Key Benefits:
Minister of Health and Sports and Minister of Food, Agriculture and Fisheries,
In view of Commission Directive 2009/9/EC of 10 February 2009 amending Directive 2001/82/EC of the European Parliament and the amended Council of 6 November 2001 establishing a Community Code on Veterinary Drugs;
Considering the Public Health Code;
On the proposal of the Director General of the French Food Safety Agency dated 24 August 2009,
Stop:
The file attached to requests for marketing authorization referred to in articles R. 5141-16, R. 5141-18 and R. 5141-20 of the Public Health Code for a veterinary drug is established according to the provisions set out in the Appendix to this Order.
These files are submitted in accordance with the instructions in the "Notice to applicants for authorization to market veterinary drugs in the Member States of the European Community" published by the European Commission in the regulation of medicines in the European Union (Volume 6B).
The decision of 6 May 2008 setting out the nature and modalities for the presentation of administrative information and scientific documentation provided in support of applications for marketing authorization referred to in articles R. 5141-16, R. 5141-18 and R. 5141-20 of the Public Health Code is repealed.
The Director General of the French Food Safety Agency is responsible for the execution of this Order, which will be published in the Official Journal of the French Republic.
A N N E X E
CHEMICAL, PHARMACEUTIQUES AND ANALYTIQUES, INNOCUITY TESTS AND ANALYSIS OF RESIDUS, PRECLINICAL AND CLINICAL TESTS
INTRODUCTION AND GENERAL PRINCIPLES
1. The information and documents that are attached to the application for market authorization under the articles L. 5141-5, R. 5141-16, R. 5141-18 and R. 5141-20 of the Public Health Code or articles 12 to 13 quinquies of the Directive are prepared in accordance with the requirements of this annex and taking into account the guidelines published by the Commission in the Regulation of Drugs in the European Union (The rules governing medicinal products in the European Union, volume 6B, Notice to applicants, Veterinary medicinal Presentation).
2. When preparing the application file for marketing authorization, applicants also take into consideration the current state of knowledge on veterinary drugs and the scientific guidelines on the quality, safety and effectiveness of veterinary drugs adopted by the European Agency for Drugs, as well as other community-based guidelines on pharmaceuticals published by the Commission in the various volumes of The regulation of drugs in the European Union.
3. With respect to veterinary drugs other than immunological veterinary drugs, all relevant monographs, including general monographs and general chapters of the European Pharmacopoeia, are applicable with respect to the part of the quality file (physico-chemical, biological and microbiological tests). With respect to immunological veterinary drugs, all relevant monographs, including the general monographs and general chapters of the European Pharmacopoeia, are applicable with respect to the parts of the file on quality, safety and effectiveness.
4. The manufacturing process complies with the requirements of theArticle L. 5142-3 of the Public Health Code and the decision of September 22, 2008 of the Director General of the French Food Safety Agency on Good Manufacturing Practices for Veterinary Drugs or Directive 91 / 412 / EEC of the Commission establishing the principles and guidelines for good manufacturing practices for veterinary medicines as well as the principles and guidelines for good manufacturing practices (GMP), published by the Commission in Regulation of Drugs in the European Union, volume 4.
5. Any useful information for the assessment of the relevant veterinary drug, whether favourable or unfavourable, is attached to the application. In particular, all relevant details concerning any incomplete or abandoned testing or testing of the veterinary drug should be provided.
6. Non-clinical trials, namely pharmacological, toxicological, residue analysis and safety tests, and clinical trials are conducted in accordance with the principles of good practices applicable to each area of activity.
For non-clinical trials, the tests are conducted in accordance with the provisions concerning good laboratory practices provided for in the January 28, 2005 Order on Good Laboratory Practices for Veterinary Drugs and their Inspection and Verification Procedures and the issuance of documents attesting to their compliance or Directive 2004 / 10 / EC of the European Parliament and of the Council of 11 February 2004 on the approximation of legislative, regulatory and administrative provisions on the application of the principles of good laboratory practices and the monitoring of their application for chemical testing.
7. All experiments on animals are conducted in accordance with the provisions relating to animal experimentation of sub-section 3 of Chapter 5 of Title I of Book II of the Rural Code and the decrees of April 19, 1988 fixing the conditions for the granting of permission to practise experiments on animals and fixing the conditions for the accreditation, development and operation of the facilities of animal experimentation, 1998 EEC of the Council of 24 November 1986, amended by Directive 2003 / 65 / EC of the European Parliament and of the Council of 22 July 2003 concerning the approximation of the legislative, regulatory and administrative provisions of the Member States concerning the protection of animals used for experimental purposes or for other scientific purposes.
