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Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on veterinary medicinal products and repealing Directive 2001/82/EC (Text with EEA relevance)

Type Regulation

Publication 2018-12-11

Last updated 2022-01-28

State In force

Department Council of the European Union, European Parliament

Source EUR-Lex

articles 160

Reform history JSON API

(a) a veterinary medicinal product authorised under this Regulation in the relevant Member State or in another Member State for use in the same or in another food-producing terrestrial animal species for the same indication, or for another indication;

(b) if there is no veterinary medicinal product as referred to in point (a) of this paragraph, a veterinary medicinal product authorised under this Regulation in the relevant Member State for use in a non-food-producing animal species for the same indication;

(d) if there is no medicinal product as referred to in point (a), (b) or (c) of this paragraph, a veterinary medicinal product prepared extemporaneously in accordance with the terms of a veterinary prescription.

Article 114

Use of medicinal products for food-producing aquatic species

By way of derogation from Article 106(1), where there is no authorised veterinary medicinal product in a Member State for an indication concerning a food-producing aquatic species, the veterinarian responsible may, under his or her direct personal responsibility, and in particular to avoid causing unacceptable suffering, treat the animals concerned with the following medicinal product:

(a) a veterinary medicinal product authorised under this Regulation in the relevant Member State or in another Member State for use in the same or in another food-producing aquatic species and for the same indication or for another indication;

(b) if there is no veterinary medicinal product as referred to in point (a) of this paragraph, a veterinary medicinal product authorised under this Regulation in the relevant Member State or in another Member State for use with a food-producing terrestrial species containing a substance present in the list established in accordance with paragraph 3;

(c) if there is no veterinary medicinal product as referred to in point (a) or (b) of this paragraph, a medicinal product for human use authorised in accordance with Directive 2001/83/EC or Regulation (EC) No 726/2004 and containing substances present in the list established in accordance with paragraph 3 of this Article; or

By way of derogation from points (b) and (c) of paragraph 1, and until the list referred to in paragraph 3 is established, the veterinarian responsible may, under his or her direct personal responsibility and in particular to avoid causing unacceptable suffering, exceptionally treat food-producing aquatic species of a particular holding with the following medicinal product:

(a) a veterinary medicinal product authorised under this Regulation in the relevant Member State or in another Member State for use with a food-producing terrestrial animal species;

(b) if there is no veterinary medicinal product as referred to in point (a) of this paragraph, a medicinal product for human use authorised in accordance with Directive 2001/83/EC or Regulation (EC) No 726/2004.

The Commission, when adopting those implementing acts, shall take account of the following criteria:

(a) risks to the environment if the food-producing aquatic species are treated with those substances;

(b) impact on animal and public health if the food-producing aquatic species affected cannot receive an antimicrobial listed in accordance with Article 107(6);

(c) availability or lack of availability of other medicinal products, treatments or measures for prevention or treatment of diseases or certain indications in food-producing aquatic species.

Article 115

Withdrawal period for medicinal products used outside the terms of the marketing authorisation in food-producing animal species

For the purpose of Articles 113 and 114, unless a medicinal product used has a withdrawal period provided in its summary of the product characteristics for the animal species in question, a withdrawal period shall be set by the veterinarian in accordance with the following criteria:

(a) for meat and offal from food-producing mammals and poultry and farmed game birds the withdrawal period shall not be less than: (i) the longest withdrawal period provided in its summary of the product characteristics for meat and offal multiplied by factor 1,5; (ii) 28 days if the medicinal product is not authorised for food-producing animals; (iii) one day, if the medicinal product has a zero withdrawal period and is used in a different taxonomic family than the target species authorised;

(b) for milk from animals producing milk for human consumption the withdrawal period shall not be less than: (i) the longest withdrawal period for milk provided in the summary of the product characteristics for any animal species multiplied by factor 1,5; (ii) seven days, if the medicinal product is not authorised for animals producing milk for human consumption; (iii) one day, if the medicinal product has a zero withdrawal period;

(c) for eggs from animals producing eggs for human consumption the withdrawal period shall not be less than: (i) the longest withdrawal period for eggs provided in the summary of the product characteristics for any animal species multiplied by factor 1,5; (ii) 10 days, if the product is not authorised for animals producing eggs for human consumption;

(d) for aquatic species producing meat for human consumption the withdrawal period shall not be less than: (i) the longest withdrawal period for any of the aquatic species indicated in the summary of the product characteristics multiplied by factor of 1,5 and expressed as degree-days; (ii) if the medicinal product is authorised for food-producing terrestrial animal species, the longest withdrawal period for any of the food-producing animal species indicated in the summary of product characteristics multiplied by a factor of 50 and expressed as degree-days, but not exceeding 500 degree-days; (iii) 500 degree-days, if the medicinal product is not authorised for food-producing animal species; (iv) 25 degree-days if the highest withdrawal period for any animal species is zero.

Article 116

Health situation

By way of derogation from Article 106(1), a competent authority may allow the use in its territory of veterinary medicinal products not authorised in that Member State, where the situation of animal or public health so requires, and the marketing of those veterinary medicinal products is authorised in another Member State.

Article 117

Collection and disposal of waste of veterinary medicinal products

Member States shall ensure that appropriate systems are in place for the collection and disposal of waste of veterinary medicinal products.

Article 118

Animals or products of animal origin imported into the Union

Section 4

Advertising

Article 119

Advertising of veterinary medicinal products

Article 120

Advertising of veterinary medicinal products subject to veterinary prescription

The advertising of veterinary medicinal products that are subject to veterinary prescription in accordance with Article 34 shall be allowed only when made exclusively to the following persons:

(a) veterinarians;

(b) persons permitted to supply veterinary medicinal products in accordance with national law.

By way of derogation from paragraph 1 of this Article, advertising of veterinary medicinal products that are subject to veterinary prescription in accordance with Article 34 to professional keepers of animals may be permitted by the Member State provided the following conditions are met:

(a) the advertising is limited to immunological veterinary medicinal products;

(b) the advertising includes an express invitation to the professional keepers of animal to consult the veterinarian about the immunological veterinary medicinal product.

Article 121

Promotion of medicinal products used in animals

Article 122

Implementation of advertising provisions

Member States may lay down any procedures they deem necessary for the implementation of Articles 119, 120 and 121.

CHAPTER VIII

INSPECTIONS AND CONTROLS

Article 123

Controls

Competent authorities shall carry out controls of the following persons:

(a) manufacturers and importers of veterinary medicinal products and active substances;

(b) distributors of active substances;

(d) holders of a wholesale distribution authorisation;

(e) retailers;

(f) owners and keepers of food-producing animals;

(g) veterinarians;

(h) holders of a registration for homeopathic veterinary medicinal products;

(i) holders of veterinary medicinal products referred to in Article 5(6); and

(j) any other persons having obligations under this Regulation.

The risk-based controls referred to in paragraph 2 shall be carried out by the competent authorities taking account of at least:

(a) the intrinsic risks associated with the activities of the persons referred to in paragraph 1 and the location of their activities;

(b) the past record of the persons referred to paragraph 1 as regards the results of controls performed on them and their previous compliance;

(d) the potential impact of non-compliance on public health, animal health, animal welfare and the environment.

Inspections may be carried out as part of the controls. Such inspections may be made unannounced. During those inspections the representatives of a competent authority shall at least be empowered to:

(a) inspect the premises, equipment, means of transport, records, documents and systems, related to the objective of the inspection;

(b) inspect and take samples with a view to submitting them for an independent analysis by an Official Medicines Control Laboratory or by a laboratory designated for that purpose by a Member State;

(d) carry out the same controls on any parties performing the tasks required under this Regulation with, for or on behalf of the persons referred to in paragraph 1.

