animals;
(b) the disease to which the product is intended to confer immunity is
largely absent from the territory in question.
The Member State may also invoke the provisions of the first subpara-
graph in order to withhold marketing authorisation in accordance witha decentralised procedure as provided for in Articles 31 to 43.
2. The competent authorities of the Member States shall inform the
Commission of all instances in which the provisions of paragraph 1 are
applied.
TITLE VII
PHARMACOVIGILANCE
Article 72
1. Member States shall take all appropriate measures to encourage
the reporting to the competent authorities of suspected adverse reac-tions to veterinary medicinal products.
2. Member States may impose specific requirements on veterinary
practitioners and other health-care professionals in respect of thereporting of suspected serious or unexpected adverse reactions andhuman adverse reactions.2001L0082 — EN — 30.04.2004 — 001.001 — 41
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Article 73
In order to ensure the adoption of appropriate and harmonised regula-
tory decisions concerning the veterinary medicinal products authorisedwithin the Community, having regard to information obtained aboutsuspected adverse reactions to veterinary medicinal products under
normal conditions of use, Member States shall administer a veterinary
pharmacovigilance system. This system shall be used to collect infor-mation useful in the surveillance of veterinary medicinal products,with particular reference to adverse reactions in animals and in humanbeings relating to the use of veterinary medicinal products, and to eval-uate such information scientifically.
Such information shall be collated with available data on the sale and
prescription of veterinary medicinal products.
Member States shall ensure that suitable information collected within
this system is communicated to other Member States and the Agency.This information shall be recorded in the database referred to in point
(k) of the second subparagraph of Article 57(1) of Regulation (EC)
No 726/2004 and shall be permanently accessible to all Member Statesand without delay to the public.
This system also takes into account any available information related to
the lack of expected efficacy, off-label use, investigations of thevalidity of the withdrawal period and on potential environmentalproblems, arising from the use of the product, interpreted in accordancewith the Commission guidelines referred to in Article 77(1), which may
have an impact on the evaluation of their benefits and risks.
Article 73a
The management of funds intended for activities connected with phar-
macovigilance, the operation of communication networks and marketsurveillance shall be under the permanent control of the competentauthorities in order to guarantee their independence.
Article 74
The marketing authorization holder shall have permanently and
continuously at his disposal an appropriately qualified person respon-sible for pharmacovigilance.
That qualified person shall reside in the Community and shall be
responsible for the following:
(a) the establishment and maintenance of a system which ensures that
information about all suspected adverse reactions which arereported to the personnel of the company, including its representa-tives, is collected and collated in order to be accessible at least atone point within the Community;
(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 autho-rities, in accordance with the guidance referred to in Article 77(1);
(c) ensuring that any 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 informa-tion about the volume of sales or prescriptions of the veterinarymedicinal product concerned;
(d) the provision to the competent authorities, of any other information
relevant to the evaluation of the benefits and risks afforded by a2001L0082 — EN — 30.04.2004 — 001.001 — 42
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veterinary medicinal product, including appropriate information on
post-marketing surveillance studies.
Article 75
1. The marketing authorisation holder shall maintain detailed
records of all suspected adverse reactions occurring within the Commu-nity or in a third country.
Save in exceptional circumstances, these reactions shall be communi-
cated electronically in the form of a report in accordance with the
guidelines referred to in Article 77(1).
2. The marketing authorisation holder shall record all suspected
serious adverse reactions and human adverse reactions relating to theuse of veterinary medicinal products that are brought to his attention,and report them promptly to the competent authority of the MemberState on whose territory the incident occurred, and no later than 15
days following receipt of the information.
The marketing authorisation holder shall also record all suspected
serious adverse reactions and human adverse reactions related to theuse of veterinary medicinal products of which he can reasonably beexpected to have knowledge, and report them promptly to the compe-tent authority of Member State on whose territory the incident
occurred, and no later than 15 days following receipt of the informa-
tion.
3. The marketing authorisation holder shall ensure that all suspected
serious unexpected adverse reactions, human adverse reactions and anysuspected transmission via a veterinary medicinal product of any infec-tious agent occurring on the territory of a third country are reported
promptly in accordance with the guidelines referred to in Article
77(1), so that they are available to the Agency and the competentauthorities of the Member States in which the veterinary medicinalproduct is authorised, and no later than 15 days following the receiptof the information.
4. By way of derogation from paragraphs 2 and 3, in the case of
veterinary medicinal products which are covered by Directive 87/22/
EEC, have benefited from the authorisation procedures under Articles31 and 32 of this Directive or have been the subject of the proceduresprovided for in Articles 36, 37 and 38 of this Directive, the marketingauthorisation holder shall additionally ensure that all suspected serious
adverse reactions and human adverse reactions occurring in the
Community are reported in such a way so as to be accessible to thereference Member State or a competent authority designated as refer-ence Member State. The reference Member State shall assumeresponsibility for the analysis and follow-up of any such adverse reac-tions.
5. Unless other requirements have been laid down as a condition for
the granting of the marketing authorisation or subsequently as indicatedin the guidelines referred to in Article 77(1), reports of all adversereactions shall be submitted to the competent authorities in the formof a periodic safety update report, immediately upon request or at leastevery six months after authorisation until the placing on the market.
Periodic safety update reports shall also be submitted immediately
upon request or at least every six months during the first two yearsfollowing the initial placing on the market and once a year for thefollowing two years. Thereafter, the reports shall be submitted atthree-yearly intervals, or immediately upon request.
The periodic safety update reports shall include a scientific evaluation
of the risk-benefit balance of the veterinary medicinal product.
6. Amendments to paragraph 5 may be adopted in accordance with
the procedure referred to in Article 89(2) in the light of the experiencegained from its operation.
7. Following the granting of a marketing authorisation, the holder of
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to in paragraph 5 of this Article in accordance with the procedure laid
down by Commission Regulation (EC) No 1084/2003 (1).
8. The holder of a marketing authorisation may not communicate
information relating to pharmacovigilance concerns to the generalpublic in relation to its authorised veterinary medicinal product withoutgiving prior or simultaneous notification to the competent authority.
In any case, the marketing authorisation holder shall ensure that such
information is presented objectively and is not misleading.
Member States shall take the necessary measures to ensure that a
marketing authorisation holder who fails to discharge these obligationsis subject to effective, proportionate and dissuasive penalties.
Article 76
1. The Agency, in collaboration with Member States and the
Commission, shall set up a data-processing network to facilitate the
exchange of pharmacovigilance information regarding veterinarymedicinal products marketed in the Community in order to allow thecompetent authorities to share the information at the same time.
2. Making use of the network foreseen in the first paragraph,
Member States shall ensure that reports of suspected serious adverse
reactions and human adverse reactions, in accordance with theguidance referred to in Article 77(1), that have taken place on theirterritory are immediately made available to the Agency and the otherMember States, and in any case within 15 calendar days of their noti-
fication, at the latest.
3. The Member States shall ensure that reports of suspected serious
adverse reactions and human adverse reactions, that have taken placeon their territory are immediately made available to the marketing
authorisation holder, and in any case within 15 calendar days of their
notification at the latest.
Article 77
1. In order to facilitate the exchange of information about pharma-
covigilance within the Community, the Commission, in consultationwith the Agency, Member States and the interested parties, shall drawup guidance on the collection, verification and presentation of adverse
reaction reports, including technical requirements for electronic
exchange of veterinary pharmacovigilance information in accordancewith internationally agreed terminology.
In accordance with those guidelines, the marketing authorisation holder
shall use internationally agreed veterinary medical terminology for the
transmission of reports on adverse reactions.
The Commission shall publish the guidelines, which shall take account
of international harmonisation work achieved in the field of pharma-covigilance.
2. For the interpretation of the definitions referred to in Article 1
points 10 to 16 and principles outlined in this title, the marketingauthorisation holder and the competent authorities shall refer to thedetailed guidance referred to in paragraph 1.
Article 78
1. Where, as a result of the evaluation of veterinary pharmacovigi-
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should be suspended, withdrawn or varied to restrict the indications or
availability, amend the posology, add a contraindication or add a newprecautionary measure, it shall forthwith inform the Agency, the other
Member States and the marketing authorization holder.
2. If urgent action is necessary for protecting human or animal
health, the Member State concerned may suspend the marketing author-isation of a veterinary medicinal product, provided that the Agency, theCommission and the other Member States are informed on thefollowing working day at the latest.
3. When the Agency is informed in accordance with paragraphs 1 or
2, it shall give its opinion as soon as possible, according to the urgencyof the matter.
On the basis of this opinion, the Commission may request all Member
States in which the veterinary medicinal is marketed to take temporarymeasures immediately.
Final measures shall be adopted in accordance with the procedure
referred to in Article 89(3).
Article 79
Any amendments which may be necessary to update the provisions of
Articles 72 to 78 to take account of scientific and technical progressshall be adopted in accordance with the procedure referred to in Article89(2).
TITLE VIII
SUPERVISION AND SANCTIONS
Article 80
1. The competent authority of the Member State concerned shall
ensure, by means of repeated inspections and, if necessary, unan-nounced inspections, and where appropriate, by asking an OfficialMedicines Control Laboratory or a laboratory designated for thatpurpose to conduct tests on samples, that the legal requirementsrelating to veterinary medicinal products are complied with.
The competent authority may also carry out unannounced inspections
at the premises of manufacturers of active substances used as startingmaterials for veterinary medicinal products, and of the premises of themarketing authorisation holder whenever it considers that there are
grounds for suspecting non-compliance with the provisions of Article
51. Such inspections may also be carried out at the request of anotherMember State, the Commission or the Agency.
In order to verify whether the data submitted in order to obtain a
conformity certificate comply with the monographs of the European
Pharmacopoeia, the standardisation body for nomenclatures and qualitynorms within the meaning of the Convention relating to the elaborationof a European Pharmacopoeia (
1) (European Directorate for the Quality
of Medicines) may ask the Commission or the Agency to request suchan inspection when the starting material concerned is the subject of a
European Pharmacopoeia monograph.
The competent authority of the Member State concerned may carry out
inspections of starting material manufacturers at the manufacturer'sown request.2001L0082 — EN — 30.04.2004 — 001.001 — 45
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Such inspections shall be carried out by authorised representatives of
the competent authority who shall be empowered to:
(a) inspect manufacturing or trading establishments and any labora-
tories entrusted by the holder of the manufacturing authorisationwith the task of carrying out control tests pursuant to Article 24;
(b) take samples including with a view to an independent analysis by
an Official Medicines Control Laboratory or by a laboratory desig-
nated for that purpose by a Member State;
(c) examine any documents relating to the object of the inspection,
subject to the provisions in force in the Member States on 9 October
1981 placing restrictions on these powers with regard to thedescription of the manufacturing method;
(d) inspect the premises, records and documents of marketing authori-
sation holders or any firms performing the activities described inTitle VII, and in particular Articles 74 and 75 thereof, on behalfof a marketing authorisation holder.
2. Member States shall take all appropriate measures to ensure that
the manufacturing processess used in the manufacture of immunolo-gical veterinary medicinal products are completely validated andbatch-to-batch consistency is ensured.