8. For the purpose of monitoring the risk and profit assessment, any new information not included in the original application and any information relating to pharmacovigilance shall be communicated to the French Food Safety Agency. After the issuance of a marketing authorization, any change in the file data is submitted to the French Food Safety Agency in accordance with the requirements of the articles R. 5141-35 et seq. of the Public Health Code and Commission Regulation (EC) No 1234 / 2008 of 24 November 2008, with respect to authorized veterinary drugs as defined in section 1 of this Regulation.
9. In the case of applications for authorization to market veterinary drugs recommended for animal species or for indications representing limited market niches, a more flexible approach can be adopted. In such cases, the relevant guidelines and/or scientific advice should be considered.
This annex is divided into four headings:
Title I describes the requirements for veterinary drugs other than immunological veterinary drugs.
Title II describes the requirements for immunological veterinary drugs.
Title III describes specific types of marketing authorization files and related requirements.
Title IV describes the requirements for records of certain types of veterinary drugs.
References to the directive in this annex refer to Directive 2001 / 82 / EC of the European Parliament and of the Council of 6 November 2001 establishing a Community Code on Amended Veterinary Drugs.
PART I
EXIGENCES RELATING TO VETURAL MEDIUMMENTS OTHER THAN IMMUNOLOGICAL VETURAL MEDIUMMENTS
The following requirements apply to veterinary drugs other than immunological veterinary drugs, unless otherwise provided in headings III and IV.
PART I
SUMMARY OF THE WORKSHOP
A. ― ADMINISTRATIVE INFORMATION
1. General information
The veterinary drug that is the subject of the application is identified by its name and by the name of the active substance(s) that it contains, by the dosage and pharmaceutical form, the mode and route of administration as well as by a description of the final presentation of the drug, including external packaging, labelling and notice.
The applicant shall indicate its name and address, the name and address of the manufacturers and sites involved in the different stages of production, quality control and release of the lots (including manufacturers of the active substance(s)) and, where applicable, the name and address of the importer.
The applicant attached to the administrative information a document certifying that the manufacturers concerned as defined in theArticle L. 5142-2 of the Public Health Code or section 44 of the directive are authorized to produce the relevant veterinary drugs as defined in section L. 5142-2 of the Public Health Code or section 44 of the directive as well as the list of countries where an authorization has been issued, a copy of all summaries of the characteristics of the product according to thearticle R. 5141-15 or Article 14 of the directive as approved by the Member States, and the list of countries in which a request has been submitted or refused.
The applicant specifies the number and title of the documentation volumes submitted in support of the application and mentions, where applicable, the nature of the samples provided.
2. Information on pharmacovigilance
The applicant presents the pharmacovigilance system of the relevant veterinary drug or the company responsible for marketing.
The description of the pharmacovigilance system provides an overview of the general organization adopted by the licensee of the marketing authorization for personnel, data collection and storage tools, the quality management system applied to this field and the use of subcontracting. It specifies the geographical location of the sites involved in this system in the European Union and, possibly, the location of subcontractors and the contractual relationship between the holder and subcontractors.
The information provided under pharmacovigilance is prepared and presented in accordance with volume 9B published in the Regulation of Drugs in the European Union (Guidelines of pharmacovigilance for veterinary medicinal products for veterinary use).
2. Information on the person charged
of Veterinary Pharmacovigilance
This section includes:
- the name, first name and contact information of the person responsible for veterinary pharmacovigilance;
a summary of his curriculum vitae;
― a summary of his worksheet or postcard;
― the description of the pleading procedure in the event of the absence of the person responsible for veterinary pharmacovigilance;
a signed certificate, by the holder of the marketing authorization and the person responsible for veterinary pharmacovigilance, certifying the availability of the person responsible for veterinary pharmacovigilance and the provision of the means necessary for the collection and notification of any adverse effects occurring either in the European Union or in a third country.
2. 2. Organizational information
Diagrams are provided to present synthetically:
― the organization of the pharmacovigilance system of the licensee of marketing authorization with the positioning of the person responsible for veterinary pharmacovigilance in the general flow of the licensee and, where applicable, the various sites where veterinary pharmacovigilance operations are taking place;
- the circuit of declarations of any origin (from the declarant to the transmission to the authorities).
In the case of recourse to subcontractors, the relevant information is indicated in point 2. 5.
2. 3. Information on procedures
Pharmacovigilance operations or activities are subject to procedures, work instructions. The applicant shall provide a list of the written procedures available, upon request, within 48 hours.
Areas not covered by documents include:
― the activities of the person responsible for veterinary pharmacovigilance, its suppleance;
― collection, processing (data);
- the follow-up of statements;
- the detection of duplicates;
- monitoring of the transmission of serious cases within fifteen days;
e-submission of statements;
- updated periodic security reports;
- pharmacovigilance activities applicable to all drugs;
– the detection signal and the day before;
― the assessment of the profit-risk ratio;
the information of the competent authorities and health professionals of any change in the risk-benefit ratio of veterinary drugs, etc.;
― the interaction between the safety profile of veterinary drugs and quality defects;
― responses to requests for information from the competent authorities;
- the management of the crisis situation;
- the administration and use of databases or other recording systems;
- the internal audit of the pharmacovigilance system;
- training;
- archiving.