Article 124

Audits by the Commission

The Commission may carry out audits in Member States on their competent authorities for the purpose of confirming the appropriateness of the controls carried out by those competent authorities. Such audits shall be coordinated with the relevant Member State and shall be carried out in a manner which avoids unnecessary administrative burden.

After each audit, the Commission shall draft a report containing, where appropriate, recommendations to the relevant Member State. The Commission shall send the draft report to the competent authority for comments and shall take into account any such comments in drawing up the final report. The final report and the comments shall be made public by the Commission.

Article 125

Certificate of suitability

In order to verify whether the data submitted for obtaining a certificate of suitability complies with the monographs of the European Pharmacopoeia, the standardisation body for nomenclatures and quality norms within the meaning of the Convention on the elaboration of a European Pharmacopoeia accepted by Council Decision 94/358/EC (⁹) (European Directorate for the Quality of Medicines and Healthcare (‘EDQM’)) may ask the Commission or the Agency to request an inspection by a competent authority when the starting material concerned is subject to a European Pharmacopoeia monograph.

Article 126

Specific rules on pharmacovigilance inspections

Article 127

Proof of the product quality for veterinary medicinal products

Article 128

Proof of the product quality specific for immunological veterinary medicinal products

For immunological veterinary medicinal products authorised under the centralised procedure, the list of tests to be repeated by the control laboratory may be reduced only upon agreement of the Agency.

CHAPTER IX

RESTRICTIONS AND PENALTIES

Article 129

Temporary safety restrictions

The competent authority and, in the case of centrally authorised veterinary medicinal products, also the Commission may, in the event of a risk to public or animal health or to the environment that requires urgent action, impose temporary safety restrictions on the marketing authorisation holder and other persons having obligations under this Regulation. Those temporary safety restrictions may include:

(a) restriction of supply of the veterinary medicinal product at the request of the competent authority and, in the case of centrally authorised veterinary medicinal products, also at the request of the Commission to the competent authority;

(b) restriction of the use of the veterinary medicinal product at the request of the competent authority and, in the case of centrally authorised veterinary medicinal products, also at the request of the Commission to the competent authority;

(c) suspension of a marketing authorisation by the competent authority having granted that marketing authorisation and, in the case of centrally authorised veterinary medicinal products, by the Commission.

Article 130

Suspending, revoking, or varying the terms, of marketing authorisations

The competent authority or, in the case of centralised marketing authorisations, the Commission may suspend or revoke the marketing authorisation or request the marketing authorisation holder to submit an application for a variation to the terms of the marketing authorisation, as applicable, in the case of one or more of the following reasons:

(a) the marketing authorisation holder does not comply with the requirements set out in Article 58;

(b) the marketing authorisation holder does not comply with the requirements set out in Article 127;

(d) the marketing authorisation holder does not fulfil its obligations laid down in Article 77;

(e) the qualified person responsible for pharmacovigilance does not fulfil his or her tasks as laid down in Article 78.

Following an opinion of the Agency, the Commission shall adopt, where necessary, provisional measures, which shall be applied immediately. The Commission shall, by means of implementing acts, take a final decision. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 145(2).

Article 131

Suspending or revoking a wholesale distribution authorisation

In the event of non-compliance with the requirements laid down in Article 101, other than paragraph 3 thereof, the competent authority may, without prejudice to any other appropriate measures under national law, take one or more of the following measures:

(a) suspend the wholesale distribution authorisation;

(b) suspend the wholesale distribution authorisation for one or more categories of veterinary medicinal products;

Article 132

Removal of importers, manufacturers and distributors of active substance from the manufacturing and wholesale distribution database

In the event of non-compliance by importers, manufacturers and distributors of active substances with the requirements laid down in Article 95, the competent authority shall, temporarily or definitively, remove those importers, manufacturers and distributors from the manufacturing and wholesale distribution database.

Article 133

Suspending or revoking manufacturing authorisations

In the event of non-compliance with the requirements laid down in Article 93, the competent authority shall, without prejudice to any other appropriate measures under national law, take one or more of the following measures:

(a) suspend the manufacture of veterinary medicinal products;

(b) suspend imports of veterinary medicinal products from third countries;

(d) suspend or revoke the manufacturing authorisation for one or more activities in one or more manufacturing sites.

Article 134

Prohibiting the supply of veterinary medicinal products

In the event of a risk to public or animal health or to the environment, the competent authority or, in the case of centrally authorised veterinary medicinal products, the Commission, shall prohibit the supply of a veterinary medicinal product and require the marketing authorisation holder or suppliers to cease the supply or recall of the veterinary medicinal product from the market if any of the following conditions apply:

(a) the benefit-risk balance of the veterinary medicinal product is no longer positive;

(b) the qualitative or quantitative composition of the veterinary medicinal product is not as stated in the summary of the product characteristics referred to in Article 35;

(d) the control tests referred to in Article 127(1) have not been carried out; or

(e) the incorrect labelling might lead to a serious risk to animal or public health.

Article 135

Penalties imposed by Member States

Member States shall, by 28 January 2022, notify the Commission of those rules and of those measures and shall notify it, without delay, of any subsequent amendments affecting them.

Article 136

Financial penalties imposed by the Commission on holders of marketing authorisation for centrally authorised veterinary medicinal products

The Commission may, insofar as specifically provided for in the delegated acts referred to in point (b) of paragraph 7, impose the financial penalties referred to in paragraph 1 also on a legal entity or legal entities other than the marketing authorisation holder provided that such entities form part of the same economic entity as the marketing authorisation holder and that such other legal entities:

(a) exerted a decisive influence over the marketing authorisation holder; or

(b) were involved in, or could have addressed, such failure to comply with the obligation by the marketing authorisation holder.

For the purposes of paragraph 1, the Commission shall also take into account:

(a) any infringement procedure initiated by a Member State against the same marketing authorisation holder on the basis of the same legal grounds and the same facts; and

(b) any sanctions, including penalties, already imposed on the same marketing authorisation holder on the basis of the same legal grounds and the same facts.

Where the marketing authorisation holder continues to fail to comply with its obligations referred to in paragraph 1, the Commission may adopt a decision imposing periodic penalty payments per day not exceeding 2,5 % of the marketing authorisation holder’s average daily Union turnover in the business year preceding the date of that decision.

Periodic penalty payments may be imposed for a period running from the date of notification of the relevant Commission's decision until the failure to comply with the obligation by the marketing authorisation holder, as referred to in paragraph 1, has been brought to an end.

The Commission shall adopt delegated acts in accordance with Article 147 in order to supplement this Regulation by laying down:

(a) procedures to be applied by the Commission when imposing fines or periodic penalty payments, including rules on the initiation of the procedure, measures of inquiry, rights of defence, access to file, legal representation and confidentiality;

(b) further detailed rules on the imposition by the Commission of financial penalties on legal entities other than the marketing authorisation holder;

(d) elements to be taken into account by the Commission when setting the level of, and imposing, fines and periodic penalty payments, as well as the conditions and methods for their collection.

CHAPTER X

REGULATORY NETWORK

Article 137

Competent authorities

Article 138

Scientific opinion for international organisations for animal health

Article 139

Committee for Veterinary Medicinal Products

The Committee shall establish its own rules of procedure. Those rules shall, in particular, lay down:

(a) procedures for appointing and replacing the Chair;

(b) the appointment of members of any working parties or scientific advisory groups on the basis of the lists of accredited experts referred to in the second subparagraph of Article 62(2) of Regulation (EC) No 726/2004 and procedures for consultation of working parties and scientific advisory groups;

(c) a procedure for urgent adoption of opinions, particularly in relation to the provisions of this Regulation on market surveillance and pharmacovigilance.

The rules of procedure shall enter into force after receiving a favourable opinion from the Commission and the Management Board of the Agency.