3. The authorised representatives of the competent authority shall
report after each of the inspections mentioned in paragraph 1 onwhether the principles and guidelines on good manufacturing practicereferred to in Article 51 or, where appropriate, the requirements set
out in Title VII, are being complied with. The inspected manufacturer
or market authorisation holder shall be informed of the content of suchreports.
4. Without prejudice to any arrangements which may have been
concluded between the Community and a third country, a MemberState, the Commission or the Agency may require a manufacturer
established in a third country to undergo an inspection as referred to
in paragraph 1.
5. Within 90 days after an inspection as referred to in paragraph 1, a
certificate of good manufacturing practice shall be issued to the manu-facturer if the inspection established that the manufacturer in question
is complying with the principles and guidelines on good manufacturing
practice as provided for by Community law.
In the event of an inspection carried out at the request of the European
Pharmacopoeia, a certificate of compliance with the monograph shallbe issued, if appropriate.
6. Member States shall enter the certificates of good manufacturing
practice which they issue in a Community database managed by the
Agency on behalf of the Community.
7. If the outcome of the inspection as referred to in paragraph 1 is
that the manufacturer does not comply with the principles and guide-lines of good manufacturing practice as provided for by Community
legislation, the information shall be entered in the Community database
as referred to in paragraph 6.
Article 81
1. Member States shall take all appropriate measures to ensure that
the marketing authorization holder and, where appropriate, the holder
of the manufacturing authorization furnish proof of the control testscarried out on the veterinary medical product and/or on the constituentsand intermediate products of the manufacturing process, in accordancewith the methods laid down for the purposes of marketing authoriza-tion.2001L0082 — EN — 30.04.2004 — 001.001 — 46
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2. For the purposes of implementing paragraph 1, Member States
may require the marketing authorization holder for immunologicalveterinary medicinal products to submit to the competent authorities
copies of all the control reports signed by the qualified person in accor-
dance with Article 55.
The marketing authorization holder for immunological veterinary
medicinal products shall ensure that an adequate number of representa-tive samples of each batch of veterinary medical products is held instock at least up to the expiry date, and provide samples promptly tothe competent authorities on request.
Article 82
1. Where it considers it necessary for reasons of human or animal
health, a Member State may require the marketing authorisation holder
for an immunological veterinary medicinal product to submit samples
of batches of the bulk product and/or veterinary medicinal product forcontrol by an Official Medicines Control Laboratory before the productis put into circulation.
2. On request by the competent authorities, the marketing authorisa-
tion holder shall promptly supply the samples referred to in paragraph1, together with the reports of the control referred to in Article 81(2).
The competent authority shall inform all the other Member States in
which the veterinary medicinal product is authorised as well as theEuropean Directorate for the Quality of Medicines of its intention tocontrol batches or the batch in question.
In such cases, the competent authorities of another Member State shall
not apply the provisions of paragraph 1.
3. After studying the control reports referred to in Article 81(2), the
laboratory responsible for the control shall repeat, on the samplesprovided, all the tests carried out by the manufacturer on the finishedproduct, in accordance with the relevant provisions shown in thedossier for marketing authorisation.
The list of tests to be repeated by the laboratory responsible for the
control shall be restricted to justified tests, provided that all MemberStates concerned, and if appropriate the European Directorate for the
Quality of Medicines, agree to this.
For immunological veterinary medicinal products authorised under
Regulation (EC) No 726/2004, the list of tests to be repeated by the
control laboratory may be reduced only after agreement by the Agency.
4. All Member States concerned shall recognise the results of the
tests.
5. Unless the Commission is informed that a longer period is neces-
sary to conduct the tests, Member States shall ensure that this control is
completed within 60 days of receipt of the samples.
The competent authority shall notify the other Member States
concerned, the European Directorate for the Quality of Medicines, the
marketing authorisation holder and, if appropriate, the manufacturer, of
the results of the tests within the same period of time.
If a competent authority concludes that a batch of a veterinary medic-
inal product is not in conformity with the control report of the
manufacturer or the specifications provided for in the marketingauthorisation, it shall take all the necessary measures vis-a-vis themarketing authorisation holder and the manufacturer, where appro-priate, and shall inform accordingly the other Member States in whichthe veterinary medicinal product is authorised.2001L0082 — EN — 30.04.2004 — 001.001 — 47
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Article 83
1.►M1 Member States' competent authorities shall suspend,
revoke, withdraw or vary marketing authorisations when it is clearthat:◄
(a) the risk-benefit assessment of the veterinary medicinal product is,
under the authorised conditions of use, unfavourable, particularregard being had to the benefits for animal health and welfare andto consumer safety, when the authorisation concerns a veterinarymedicinal product for zootechnical use;
(b) the veterinary medicinal product does not have any therapeutic
effect on the species of animal for which the treatment is intended;
(c) its qualitative and quantitative composition is not as stated;
(d) the recommended withdrawal period is inadequate to ensure that
foodstuffs obtained from the treated animal do not contain residueswhich 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;
(f) information given in the application documents pursuant to Articles
12 to 13d and 27 is incorrect;
(g) the control tests referred to in Article 81(1) have not been carried
out.
However, when a Community legislative framework is in the course of
being adopted, the competent authority may refuse authorisation for a
veterinary medicinal product where such action is necessary for theprotection of public health, consumer and animal health.
2.►
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withdrawn or varied when it is established that: ◄
(a) the particulars supporting the application, as provided for in Arti-
cles 12 to 13d, have not been amended in accordance with Article27(1) and (5);
(b) any new information as referred to in Article 27(3) has not been
communicated to the competent authorities.
Article 84
1. Without prejudice to Article 83, Member States shall take all
necessary measures to ensure that supply of a veterinary medicinal
product is prohibited and that the medicinal product concerned is with-drawn form the market where:
(a) it is clear that the risk-benefit assessment of the veterinary medic-
inal product is, under the authorised conditions of use,unfavourable, particular regard being had to the benefits for animalhealth and welfare and to the safety and health benefits for theconsumer, when the authorisation concerns a veterinary medicinalproduct for zootechnical use;2001L0082 — EN — 30.04.2004 — 001.001 — 48
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(b) the veterinary medicinal product has no therapeutic effect on the
species of animal for which the treatment was intended;
(c) the qualitative and quantitative composition of the veterinary
medicinal product is not as stated;
(d) the recommended withdrawal period is inadequate to ensure that
foodstuffs obtained from the treated animal do not contain residueswhich might constitute a health hazard to the consumer;
(e) the control tests referred to in Article 81(1) have not been carried
out, or any other requirement or obligation relating to the grant ofthe manufacturing authorization referred to in Article 44(1) has notbeen complied with.
2. The competent authority may confine the prohibition on supply
and withdrawal from the market solely to the contested productionbatches.
Article 85
1. The competent authority of a Member State shall suspend or
withdraw the manufacturing authorization for a category of prepara-tions or for all preparations if any of the requirements laid down inArticle 45 are no longer met.
2. The competent authority of a Member State may, in addition to
the measures provided for in Article 84, either suspend manufacture
or imports of veterinary medicinal products from third countries orsuspend or withdraw the manufacturing authorization for a category ofpreparations or for all preparations in the event of non-compliance withthe provisions regarding manufacture or imports from third countries.
3. Member States shall prohibit the advertising to the general public
of veterinary medicinal products that:
(a) in accordance with Article 67, are available on veterinary prescrip-
tion only; or
(b) contain psychotropic drugs or narcotics, such as those covered by
the United Nations Conventions of 1961 and 1971.
Article 86
The provisions of this Title shall apply to homeopathic veterinary
medicinal products.
Article 87
Member States shall take appropriate measures to encourage veterinar-
ians and other professionals concerned to report to the competent
authorities any adverse reaction of veterinary medicinal products.
TITLE IX
STANDING COMMITTEE
Article 88
Any changes which are necessary in order to adapt Annex I to take
account of technical progress shall be adopted in accordance with theprocedure referred to in Article 89(2).
Article 89
1. The Commission shall be assisted by a Standing Committee on
Veterinary Medicinal Products for the Adaptation to Technical Progressof the Directives on the Removal of Technical Barriers to Trade in theVeterinary Medicinal Products Sector, (hereinafter referred to as the‘Standing Committee’.2001L0082 — EN — 30.04.2004 — 001.001 — 49
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2. Where reference is made to this paragraph, Articles 5 and 7 of
Decision 1999/468/EC shall apply, having regard to the provisions ofArticle 8 thereof.
The period laid down in Article 5(6) of Decision 1999/468/EC shall be
set at three months.
3. Where reference is made to this paragraph, Articles 4 and 7 of
Decision 1999/468/EC shall apply, having regard to the provisions ofArticle 8 thereof.
The period laid down in Article 4(3) of Decision 1999/468/EC shall be
set at one month.
4. The Standing Committee shall adopt its rules of procedure. These
rules of procedure shall be made public.
TITLE X
GENERAL PROVISIONS
Article 90
Member States shall take all necessary measures to ensure that the
competent authorities concerned communicate the appropriate informa-tion to each other, particularly regarding compliance with therequirements adopted for the authorisations referred to in Article 44,for the certificates referred to in Article 80(5) or for authorisation to
place products on the market.
Upon reasoned request, Member States shall forthwith communicate
the reports referred to in Article 80(3) to the competent authorities of
another Member State.
The conclusions reached following an inspection as referred to in
Article 80(1) carried out by the inspectors of the Member State
concerned shall be valid for the Community.
However, by way of exception, if a Member State has not been able,
for serious reasons of human or animal health, to accept the conclu-
sions of an inspection as referred to in Article 80(1), that Member
State shall forthwith inform the Commission and the Agency. TheAgency shall inform the Member States concerned.
When the Commission is informed of such serious reasons, it may,
after consulting the Member States concerned, ask the inspector of thecompetent supervisory authority to carry out a new inspection; theinspector may be accompanied by two other inspectors from MemberStates that are not parties to the disagreement.
Article 91
1. Each Member State shall take all appropriate measures to ensure
that the Agency is informed immediately of decisions grantingmarketing authorization and of all decisions refusing or withdrawingmarketing authorization, cancelling a decision refusing or withdrawingmarketing authorization, prohibiting supply or withdrawing a productfrom the market, together with the reasons on which such decisions
are based.
2. The marketing authorization holder shall be obliged to notify the
Member States forthwith of any action taken by him to suspend the
marketing of a veterinary medicinal product or to withdraw a product
from the market, together with the reasons for such action if it concernsthe effectiveness of the veterinary medicinal product or the protectionof public health. Member States shall ensure that this information isbrought to the attention of the Agency.
3. Member States shall ensure that appropriate information about
actions taken pursuant to paragraphs 1 and 2 which may affect theprotection of health in third countries is forthwith brought to the atten-2001L0082 — EN — 30.04.2004 — 001.001 — 50
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tion of the relevant international organizations, with a copy to the
Agency.