2. 4. Information on databases
This section includes a list of databases dedicated to the collection of pharmacovigilance declarations with their brief functional description, specifying the location of the centralized database.
The latter covers, inter alia, the following operations: the collection, monitoring, processing of security information received from different origins, the development of updated periodic security reports, the detection of signals, the codification of clinical signs, the monitoring and sorting of adverse effects, the functionality to generate files compatible with the electronic submission of adverse reaction reports to competent national authorities, etc.
2. 5. Information on subcontractors
The main contracts of subcontracting for the conduct of the various activities of pharmacovigilance, the nature of the agreements reached between the market authorization holder and the marketing structures and their respective responsibilities for pharmacovigilance activities are described.
In case of specific subcontracting related to a veterinary drug, they are summarized in a specific addendum to the veterinary drug.
2. 6. Training information
A brief description of the organization of the training provided to pharmacovigilance staff is given. The structures responsible for updating staff records, monitoring training, curriculum vitae, job descriptions and functions are appointed.
2. 7. Information on documentation
The main sites where different types of pharmacovigilance documentation are retained are described. 2. 8. Quality assurance information
The quality assurance system of the marketing authorization holder is described by specifying the organization of activities, the responsibilities for pharmacovigilance operations, documentation and the conduct of corrective and preventive actions.
Responsibilities for the audit of the pharmacovigilance system, including subcontractors, are also specified.
B. ― SUMMARY OF PRODUCT FEATURES,
AND NOTICE
The applicant proposes a summary of the product characteristics, in accordance with theArticle R. 5141-15 of the Public Health Code or section 14 of the directive.
A proposal for text for labelling of primary packaging and outer packaging should be provided in accordance with Articles R. 5141-73 to R. 5141-75 of the Public Health Code or under heading V of the directive, as well as a notice when required under the directiveArticle R. 5141-76 of the Public Health Code or section 61 of the directive.
C. ∙ DETAILLED AND CRITICAL SUMMARY
In accordance with 2° of article R. 5141-16 of the Public Health Code or in section 12, paragraph 3, of the directive, critical and detailed summaries of the results of pharmaceutical trials (physico-chemical, biological or microbiological), safety tests, residue study, preclinical tests, clinical trials, and tests to assess the risks that the veterinary drug may pose to the environment should be provided.
Each detailed and critical summary is based on the state of scientific knowledge at the time of filing the application. It contains an assessment of the various controls and tests that constitute the marketing authorization file, and addresses all relevant issues for the evaluation of the quality, safety and effectiveness of the veterinary drug. It provides detailed results of controls and tests performed, and accurate bibliographic references.
All important data are summarized in an annex and, to the extent possible, presented as tables or graphs. Detailed and critical summaries and annexes contain specific references to the information contained in the main documentation.
Detailed and critical summaries are signed, dated and accompanied by information on the author's titles, training and professional experience. The author's professional links with the applicant are specified.
In the case of an application involving an animal species or indications representing limited market niches, where the active substance has been included in an authorized human-use drug in accordance with the requirements in force, it is possible, in order to replace the summary of the documentation relating to the active substance or product, to use the overall summary of the quality provided by thearrested on 23 April 2004 establishing the standards and protocols applicable to analytical, toxicological and pharmacological tests and clinical documentation to which the drugs or products referred to in theArticle L. 5121-8 of the Public Health Code. The format used for this part of the folder can be that of the common technical folder (or DTC).
PART II
PHARMACEUTICAL DATA (PHYSICO-CHIMIC,
BIOLOGICAL OR MICROBIOLOGICAL) (QUALITY)
Basic principles and requirements
The information and documents relating to pharmaceutical testing that are attached to the application for market authorization pursuant to 2° of section R. 5141-16 of the Public Health Code or to the first dash of item j of section 12, paragraph 3, of the Directive are submitted in accordance with the requirements set out below.
Pharmaceutical data (chemical, biological or microbiological) include information on the manufacturing process, characterization and properties, procedures and requirements of quality control, and a description of the composition, development and presentation of the veterinary drug, for the active substance(s) and for the finished veterinary drug.
All monographs, including general monographs and general chapters of the European Pharmacopoeia or, if not, the pharmacopoeia of a Member State, are applicable.
All test procedures meet the criteria for analysis and quality control of raw materials and finished product, and take into consideration the guidelines and requirements in place. The results of the validation studies are provided.