Article 140

Members of the Committee

Article 141

Tasks of the Committee

The Committee shall have the following tasks:

(a) carry out the tasks conferred on it under this Regulation and Regulation (EC) No 726/2004;

(b) prepare scientific opinions of the Agency on questions relating to the evaluation and use of veterinary medicinal products;

(c) prepare opinions on scientific matters concerning the evaluation and use of veterinary medicinal products on the request of the Executive Director of the Agency or the Commission;

(d) prepare opinions of the Agency on questions concerning the admissibility of applications submitted in accordance with the centralised procedure, and on granting, varying, suspending or revoking marketing authorisations for centrally authorised veterinary medicinal products;

(e) take due account of any request made by Member States for scientific opinions;

(f) provide guidance on important questions and issues of general scientific nature;

(g) give a scientific opinion, in the context of cooperation with the World Organisation for Animal Health, concerning the evaluation of certain veterinary medicinal products intended exclusively for markets outside the Union;

(h) advise on the maximum limits for residues of veterinary medicinal products and biocidal products used in animal husbandry which may be accepted in foodstuffs of animal origin in accordance with Regulation (EC) No 470/2009;

(i) provide scientific advice on the use of antimicrobials and antiparasitics in animals in order to minimise the occurrence of resistance in the Union, and update that advice when needed;

(j) provide objective scientific opinions to the Member States on the questions which are referred to the Committee.

Article 142

Coordination group for mutual recognition and decentralised procedures for veterinary medicinal products

Article 143

Members of the coordination group

Article 144

Tasks of the coordination group

The coordination group shall have the following tasks:

(a) examine questions concerning mutual recognition and decentralised procedures;

(b) examine advice from the pharmacovigilance working party of the Committee concerning risk management measures in pharmacovigilance related to veterinary medicinal products authorised in Member States and issue recommendations to the Member States and to the marketing authorisation holders, as necessary;

(d) provide recommendations to Member States whether a specific veterinary medicinal product or a group of veterinary medicinal products is to be considered a veterinary medicinal product within the scope of this Regulation;

(e) coordinate the selection of the lead authority responsible for the assessment of the results of the signal management process referred to in Article 81(4);

(f) draw up and publish an annual list of reference veterinary medicinal products which shall be subject to harmonisation of the summaries of product characteristics in accordance with Article 70(3).

CHAPTER XI

COMMON AND PROCEDURAL PROVISIONS

Article 145

Standing Committee on Veterinary Medicinal Products

Article 146

Amendments to Annex II

Article 147

Exercise of the delegation

Article 148

Data protection

CHAPTER XII

TRANSITIONAL AND FINAL PROVISIONS

Article 149

Repeal

Directive 2001/82/EC is repealed.

References to the repealed Directive shall be construed as references to this Regulation and shall be read in accordance with the correlation table set out in Annex IV.

Article 150

Relation with other Union acts

Article 151

Prior applications

Article 152

Existing veterinary medicinal products, marketing authorisations and registrations

The first subparagraph of this paragraph shall not apply to marketing authorisations for antimicrobial veterinary medicinal products containing antimicrobials which have been reserved for treatment in humans in accordance with implementing acts referred to in Article 37(5).

Article 153

Transitional provisions regarding delegated and implementing acts

When adopting the delegated and implementing acts referred to in this Article, the Commission shall allow sufficient time between their adoption and their start of application.

Article 154

Establishment of the pharmacovigilance database and of the manufacturing and wholesale distribution database

Without prejudice to the date of application of this Regulation, the Agency, in collaboration with the Member States and the Commission, shall, in accordance with Articles 74 and 91 respectively, ensure the establishment of the pharmacovigilance database and of the manufacturing and wholesale distribution database at the latest by 28 January 2022.

Article 155

Initial input to the product database by competent authorities

At the latest by 28 January 2022, the competent authorities shall submit, electronically, information on all veterinary medicinal products authorised in their Member State at that time to the Agency, using the format referred to in point (a) of Article 55(3).

Article 156

Review of rules for environmental risk assessment

By 28 January 2022, the Commission shall present a report to the European Parliament and to the Council on a feasibility study of an active substance based review system (‘monographs’) and other potential alternatives for the environmental risk assessment of veterinary medicinal products, to be accompanied, if appropriate, by a legislative proposal.

Article 157

Commission report on traditional herbal products used to treat animals

The Commission shall report to the European Parliament and to the Council by 29 January 2027, on traditional herbal products used to treat animals in the Union. If appropriate, the Commission shall make a legislative proposal in order to introduce a simplified system for registering traditional herbal products used to treat animals.

The Member States shall provide information to the Commission on such traditional herbal products within their territories.

Article 158

Review of measures regarding animals of the equine species

No later than 29 January 2025, the Commission shall present a report to the European Parliament and to the Council on its assessment of the situation as regards the treatment with medicinal products of animals of the equine species and their exclusion from the food chain, including with regard to imports of animals of the equine species from third countries, to be accompanied by any appropriate action by the Commission taking into account, in particular, public health, animal welfare, the risks of fraud and the level playing field with third countries.

Article 159

Transitional provisions regarding certain certificates of good manufacturing practice

Without prejudice to the date of application of this Regulation, the obligations regarding certificates of good manufacturing practice for inactivated immunological veterinary medicinal products which are manufactured from pathogens and antigens obtained from an animal or animals in an epidemiological unit and used for the treatment of that animal or those animals in the same epidemiological unit or for the treatment of an animal or animals in a unit having a confirmed epidemiological link shall only start to apply from the date of application of the implementing acts laying down specific measures on good manufacturing practice for those veterinary medicinal products referred to in Article 93(2).

Article 160

Entry into force and application

This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union.

It shall apply from 28 January 2022.

This Regulation shall be binding in its entirety and directly applicable in all Member States.

ANNEX I

INFORMATION REFERRED TO IN POINT (A) OF ARTICLE 8(1)

1.Legal basis for the application for the marketing authorisation

2.Applicant

2.1.Name or company name and permanent address or registered place of business of the applicant

2.2.Name or company name and permanent address or registered place of business of manufacturer(s) or importer(s) of the finished veterinary medicinal product and name or company name and permanent address or registered place of business of the manufacturer of the active substance(s)

2.3.Name and address of the sites involved in the different stages of the manufacturing, importing, control and batch release

3.Identification of the veterinary medicinal product

3.1.Name of the veterinary medicinal product and Anatomical Therapeutic Chemical Veterinary code (ATCvet Code)

3.2.Active substance(s) and, if applicable, diluent(s)

3.3.Strength or, in case of immunological veterinary medicinal product, biological activity, potency or titre

3.4.Pharmaceutical form

3.5.Route of administration

3.6.Target species

4.Manufacturing and pharmacovigilance information

4.1.Proof of a manufacturing authorisation or certificate of good manufacturing practice

4.2.Reference number of pharmacovigilance system master file

5.Veterinary medicinal product information

5.1.Proposed summary of the product characteristics drawn up in accordance with Article 35

5.2.Description of the final presentation of the veterinary medicinal product, including packaging and labelling

5.3.Proposed text of the information to be provided on the immediate packaging, outer packaging and the package leaflet in accordance with Articles 10 to 16

6.Other information

6.1.List of countries in which a marketing authorisation has been granted or revoked for the veterinary medicinal product

6.2.Copies of all the summaries of product characteristics as included in the terms of marketing authorisations granted by Member States

6.3.List of countries in which an application has been submitted or refused

6.4.List of Member States in which the veterinary medicinal product is to be placed on the market

6.5.Critical expert reports on quality, safety and efficacy of the veterinary medicinal product.

ANNEX II

SECTION I

GENERAL PRINCIPLES AND REQUIREMENTS

I.1. General principles

I.1.1.The documentation accompanying an application for a marketing authorisation pursuant to Articles 8, and 18 to 25 shall be presented in accordance with the requirements set out in this Annex and shall take into account the guidance documents published by the Commission and the requirements for electronic format published by the Agency.