Article 92
Member States shall communicate to each other all the information
necessary to guarantee the quality and safety of homeopathic veterinarymedicinal products manufactured and marketed within the Community,and in particular the information referred to in Articles 90 and 91.
Article 93
1. At the request of the manufacturer or exporter of veterinary
medicinal products, or the authorities of an importing third country,Member States shall certify that such manufacturer is in possession ofthe manufacturing authorization. When issuing such certificates,Member States shall comply with the following conditions:
(a) they shall have regard to the prevailing administrative arrange-
ments of the World Health Organization;
(b) for veterinary medicinal products intended for export which are
already authorized in their territory, they shall supply the summary
of the product characteristics as approved in accordance withArticle 25 or, in the absence thereof, an equivalent document.
2. Where the manufacturer is not in possession of an authorization
to place the product on the market, he shall provide the authoritiesresponsible for establishing the certificate referred to in the first para-graph with a declaration explaining why such authorization is notavailable.
Article 94
Any decision referred to in this Directive, taken by the competent
authorities of the Member States, may only be taken on the groundsset out in this Directive and shall state in detail the reasons on whichit is based.
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
current legislation and the time allowed for seeking such remedies.
Decisions to grant or revoke a marketing authorisation shall be made
publicly available.
Article 95
Member States shall not permit foodstuffs for human consumption to
be taken from test animals unless the competent authorities have estab-lished an appropriate withdrawal period. The withdrawal period shalleither:
(a) be at least as laid down in Article 11(2), including, where appro-
priate, a safety factor reflecting the nature of the substance beingtested; or
(b) if maximum residue limits have been established by the Commu-
nity in accordance with Regulation (EEC) No 2377/90, ensure thatthis maximum limit will not be exceeded in foodstuffs.
Article 95a
Member States shall ensure that appropriate collection systems are in
place for veterinary medicinal products that are unused or expired.
Article 95b
When a veterinary medicinal product is to be authorised in accordance
with Regulation (EC) No 726/2004 and the Scientific Committee in itsopinion refers to recommended conditions or restrictions with regard tothe safe and effective use of the veterinary medicinal product as2001L0082 — EN — 30.04.2004 — 001.001 — 51
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provided for in Article 34(4)(d) of that Regulation, a decision
addressed to Member States shall be adopted in accordance with theprocedure laid down in Articles 37 and 38 of this Directive, for the
implementation of those conditions or restrictions.
TITLE XI
FINAL MEASURES
Article 96
Directives 81/851/EEC, 81/852/EEC, 90/677/EEC and 92/74/EEC
referred to in Annex II, Part A are repealed, without prejudice to theobligations of the Member States in respect of the deadline for transpo-sition laid down in Annex II, Part B.
The reference made to the said Repealed Directives shall be construed
as references to this Directive and should be read in accordance with
the correlation table set out in Annex III.
Article 97
This Directive enters into force on the 20
thday following that of its
publication in the Official Journal of the European Communities .
Article 98
This Directive is addressed to the Member States.2001L0082 — EN — 30.04.2004 — 001.001 — 52
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ANNEX I
REQUIREMENTS 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 pursuant to Articles 12 and 13(1) shall be presented in accordance
with the requirements set out in this Annex and taking account of the guidance
contained in the ‘Notice to applicants for marketing authorizations for veterinary
medicinal products in the Member States of the European Community’,
published by the Commission in The rules governing medicinal products in the
European Community , volume V: Veterinary Medicinal Products .
In assembling the dossier for application for marketing authorization, applicants
shall take into account the Community guidelines relating to the quality, safety
and efficacy of veterinary medicinal products published by the Commission in
The rules governing 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 unfavour-
able to the product. In particular, all relevant details shall be given of any
incomplete or abandoned test or trial relating to the veterinary medicinal
product. Moreover, after marketing authorization, any information not in the
original application, pertinent to the benefit/risk assessment, shall be submitted
forthwith to the competent authority.
Member States ensure that all experiments on animals are conducted in accor-
dance 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 scien-
tific purposes (1).
The provisions of Title I of this Annex shall apply to veterinary medicinal
products other than immunological veterinary medicinal products.
The provisions of Title II of this Annex shall apply to immunological veterinary
medicinal products.
TITLE I
Requirements for veterinary medicinal products other than immunological
veterinary medicinal products
PART 1
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 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 manufacturers and the sites involved in the different stages
of the manufacture (including the manufacturer of the finished product and the
manufacturer(s) of the active substance(s)), and where relevant the name and
address of the importer.
The applicant shall identify the number 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 manu-
facturer is authorized to produce the veterinary medicinal products concerned, as
defined in Article 44, together with a list of countries in which authorization has
been granted, copies of all the summaries of product characteristics in accor-
dance with Article 14 as approved by Member States and a list of countries in
which an application has been submitted.2001L0082 — EN — 30.04.2004 — 001.001 — 53
(1) OJ L 358, 18.12.1986, p. 1.
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B. SUMMARY OF PRODUCT CHARACTERISTICS
The applicant shall propose a summary of the product characteristics, in accor-
dance 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 product, together with a
package insert where one is required.
C. EXPERT REPORTS
In accordance with Article 15(2) and (3), expert reports must be provided on the
analytical documentation, the pharmacotoxicological documentation, the resi-
dues documentation and the clinical documentation.
Each expert report shall consist of a critical evaluation of the various tests and/
or trials which have been carried out in accordance with this Directive, and
bring out all the data relevant for evaluation. The expert shall give his opinion
as to whether sufficient guarantees have been provided as to the quality, safety
and efficacy of the product concerned. A factual summary is not sufficient.
All important data shall be summarized in an appendix to the expert report,
whenever possible in tabular or graphic form. The expert report and the summa-
ries shall contain precise cross references to the information contained in the
main documentation.
Each expert report shall be prepared by a suitably qualified and experienced
person. It shall be signed and dated by the expert, and attached to the report
shall be brief information about the educational background, training and occu-
pational experience of the expert. The professional relationship of the expert to
the applicant shall be declared.
PART 2
Analytical (physico-chemical, biological or microbiological) tests of veter-
inary medicinal products other than immunological veterinary medicinal
products
All test procedures shall correspond to the state of scientific progress at the time
and shall be validated procedures; results of the validation studies shall be
provided.
All the test procedure(s) shall be described in sufficiently precise detail so as to
be reproducible in control tests, carried out at the request of the competent
authority; any special apparatus and equipment which may be used shall bedescribed 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 the European Pharmaco-
poeia 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 submitted 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, stabilisers,
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, gela-
tine capsules, etc.
These particulars shall be supplemented by any relevant data concerning
the container and, where appropriate, its manner of closure, together with
details of devices with which the medicinal product will be used or admi-
nistered and which will be delivered with the medicinal product.
2. The ‘usual terminology’, to be used in describing the constituents of medic-
inal 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 Member2001L0082 — EN — 30.04.2004 — 001.001 — 54
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States, the main title at the head of the monograph in question, with
reference to the pharmacopoeia concerned,
— in respect of other substances, the international non-proprietary name
recommended by the World Health Organization (WHO), 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, supple-
mented, where appropriate, by any other relevant details,
— in respect of colouring matter, designation by the ‘E’ code assigned to
them in Council Directive 78/25/EEC of 12 December 1977 on the
approximation of the rules of the Member States concerning the
colouring matters authorized for use in medicinal products (1).
3. Quantitative particulars
3.1. In order to give ‘quantitative particulars’ of 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-unit 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 unambiguous 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 the 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 preparation,
— in respect of syrups, emulsions, granular preparations and other pharma-
ceutical forms to be administered in measured quantities, by the mass
or units of biological activity of each active substance per measured
quantity.
3.2. Active substances present in the form of compounds or derivatives shall be
described quantitatively by their total mass, and if necessary or relevant, by
the mass of the active entity or entities of the molecule.
3.3. For medicinal products containing an active substance which is the subject
of an application for marketing authorization in any Member State for the
first time, the quantitative statement of an active substance which is a salt
or hydrate shall be systematically expressed in terms of the mass of the
active entity or entities in the molecule. All subsequently authorized medic-
inal products in the Member States shall have their quantitative
composition stated in the same way for the same active substance.
4. Development pharmaceutics
An explanation shall be provided with regard to the choice of composition,
constituents and container and the intended function of the excipients in the
finished product. This explanation shall be supported by scientific data on
development pharmaceutics. The overage, with justification thereof, shall
be stated.
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,2001L0082 — EN — 30.04.2004 — 001.001 — 55
(1) OJ L 11, 14.1.1978, p. 18. Directive as last amended by the 1985 Act of Accession.
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— 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 neces-
sary; mention shall be made of any substances that may disappear in the
course of manufacture; any overage shall be indicated and justified,
— a statement of the stages of manufacture at which sampling is carried out for
in-process control tests, where other data in the documents supporting the
application show such tests to be necessary for the quality control of the
finished product,
— experimental studies validating the manufacturing process, where a non-stan-
dard method of manufacture is used or where it is critical for the product,
— for sterile products, details of the sterilization processes and/or aseptic proce-
dures used.
C. CONTROL OF STARTING MATERIALS
1. For the purposes of this paragraph, ‘starting materials’ shall mean all the
constituents of the medicinal product and, if necessary, of its container, as
referred to in Section A, point 1, above.
In the case of:
— an active substance not described in the European Pharmacopoeia or in
the pharmacopoeia of a Member State,
— an active substance described in the European Pharmacopoeia or in the
pharmacopoeia of a Member State when prepared by a method liable to
leave impurities not mentioned in the pharmacopoeial monograph and
for which the monograph is 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 manufacturing method,
quality control during manufacture and process validation to be supplied
directly to the competent authorities by the manufacturer of the active
substance. In this case, the manufacturer shall however provide the appli-
cant 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 applica-
tion 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 (j) 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 pharmacopoeias
The monographs of the European Pharmacopoeia shall be applicable to all
substances appearing in it.
In respect of other substances, each Member State may require observance
of its own national pharmacopoeia with regard to products manufactured in
its territory.
Constituents fulfilling the requirements of the European Pharmacopoeia or
the pharmacopoeia of one of the Member States shall be deemed to comply
sufficiently with Article 12(3)(i). In this case the description of the analy-
tical methods may be replaced by a detailed reference to the
pharmacopoeia in question.
However, where a starting material in the European Pharmacopoeia or in
the pharmacopoeia of a Member State has been prepared by a method
liable to leave impurities not controlled in the pharmacopoeia monograph,
these impurities and their maximum tolerance limits must be declared and a
suitable test procedure must be described.
Colouring matter shall, in all cases, satisfy the requirements of Council
Directive 78/25/EEC.
The routine tests carried out on each batch of starting materials must be as
stated in the application for marketing authorization. If tests other than
those mentioned in the pharmacopoeia are used, proof must be supplied
that the starting materials meet the quality requirements of that pharmaco-
poeia.2001L0082 — EN — 30.04.2004 — 001.001 — 56
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In cases where a specification contained in a monograph of the European
Pharmacopoeia or in the national pharmacopoeia of a Member State might
be insufficient to ensure the quality of the substance, the competent autho-
rities 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 accompa-
nied where necessary by the validation of the test procedures contained in
the monograph and by a translation where appropriate.