The test procedure(s) are detailed in order to be reproducible during the checks performed at the request of the French Food Safety Agency; the particular material that could be used is the subject of a sufficient description, with a possible drawing in support. If necessary, the formula of laboratory reagents is supplemented by the method of preparation. For test procedures in the European Pharmacopoeia or in the pharmacopoeia of a Member State, this description may be replaced by a specific reference to the pharmacopoeia in question. Where applicable, the chemical and biological references of the European Pharmacopoeia should be used. If other formulations and reference standards are used, they are identified and described in detail.
In the case of an application involving an animal species or indications representing more limited market niches, where the active substance has been included in a licensed human drug in accordance with the existing requirements, the chemical, pharmaceutical and biological/microbiological data provided for in the Order of April 23, 2004 setting the standards and protocols applicable to the analytical, toxicological and pharmacological tests as well as to the clinical documentation to which the drugs or products mentioned are subjected. The format used for this part of the folder can be that of the common technical folder (or DTC).
A. ― QUALITATIVE AND QUANTITATIVE COMPOSITIONS
COMPONENTS
1. Quality composition
By "Qualitative Composition" of all components of the medication, you must hear the designation or description:
- the active substance(s);
- components of excipients, regardless of the nature or quantity implemented, including dyes, preservatives, adjuvants, stabilizers, thickening, emulsifiers, taste correctors, flavourings;
– elements of pharmaceutical forming (capsules, capsules...) intended to be ingested by animals or, more generally, to be administered to them.
These indications are supplemented by any useful information on primary conditioning and, possibly, outdoor conditioning and, if applicable, on its closure mode, as well as on devices with which the drug will be used or administered and which will be provided with the drug.
2. Common terms
By "usual terms" to designate components of veterinary medicines, it must be understood, without prejudice to the application of the other provisions provided for in the 3° of article R. 5141-14 of the Public Health Code or paragraph 3 (c) of Article 12 of the Directive:
- for components in the European Pharmacopoeia or, if not, the pharmacopoeia of a Member State, obligatoryly the main name, retained by the monograph concerned, with reference to the said pharmacopoeia;
- for other components, the international common name recommended by the World Health Organization, which may be accompanied by another common name or, if not, by the exact scientific name; components without international common name or exact scientific designation will be designated by the indication of origin and method of obtaining, if any, supplemented by any useful clarification;
for colouring materials, the designation by the number "E" that is assigned to them by Directive 2009 / 35 / EC of the European Parliament and of the Council of 23 April 2009 on substances that can be added to drugs for their coloring and Annex I of Directive 94 / 36 / EC.
3. Quantitative composition
3. 1. In order to give the "quantitative composition" of all active substances of the veterinary drug, according to the pharmaceutical form, the mass or number of units of biological activity must be specified for each active substance either per unit of seizure or per unit of mass or volume.
Biological activity units are used for substances that cannot be chemically defined. When the World Health Organization has defined an international unit of biological activity, it is used. When there is no international unit, biological activity units are expressed in such a way as to unequivocally inform the activity of the substance by using the European Pharmacopoeia units as a priority.
Whenever possible, biological activity per mass or volume unit is indicated. These indications are supplemented:
- for preparations intended for a single administration, by the mass or biological activity units of each active substance contained in the unitary primary packaging, taking into account the usable volume, if applicable after replenishment;
- for veterinary drugs to be administered by drops, by the mass or units of biological activity of each active substance contained by drop or contained in the number of drops corresponding to 1 ml or 1 g of the preparation;
- for syrups, emulsions, granules and other pharmaceutical forms to be administered according to measurements, by the mass or units of biological activity of each active substance per measure.
3. 2. Substances active in the state of compounds or derivatives are quantitatively designated by their overall mass and, if necessary or significant, by the mass of the active fraction(s) of the molecule.
3. 3. For veterinary drugs containing an active substance that is the subject of, for the first time, an application for market authorization in one of the Member States, the quantitative composition of an active substance that is a salt or hydrate is systematically expressed based on the mass of the fraction or active fractions of the molecule. Subsequently, the quantitative composition of all veterinary drugs authorized in the Member States will be expressed in the same way as for the same active substance.
4. Galanic development
The choice of composition, components, primary conditioning, possible additional packaging and external conditioning, as appropriate, as well as the expected function of excipients in the finished product and the manufacturing mode of the finished product are explained and justified by scientific data relating to galenic development. Overdose in manufacturing and its justification are indicated. It should be demonstrated that the microbiological characteristics (microbial purity and antimicrobial activity) and the instructions for use are appropriate for the intended use specified in the application file for marketing authorization.
B. ― FABRICATION MODE DESCRIPTION
The name, address and responsibility of each manufacturer and each proposed production site or facility associated with manufacturing and testing should be indicated.
The description of the method of manufacture, together with the application for authorization, pursuant to the 2° of section R. 5141-16 of the Public Health Code or the point d of paragraph 3 of section 12 of the Directive, is set out in such a way as to give a satisfactory idea of the nature of the operations being carried out.