I.1.2.In assembling the dossier for application for a marketing authorisation, applicants shall also take into account the most up-to-date veterinary medicinal knowledge and the scientific guidelines relating to the quality, safety and efficacy of veterinary medicinal products published by the Agency.

I.1.3.For veterinary medicinal products, all relevant monographs of the European Pharmacopoeia, including general monographs and the general chapters, are applicable for the appropriate parts of the dossier.

I.1.4.The manufacturing processes for the active substance(s) and finished product shall comply with Good Manufacturing Practice (GMP).

I.1.5.All information which is relevant to the evaluation of the veterinary medicinal product concerned shall be included in the application, whether favourable or unfavourable to the product. In particular, all relevant details related to any incomplete or abandoned study or trial relating to the veterinary medicinal product shall be given.

I.1.6.Pharmacological, toxicological, residue and pre-clinical safety studies shall be carried out in conformity with the provisions related to Good Laboratory Practice (GLP) laid down in Directives 2004/10/EC (¹⁴) and 2004/9/EC (¹⁵) of the European Parliament and of the Council.

I.1.7.All experiments on animals shall be conducted taking into account the principles laid down in Directive 2010/63/EU, notwithstanding the place of conduct of the experiments.

I.1.8.The environmental risk assessment connected with the release of veterinary medicinal products containing or consisting of Genetically Modified Organisms (GMOs) within the meaning of Article 2 of Directive 2001/18/EC shall be provided in the dossier as a separate document. The information shall be presented in accordance with the provisions of Directive 2001/18/EC, taking into account guidance published by the Commission.

I.1.9.The applicant shall confirm in Part 1 of the dossier for an application for marketing authorisation that all submitted data relevant to the quality, safety and efficacy of the veterinary medicinal product, including data publicly available, are not subject to protection of technical documentation.

I.2. Dossier composition requirements

Any dossier for an application for marketing authorisation for a veterinary medicinal product shall consist of the following parts:

Part 1 shall include administrative information as outlined in Annex I, as follows:

(a) Part 1A: points 1 to 4 and 6.1 to 6.4;

(b) Part 1B: point 5;

With regard to Part 1B, point 5.1, in connection to Article 35(1), point (l), an application proposing classification of a veterinary medicinal product as "not subject to veterinary prescription" shall include a critical review of the product characteristics in order to justify the suitability of such classification taking into consideration target and non-target animal safety, public health as well as environmental safety, as outlined in the criteria given in Article 34(3), points (a) to (g).

Each critical expert report shall be prepared with regard to the state of scientific knowledge at the time of submission of the application. It shall contain an evaluation of the various tests and trials which constitute the marketing authorisation dossier, and shall address all aspects relevant to the assessment of the quality, safety and efficacy of the veterinary medicinal product. It shall give detailed results of the tests and trials submitted and precise bibliographic references. Copies of the bibliographic references cited shall be provided.

The critical expert reports shall be signed and dated by the author of those reports, and information about the author’s educational background, training and occupational experience shall be attached. The professional relationship of the author with the applicant shall be declared.

The critical expert reports and the appendices shall contain precise and clear cross-references to the information contained in the technical documentation.

Where Part 2 is presented using the format of the Common Technical Document (CTD), the quality overall summary (QOS) shall be used for the critical expert report on quality.

For Parts 3 and 4 the critical expert report shall also include a tabulated summary of all technical documentation and relevant data submitted.

(1)The pharmaceutical quality (physicochemical, biological or microbiological) data shall include for the active substance(s) and for the finished veterinary medicinal product information on the manufacturing process, the characterisation and properties, the quality control procedures and requirements, the stability as well as a description of the composition, the development and presentation of the veterinary medicinal product.

(2)All monographs, including specific monographs, general monographs and general chapters of the European Pharmacopoeia are applicable. For immunological veterinary medicinal products, all monographs, including specific monographs, general monographs and general chapters of the European Pharmacopoeia are applicable, unless otherwise justified. In the absence of a European Pharmacopoeia monograph, the monograph of a Member State pharmacopoeia may be applied. In cases where a substance is described neither in the European Pharmacopoeia nor in the pharmacopoeia of a Member State, compliance with the monograph of a third country pharmacopoeia may be accepted if its suitability is demonstrated; in such cases, the applicant shall submit a copy of the monograph accompanied by a translation where appropriate. Data to demonstrate the ability of the monograph to adequately control the quality of the substance shall be presented.

(3)If tests other than those mentioned in the pharmacopoeia are used, the use of such tests shall be justified by providing proof that the materials, if tested in accordance with the pharmacopoeia, would meet the quality requirements of the relevant pharmacopoeial monograph.

(4)All test procedures for analysis and quality control shall take account of established guidance and requirements. The results of the validation studies shall be provided. All the test procedure(s) shall be described in sufficient detail so as to be reproducible in control tests, carried out at the request of the competent authority and in order to be properly assessed by the competent authority. Any special apparatus and equipment, which may be used shall be described in adequate manner, accompanied by a diagram, if relevant. 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 Pharmacopoeia or the pharmacopoeia of a Member State, this description may be replaced by a detailed reference to the pharmacopoeia in question.

(5)Where available, chemical and biological reference material of the European Pharmacopoeia shall be used. If other reference preparations and standards are used, they shall be identified and described in detail.

(6)The pharmaceutical quality (physicochemical, biological or microbiological) data for the active substance and/or the finished product may be included in the dossier in Common Technical Document (CTD) format.

(7)For biological veterinary medicinal products, including immunologicals, information on solvents needed for making the final product preparation shall be included in the dossier. A biological veterinary medicinal product is regarded as one product even when more than one solvent is required so that different preparations of the final product can be prepared, which may be for administration by different routes or methods of administration. Solvents supplied with biological veterinary medicinal products may be packed together with the active substance vials or separately.

(8)In accordance with Directive 2010/63/EU and the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes, tests shall be carried out in such a way as to use the minimum number of animals and to cause the least pain, suffering, distress or lasting harm. If available, an alternative in vitro test shall be used when this leads to replacement or reduction of animal use or reduction of suffering.

(1)The dossier on the safety studies shall include the following:

(a) synthesis of the tests which have been carried out in compliance with this Part, with detailed references to the published literature containing an objective discussion of all the results obtained. Omission of any tests or trials listed and inclusion of an alternative type of study shall be indicated and discussed;

(b) statement of compliance with GLP for pre-clinical safety studies, where applicable, together with a discussion of the contribution that any non-GLP study may make to the overall risk assessment, and justification of non-GLP status.

(2)The dossier shall include the following:

(a) an index of all studies and trials included in the dossier;

(b) a justification for the omission of any type of study and trial;

(d) a discussion of the contribution that any non-GLP study or trial may make to the overall risk assessment and justification of non-GLP status.

(1)The dossier on efficacy shall include all pre-clinical and clinical documentation, whether favourable or unfavourable to the veterinary medicinal products, in order to enable an objective overall assessment of the benefit/risk balance of the product.

(2)The dossier on the efficacy studies shall include the following:

(b) a statement of compliance with GLP for pre-clinical safety studies, where applicable, together with a discussion of the contribution that any non-GLP study may make to the overall risk assessment, and justification of non-GLP status.

(3)The dossier shall include the following:

(a) an index of all studies included in the dossier;

(b) a justification for the omission of any type of study;

(4)The purpose of the trials described in this Part is to demonstrate the efficacy of the 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 authorisation.

(5)All efficacy trials shall be conducted in accordance with a fully considered detailed 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.

(6)Clinical trials (field trials) shall be conducted in accordance with established principles of good clinical practice, unless otherwise justified.

(7)Before the commencement of any field 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 consequences of participation in the trial for the subsequent disposal of treated animals or for the taking of foodstuffs from treated animals.

