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REQUIREMENTS REFERRED TO IN ARTICLE 8(1), POINT (B)

Table of Contents SECTION I GENERAL PRINCIPLES AND REQUIREMENTS I.1. General principles I.2. Dossier composition requirements I.2.1. Part 1: Summary of the dossier I.2.2. Part 2: Quality documentation (physicochemical, biological or microbiological information) I.2.3. Part 3: Safety documentation (safety and residues tests) I.2.4. Part 4: Efficacy documentation (pre-clinical studies and clinical trial(s)) I.2.5. Detailed requirements for different types of veterinary medicinal products or marketing authorisation dossiers SECTION II REQUIREMENTS FOR VETERINARY MEDICINAL PRODUCTS OTHER THAN BIOLOGICAL VETERINARY MEDICINAL PRODUCTS II.1. Part 1: Summary of the dossier II.2. Part 2: Quality documentation (physicochemical, biological or microbiological information) II.2A. Product description II.2A1. Qualitative and quantitative composition II.2A2. Product development II.2B. Description of the manufacturing method II.2C. Production and control of starting material II.2C1. Active substance(s) II.2C1.1. Active substances listed in pharmacopoeias II.2C1.2. Active substances not listed in a pharmacopoeia II.2C1.3. Physicochemical characteristics liable to affect bioavailability II.2C2. Excipients II.2C3. Packaging (container-closure systems) II.2C3.1. Active substance II.2C3.2. Finished product II.2C4. Substances of biological origin II.2D. Control tests carried out on isolated intermediates during the manufacturing process II.2E. Control tests on the finished product II.2E1. General characteristics of the finished product II.2E2. Identification and assay of active substance(s) II.2E3. Identification and assay of excipient components II.2E4. Microbiological controls II.2E5. Batch-to-batch consistency II.2E6. Other controls II.2F. Stability test II.2F1. Active substance(s) II.2F2. Finished product II.2G. Other information II.3 Part 3: Safety documentation (safety and residues tests) II.3A. Safety tests II.3A1. Precise identification of the product and of its active substance(s) II.3A2. Pharmacology II.3A2.1. Pharmacodynamics II.3A2.2. Pharmacokinetics II.3A3. Toxicology II.3A4. Other requirements II.3A.4.1. Special studies II.3A.4.2. Observations in humans II.3A.4.3. Development of resistance and related risk in humans II.3A5. User safety II.3A6. Environmental risk assessment II.3B. Residue tests II.3B1. Identification of the product II.3B2. Depletion of residues (metabolism and residue kinetics) II.3B3. Residue analytical method II.4. Part 4: Efficacy documentation (pre-clinical studies and clinical trial(s)) II.4A. Pre-clinical studies II.4A1. Pharmacology II.4A.1.1. Pharmacodynamics II.4A.1.2. Pharmacokinetics II.4A2. Development of resistance and related risk in animals II.4A3. Dose determination and confirmation II.4A4. Tolerance in the target animal species II.4B. Clinical trial(s) II.4B1. General principles II.4B2. Documentation II.4B2.1. Results of pre-clinical studies II.4B2.2. Results of clinical trials SECTION III REQUIREMENTS FOR BIOLOGICAL VETERINARY MEDICINAL PRODUCTS SECTION IIIa REQUIREMENTS FOR BIOLOGICAL VETERINARY MEDICINAL PRODUCTS OTHER THAN IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS IIIa.1. Part 1: Summary of the dossier IIIa.2. Part 2: Quality documentation (physicochemical, biological or microbiological information) IIIa.2A. Product description IIIa.2A1. Qualitative and quantitative composition IIIa.2A2. Product development IIIa.2A3. Characterisation IIIa.2A3.1. Elucidation of structure and other characteristics IIIa.2A3.2. Impurities IIIa.2B. Description of the manufacturing method IIIa.2C. Production and control of starting materials IIIa.2C1. Starting materials listed in pharmacopoeias IIIa.2C2. Starting materials not listed in a pharmacopoeia IIIa.2C2.1. Starting materials of biological origin IIIa.2C2.2. Starting materials of non-biological origin IIIa.2D. Control tests during the manufacturing process IIIa.2E. Control tests on the finished product IIIa.2E1 Finish product specification IIIa.2E2 Method descriptions and validation of release tests IIIa.2E3. Reference standards or materials IIIa.2F. Batch-to-batch consistency IIIa.2F1. Active substance IIIa.2F2. Finished product IIIa.2G. Stability tests IIIa.2H. Other information IIIa.3. Part 3: Safety documentation (safety and residues tests) IIIa.3A. Safety tests IIIa.3A1. Precise identification of the product and of its active substance(s): IIIa.3A2. Pharmacology IIIa.3A2.1. Pharmacodynamics IIIa.3A2.2. Pharmacokinetics