For this purpose, this description shall include:
― the mention of the various stages of manufacturing to assess whether the processes used for pharmaceutical forming could not cause alteration of the components;
- in case of continuous manufacture, all information on the guarantees of homogeneity of the finished product;
― the actual manufacturing formula with quantitative indication of all substances used, however, the quantities of excipients that may be given in an approximate manner to the extent that the pharmaceutical form requires it; mention will be made of products disappearing during manufacturing; any overdose being indicated and justified;
- the designation of the manufacturing stages to which samples are collected for the production tests and the limits applied, when these tests appear necessary for the quality control of the finished product by the other elements of the record;
- experimental manufacturing process validation studies and, where applicable, a process validation program for batches at the production scale;
- for sterile drugs, where sterilization conditions do not correspond to pharmacopoeia are used, information on aseptic procedures and/or sterilization processes implemented.
C. ∙ CONTROL OF FIRST
1. General requirements
For the purposes of this section, all components of the veterinary drug must be understood by "the raw materials" and, if necessary, the primary packaging, including its closing device, as referred to in section A, point 1, above.
The file includes specifications and information for the tests to be conducted for the quality control of all the raw material batches.
The routine tests to be performed on each batch of raw material are reported in the application for marketing authorization. If other tests than those mentioned in a pharmacopoeia are used, it should be justified by providing evidence that raw materials meet the quality requirements of this pharmacopoeia.
When a certificate of conformity has been issued by the European Directorate for the quality of medicines for a raw material, an active substance or an excipient, this certificate is the reference to the relevant monograph of the European Pharmacopoeia.
When reference is made to a certificate of conformity, the manufacturer shall, in writing, provide the applicant with assurance that the manufacturing process has not been modified since the issuance of the certificate of conformity by the European Directorate for the quality of the medications.
In order to prove that the raw materials are in compliance with the specified specification, there is a need to submit analytical certificates.
1. Active substances
The name, address and responsibility of each manufacturer and each proposed production site or facility associated with the manufacture and testing of an active substance should be indicated.
For a well-defined active substance, the manufacturer of the active substance or the applicant may ensure that the following information is directed directly to the French Food Safety Agency by the manufacturer of the active substance. This information is addressed in a document presented according to the recommendations described in the European explanatory note "Guideline on Active Substance Master File Procedure" (ASMF). This document includes:
(a) A detailed description of the manufacturing process;
(b) A description of the quality control operations under construction;
(c) A description of process validation.
In this case, the manufacturer provides the applicant with all necessary data that will enable the applicant to assume its own responsibility for the veterinary drug. The manufacturer undertakes in writing to the applicant to guarantee the manufacturing consistency of one batch to another and to refrain from modifying the manufacturing process or specifications without keeping it informed. Documents and information in support of such an amendment are provided to the French Food Safety Agency; these documents and information are also provided to the applicant when they relate to the portion of the "ASMF" that is accessible to the applicant.
In addition, where a certificate of conformity for the active substance is not available, information on the method of manufacture, quality control and impurities should be provided, together with a demonstration of the molecular structure:
1. Information on the manufacturing process including a description of the process of manufacturing the active substance that constitutes the applicant's commitment to the manufacture of the active substance. All the materials required to manufacture the active substance(s) should be listed, identifying which stage(s) each substance is used in the process. Information on the quality and control of these materials is provided. Data demonstrating that materials meet appropriate standards for intended use are presented.
2. The quality control information mentioning the tests (including acceptance criteria) at each critical stage including data on the quality and control of intermediate products, process validation and/or evaluation studies, if applicable. They also include validation data for the analytical methods applied to the active substance, if applicable.
3. Information on impurities indicating foreseeable impurities and the levels and nature of the observed impurities. They also contain, where applicable, data on the safety of these impurities.
4. For biotechnological veterinary drugs, the demonstration of the molecular structure includes the schematic sequence of aminoacids and the relative molecular mass.
1. 1. Active substances in pharmacopoeia
The general and specific monographs of the European Pharmacopoeia are required for all active substances included in it.
The conformity of components to the requirements of the European Pharmacopoeia or the pharmacopoeia of a Member State is sufficient for the application of the provisions of the 7th of Article R. 5141-16 of the Public Health Code or of Article 12, paragraph 3, of the Directive. In this case, the description of analytical methods and procedures can be replaced in each section concerned by an appropriate reference to the pharmacopoeia in question.
In the event that a specification of a monograph of the European Pharmacopoeia or the pharmacopoeia of a Member State would not be sufficient to guarantee the quality of the product, the French Food Safety Agency may require the applicant more appropriate specifications, including limits, determined using validated analytical procedures, which apply to specific impurities.
It informs the authorities responsible for the pharmacopoeia in question. The licensee of the marketing authorization shall provide the authorities of this pharmacopoeia with information regarding the potential failure of the monograph and the additional specifications that have been applied.