1.2. Starting materials not in a pharmacopoeia
Constituents which are not given in any pharmacopoeia shall be described
in the form of a monograph under the following headings:
(a) the name of the substance, meeting the requirements of Section A point
2, shall be supplemented by any trade or scientific synonyms;
(b) the definition of the substance, set down in a form similar to that used
in the European Pharmacopoeia , shall be accompanied by any neces-
sary 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 suffi-
ciently detailed to characterise 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 carried out as a routine matter;
(d) purity tests shall be described in relation to the sum total of predictable
impurities, especially those which may have a harmful effect, and, if
necessary, those which, having regard to the combination of substances
to which the application refers, might adversely affect the stability of
the medicinal product or distort analytical results;
(e) with regard to complex substances of plant or animal origin, a distinc-
tion must be made between the case where multiple pharmacological
effects render chemical, physical or biological control of the principal
components necessary, and the case of substances containing one or
more groups of principles having similar activity, in respect of which
an overall method of assay may be accepted;
(f) when materials of animal origin are used, measures to ensure freedom
from potentially pathogenic agents shall be described;
(g) any special precautions that may be necessary during storage of the
starting material and, if necessary, the maximum period of storage
before retesting shall be given.
1.3. Physico-chemical characteristics liable to affect bioavailability
The following items of information concerning active substances, whether
or not listed in the pharmacopoeias, shall be provided as part of the general
description of 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,
— oil/water coefficient of partition (
1).
The first three indents are not applicable to substances used solely in solu-
tion.
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 veter-
inary medicinal products, the origin and history of starting materials shall
be described and documented.2001L0082 — EN — 30.04.2004 — 001.001 — 57
(1) The competent authorities may also request the pK/pH values if they think that this
information is essential.
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The description of the starting material shall include the manufacturing
strategy, purification/inactivation procedures with their validation and all
in-process control procedures designed to ensure the quality, safety and
batch to batch consistency of the finished product.
2.1. When cell banks are used, the cell characteristics shall be shown to have
remained unchanged at the passage level used for the production and
beyond.
2.2. Seed materials, cell banks, pools of serum and other material of biological
origin and, whenever possible, the source materials from which they are
derived shall be tested for adventitious agents.
If the presence of potentially pathogenic adventitious agents is inevitable,
the material shall be used only when further processing ensures their elim-
ination and/or inactivation, and this shall be validated.
D. SPECIFIC MEASURES CONCERNING THE PREVENTION OF THE
TRANSMISSION OF ANIMAL SPONGIFORM ENCEPHALOPATHIES
The applicant must demonstrate that the veterinary medical product is manufac-
tured in accordance with the Note for Guidance on minimising the risk of
transmitting animal spongiform encephalopathy agents via veterinary medicinal
products and its updates, published by the European Commission in Volume 7
of its publication ‘The rules governing medicinal products in the European
Community’.
E. CONTROL TESTS CARRIED OUT AT INTERMEDIATE STAGES OF
THE MANUFACTURING PROCESS
The particulars and documents accompanying an application for marketing
authorization, pursuant to Article 12(3)(i) and (j) 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 ensuring
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, particularly if the substance is essentially defined by its
manufacturing method.
F. 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 continuous
production process, all the units manufactured in a given period of time.
The application for marketing authorization shall list 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
shall be indicated.
The particulars and documents accompanying the application for marketing
authorization pursuant to Article 12(3)(i) and (j) and also Article 13(1),
shall include particulars relating to control tests on the finished product at
release. They shall be submitted in accordance with the following require-
ments.
The provisions of the general monographs of the European Pharmaco-
poeia , or failing that, of a Member State, shall 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.
1.1. General characteristics of the finished product
Certain tests of the general characteristics of a product shall always be
included among the tests on the finished product. These tests shall, wher-
ever applicable, relate to the control of average masses and maximum2001L0082 — EN — 30.04.2004 — 001.001 — 58
▼B
deviations, to mechanical, physical or microbiological tests, organoleptic
characteristics, physical characteristics such as density, pH, refractive
index, etc. For each of these characteristics, standards and tolerance limits
shall be specified by the applicant in each particular case.
The conditions of the tests, where appropriate, the equipment/apparatus
employed and the standards shall be described in precise details whenever
they are not given in the European Pharmacopoeia or the pharmacopoeia
of the Member States; the same shall apply in cases where the methods
prescribed by such pharmacopoeias are not applicable.
Furthermore, solid pharmaceutical forms having to be administered orally
shall be subjected to in vitro studies on the liberation and dissolution rate
of the active substance or substances; these studies shall also be carried out
where administration is by another means if the competent authorities of
the Member State concerned consider this necessary.
1.2. Identification and assay of active substance(s)
Identification and assay 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.
Unless there is appropriate justification, the maximum acceptable deviation
in the active substance content of the finished product shall not exceed
± 5 % at the time of manufacture.
On the basis of the stability tests, the manufacturer must propose and
justify maximum acceptable tolerance limits in the active substance content
of the finished product up to the end of the proposed shelf-life.
In certain exceptional cases of particularly complex mixtures, where assay
of active substances which are very numerous or present in very low
amounts would necessitate an intricate investigation difficult to carry out
in respect of each production batch, the assay of one or more active
substances in the finished product may be omitted, on the express condition
that such assays are made at intermediate stages in the production process.
This relaxation may not be extended to the characterization of the
substances concerned. This simplified technique shall be supplemented by
a method of quantitative evaluation, enabling the competent authority to
have the conformity of the medicinal product with its specification verified
after it has been placed on the market.
Anin vivo orin vitro biological assay shall be obligatory when physico-
chemical methods cannot provide adequate information on the quality of
the product. Such an assay shall, whenever possible, include reference
materials and statistical analysis allowing calculation of confidence limits.
Where these tests cannot be carried out on the finished product, they may
be performed at an intermediate stage, as late as possible in the manufac-
turing process.
Where the particulars given in section B show that a significant overage of
an active substance is employed in the manufacture of the medicinal
product, the description of the control tests on the finished product shall
include, where appropriate, the chemical and, if necessary, the toxico-phar-
macological investigation of the changes that this substance has undergone,
and possibly the characterization and/or assay of the degradation products.
1.3. Identification and assay of excipient 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 78/25/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 adversely physiological functions; an upper and lower limit test shall
be obligatory in respect of the excipient if it is liable to affect the bio-avail-
ability 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 under-
taken as a matter of routine in order to verify the quality of the product.2001L0082 — EN — 30.04.2004 — 001.001 — 59
▼B
G. STABILITY TEST
The particulars and documents accompanying the application for marketing
authorization pursuant to Article 12(3)(f) and (i) shall be submitted in accor-
dance 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 required, supported
by relevant stability data.
In the case of multi-dose vials, stability data shall be presented to justify a shelf
life for the vial after it has been punctured for the first time.
Where a finished product is liable to give rise to degradation products, the appli-
cant must declare these and indicate characterization methods and test
procedures.
The conclusions shall contain the results of analyses, justifying the proposed
shelf life under the recommended storage conditions and the specifications of
the finished product at the end of the shelf life of the finished product under
these recommended storage conditions.
The maximum acceptable 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.
PART 3
Safety and residues testing
The particulars and documents which shall accompany the application for
marketing authorization pursuant to Articles 12(3)(j) and 13(1) shall be
submitted in accordance with the requirements below.
Member States shall ensure that the tests are carried out in accordance with the
provisions relating to good laboratory practice laid down by Council Directive
87/18/EEC of 18 December 1986 on the harmonization of laws, regulations
and administrative provisions relating to the application of the principles of
good laboratory practice and the verification of their applications for tests on
chemical substances (1) and Council Directive 88/320/EEC of 9 June 1988 on
the inspection and verification of good laboratory practice (GLP) (2).
A. SAFETY TESTING
Chapter I
Performance of tests
1. Introduction
The safety documentation shall show:1. the potential toxicity of the medicinal product and any dangerous or
undesirable effects which may occur under the proposed conditions
of use in animals; these should be evaluated in relation to the severity
of the pathological condition concerned;
2. the potential harmful effects to man of residues of the veterinary
medicinal product or substance in foodstuffs obtained from treated
animals and what difficulties these residues may create in the indus-
trial processing of foodstuffs;
3. the potential risks which may result from the exposure of human
beings to the medicinal product, for example during its administration
to the animal;2001L0082 — EN — 30.04.2004 — 001.001 — 60
(1) OJ L 15, 17.1.1987, p. 29. Directive as last amended by Commission Directive 1999/
11/EC (OJ L 77, 23.3.1999, p. 8).
(2) OJ L 145, 11.6.1988, p. 35. Directive as last amended by Commission Decision 1999/
12/EC (OJ L 77, 23.3.1999, p. 22).
▼B
4. the potential risks for the environment resulting from the use of the
medicinal product.
All results shall be reliable and valid generally. Whenever appropriate,
mathematical and statistical procedures shall be used in designing the
experimental methods and in evaluating the results. Additionally, clini-
cians shall be given information about the therapeutic potential of the
product and about the hazards connected with its use.
In some cases it may be necessary to test the metabolites of the parent
compound where these represent the residues of concern.
An excipient used in the pharmaceutical field for the first time shall be
treated like an active substance.
2. Pharmacology
Pharmacological studies are of fundamental importance in clarifying the
mechanisms by which the medicinal product produces its therapeutic
effects and therefore pharmacological studies conducted in experimental
and target species of animal should be included in Part 4.
However, pharmacological studies may also assist in the understanding of
toxicological phenomena. Moreover, where a medicinal product produces
pharmacological effects in the absence of a toxic response, or at doses
lower than those required to elicit toxicity, these pharmacological effects
shall be taken into account during the evaluation of the safety of the
medicinal product.
Therefore the safety documentation shall always be preceded by details of
pharmacological investigations undertaken in laboratory animals and all
relevant information observed during clinical studies in the target animal.
3. Toxicology
3.1. Single-dose toxicity
Single-dose toxicity studies can be used to predict:
— the possible effects of acute overdosage in the target species,
— the possible effects of accidental administration to humans,— the doses which may usefully be employed in the repeat dose studies.
Single dose toxicity studies should reveal the acute toxic effects of the
substance and the time course for their onset and remission.
These studies should normally be carried out in at least two mammalian
species. One mammalian species may be replaced, if appropriate, by an
animal species for which the medicinal product is intended. At least two
different routes of administration should normally be studied. One of
these may be the same as, or similar to, that proposed for the 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.
In order to reduce the number and suffering of the animals involved, new
protocols for single dose toxicity testing are continually being developed.
Studies carried out in accordance with these new procedures when prop-
erly 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-producing animals, a repeated dose toxicity study in one species
of experimental animal will normally be sufficient. This study may be
replaced 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 give 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 knowl-
edge of the metabolism of the product in animals and man. The test2001L0082 — EN — 30.04.2004 — 001.001 — 61
▼B
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 beha-
viour, growth, haematology and physiological tests, especially those
relating to the excretory organs, and also on autopsy reports and accom-
panying histological data. The choice and range of each group of tests
depends on the species of animal used and the state of scientific knowl-
edge at the time.