(1)Detailed requirements for different types of veterinary medicinal products or specific types of marketing authorisation dossiers are outlined in the following Sections of this Annex:

(a) Section II describes the standardised requirements for applications for veterinary medicinal products other than biological veterinary medicinal products;

(b) Section III describes the standardised requirements for applications for biological veterinary medicinal products: (i) Section IIIa describes the standardised requirements for applications for biological veterinary medicinal products other than immunological veterinary medicinal products; (ii) Section IIIb describes the standardised requirements for applications for immunological veterinary medicinal products;

(d) Section V describes the dossier requirements for particular types of veterinary medicinal products.

SECTION II

REQUIREMENTS FOR VETERINARY MEDICINAL PRODUCTS OTHER THAN BIOLOGICAL VETERINARY MEDICINAL PRODUCTS

The following detailed requirements shall apply to veterinary medicinal products other than biological veterinary medicinal products, except where otherwise set out in Section IV.

II.1. Part 1: Summary of the dossier

Please refer to Section I.

II.2. Part 2: Quality documentation (physicochemical, biological or microbiological information)

(1)Qualitative composition of all the constituents of the medicinal product shall mean the designation or description of:

(a) active substance(s);

(b) excipients, the constituents of the excipients, whatever their nature or the quantity used, including colouring matter, preservatives, adjuvants, stabilisers, thickeners, emulsifiers, flavouring and aromatic substances;

(c) other constituents, intended to be ingested or otherwise administered to animals, of the outer covering of the veterinary medicinal products, such as capsules, gelatine capsules, intraruminal devices;

(d) any relevant data concerning the immediate packaging and if relevant the outer packaging and, where appropriate, its manner of closure, together with details of devices with which the veterinary medicinal product will be used or administered and which will be supplied with the medicinal product.

(2)The usual terminology to be used in describing the constituents of veterinary medicinal products means, notwithstanding the application of the other provisions of Article 8:

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

(b) in respect of other substances, the international non-proprietary name (INN) recommended by the World Health Organisation (WHO), which may be accompanied by another non-proprietary name, or, failing these, the exact scientific designation;

(c) constituents not having an international non-proprietary name or an exact scientific designation shall be described by a statement of how and from what they were prepared, supplemented, where appropriate, by any other relevant details;

(d) in respect of colouring matter, designation by the ‘E’ code assigned to them by Directive 2009/35/EC of the European Parliament and Council.

(3)In order to give the quantitative composition of all the active substances and excipients of the veterinary 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 and excipient.

(4)Units of biological activity shall be used for substances which cannot be defined chemically. Where an international unit of biological activity has been defined, 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 by using where applicable the European Pharmacopoeia Units.

(5)Quantitative composition shall be supplemented:

(a) in respect of single-dose 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;

(b) in respect of veterinary medicinal products to be administered by drops: by the mass or units of biological activity of each active substance contained per drop or contained in the number of drops corresponding to 1 ml or 1 g of the preparation;

(c) in respect of pharmaceutical forms to be administered in measured quantities: by the mass or units of biological activity of each active substance per measured quantity.

(6)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.

(7)For veterinary medicinal products containing an active substance which is the subject of an application for marketing authorisation in the Union 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 authorised veterinary medicinal products in the Member States shall have their quantitative composition stated in the same way for the same active substance.

(1)An explanation shall be provided with regard to the choice of composition, constituents, packaging, the intended function of the excipients in the finished product and the method of manufacture including justification of the selection of the method and details of the sterilisation processes and/or aseptic procedures used of the finished product. This explanation shall be supported by scientific data on development pharmaceutics. Any overage, with justification thereof, shall be stated. The microbiological characteristics (microbiological purity and antimicrobial activity) and usage instructions shall be proven to be appropriate for the intended use of the veterinary medicinal product as specified in the marketing authorisation application dossier.

(2)A study of the interaction between finished product and the primary packaging shall be submitted wherever the risk of such interaction is regarded as possible, especially where injectable preparations are concerned.

(3)The proposed pack sizes shall be justified in relation to the proposed route of administration, the posology and the target species in particular for antimicrobial (active) substances.

(4)When a dosing device is provided with the finished product, the accuracy of the doses(s) shall be demonstrated.

(5)When an accompanying test is recommended to be used with the finished product (e.g. a diagnostic test), relevant information about the test shall be provided.

(6)For veterinary medicinal products intended for incorporation into feed, information shall be provided on inclusion rates, instructions for incorporation, homogeneity in-feed and compatibility/suitable feed.

(1)The description of the manufacturing method accompanying the application for marketing authorisation pursuant to Article 8 shall be drafted in such a way as to give an adequate synopsis of the nature of the operations employed.

(2)For that purpose, it shall include at least:

(a) the actual manufacturing formula for the proposed commercial batch size(s), with the quantitative particulars of all the substances used. Any substances that may disappear in the course of manufacture shall be stated; any overage shall be indicated;

(b) description of the various stages of manufacture with information on process operating conditions, in a narrative way accompanied by a process flow chart;

(c) in the case of continuous manufacture, full details of precautions taken to ensure the homogeneity of the finished product. Information as to how a batch is defined shall be provided (for example, expressed in terms of a period of time or a quantity of product, and may be expressed as ranges);

(d) a list of in-process controls including the stage of manufacture at which they are conducted and the acceptance criteria;

(e) experimental studies validating the manufacturing process and, where appropriate, a process validation scheme for production scale batches;

(f) for sterile products, where non-pharmacopoeial sterilisation conditions are used, details of the sterilisation processes and/or aseptic procedures used.

(1)For the purposes of this point, ‘starting materials’ shall mean active substances, excipients and packaging (immediate packaging with its closure system and, if applicable, outer packaging and any dosing device supplied with the veterinary medicinal product).

(2)The dossier shall include the specifications and information on the tests to be conducted for quality control of all batches of starting materials.

(3)The routine tests carried out on starting materials shall be carried out in the same manner as stated in the dossier.

(4)Where a certificate of suitability has been issued by the European Directorate for the Quality of Medicines and HealthCare for a starting material, active substance or excipient, that certificate constitutes the reference to the relevant monograph of the European Pharmacopoeia.

(5)Where a certificate of suitability is referred to, the manufacturer shall give an assurance in writing to the applicant that the manufacturing process has not been modified since the granting of the certificate of suitability by the European Directorate for the Quality of Medicines and HealthCare. In case the field ‘box of access’ in the certificate is completed and signed, that requirement shall be deemed to be fulfilled without the need for additional assurance.

(6)Certificates of analysis shall be presented for the starting materials in order to demonstrate compliance with the defined specification.

(1)The required data shall be submitted in one of the three ways as detailed in points (2) to (4).

(2)The following details shall be submitted:

(a) information on the identity, structure and a list of physicochemical and other relevant properties of the active substance shall be provided, in particular physicochemical properties that potentially affect the safety and efficacy of the active substance. Where relevant, evidence of molecular structure shall include the schematic amino acid sequence and relative molecular mass;

(b) information on the manufacturing process shall include a description of the active substance manufacturing process that represents the applicant’s commitment for the manufacture of the active substance. All materials needed in order to manufacture the active substance(s) shall be listed, identifying where each material is used in the process. Information on the quality and control of those materials shall be provided. Information demonstrating that materials meet standards which are appropriate for their intended use shall be provided;

(c) information on quality control shall contain tests (including acceptance criteria) carried out at every critical step, information on the quality and control of intermediates and process validation and/or evaluation studies as appropriate. It shall also contain validation data for the analytical methods applied to the active substance, where appropriate;

(d) information on impurities shall indicate predictable impurities together with the levels and nature of observed impurities. It shall also contain information on the safety of those impurities where relevant.