IIIa.3A3. Toxicology IIIa.3A3.1. Single-dose toxicity IIIa.3A3.2. Repeat-dose toxicity IIIa.3A3.3. Tolerance in the target species IIIa.3A3.4. Reproductive toxicity including developmental toxicity IIIa.3A3.5. Genotoxicity IIIa.3A3.6. Carcinogenicity IIIa.3A3.7. Exceptions IIIa.3A4. Other requirements IIIa.3A4.1. Special studies IIIa.3A4.2. Observations in humans IIIa.3A4.3. Development of resistance and related risk in humans IIIa.3A5. User safety IIIa.3A6. Environmental risk assessment IIIa.3A6.1. Environmental risk assessment of veterinary medicinal products not containing or consisting of genetically modified organisms IIIa.3A6.2. Environmental risk assessment for veterinary medicinal products containing or consisting of genetically modified organisms IIIa.3B. Residue tests IIIa.3B1. Identification of the product IIIa.3B2. Depletion of residues IIIa.3B3. Residue analytical method IIIa.4. Part 4: Efficacy documentation (pre-clinical studies and clinical trial(s)) IIIa.4A. Pre-clinical studies IIIa.4A1. Pharmacology IIIa.4A1.1. Pharmacodynamics IIIa.4A1.2. Pharmacokinetics IIIa.4A2. Development of resistance and related risk in animals IIIa.4A3. Dose determination and confirmation IIIa.4A4. Tolerance in the target animal species IIIa.4B. Clinical trials IIIa.4B1. General principles IIIa.4B2. Documentation IIIa.4B2.1. Clinical trials IIIa.4B2.2. Clinical trials SECTION IIIb REQUIREMENTS FOR IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS IIIb.1. Part 1: Summary of the dossier IIIb.2. Part 2: Quality documentation (physicochemical, biological and microbiological information) IIIb.2.A. Product description IIIb.2A1. Qualitative and quantitative composition IIIb.2A2. Product development IIIb.2B. Description of the manufacturing method IIIb.2C. Production and control of starting materials IIIb.2C1. Starting materials listed in pharmacopoeias IIIb.2C2. Starting materials not listed in a pharmacopoeia IIIb.2C2.1. Starting materials of biological origin IIIb.2C2.2. Starting materials of non-biological origin IIIb.2D. Control tests during the manufacturing process IIIb.2E. Control tests on the finished product IIIb.2F. Batch-to-batch consistency IIIb.2G. Stability tests IIIb.2H. Other information IIIb.3. Part 3: Safety documentation (safety and residues tests) IIIb.3A. General requirements IIIb.3B. Pre-clinical studies IIIb.3C. Clinical trials IIIb.3D. Environmental risk assessment IIIb.3E. Assessment required for veterinary medicinal products containing or consisting of genetically modified organisms IIIb.3F. Residue tests to be included in the laboratory studies IIIb.4. Part 4: Efficacy documentation (pre-clinical studies and clinical trial(s)) IIIb.4A. General requirements IIIb.4B. Pre-clinical studies IIIb.4C. Clinical trials SECTION IV REQUIREMENTS FOR SPECIFIC MARKETING AUTHORISATION APPLICATIONS IV.1. Applications for generic veterinary medicinal products IV.2. Applications for hybrid veterinary medicinal products IV.3. Applications for combination veterinary medicinal products IV.4. Applications based on informed consent IV.5. Applications based on bibliographic data IV.6. Applications for limited markets IV.7. Applications in exceptional circumstances SECTION V REQUIREMENTS FOR MARKETING AUTHORISATION APPLICATIONS FOR PARTICULAR VETERINARY MEDICINAL PRODUCTS V.1. Novel therapies veterinary medicinal products V.1.1 General requirements V.1.2. Quality requirements V.1.3. Safety requirements V.1.4. Efficacy requirements V.1.5. Specific data requirements for particular types of novel therapy products V.1.5.1. Principles V.1.5.2. Gene therapy veterinary medicinal products V.1.5.3. Regenerative medicine, tissue engineering and cell therapy veterinary medicinal products V.1.5.4. Veterinary medicinal product specifically designed for phage therapy V.1.5.5. Veterinary medicinal product issued from nanotechnologies V.1.5.6. RNA antisense therapy and RNA interference therapy products V.2. Vaccine antigen master file V.3. Multi-strain dossier V.4. Vaccine platform technology V.5. Authorised homeopathic veterinary medicinal products

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 () and 2004/9/EC () 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: I.2.1. Part 1: Summary of the dossier 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;

(c) Part 1C: point 6.5.

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. I.2.2. Part 2: Quality documentation (physicochemical, biological or microbiological information)

(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.