In the case of new combinations of known substances which have been
investigated in accordance with the provisions of this Directive, the
repeated-dose tests may, except where toxicity tests have demonstrated
potentiation or novel toxic effects, be suitably modified by the investi-
gator, who shall submit his reasons for such modifications.
3.3. Tolerance in the target species
Details should be provided of any signs of intolerance which have been
observed during studies conducted in the target species in accordance
with the requirements of Part 4, Chapter I, Section B. The studies
concerned, 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 teratogenicity
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-
producing animals, the study of the effects on reproduction shall be
carried out in the form of a two-generation study on at least one species,
usually a rodent. The substance or product 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 F1 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
teratogenicity, 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 function.
In the case of substances or medicinal products which are not intended
for use in food producing animals, 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.
3.5. Mutagenicity
Mutagenicity tests are intended to assess the potential of substances to
cause transmissible changes in the genetic material of cells.
Any new substance intended for use in veterinary medicinal products
must be assessed for mutagenic properties.2001L0082 — EN — 30.04.2004 — 001.001 — 62
▼B
The number and types of tests and the criteria for the evaluation of the
results shall depend on the state of scientific knowledge when the appli-
cation is submitted.
3.6. Carcinogenicity
Long term animal carcinogenicity studies will usually be required for
substances to which human beings will be exposed
— which have a close chemical analogy with known carcinogens,
— which during mutagenicity testing produced results indicating a possi-
bility 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 carcinogenicity studies and
evaluating their results.
3.7. Exceptions
Where a medicinal product is intended for topical use, systemic absorp-
tion 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).
4. Other requirements
4.1. Immunotoxicity
Where the effects observed during repeated dose studies in animals
include specific changes in lymphoid 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 additional studies
of the effects 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 of residues
4.2.1. Potential effects on the human gut flora
The microbiological risk presented by residues of anti-microbial
compounds for the human intestinal flora shall be investigated in accor-
dance 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 proces-
sing
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 reasons should be stated.
5. Ecotoxicity
5.1. 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 any precautionary
measures which may be necessary to reduce such risks.2001L0082 — EN — 30.04.2004 — 001.001 — 63
▼B
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)(j) and 13(1).
5.3. This assessment shall normally be conducted in two phases.
In the first phase, the investigator shall assess the potential extent of
exposure to the environment of the product, its active substances or rele-
vant metabolites, taking into account:
— 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 relevant
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 exposure of the product
to the environment, and the available information about the physical/
chemical, pharmacological and/or toxicological properties of the
compound which has been 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.
5.5. As appropriate, further investigation may be required of:
— fate and behaviour in soil,
— fate and behaviour in water and air,— effects on aquatic organisms,— effects on other non-target organisms.
These further investigations shall be carried out in accordance with the
test protocols laid down in Annex V of Council Directive 67/548/EEC
of 27 June 1967 on the approximation of laws, regulations and adminis-
trative provisions relating to the classification, packaging and labelling of
dangerous substances (
1), or where an end point is not adequately covered
by these protocols, in accordance with other internationally recognizedprotocols on the veterinary medicinal product and/or the active
substance(s) 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.
Chapter II
Presentation of particulars and documents
As in any scientific work, the dossier of safety tests shall include the following:
(a) an introduction defining the subject, accompanied by any useful bibliogra-
phical references;
(b) the detailed identification of the substance under review, including:
— international non-proprietary name (INN),
— International Union of Pure and Applied Chemistry Name (IUPAC),— Chemical Abstract Service (CAS) number,— therapeutical and pharmacological classification,— synonyms and abbreviations,— structural formula,
— molecular formula,
— molecular weight,— degree of impurity,— qualitative and quantitative composition of impurities,— description of physical properties,— melting point,— boiling point,
— vapour pressure,
— solubility in water and organic solvents expressed in g/l, with indication
of temperature,
— density,2001L0082 — EN — 30.04.2004 — 001.001 — 64
(1) OJ 196, 16.8.1967, p. 1. Directive as last amended by Commission Directive 2000/33/
EC (OJ L 136, 8.6.2000, p. 90).
▼B
— 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 mate-
rials 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);
(d) all the results obtained, whether favourable or unfavourable. The original
data should be described in sufficient detail to allow the results to be criti-
cally evaluated independently of their interpretation by the author. By way
of explanation, 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, 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 and any possible incompatibilities;
(g) a detailed description and a thorough discussion of the results of the study
of the safety of residues in food, and its relevance for the evaluation of
potential risks presented by residues to humans. This discussion shall be
followed by proposals to ensure that any danger to man is eliminated by
applying internationally recognized assessment criteria, for example: no
observed effect level in animals, proposals for a choice of safety factor and
for acceptable daily intake (ADI);
(h) a thorough discussion of any risks for persons preparing the medicinal
product or administering it to animals, followed by proposals for appropriate
measures to reduce such risks;
(i) a thorough discussion of the risks which use of the veterinary medicinal
product under the practical conditions proposed may represent for the envir-
onment followed by appropriate proposals to reduce such risks;
(j) all information necessary to acquaint the clinician as fully as possible with
the utility of the proposed product. The discussion will be supplemented by
suggestions as to side-effects and possible treatment for acute toxic reac-
tions in animals to which the product is to be administered;
(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 knowl-
edge at the time the application is submitted together with a detailed
summary of all the results of the relevant safety tests and precise bibliogra-
phical references.
B. RESIDUE TESTING
Chapter I
Performance of tests
1. Introduction
For the purposes of this Directive, ‘residues’ means all active substances or
metabolites thereof which remain in meat or other foodstuffs produced
from the animal to which the medicinal product in question has been admi-
nistered.
The purpose of studying residues is to determine whether, and if so under
what conditions and to what 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 resi-
dues are present in the animals treated under recommended conditions of
use and investigating the effects of those residues.
In the case of veterinary medicinal products intended for use in food-produ-
cing animals, the residue documentation shall show:
1. to what extent, and how long, do residues of the veterinary medicinal
product or its metabolites persist in the tissues of the treated animal or
foodstuffs obtained therefrom;
2. that in order to prevent any risk to the health of the consumer of food-
stuffs of treated animals, or difficulties in the industrial processing of
foodstuffs, it is possible to establish realistic withdrawal periods which
can be observed under practical farming conditions;2001L0082 — EN — 30.04.2004 — 001.001 — 65
▼B
3. that practical analytical methods suitable for routine use are available to
verify compliance with the withdrawal period.
2. Metabolism and residue kinetics
2.1. Pharmacokinetics (absorption, distribution, biotransformation, excretion)
The purpose of pharmacokinetic studies with respect to residues of veter-
inary medicinal products is to evaluate the absorption, distribution,
biotransformation and excretion of the product in the target species.
The final product, or a formulation which is bioequivalent, shall be admi-
nistered to the target species at the maximum recommended dose.
Having regard to the method of administration, the extent of absorption of
the medicinal product shall be fully described. If it is demonstrated that
systemic absorption of products for topical application is negligible, further
residue studies will not be required.
The distribution of the medicinal product in the target animal shall be
described; the possibility of plasma protein binding, or passage into milk
or eggs and of the accumulation of lipophilic compounds shall be consid-
ered.
The pathways for the excretion of the product from the target animal shall
be described. The major metabolites shall be identified and characterised.
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 specified.
3. Routine analytical method for the detection of residues
Analytical procedures shall be proposed which can be carried out in the
course of a routine examination and which have 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:
— specificity,
— 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 appli-
cation is submitted.
Chapter II
Presentation of particulars and documents
As in any scientific work, the dossier of residue tests shall include the
following:
(a) an introduction defining the subject, accompanied by any useful bibliogra-
phical references;
(b) a detailed identification of the medicinal, including:
— composition,
— purity,
— batch identification,— relationship to the final product,
— specific activity and radio-purity of labelled substances,2001L0082 — EN — 30.04.2004 — 001.001 — 66
▼B
— 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 mate-
rials 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 criti-
cally 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 knowl-
edge at the time the application is submitted together with a detailed
summary of the results of the residue tests and precise bibliographical refer-
ences.
PART 4
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.
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 administration, formula-
tion, 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 experimental 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 certain 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 pharmaco-
kinetic studies shall demonstrate those interactions which might make the
combination itself of value in clinical use. In the second case, where scientific
justification for the medicinal combination is sought through clinical experimen-
tation, the investigation shall determine whether the effects expected from the2001L0082 — EN — 30.04.2004 — 001.001 — 67
▼B
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.
A.2. Pharmacokinetics
Basic pharmacokinetic information concerning a new active substance is gener-
ally useful in the clinical context.
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 of these parameters to investigate the relationships between dosage
regimen, plasma and tissue concentration and pharmacologic, therapeutic
or toxic effects.
In target species, pharmacokinetic studies are, as a rule, necessary in order to
employ drugs with the greatest possible efficacy and safety. Such studies are
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 investi-
gated in accordance with the provisions of this Directive, pharmacokinetic
studies of the fixed combination are not required if it can be justified that 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 bioequiva-
lence:
— when comparing a reformulated medicinal product with the existing one,
— when comparing a new method or route of administration with an estab-
lished one,
— in all cases referred to in Article 13(1).
B. TOLERANCE IN THE TARGET SPECIES OF ANIMAL
The purpose of this study, which shall be carried out with all animal species for
which the medicinal product is intended, is to carry out in all such animal
species local and general tolerance trials designed to establish a tolerated dosage
wide enough to allow an adequate safety margin and the clinical symptoms of
intolerance using the recommended route or routes, in so far as this may be
achieved by increasing the therapeutic dose and/or the duration of treatment.
The report on the trials shall contain as many details as possible of the expected
pharmacological effects and the adverse reactions; the latter shall be assessedwith due regard to the fact that the animals used may be of very high value.
The medicinal product shall be administered at least via the recommended route
of administration.
C. RESISTANCE
Data on the emergence of resistant organisms are necessary in the case of
medicinal products used for the prevention or treatment of infectious diseases
or parasitic infestations in animals.
Chapter II
Clinical requirements
1.General principles
The purposes 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, clinical trials shall be carried out with control animals
(controlled clinical trials). The effect obtained should be compared with a
placebo or with absence of treatment and/or with the effect of an authorized
medicinal product known to be of therapeutic value. All the results obtained,
whether positive or negative, shall be reported.2001L0082 — EN — 30.04.2004 — 001.001 — 68
▼B
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.
In the case of a veterinary medicinal product intended primarily for use as a
performance enhancer, particular attention shall be given to:
— the yield of animal produce,
— the quality of animal produce (organoleptic, nutritional, hygienic and
technological qualities),
— nutritional efficiency and growth of animal,— the general status of health of the animal.
Experimental data shall be confirmed by data obtained under practical field
conditions.
Where, in respect of particular therapeutic indications, the applicant can
show that he is unable to provide comprehensive data on therapeutic effect
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 veterinary
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 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 collection, documentation and verification of clinical trials shall be
required.