(3)Active Substance Master File

For a non-biological active substance, the applicant may arrange for the information on active substance in point (2) to be supplied directly to the competent authorities by the manufacturer of the active substance as an Active Substance Master File. In this case, the manufacturer of the active substance shall provide the applicant with all the data (applicant’s part of the Active Substance Master File) which may be necessary for the latter to take responsibility for the veterinary medicinal product. A copy of the data provided by the active substance manufacturer to the applicant shall be included in the medicinal product dossier. The manufacturer of the active substance 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.

(4)Certificate of suitability issued by the European Directorate for the Quality of Medicines and HealthCare

The certificate of suitability and any additional data relevant to the dosage form not covered by the certificate of suitability shall be provided.

(1)Active substances fulfilling the requirements of the European Pharmacopoeia or, in the absence of a European Pharmacopoeia monograph, the pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with Article 8. In this case the description of the analytical methods and procedures shall be replaced in each relevant section by an appropriate reference to the pharmacopoeia in question.

(2)In cases where a specification contained in a monograph of the European Pharmacopoeia or in the national pharmacopoeia of a Member State is insufficient to ensure the quality of the substance, the competent authorities may request more appropriate specifications from the applicant, including acceptance criteria for specific impurities with validated test procedures.

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

(1)Active substances which are not listed in any pharmacopoeia shall be described in the form of a monograph under the following headings:

(a) the name of the constituent, meeting the requirements of Part II.2A1, point (2) shall be supplemented by any trade or scientific synonyms;

(b) the definition of the substance, set down in a form similar to that used in the European Pharmacopoeia, shall be accompanied by any necessary explanatory evidence, in particular concerning the molecular structure. Where substances may only be described by their manufacturing method, the description shall be sufficiently 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 each individual predictable impurity, 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) tests and acceptance criteria to control parameters relevant to the finished product, such as sterility shall be described and methods shall be validated where relevant;

(f) with regard to complex substances of plant or animal origin, a distinction shall 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.

(2)Those data shall demonstrate that the proposed set of test procedures is sufficient to control the quality of the active substance from the defined source.

The following data concerning active substances shall be provided as part of the general description of the active substances if the bioavailability of the veterinary medicinal product depends on them:

(a) crystalline form and solubility;

(b) particle size;

(d) oil/water coefficient of partition;

(e) pK/pH values.

Points (a) to (c) are not applicable to substances used solely in solution.

(1)Excipients fulfilling the requirements of the European Pharmacopoeia or, in the absence of a European Pharmacopoeia monograph, the pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with Article 8. In that case, the description of the analytical methods and procedures shall be replaced in each relevant section by an appropriate reference to the pharmacopoeia in question. Where appropriate, additional tests to control parameters such as particle size, sterility, and/or residual solvents, shall supplement the requirements of the monograph.

(2)In the absence of a pharmacopoeial monograph a specification shall be proposed and justified. The requirements for specifications as set out in Part II.2C1.2(1) points (a) to (e) for the active substance shall be followed. The proposed methods and their supporting validation data shall be presented.

(3)A declaration shall be submitted to confirm that colouring matters for inclusion in veterinary medicinal products satisfy the requirements of Directive 2009/35/EC of the European Parliament and of the Council (¹⁶) except where the application for a marketing authorisation concerns certain veterinary medicinal products for topical use, such as medicated collars and ear tags.

(4)A declaration shall be submitted to confirm that colouring matters used meet the purity criteria laid down in Commission Regulation (EU) No 231/2012 (¹⁷).

(5)For novel excipients, that is to say excipient(s) used for the first time in the Union in a veterinary medicinal product or by a new route of administration, details of manufacture, characterisation, and controls, with cross references to support both clinical and non-clinical safety data shall be provided. For colouring matters, the declarations of compliance in points (3) and (4) shall be considered sufficient.

(1)Information on the container and its closure system for the active substance including the identity of each immediate packaging material and their specifications shall be given. The level of information required shall be determined by the physical state (liquid, solid) of the active substance.

(2)Where a certificate of suitability for the active substance from the proposed source is submitted and specifies a container and its closure system, the detailed information on these for the active substance from that source may be replaced by a reference to the valid certificate of suitability.

(3)Where an Active Substance Master File from the proposed source is submitted and specifies a container and its closure system, the detailed information on these for the active substance from that source may be replaced by a reference to the Active Substance Master File.

(1)Information on the container and its closure system and any device for the finished product including the identity of each immediate packaging material and their specifications shall be given. The level of information required shall be determined by the route of administration of the veterinary medicinal product and the physical state (liquid, solid) of the dosage form.

(2)In the absence of a pharmacopoeial monograph, a specification shall be proposed and justified for the packaging material.

(3)For packaging materials that are used for the first time in the Union and that are in contact with the product, information on their composition, manufacture and safety shall be presented.

(1)Information on the source, processing, characterisation and control of all materials of biological origin (human, animal, herbal or from microorganisms) used in the manufacture of the veterinary medicinal products shall be provided, including viral safety data, in accordance with relevant guidelines.

(2)Documentation shall be supplied to demonstrate that materials originating from animal species relevant for the transmission of transmissible spongiform encephalopathies (TSE) comply with the Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products, as well as with the corresponding monograph of the European Pharmacopoeia. Certificates of Suitability issued by the European Directorate for the Quality of Medicines and HealthCare, with reference to the relevant monograph of the European Pharmacopoeia, may be used to demonstrate compliance.

(1)For the purposes of this section, ‘isolated intermediate’ shall mean partly processed material that may be stored for a defined amount of time and that shall undergo further processing step(s) before it becomes finished product.

(2)A specification shall be set for each intermediate and the analytical methods shall be described and validated, if applicable.

(3)Information on the primary packaging of the intermediate product shall be provided if different from that for the finished product.

(4)A shelf life and storage conditions for the intermediate product shall be defined on the basis of the data resulting from stability studies.

(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 sterilisation operations. In case of continuous manufacture, the batch size may be expressed in terms of a period of time or a quantity of product, and may be expressed as ranges.

(2)The tests, which are carried out on the finished product shall be listed. A justification for the proposed specification shall be provided. The frequency of the tests which are not carried out routinely shall be stated and justified. Acceptance criteria for release shall be indicated.

(3)The dossier shall include particulars relating to control tests on the finished product at release and their validation. They shall be submitted in accordance with the following requirements.

(4)If test procedures and acceptance criteria other than those mentioned in the relevant monographs and general chapters of the European Pharmacopoeia, or failing this, in the pharmacopoeia of a Member State are used, those procedures and criteria shall be justified by providing proof 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)Certain tests of the general characteristics of a product shall always be included among the tests on the finished product. Those tests shall, wherever applicable, relate to the control of average masses/volumes and maximum deviations, to mechanical, physical tests, visual appearance, physical characteristics such as, pH or particle size. For each of those characteristics, standards and acceptance criteria shall be specified by the applicant.

(2)The conditions of the tests, where appropriate, the equipment/apparatus employed and the standards shall be described in sufficient detail whenever they are not given in the European Pharmacopoeia or the pharmacopoeia of a Member State; the same shall apply in cases where the methods prescribed by such pharmacopoeias are not applicable.

(1)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.

(2)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.

(3)In certain 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. That simplified technique may not be extended to the characterisation of the substances concerned. It 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.

(4)An in vivo or in vitro biological assay shall be obligatory when physicochemical 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 those tests cannot be carried out on the finished product, they may be performed at an intermediate stage, as late as possible in the manufacturing process.

(5)The maximum acceptable levels of individual and total degradation products immediately following manufacture shall be indicated. The rationale for the inclusion or exclusion of degradation products in the specification shall be presented.

An identification test and an upper and lower limit test shall be obligatory for each individual antimicrobial preservative and for any excipient that is liable to affect the bioavailability of the active substance, unless the bioavailability is guaranteed by other appropriate tests. An identification test and an upper limit test shall be obligatory for any antioxidant and for any excipient liable to adversely affect physiological functions, with a lower limit test also included for antioxidants at time of release.