When, for an active substance, there is no monograph in the European Pharmacopoeia, but this substance is described in the pharmacopoeia of a Member State, this monograph may be used.
When an active substance is not described in the European Pharmacopoeia or in the pharmacopoeia of a Member State, the reference to a monograph of a pharmacopoeia of a third country may be accepted if its conformity is certified; in this case, the applicant shall submit a copy of the monograph, accompanied, if any, by a translation. Data showing the ability of the monograph to appropriate control of the quality of the active substance should be presented.
1. 1. 2. Active substances not listed in a pharmacopoeia
The components in no pharmacopoeia are the subject of a monograph covering each of the following headings:
(a) The name of the component, meeting the requirements of section A, point 2 above, supplemented by synonyms either commercial or scientific;
(b) The definition of the substance conforming to that used for the European Pharmacopoeia, together with all necessary justifications, particularly with regard to the molecular structure. For substances that can only be defined by their method of manufacture, it is sufficiently detailed to characterize a constant substance as to its composition and effects;
(c) Any means of identification ventilated into complete techniques as used in the development of the substance and in tests to be carried out in routine;
(d) The purity tests described according to each of the foreseeable impurities, including those that may have a harmful effect and, if necessary, those that, given the association of substances subject to demand, may have an adverse effect on the stability of the drug or disrupt analytical results;
(e) The analyses and limits used to control parameters important to the finished product, such as particle size and sterility, described and validated methods, if applicable;
(f) With respect to complex products of plant or animal origin, distinguishing from the case where multiple pharmacological actions require chemical, physical and biological control of the main components and the case of products containing one or more groups of similar activity principles, for which can be accepted a global method of dosage.
These data demonstrate that the proposed set of test procedures is sufficient to control the quality of the active substance from the specified source.
1. 1. 3. Physical-chemical characteristics
likely to affect bioavailability
The following information regarding active substances registered or not in pharmacopoeia is provided as part of the general description of active substances, where they condition the bioavailability of the veterinary drug:
crystalline shape and solubility coefficients;
– particle size, if applicable after spraying;
- state of hydration;
- oil/water sharing coefficient;
- values pK / pH.
The first three dashes do not apply to substances used only in solution.
1. 2. Excipients
The general and specific monographs of the European Pharmacopoeia are required for all substances contained therein.
Excipients comply with the requirements of the appropriate monograph of the European Pharmacopoeia. When such a monograph does not exist, it is possible to refer to the pharmacopoeia of a Member State. In the absence of such a monograph, it is possible to refer to the pharmacopoeia of a third country. In this case, the conformity of this monograph is certified. Where applicable, additional analyses to control parameters such as particle size, sterility and residual solvents complement the requirements of the monograph. In the absence of any monograph in a pharmacopoeia, a specification is proposed and justified. Specification requirements should be met as described in Section 1. 1. 2, points a to e, concerning active substances. The proposed methods and validation data are presented.
Coloring materials intended to be incorporated in veterinary drugs meet the requirements of Directive 2009 / 35 / EC of the European Parliament and of the Council of 23 April 2009 on substances that can be added to drugs for colouring, with the exception of certain veterinary drugs for topical use, such as insecticide collars and atrial marks, for which the use of other colouring materials is justified.
Coloring materials meet the purity criteria defined in Directive 95 / 45 / CE of the modified Commission.
For new excipients, i.e. excipients or excipients used for the first time in a veterinary drug or following a new route of administration, the complete details of manufacturing, characterization and controls should be provided, along with references to clinical and non-clinical safety data.
1. 3. Primary packaging closure system
1. 3. 1. Active
Information on the closure system of the primary conditioning of the active substance should be provided. The required level of information is determined by the physical (liquid, solid) state of the active substance.
1. 3. 2. Finished product
Information on the primary packaging closure system of the finished product should be provided. The level of information required is determined through the administration of the veterinary drug and by the physical (liquid, solid) state of the pharmaceutical form.
Packaging materials comply with the requirements of the appropriate monograph of the European Pharmacopoeia.
When such a monograph does not exist, it is possible to refer to the pharmacopoeia of a Member State. In the absence of such a monograph, it is possible to refer to the pharmacopoeia of a third country. In this case, the conformity of this monograph is certified.
In the absence of any monograph in a pharmacopoeia, a specification is proposed and justified for packaging materials.
Scientific data should be provided on the choice and conformity of packaging materials.
For new packaging materials in contact with the product, information should be provided on their composition, manufacture and safety.
Specifications and, where applicable, performance data are presented for any dosage or administration device provided with the veterinary drug.
1. 4. Substances of biological origin
When raw materials such as micro-organisms, plant or animal tissues, cells or biological fluids (including blood) of human or animal origin, or biotechnological cell constructions are used in the manufacture of the veterinary drug, the origin and history of raw materials are described and documented.