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 parti-
cular, the animal owner shall be informed in writing of the consequences 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.
Unless the trial is conducted with a blind design, the provisions of Articles
58, 59 and 60 concerning the labelling of veterinary medicinal products shall
apply by analogy to the labelling of formulations intended for use in veter-
inary clinical trials. In all cases, the words ‘for veterinary clinical trial use
only’ shall appear prominently and indelibly upon the labelling.
Chapter III
Particulars and documents
As in any scientific work, the dossier on efficacy shall include an introduction
defining the subject accompanied by any useful 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.
1. Records of pre-clinical observations
Wherever possible, particulars shall be given of the results of:
(a) tests demonstrating pharmacological actions;2001L0082 — EN — 30.04.2004 — 001.001 — 69
▼B
(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.
Additionally the following particulars shall be provided in all pre-clinical
studies:
(a) a summary;
(b) a detailed experimental protocol giving a description of the methods,
apparatus and materials used, details such as species, age, weight, sex,
number, breed or strain of animals, identification of animals, dose,
route and schedule of administration;
(c) a statistical analysis of the results where relevant;
(d) an objective discussion of the results obtained, leading to conclusions
on the safety and efficacy of the product.
Total or partial omission of these data must be explained.
2.1. Records of clinical observations
All the particulars shall be supplied by each of the investigators on indivi-
dual 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;
(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, identifi-
cation of trial animals, species, 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 course of any inter-
current diseases;
(f) diagnosis and means used to make it;
(g) symptoms and severity of the disease, if possible according to conven-
tional criteria;
(h) the precise identification of the clinical trial formulation used in the
trial;
(i) dosage of the medicinal product, method, route and frequency of
administration and precautions, if any, taken during administration
(duration of injection, etc.);
(j) duration of treatment and period of subsequent observation;
(k) all details concerning medicinal products (other than that under study)
which have been administered during the period of examination, either
prior to or concurrently with the test product and, in the latter case,
details of the interactions observed;
(l) all results of the clinical trials (including unfavourable or negative
results) with a full statement of the clinical observations and the
results of the objective tests of activity (laboratory analyses, physiolo-
gical tests), required to evaluate the application; the techniques used
must be specified, and the significance of any variations in the results
explained (e.g. 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 relation-
ship shall be investigated if possible;
(n) effect of animals' performance (e.g. 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;2001L0082 — EN — 30.04.2004 — 001.001 — 70
▼B
(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.
2.2. Summary and conclusions of clinical observations
In respect of each clinical trial, the clinical observations shall be summar-
ized in a synopsis of the trials and the results thereof, indicating in
particular:
(a) the number of controls, the number of animals treated either individu-
ally or collectively, with a breakdown according to species, breed or
strain, age and sex;
(b) the number of animals withdrawn prematurely from the trials and the
reasons for such withdrawal;
(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 different route;
(d) the frequency of observed adverse reactions;
(e) observations as to the effect on performance (e.g. 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 rearing or feeding, or the purpose for which
they are intended, or animals the physiological or pathological condi-
tion 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 experi-
mental 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-indica-
tions, 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 concerning the safety and the efficacy of the product when
compared with the separate administration of the active substances
involved.
3. Concluding 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 scien-
tific knowledge at the time the application is submitted together with a
detailed summary of the results of the tests and trials submitted and precise
bibliographic references.
TITLE II
Requirements for immunological veterinary medicinal products
Without prejudice to the specific requirements laid down by Community legisla-
tion for the control and eradication of animal desease, the following
requirements shall apply to immunological veterinary medicinal products.
PART 5
Summary of the 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,2001L0082 — EN — 30.04.2004 — 001.001 — 71
▼B
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 stages
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 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 copies of a document showing that
the manufacturer is authorized to produce immunological veterinary medicinal
products, as defined in Article 44 (with a brief description of the production
site). Moreover, the list of organisms handled at the production site shall be
given.
The applicant shall submit a list of countries in which authorization has been
granted, copies of all the summaries of product characteristics in accordance
with Article 14 as approved by Member States and a list of countries in which
an application has been submitted.
B. SUMMARY OF PRODUCT CHARACTERISTICS
The applicant shall propose a summary of the product characteristics, in accor-
dance 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.
C. EXPERT REPORTS
In accordance with Article 15(2) and (3) expert reports must be provided on all
aspects of the documentation.
Each expert report shall consist of a critical evaluation of the various tests and/
or trials, which have been carried out in accordance with this Directive, and
bring out all the data relevant for evaluation. The expert shall give his opinion
as to whether sufficient guarantees have been provided as to the quality, safety
and efficacy of the product concerned. A factual summary is not sufficient.
All important data shall be summarized in an appendix to the expert report,
whenever possible in tabular or graphic form. The expert report and the summa-
ries shall contain precise cross references to the information contained in the
main documentation.
Each expert report shall be prepared by a suitably qualified and experienced
person. It shall be signed and dated by the expert, and attached to the report
shall be brief information about the educational background, training and occu-
pational experience of the expert. The professional relationship of the expert to
the applicant shall be declared.
PART 6
Analytical (physico-chemical, biological or microbiological) tests of immu-
nological veterinary medicinal products
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 supplemented, if necessary, by the manufac-
turing method. In the case of test procedures included in the European
Pharmacopoeia or the pharmacopoeia of a Member State, this description may
be replaced by a detailed reference to the pharmacopoeia in question.2001L0082 — EN — 30.04.2004 — 001.001 — 72
▼B
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 submitted in
accordance with the following requirements.
1. Qualitative particulars
‘Qualitative particulars’ of all the constituents of the immunological veter-
inary 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 nature or the quantity
used, including preservatives, stabilisers, emulsifiers, colouring matter,
flavouring, aromatic substances, markers, etc.,
— the constituents of the pharmaceutical form administered to animals.
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 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 immu-
nological 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 obli-
gatory for all such substances, with reference to the pharmacopoeia
concerned,
— in respect of other substances, the international non-proprietary name
recommended by the World Health Organization, which may be accom-
panied 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, supple-
mented, where appropriate, by any other relevant details,
— in respect of colouring matter, designation by the ‘E’ code assigned to
them in Directive 78/25/EEC.
3. Quantitative particulars
In order to give the ‘quantitative particulars’ of the active substances of an
immunological veterinary medicinal product, it is necessary to specify
whenever possible the number of organisms, the specific protein content,
the mass, the number of International Units (IU) or units of biological
activity, either per dosage-unit or volume, and with regard to the adjuvant
and to the constituents of the excipients, 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
shall be used.
The units of biological activity for which no published data exist shall be
expressed in such a way as to provide unambiguous information on the
activity of the ingredients, e.g. by stating the immunological effect on
which the method of determining the dose is based.
4. Development pharmaceutics
An explanation shall be provided with regard to the composition, compo-
nents and containers, supported by scientific data on development
pharmaceutics. The overage, with justification thereof, shall be stated. The
efficacy of any preservative system shall be demonstrated.
B. DESCRIPTION OF MANUFACTURING METHOD OF THE FINISHED
PRODUCT
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 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 products, such
as microbiological contamination,2001L0082 — EN — 30.04.2004 — 001.001 — 73
▼B
— in the case of continuous manufacture, full details concerning precautions
taken to ensure the homogeneity and consistency of each batch of the
finished product,
— mention of substances which cannot be recovered in the course of manufac-
ture,
— the details of the blending, with the quantitative particulars of all the
substances used,
— a statement of the stage of manufacture at which sampling is carried out for
in-process control tests.
C. PRODUCTION AND CONTROL OF STARTING MATERIALS
For the purposes of this paragraph ‘starting materials’ means all components
used in the production of the immunological veterinary medicinal product.
Culture media used for the production of the active substance are considered as
one single starting material.
In the case of:
— an active substance not described in the European Pharmacopoeia or in the
pharmacopoeia of a Member State,
or
— an active substance described in the European Pharmacopoeia or in the
pharmacopoeia of a Member State when prepared by a method liable to
leave impurities not mentioned in the pharmacopoeial monograph and for
which the monograph is 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 manufacturing method, quality control
during manufacture and process validation to be supplied directly to the compe-
tent 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 (j) 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 accordance 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
its territory.
Components 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 analy-
tical methods may be replaced by a detailed reference to the
pharmacopoeia in question.
Reference to pharmacopoeias of third countries may be permitted in cases
where the substance is described neither in the European Pharmacopoeia
nor in the national pharmacopoeia concerned; in that case the monograph
shall be submitted, accompanied where necessary by a translation for which
the applicant will be responsible.
Colouring matter shall, in all cases, satisfy the requirements of Council
Directive 78/25/EEC.
The routine tests carried out on each batch of starting materials must be as
stated in the application for marketing authorization. If tests other thanthose mentioned in the pharmacopoeia are used, proof must be supplied
that the starting materials meet the quality requirements of that pharmaco-
poeia.
In cases where a specification or other provisions contained in a mono-
graph of the European Pharmacopoeia or in the national pharmacopoeia
of a Member State might be insufficient to ensure the quality of the
substance, the competent authorities may request more appropriate specifi-
cations from the applicant for marketing authorization.
The competent authorities shall inform the authorities responsible for the
pharmacopoeia in question. The applicant for marketing authorization shall2001L0082 — EN — 30.04.2004 — 001.001 — 74
▼B
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 accompa-
nied where necessary by the validation of the test procedures contained in
the monograph and by a translation where appropriate. For active ingredi-
ents, demonstration of the ability of the monograph adequately to control
their quality shall be presented.
2. 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 veter-
inary 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 docu-
mented. 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 of the
sequence of DNA or RNA effectively inserted, oligonucleotidic 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 genetic stability.
Seed materials, including cell banks and raw serum for anti-serum produc-
tion shall be tested for identity and adventitious agents.
Information shall be provided on all substances of biological origin used at
any stage in the manufacturing procedure. The information shall include:
— details of the source of the materials,
— details of any processing, purification and inactivation applied, with
data on the validation of these process and in-process controls,
— details of any tests for contamination carried out on each batch of the
substance.
If the presence of adventitious agents is detected or suspected, the corre-
sponding material shall be discarded or used in very exceptional
circumstances only when further processing of the product ensures 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 produc-
tion.
For live attenuated vaccines, proof of the stability of the attenuation char-
acteristics 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 origin
The description shall be given in the form of a monograph under the
following headings:
— the name of the starting material meeting the requirements of point 2 of
Section A shall be supplemented 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 in 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 refers, 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 purity of each batch
of the starting material,2001L0082 — EN — 30.04.2004 — 001.001 — 75
▼B
— any special precautions which may be necessary during storage of the
starting material and, if necessary, its storage life shall be given.
D. SPECIFIC MEASURES CONCERNING THE PREVENTION OF THE
TRANSMISSION OF ANIMAL SPONGIFORM ENCEPHALOPATHIES
The applicant must demonstrate that the veterinary medical product is manufac-
tured in accordance with the Note for Guidance on minimising the risk of
transmitting animal spongiform encephalopathy agents via veterinary medicinal
products and its updates, published by the European Commission in Volume 7
of its publication ‘The rules governing medicinal products in the European
Community’.