Particulars of microbiological tests, such as sterility and bacterial endotoxins, shall be included in the analytical particulars wherever such tests shall be undertaken as a matter of routine in order to verify the quality of the product.

In order to ensure the quality of the product is consistent from batch to batch and to demonstrate conformity with the specification, batch data shall be provided giving the results for all tests performed in general on [3] batches manufactured at the proposed manufacturing site(s) according to the described production process.

Any other test considered necessary to confirm the quality of the medicinal product shall be controlled.

(1)A retest period and storage conditions for the active substance shall be specified except when the manufacturer of the finished product fully retests the active substance immediately before its use in the manufacture of the finished product.

(2)Stability data shall be presented to provide evidence on how the quality of an active substance varies with time under the influence of a variety of environmental factors and to support the defined retest period and storage conditions, if applicable. The type of stability studies conducted, protocols used, the analytical procedures used and their validation together with the detailed results shall be presented.

(3)Where a certificate of suitability for the active substance from the proposed source is available and specifies a retest period and storage conditions, stability data for the active substance from that source may be replaced by a reference to the valid certificate of suitability.

(4)Where an Active Substance Master File from the proposed source is submitted and specifies stability data, the detailed information on the stability for the active substance from that source may be replaced by a reference to the Active Substance Master File.

(1)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.

(2)The type of stability studies conducted, protocols used, the analytical procedures used and their validation together with the detailed results shall be presented.

(3)Where a finished product requires reconstitution or dilution prior to administration, details of the proposed shelf life and specification for the reconstituted/diluted product are required, supported by relevant stability data.

(4)In the case of multi-dose containers, where relevant, stability data shall be presented to justify a shelf life for the product after it has been broached or opened for the first time and an in-use specification shall be defined.

(5)Where a finished product is liable to give rise to degradation products, the applicant shall declare those products and indicate the identification methods and test procedures used.

(6)Where the stability data show that the assay of the active substance declines on storage, the description of the control tests on the finished product shall include, where appropriate, the chemical and, if necessary, the toxico-pharmacological investigation of the changes that this substance has undergone, and possibly the characterisation and/or assay of the degradation products.

(7)The maximum acceptable level of individual and total degradation products at the end of shelf life shall be indicated and justified.

(8)On the basis of the stability test results, the tests and their acceptance criteria, that are carried out on the finished product over the course of the shelf life shall be listed and justified.

(9)The conclusions shall contain the results of analyses, justifying the proposed shelf life and if appropriate, the in-use shelf life, under the recommended storage conditions.

(10)Additionally, for veterinary medicinal products intended for incorporation into feed, information shall be provided on the stability and the proposed shelf life after incorporation into feed. A specification for the medicated feed manufactured using those veterinary medicinal products in accordance with the recommended instructions for use shall also be provided.

Information relating to the quality of the veterinary medicinal product not covered elsewhere in this Part may be included in the dossier under this point.

II.3 Part 3: Safety documentation (safety and residues tests)

(1)Each study report shall include:

(a) a copy of the study plan (protocol);

(b) a statement of compliance with good laboratory practice, where applicable;

(d) a description and justification of the test system;

(e) a description of the results obtained, in sufficient detail, to allow the results to be critically evaluated independently of their interpretation by the author;

(f) a statistical analysis of the results where appropriate;

(g) a discussion of the results, with comment on observed and no-observed-effect levels, and on any unusual findings;

(h) the name of the laboratory;

(i) the name of the study director;

(j) signature and date;

(k) place and period of time during which the study was undertaken;

(l) key for abbreviations and codes, irrespective of whether they are internationally accepted or not;

(m) description of mathematical and statistical procedures.

(2)Published studies may be accepted if they contain a sufficient amount of data and sufficient details to allow an independent assessment. The experimental techniques shall be described in such detail as to allow them to be reproduced, and the investigator shall establish their validity. Summaries of studies for which detailed reports are not available shall not be accepted as valid documentation. When the substance has been previously evaluated for the establishment of maximum residues limit (‘MRL’) to address certain safety requirements reference may be made to the European public MRL assessment reports (‘EPMARs’). Where reference to EPMAR is made there is no need to submit studies already evaluated as part of the MRL evaluation; only new studies not available for the MRL assessment shall be provided. If the route of exposure (for example, for the user) is not identical to the route used in accordance with Commission Regulation (EU) 2018/782 (¹⁸), new studies might be necessary.

(1)The safety documentation shall be adequate for assessment of:

(a) the potential toxicity of the veterinary medicinal product and any dangerous or undesirable effects in target species which may occur under the proposed conditions of use;

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

(2)In some cases it may be necessary to test the metabolites of the parent compound where these represent the residues of concern.

(3)An excipient used for the first time in a veterinary medicinal product or by a new route of administration shall be treated in the same way as an active substance.

(a) International Non-proprietary Name (INN);

(b) International Union of Pure and Applied Chemistry Name (IUPAC);

(d) therapeutic, pharmacological and chemical classification;

(e) synonyms and abbreviations;

(f) structural formula;

(g) molecular formula,

(h) molecular weight;

(i) degree of purity;

(j) qualitative and quantitative composition of impurities;

(k) description of physical properties: (i) melting point, (ii) boiling point, (iii) vapour pressure, (iv) solubility in water and organic solvents expressed in g/l, with indication of temperature, (v) density, (vi) refraction of light, optical rotation, etc.;

(l) formulation of the product.

(1)Pharmacological studies are of fundamental importance in clarifying the mechanisms by which the veterinary medicinal product produces its therapeutic effects, and therefore pharmacological studies conducted in experimental and target species of animal shall be included. Cross reference may be made, if applicable, to studies submitted in Part 4 of the dossier.

(2)Where a veterinary medicinal product produces pharmacological effects in the absence of a toxic response, or at doses lower than those required to elicit toxicity, those pharmacological effects shall be taken into account during the evaluation of the safety for the user of the veterinary medicinal product.

(3)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.

Information on the mechanism of action of the active substance(s) shall be provided, together with information on primary and secondary pharmacodynamic effects in order to assist in the understanding of any adverse effects in the animal studies. Detailed reporting of pharmacodynamic properties relating to the therapeutic effect shall be reported in Part 4A of the dossier.

Data on the fate of the active substance and its metabolites in laboratory animals shall be provided, covering absorption, distribution, metabolism and excretion (ADME). The data shall be related to the dose/effect findings in the pharmacological and toxicological studies, to determine adequate exposure.

(1)The documentation on toxicology shall follow the guidance published by the Agency on the general approach to testing and guidance on particular studies. Generally, toxicity studies shall be conducted with the active substance(s), not with the formulated product, unless specifically required otherwise.

(2)Animal studies shall be conducted in established strains of laboratory animals for which (preferably) historical data are available.

(3)Single-dose toxicity

Single-dose toxicity studies may be used to predict:

(a) the possible effects of acute overdose in the target species;

(b) the possible effects of accidental administration to humans;

Single-dose toxicity studies shall reveal the acute toxic effects of the substance and the time course for their onset and remission.

The studies to be carried out shall be selected with a view to providing information on user safety, for example, if substantial exposure by inhalation or dermal contact of the user of the veterinary medicinal product is anticipated, those routes of exposure shall be studied.

(4)Repeat-dose toxicity

Repeat-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 those changes are related to dosage.

A repeat-dose toxicity study in one species of experimental animal shall 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 shall be chosen having regard to the proposed conditions of clinical use and/or user exposure. The applicant shall give his reasons for the extent and duration of the studies and the dosages chosen.