The description of the raw materials covers the production strategy, the purification/inactivation processes, with their validation, and all the control procedures that are being manufactured to ensure the quality, safety and conformity of the batches of the finished product.
When cell banks are used, it is shown that cell characteristics remain unchanged at the crossing level used for production and beyond. There is a need to look for the presence of foreign agents in stem material, cell banks, serum mixtures and, whenever possible, in the starting materials from which they are derived.
When raw materials of animal or human origin are used, measures to ensure the absence of potentially pathogenic agents are described.
If the presence of potentially pathogenic foreign agents is unavoidable, the corresponding substance is used only in the case where further processing ensures their elimination and/or inactivation; this removal or inactivation is validated.
It is necessary to provide evidence that the stem material, cell banks, serum lots and other animal-origin substances that play a role in the transmission of ESTs are in accordance with the Explanatory Note on the Reduction of the Risk of Transmission of Animal Spongiform Encephalopathies by Human and Veterinary Drugs and the corresponding monograph of the European Pharmacopoeia.
Certificates of conformity issued by the European Directorate for the Quality of Medicines, together with a reference to the European Pharmacopoeia monograph, may be used to prove compliance.
D. ∙ CONTROL ON INTERNATIONAL PRODUCTS
OF THE FABRICATION
The file includes information on product controls that can be performed at an intermediate stage of the manufacturing process, to ensure consistency of technical characteristics and the production process.
These controls are essential to verify the conformity of the veterinary drug to the formula, where, on an exceptional basis, the applicant presents an analytical procedure of the finished product that does not include the dosage of all active substances (or components of the excipient subject to the same requirements as active substances).
The same is true when the verifications carried out during manufacture condition the quality control of the finished product, particularly in the case where the drug is essentially defined by its manufacturing process.
When an intermediate product can be stored before subsequent processing or primary assembly, a shelf life is defined on the basis of data resulting from stability studies.
E. ∙ FINI PRODUCT CONTROL
For the control of the finished product, the lot of a drug is all units of a pharmaceutical form from the same initial quantity and having been subjected to the same series of manufacturing and/or sterilization operations or, in the case of a continuous production process, all units manufactured in a specified period of time.
The application for marketing authorization lists the tests that are routinely performed on each finished product batch. The frequency of tests that are not practiced in routine is indicated. The limits to liberation are indicated.
The file includes information on the controls on the finished product at release. These are presented in accordance with the requirements listed below.
The provisions of the relevant monographs and general chapters of the European Pharmacopoeia or, if not, the pharmacopoeia of a Member State apply to all the products defined therein.
If the procedures and limits used for testing are not those contained in the relevant monographs and the general chapters of the European Pharmacopoeia or, if not, in the pharmacopoeia of a Member State, evidence should be provided that the finished product in the relevant pharmaceutical form meets the quality requirements of that pharmacopoeia, if controlled in accordance with these monographs.
1. General characteristics of the finished product
Some controls of the general characteristics of a product are mandatory among the tests performed on the finished product. These controls, whenever possible, relate to the determination of the mean masses and maximal deviations, mechanical, physical, chemical or microbiological tests, organoleptic characteristics and physical characteristics such as density, pH and refractive index. For each of these characteristics, standards and limitations are defined, in each particular case, by the applicant.
The conditions of the experiment, if any, the equipment and equipment used and the standards are accurately described, when they are not included in the European Pharmacopoeia or in the pharmacopoeia of a Member State; the same is true in cases where the methods provided by these pharmacopoes are not applicable.
In addition, solid pharmaceutical forms, to be administered orally, are subject to in vitro studies of the release and speed of dissolution of the active substance(s), unless otherwise warranted. These studies are also conducted in the event of administration by another way, if the French Food Safety Agency considers it necessary.
2. Identification and dosage of the active substance(s)
The identification and dosing of the active substance(s) is carried out either on an average sample of the batch or on a number of intake units considered in isolation.
Unless appropriately justified, the maximum deviations acceptable for the active substance content cannot exceed ± 5% in the finished product at the time of manufacture.
Based on the stability tests, the manufacturer proposes and justifies the maximum deviation limits for the active substance content in the valid finished product up to the end of the proposed shelf life.
In some cases of particularly complex mixtures in which the dosing of active substances, many or in small proportion, requires delicate research that is difficult to apply to each batch of manufacture, it is tolerated that one or more active substances are not dosed into the finished product on express condition that the dosing is performed on intermediate products of manufacture. This simplified technique cannot be extended to the characterization of these substances. It is supplemented by a quantitative assessment method allowing the French Food Safety Agency to verify compliance with the specifications of the drug marketed.