E. CONTROL TESTS DURING PRODUCTION
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 relating to the control tests which are carried out on intermediate
products with a view to verifying the consistency of the production process
and the final product.
2.For inactivated or detoxified vaccines, inactivation or detoxification shall be
tested during each production run immediately after the inactivation or detoxifi-
cation process.
F. CONTROL TESTS ON THE FINISHED PRODUCT
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 European 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
product. 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 general 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, refrac-
tive 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 sufficiently precise detail, so that they can be
reproduced 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.
Where necessary, a specific test for identification shall also be carried out.In certain exceptional cases where assay of active substances which are
very numerous or present in very low amounts would necessitate an intri-
cate investigation difficult to carry out in respect of each production batch,
the assay of one or more active substances in the finished product may be
omitted, on the express condition that such assays are made at intermediate
stages as late as possible in the production process. This relaxation may not
be extended to the characterization of the substances concerned. This
simplified technique shall be supplemented by a method of quantitative
evaluation, enabling the competent authority to verify that the immunolo-
gical veterinary medicinal product is in accordance with its formula after
it has been placed on the market.
3. Identification and assay of adjuvants
In so far as testing procedures are available, the quantity and nature of the
adjuvant and its components shall be verified on the finished product.2001L0082 — EN — 30.04.2004 — 001.001 — 76
▼B
4. Identification and assay of excipient components
In so far as is necessary, the excipient(s) shall be subject at least to identi-
fication tests.
The test procedure proposed for identifying colouring 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
sensitive target species and by at least the recommended route of adminis-
tration posing the greatest risk.
6. Sterility and purity test
Appropriate tests to demonstrate the absence of contamination by adventi-
tious 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.
7. Inactivation
Where applicable, a test to verify inactivation shall be carried out on the
product in the final container.
8. Residual humidity
Each batch of lyophilised product shall be tested for residual humidity.
9. Batch-to-batch consistency
In order to ensure that efficacy of the product is reproducible from batch to
batch and to demonstrate conformity with specifications, potency tests
based upon in vitro orin vivo methods, including appropriate reference
materials whenever available, shall be carried out on each final bulk or
each batch of finished product, with appropriate confidence limits; in
exceptional circumstances, potency testing may be carried out at an inter-
mediate stage, as late as possible in the production process.
G. STABILITY TESTS
The particulars and documents accompanying the application for marketing
authorization pursuant to Article 12(3)(f) and (i) shall be submitted in accor-
dance with the following requirements.
A description shall be given of the tests undertaken to support 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 produced 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 required for the product reconstituted as recom-
mended. Data in support of the proposed shelf-life for the reconstituted product
shall be submitted.
PART 7
Safety testing
A. INTRODUCTION
1. The safety tests shall show the potential risks from the immunological
veterinary medicinal product which may occur under the proposed condi-
tions of use in animals: these shall be evaluated in relation to the potential
benefits of the product.2001L0082 — EN — 30.04.2004 — 001.001 — 77
▼B
Where immunological veterinary medicinal products consist of live organ-
isms, especially those which could be shed by vaccinated animals, the
potential risk to unvaccinated animals of the same or of any other poten-
tially exposed species shall be evaluated.
2. The particulars and documents which shall accompany the application for
marketing authorization pursuant to Article 12(3)(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 carried out in
conformity with the principles of good laboratory practice laid down in
Council Directives 87/18/EEC and 88/320/EEC.
B. GENERAL REQUIREMENTS
1. The safety tests shall be carried out in the target species.2. The dose to be used shall be that quantity of the product to be recom-
mended 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 described in the applica-
tion for marketing authorization.
C. LABORATORY TESTS
1. Safety of the administration of one dose
The immunological veterinary medicinal product shall be administered at
the recommended dose and by each recommended route of administration
to animals of each species and category in which it is intended for use,including animals of the minimum age of administration. The animals shall
be observed and examined for signs of systemic and local reactions. Where
appropriate, these studies shall include detailed post-mortem macroscopic
and microscopic examinations of the injection site. Other objective criteria
shall be recorded, such as rectal temperature and performance measure-
ments.
The animals shall be observed 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 one administration 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 perfor-
mance 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
effects 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 1.2001L0082 — EN — 30.04.2004 — 001.001 — 78
▼B
5. Examination of immunological functions
Where the immunological veterinary medicinal product might adversely
affect the immune response of the vaccinated animal or of its progeny,
suitable tests on the immunological functions shall be carried out.
6. Special requirements for live vaccines:
6.1. Spread of the vaccine strain
Spread of the vaccine strain from vaccinated to unvaccinated target animals
shall 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 particular attention
being paid to the predilection sites for replication of the organism. In the
case of live vaccines for well established zoonotic diseases for food produ-
cing animals, these studies must be undertaken.
6.3. Reversion to virulence of attenuated vaccines
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 this is not technically possible due to failure of the
organism to 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 the route of administration most likely to lead to rever-
sion 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 reassortment of strains
The probability of recombination or genomic reassortment with field or
other strains shall be discussed.
7. Study of residues
For immunological veterinary medicinal products, it will normally not be
necessary to undertake a study of residues. However, where adjuvants
and/or preservatives are used in the manufacture of immunological veter-
inary medicinal products, consideration shall be given to the possibility of
any residue remaining in the foodstuffs. If necessary, the effects of such
residues shall be investigated. Moreover, in the case of live vaccines for
zoonotic diseases, the determination of residues at the injection site may
be required in addition to the studies described in paragraph 6.2.
A proposal for a withdrawal period shall be made and its adequacy shall be
discussed in relation to any residue studies which have been undertaken.
8. Interactions
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)(j) and 13(1).
This assessment shall normally be conducted in two phases.2001L0082 — EN — 30.04.2004 — 001.001 — 79
▼B
The first phase of the assessment shall always be carried out: the investigator
shall assess the potential extent of exposure of the environment to the product,
its active substances, or relevant metabolites, taking into account:
— the target species and the proposed pattern of use (e.g. mass medication or
individual animal medication),
— the method of administration, in particular the likely extent to which the
product will enter directly into environmental system,
— the possible excretion of the product, its active substances or relevant meta-
bolites 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 envir-
onment to the product, the applicant shall proceed to the second phase and
evaluate the potential ecotoxicity of the product. For this purpose, he shall
consider the extent and duration of exposure of the environment to the product,
and the information about the physical/chemical, pharmacological and/or toxico-
logical properties of the compound obtained during the conduct of the other
tests and trials required by this Directive. Where necessary, further investiga-
tions on the impact of the product (soil, water, air, aquatic systems, non-target
organisms) shall be carried out.
These further investigations shall be carried out in accordance with the test
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 recognized protocols on the immunological veterinary medicinal
product and/or the active substances and/or the excreted metabolites as appro-
priate. 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.
PART 8
Efficacy trials
A. INTRODUCTION
1. The purpose of the trials described in this Part is to demonstrate or to
confirm the efficacy of the immunological veterinary medicinal 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 specific trials
contained in the application for marketing authorization.
2. The particulars and documents which shall accompany applications for
marketing authorizations pursuant to Article 12(3)(j) and 13(1) shall be
submitted in accordance with the provisions below.
3. 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 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 collection, documentation 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 writing of the conse-
quences 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
58, 59 and 60 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 REQUIREMENTS
1. The choice of vaccine strains shall be justified on the basis of epizoological
data.
2. Efficacy trials carried out in the laboratory shall be controlled trials,
including untreated control animals.2001L0082 — EN — 30.04.2004 — 001.001 — 80
▼B
In general, these trails shall be supported by trials carried out in field
conditions, including untreated control animals.
All trials shall be described in sufficiently precise details so as to be repro-
ducible in control trials, carried out at the request of the competent
authorities. The investigator shall demonstrate the validity of all the techni-
ques involved. All results shall be presented as precisely as possible.
All results obtained, whether favourable or unfavourable, shall be reported.
3. The efficacy of an immunological veterinary medicinal product shall be
demonstrated for each category of each species recommended for vaccina-
tion, by each recommended route of administration and using the proposed
schedule of administration. The influence of passively acquired and mater-
nally derived antibodies on the efficacy of a vaccine shall be adequately
evaluated. Any claims regarding the onset and duration of protection shall
be supported by data from trials.
4. The efficacy of each 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
same time as another veterinary medicinal product, they shall be shown to
be compatible.
5. Whenever a product forms part of a vaccination scheme recommended by
the applicant, the priming or booster effect or the contribution of the
product to the efficacy of the scheme as a whole shall be demonstrated.
6. The dose to be used shall be that quantity of the product to be recom-
mended for use and containing the minimum titre or potency for which
the application 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 applica-
tion 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.
C. LABORATORY TRIALS
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 target 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 challenge organism
and the route of administration of the challenge.
2. If possible, the immune mechanism (cell-mediated/humoral, local/general
classes of immunoglobulin) which is initiated after the administration of
the immunological veterinary medicinal product to target animals by the
recommended route of administration shall be specified and documented.
D. FIELD TRIALS
1. Unless justified, results from laboratory trials shall be supplemented with
data from field trials.
2. Where laboratory trials cannot be supportive of efficacy, the performance
of field trials alone may be acceptable.
PART 9
Particulars and documents concerning safety testing and efficacy trials of
immunological veterinary medicinal products
A. INTRODUCTION
As in any scientific work, the dossier of safety and efficacy studies shall include
an introduction defining the subject and indicating the tests which have been
carried out in compliance with Parts 7 and 8, as well as a summary, with refer-
ences 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:
1. a summary;2001L0082 — EN — 30.04.2004 — 001.001 — 81
▼B
2. the name of the body having carried out the studies;
3. a detailed experimental protocol giving a description of the methods, appa-
ratus 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 statis-
tical methods used;
4. in the case of control animals, whether they received a placebo or no treat-
ment;
5. all general and individual observations and results obtained (with averages
and standard deviations), whether favourable or unfavourable. The data
shall be described in sufficient detail to allow the results to be critically
evaluated independently of their interpretation by the author. The raw data
shall be presented in tabular form. By way of explanation and illustration,
the results may be accompanied by reproductions of recordings, photomi-
crographs, etc.;
6. the nature, frequency and duration of observed side-effects;
7. the number of animals withdrawn prematurely from the studies and reasons
for such withdrawal;
8. a statistical analysis of the results, where such is called for by the test
programme, and variance within the data;
9. occurrence and course of any intercurrent disease;
10. all details concerning medicinal products (other than the product under
study), the administration of which was necessary during the course of the
study;
11. an objective discussion of the results obtained, leading 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:
1. 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 obser-
vation, the serological response and other investigations carried out on the
animals after administration;
5. in the case of control animals, whether they received a placebo or no treat-
ment;
6. identification of the treated and control animals (collective or individual, as
appropriate), such as species, breeds or strains, age, weight, sex, physiolo-
gical status;
7. a brief description of the method of rearing and feeding, stating the nature
and quantity of any additives contained in the feed;
8. all the particulars on observations, performances and results (with averages
and standard deviation); individual data shall be indicated when tests and
measurements on individuals have been carried out;
9. all observations and results of the studies, whether favourable or unfavour-
able, with a full statement of the observations 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, repro-
ductive performance);
11. the number of animals withdrawn prematurely from the studies and reasons
for such withdrawal;
12. the nature, frequency and duration of observed adverse reactions;
13. occurrence and course of any intercurrent disease;
14. all details concerning medicinal products (other than the product under
study) which have been administered either prior to or concurrently with2001L0082 — EN — 30.04.2004 — 001.001 — 82
▼B
the test product or during the observation period; details of any interactions
observed;
15. an objective discussion of the results obtained, leading to conclusions on the
safety and efficacy of the product.