(5)Tolerance in the target species

A summary shall be provided of any signs of intolerance which have been observed during studies conducted, usually with the final formulation, in the target species in accordance with the requirements of Part II.4A4 (Tolerance in the target animal species). The studies concerned, the dosages at which the intolerance occurred, and the species and breeds concerned shall be identified. Details of any unexpected physiological changes shall also be provided. The full reports of those studies shall be included in Part 4 of the dossier.

(6)Reproductive toxicity including developmental toxicity

Study of the effects on reproduction

For products intended for use in breeding animals, reproductive safety studies in line with VICH GL43 shall be provided. Reproduction toxicity studies in laboratory animals are not expected for the evaluation of effects on the user.

(7)Study of developmental toxicity

For the evaluation of effects in the target animal species, developmental toxicity studies are not required for products intended only for use in non-breeding animals. For other products a study of developmental toxicity shall be performed in at least one species, which may be the target species. If the study is conducted in the target species, a summary shall be provided here, and the full report of the study shall be included in Part 4 of the dossier.

For the evaluation of user safety, standard developmental toxicity testing in accordance with standard tests based on established guidance (including VICH GL32 and OECD tests) shall be performed in all cases where significant user exposure may be expected.

(8)Genotoxicity

Tests for genotoxic potential shall be performed to reveal changes which a substance may cause in the genetic material of cells. Any substance intended to be included in a veterinary medicinal product for the first time shall be assessed for genotoxic properties.

A standard battery of genotoxicity tests in accordance with standard tests based on established guidance (including VICH GL23 and OECD tests) shall be carried out on the active substance(s).

(9)Carcinogenicity

The decision on whether carcinogenicity testing is required shall take into account the results of genotoxicity tests, structure-activity relationships and the findings in repeat dose toxicity tests that may demonstrate the potential for hyper-/neo-plastic changes.

Any known species specificity of the mechanism of toxicity shall be considered, as well as any differences in metabolism between the test species, target animal species, and human beings.

Carcinogenicity testing shall be conducted according to standard tests based on established guidance (including VICH GL28 and OECD tests).

(10)Exceptions

Where a veterinary medicinal product is intended for topical use, systemic absorption shall be investigated in the target animal species. If it is proved that systemic absorption is negligible, the repeated dose toxicity tests, the tests for reproductive and developmental toxicity and the carcinogenicity tests may be omitted, unless:

(a) under the intended conditions of use, oral ingestion of the veterinary medicinal product by the animal is to be expected, or

(b) under the intended conditions of use, oral exposure of the user of the veterinary medicinal product is to be expected.

For particular groups of substances or if the effects observed during repeated dose studies in animals include changes indicative of, for example, immunotoxicity, neurotoxicity or endocrine dysfunction, further testing shall be required, for example, sensitisation studies or delayed neurotoxicity tests. Depending on the nature of the product, it may be necessary to conduct additional studies to assess the underlying mechanism of the toxic effect or the irritation potential.

For products for which there may be exposure to skin and eyes, irritation and sensitisation studies shall be provided. Those studies shall be conducted with the final formulation.

The state of latest scientific knowledge and established guidance shall be taken into account when designing such studies and evaluating their results.

Information shall be provided showing whether the pharmacologically active substances of the veterinary medicinal product are used as medicinal products in human therapy. If that is the case, a compilation shall be made of all the effects observed (including adverse reactions) in humans and of their cause, to the extent that they may be important for the assessment of the safety of the veterinary medicinal product, where appropriate including results from published studies; where constituents of the veterinary medicinal products are themselves not used or are no longer used as medicinal products in human therapy, the reasons shall be stated, if publicly available.

The data requirements described in this point are related to antibacterial substances and may not be fully applicable to other types of antimicrobial (namely antivirals, antifungals and antiprotozoals) although, in principle, the requirements may be followed, where applicable.

Data on the potential emergence of resistant bacteria or resistance determinants of relevance for human health and which are associated with the use of veterinary medicinal products are necessary for those products. The mechanism of the development and selection of such resistance is particularly important in this regard. Where necessary, measures to limit resistance development from the intended use of the veterinary medicinal product shall be proposed by the applicant.

Resistance data relevant for clinical use of the product in target animals shall be addressed in accordance with Part II.4A2. Where relevant, cross reference shall be made to the data set out in Part II.4A2.

(1)For food-producing animals the risk assessment shall address:

(a) the identification of resistant bacteria or resistance determinants that could be associated with human illness (zoonotic and/or commensal bacteria) and are selected by the use of the antimicrobial veterinary medicinal product in target animals (hazard identification);

(b) the probability of release of the identified hazard(s) from the target animal species as a result of the use of the veterinary medicinal product under consideration;

(c) the probability of subsequent human exposure to the identified hazard(s) via the foodborne route or through direct contact, and the resulting consequences (adverse health effects) to human health. Guidance is available in VICH GL27 and EU GLs.

(2)For companion animals consideration of risk to human or public health shall address:

(a) the identification of resistant bacteria or resistance determinants that could be associated with human illness and are selected by the use of the antimicrobial veterinary medicinal product in target animals;

(b) an estimate of exposure of zoonotic and commensal bacteria in the target animal species based on the conditions of use of the veterinary medicinal product under consideration;

(c) consideration of subsequent human exposure to antimicrobial resistance (AMR), and the resulting consequences to human health.

(3)Resistance in the environment shall be addressed.

This section shall include an assessment of the effects found in Part II.3A to II.3A4 and relate this to the type and extent of human exposure to the product with a view to formulating appropriate user warnings and other risk management measures.

User safety shall be addressed in accordance with Committee for Medicinal Products for Veterinary Use (CVMP) guidelines.

(1)An environmental risk assessment shall be performed to assess the potential harmful effects that the use of the veterinary medicinal product may cause to the environment and to identify the risk of such effects. The assessment shall also identify any precautionary measures which may be necessary to reduce such risk.

(2)This assessment consists of two phases. The first phase of the assessment shall always be performed. The details of the assessment shall be provided in accordance with guidance published by the Agency. It shall indicate the potential exposure of the environment to the product and the level of risk associated with any such exposure, in particular taking into account the following items:

(a) the target animal species, and the proposed pattern of use;

(b) the method of administration, in particular the likely extent to which the product will enter directly into environmental systems;

(c) the possible excretion of the product, its active substances or relevant metabolites into the environment by treated animals; persistence in such excreta;

(d) the disposal of unused veterinary medicinal product or other waste product.

(3)In the second phase, further specific investigation of the fate and effects of the product on particular ecosystems shall be conducted, in accordance with guidance published by the Agency. 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 substance(s) concerned, including metabolites in case of an identified risk, which has been obtained during the conduct of the other tests and trials required by this Regulation, shall be taken into consideration.

(4)For products intended for food producing species, persistent, bioaccumulative and toxic (PBT) or very persistent and very bioaccumulative (vPvB) substances shall be classified according to the criteria in Annex XIII to Regulation (EC) No 1907/2006 of the European Parliament and of the Council (¹⁹) (REACH Regulation) and assessed according to the guidance for PBT and vPvB assessment of substances in veterinary medicines published by the Agency.

(1)For the purposes of this point, the definitions of Regulation (EC) No 470/2009 shall apply.

(2)The purpose of studying the depletion of residues from the edible tissues or from eggs, milk and honey (wax, if appropriate) derived from treated animals is to determine under what conditions and to what extent residues may persist in foodstuffs produced from those animals. In addition, the studies shall enable the determination of a withdrawal period.

(3)In the case of veterinary medicinal products intended for use in food-producing animals, the residue documentation shall show:

(a) to what extent, and for how long residues of the veterinary medicinal product or its metabolites persist in the edible tissues of the treated animal or in milk, eggs and/or honey (wax, if appropriate) obtained therefrom;

(b) that in order to prevent any risk to the health of the consumer of foodstuffs from treated animals, it is possible to establish realistic withdrawal periods which may be observed under practical farming conditions;

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