D. GENERAL CONCLUSIONS
General conclusions on all results of tests and trials carried out in compliance
with Parts 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 medicinal product.
E. BIBLIOGRAPHICAL REFERENCES
The bibliographical references cited in the summary mentioned under Section A
shall be listed in detail.2001L0082 — EN — 30.04.2004 — 001.001 — 83
▼B
ANNEX II
PART A
Repealed Directives and their successive amendments
(referred to by Article 96)
Council Directive 81/851/EEC (OJ L 317, 6.11.1981, p. 1)
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 92/74/EEC (OJ L 297, 13.10.1992, p. 12)
Council Directive 93/40/EEC (OJ L 214, 24.8.1993, p. 31)
Commission Directive 2000/37/EC (OJ L 139, 10.6.2000, p. 25)Council Directive 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/EECCommission Directive 1999/104/EC (OJ L 3, 6.1.2000, p. 18)
PART B
Time-limits for transposition into national law
(referred to by Article 96)
Directive Deadline for transposition
Directive 81/851/EEC 9 October 1983
Directive 81/852/EEC 9 October 1983
Directive 87/20/EEC 1 July 1987
Directive 90/676/EEC 1 January 1992
Directive 90/677/EEC 20 March 1993
Directive 92/18/EEC 1 April 1993Directive 92/74/EEC 31 December 1993
Directive 93/40/EEC 1 January 1995
1 January 1998 (Art. 1.7)
Directive 1999/104/EC 1 January 2000
Directive 2000/37/EC 5 December 20012001L0082 — EN — 30.04.2004 — 001.001 — 84
ANNEX III
CORRELATION TABLE
This Directive Dir. 65/65/EEC Dir. 81/851/EEC Dir. 81/852/EEC Dir. 90/677/EEC Dir. 92/74/EEC
Art. 1 points 1 and 2 Art. 1 points 1 and 2 Art. 1(1)
Art. 1 point 3 Art. 1(2), 2nd indent
Art. 1 point 4 Art. 1, point 3 Art. 1(1)
Art. 1 points 5 and 6 Art. 1(2), 3rd and 4th indents
Art. 1 point 7 Art. 1(2)
Art. 1 point 8 Art. 1
Art. 1 point 9 Art. 5, 3rd subparagraph,
point 8
Art. 1 points 10 to 16 Art.42b, 1st subparagraph
Art. 1 point 17 Art. 50a(1), 2nd subparagraph
Art. 1 point 18 Art.16(1)
Art. 1 point 19 Art. 18(1), footnoteArt. 2 Art. 2(1)
Art. 3 point 1, 1st subparagraph Art. 2(2), 1st indent
Art. 3 point 1, 2nd subpara-
graphArt. 2(3)
Art. 3 point 2 Art. 1(3)
Art. 3 points 3 and 4 Art. 1 points 4 and 5 and Art.
2(3)Art. 1(1)▼B2001L0082 — EN — 30.04.2004 — 001.001 — 85
This Directive Dir. 65/65/EEC Dir. 81/851/EEC Dir. 81/852/EEC Dir. 90/677/EEC Dir. 92/74/EEC
Art. 3 point 5 Art. 2(2), 3rd indent
Art. 3 point 6 Art. 1 point 4Art. 4(1) Art. 1(4)
Art. 4(2) Art. 3
Art. 5 Art. 4(1), 1st subparagraphArt. 6 Art. 4(2), 1st subparagraphArt. 7 Art. 4(1), 2nd subparagraph
Art. 8 Art. 4(1), 3rd subparagraph
Art. 9 Art. 4(3), 1st subparagraphArt. 10(1) and (2), 1st and 2nd
subparagraphsArt. 4(4), 1st and 2nd subpar-
agraphs
Art. 10(2), 3rd subparagraph Art. 2(1), 2nd subparagraph
Art. 11 Art. 4(4), 3rd subparagraphArt. 12(1) Art. 5, 1st subparagraphArt. 12(2) Art. 5, 2nd subparagraph
Art. 12(3)(a) to (i) Art. 5, 3rd subparagraph,
points 1 to 9Art. 1, 1st subparagraph
Art. 12(3)(j) Art. 5, 3rd subparagraph,
point 10, 1st subparagraph
Art. 12(3)(k) to (n) Art. 5, 3rd subparagraph,
points 11 to 14
Art. 13(1) Art. 5, 3rd subparagraph,
point 10, 2nd subparagraph▼B2001L0082 — EN — 30.04.2004 — 001.001 — 86
This Directive Dir. 65/65/EEC Dir. 81/851/EEC Dir. 81/852/EEC Dir. 90/677/EEC Dir. 92/74/EEC
Art. 13(2) Art. 1, 2nd subparagraph
Art. 14 Art. 5aArt. 15(1) Art. 6
Art. 15(2) and (3) Art. 7
Art. 16 Art. 6
Art. 17(1) Art. 7(1)
Art. 17(2) Art. 7(3)
Art. 17(3) Art. 4, 2nd subparagraph
Art. 18 Art. 8
Art. 19 Art. 9
Art. 20 first paragraph Art. 2(3)
Art. 20 second paragraph Art. 9
Art. 21 Art. 8Art. 22 Art. 8aArt. 23 Art. 9Art. 24 Art. 10
Art. 25 Art. 5b
Art. 26(1) and (2) Art. 12Art. 26(3) Art. 15(2)Art. 27(1) Art. 14(1), 1st subparagraph▼B2001L0082 — EN — 30.04.2004 — 001.001 — 87
This Directive Dir. 65/65/EEC Dir. 81/851/EEC Dir. 81/852/EEC Dir. 90/677/EEC Dir. 92/74/EEC
Art. 27(2) Art. 14(1), 2nd subparagraph
Art. 27(3) Art. 14(2)Art. 27(4) and (5) Art. 14(3) and (4)
Art. 28 Art. 15(1)
Art. 29 Art. 13Art. 30 Art. 11Art. 31(1) Art. 16(1)
Art. 31(2) Art. 16(2) Art. 2
Art. 31(3) Art. 16(3)Art. 32(1) Art. 17(3)Art. 32(2) Art. 17(1)
Art. 32(3) Art. 17(2)
Art. 32(4) Art. 17(4)Art. 33 Art. 18Art. 34 Art. 19Art. 35 Art. 20
Art. 36 Art. 21
Art. 37 Art. 22(1)Art. 38 Art. 22(2), (3) and (4)Art. 39 Art. 23▼B2001L0082 — EN — 30.04.2004 — 001.001 — 88
This Directive Dir. 65/65/EEC Dir. 81/851/EEC Dir. 81/852/EEC Dir. 90/677/EEC Dir. 92/74/EEC
Art. 40 Art. 23a
Art. 41 Art. 23b
Art. 42 Art. 23c
Art. 43 Art. 22(5)
Art. 44 Art. 24
Art. 45 Art. 25
Art. 46 Art. 26
Art. 47 Art. 28(1)
Art. 48 Art. 28(2)
Art. 49 Art. 28(3)
Art. 50 Art. 27
Art. 51 Art. 27a
Art. 52 Art. 29
Art. 53 Art. 31
Art. 54 Art. 32
Art. 55(1) Art. 30(1), 1st and 2nd
subparagraphs
Art. 55(2) Art. 30(1), 3rd subparagraph
Art. 55(3) Art. 30(2)
Art. 56 Art. 33▼B2001L0082 — EN — 30.04.2004 — 001.001 — 89
This Directive Dir. 65/65/EEC Dir. 81/851/EEC Dir. 81/852/EEC Dir. 90/677/EEC Dir. 92/74/EEC
Art. 57 Art. 3
Art. 58(1) to (3) Art. 43
Art. 58(4) Art. 47
Art. 59(1) Art. 44
Art. 59(2) Art. 45
Art. 59(3) Art. 47
Art. 60 Art. 46
Art. 61(1) Art. 48, 1st subparagraph
Art. 61(2) Art. 48, 2nd subparagraph
Art. 61(3) Art. 48, 3rd subparagraph
Art. 62 Art. 49, 1st subparagraph
Art. 63 Art. 50
Art. 64(1) Art. 2(2)
Art. 64(2) Art. 7(2)
Art. 65(1) Art. 50a(1), 1st and 3rd
subparagraphs
Art. 65(2), (3) and (4) Art. 50a(2), (3) and (4)
Art. 66 Art. 50b
Art. 67 Art. 4(3), 3rd subparagraph
Art. 68 Art. 1(5)▼B2001L0082 — EN — 30.04.2004 — 001.001 — 90
This Directive Dir. 65/65/EEC Dir. 81/851/EEC Dir. 81/852/EEC Dir. 90/677/EEC Dir. 92/74/EEC
Art. 69 Art. 50c
Art. 70 Art. 4(5)
Art. 71 Art. 4
Art. 72 Art. 42e
Art. 73 Art. 42a
Art. 74 Art. 42c
Art. 75 Art. 42d
Art. 76 Art. 42f
Art. 77(1) Art. 42g
Art. 77(2) Art. 42b
Art. 78 Art. 42h
Art. 79 Art. 42i
Art. 80(1) Art. 34, 1st and 2nd subpara-
graphs
Art. 80(2) Art. 3(1)
Art. 80(3) Art. 34, 3rd subparagraph
Art. 81(1) Art. 35
Art. 81(2) Art. 3(2)
Art. 82 Art. 3(3)
Art. 83 Art. 36▼B2001L0082 — EN — 30.04.2004 — 001.001 — 91
This Directive Dir. 65/65/EEC Dir. 81/851/EEC Dir. 81/852/EEC Dir. 90/677/EEC Dir. 92/74/EEC
Art. 84 Art. 37
Art. 85 Art. 38Art. 86 Art. 4, 1st subparagraph
Art. 87 Art. 38a
Art. 88 Art. 2a
Art. 89 Art. 42j Art. 2bArt. 90 Art. 39
Art. 91 Art. 42
Art. 92 Art. 5
Art. 93 Art. 24aArt. 94 Art. 40, 41 and 49, 2nd
subparagraph
Art. 95 Art. 4(2), 2nd subparagraphArt. 96 — — — — —Art. 97 — — — — —
Art. 98 — — — — —
Annex I Annex
Annex II — — — — —Annex III — — — — —▼B2001L0082 — EN — 30.04.2004 — 001.001 — 92