An in vitro or in vivo biological activity test is mandatory when physico-chemical methods are insufficient to inform the quality of the product. Each time this is possible, such a test includes reference materials and statistical analysis allowing the determination of confidence limits. When these tests cannot be done on the finished product, they may be carried out at an intermediate stage, as soon as possible in the manufacturing process.
When a degradation occurs during the manufacture of the finished product, the acceptable maximum rates of degradation products, for each product and for the whole, immediately after manufacture.
When the indications provided in section B above show a significant overdose in active substance for the manufacture of the drug, or when the stability data show that the dosage of the active substance decreases in storage, the description of the control methods of the finished product includes, where applicable, the chemical study, or even toxico-pharmacological, of the alteration suffered by that substance with, eventually, the characterization and/or dosage of the products.
3. Identification and dosage of excipient components
Obligatoryly be the subject of an identification test and a "higher and lower" test each individual antimicrobial preserver and any excipient likely to affect the bioavailability of the active substance, unless bioavailability is guaranteed by other appropriate tests. Obligatoryly be the subject of an identification test and a "higher limit" test of any anti-oxygen and any excipient likely to have an adverse effect on organic functions; antioxidants are also subjected to a "lower limit" test at release.
4. Safety tests
Regardless of the toxico-pharmacological tests submitted with the application for market authorization, safety tests, such as sterility testing and bacterial endotoxin research, are included in the analytical file whenever they are to be practiced routinely to verify the quality of the product.
F. ∙ STABILITY TESTS
1. Active substance (s)
A check date and the conditions for the retention of the active substance, immediately before its use in the manufacture of the finished product, must be defined, except where the substance is monographed in the European Pharmacopoeia and that the manufacturer of the finished product submits the active substance to a new complete set of controls.
The date of check-in and the conditions of conservation defined are justified by stability data. The type of stability studies carried out, the protocols used, the analytical procedures used and their validation should be presented with detailed results. The commitment to stability and a summary of the protocol are provided.
However, where there is a certificate of compliance for the proposed producer's active substance and this certificate provides a date of recognition and conditions of conservation, data on the stability of the active substance from that producer are not required.
2. Finished product
The applicant is required to describe the research that determined the proposed shelf life, the recommended conservation conditions and the specifications after the shelf life.
The type of stability studies carried out, the protocols used, the analytical procedures used and their validation should be presented with detailed results.
When a finished product is reconstituted or diluted before administration, the proposed shelf life and the specification of the reconstituted / diluted product should be specified, providing the appropriate stability data to support.
For primary packagings containing several doses, the shelf life of the product after a first opening is justified, if any, by stability data and user specifications.
When a finished product is likely to give degradation products, the applicant reports them by indicating identification methods and analysis procedures.
The conclusions include the results of the analyses justifying the proposed shelf life and, where appropriate, the duration of use, under the recommended conservation conditions, as well as the specifications of the finished product after the shelf life, and the duration of use, if applicable, of the finished product, under the recommended conservation conditions.
The maximum acceptable rate for degradation products, for each product and for all, should be indicated after the shelf life.
A study on the interaction of the product and the primary packaging is presented in all cases where a risk of this order can be considered, especially when it comes to injectable preparations.
The commitment to stability and a summary of stability tests are provided.
G. ― OTHER INFORMATION
Information on the quality of the veterinary drug not covered in the previous sections may be included in the file.
In the case of drug premixes, information should be provided on the rates and modalities of incorporation, homogeneity, compatibility and stability of drug foods, as well as the proposed shelf life. It is also necessary to provide specifications with respect to medicinal foods manufactured from premixes, in accordance with the recommended method of use.
PART III
INNOCUITY TESTS AND STUDY
Information and documents relating to safety testing and the study of residues that are attached to the application for market authorization pursuant to section 2 R. 5141-16 of the Public Health Code or the second and fourth dashes, point j, paragraph 3, of section 12 of the Directive are submitted in accordance with the requirements set out below.
A. ― INNOCUITY TESTS
Chapter I
Conduct of tests
The safety documentation highlights:
(a) The possible toxicity of the veterinary drug and its hazardous or adverse effects under the conditions of use in the animal; these should be estimated according to the severity of the pathological condition;
(b) Possible adverse effects on humans associated with residues of the veterinary drug or active substance present in foodstuffs from treated animals and the inconveniences of these residues for the industrial processing of foodstuffs;
(c) Human hazards that may possibly be associated with exposure to veterinary drug, for example at the time of administration to the animal;
(d) The potential risks to which the use of the veterinary drug exposes the environment. All results must be reliable and comprehensive. To the extent that this appears justified, mathematical and statistical processes are used for the development of experimental methods and the evaluation of results. In addition, information should be provided on the therapeutic potential of the product and the hazards associated with its use.
In some cases, it may be necessary to study the metabolites of the original compound if they represent the residues in question.
When an excipient is first used in the pharmaceutical field, it is considered an active substance.
1. Accurate identification of product
and its or its active substances
the international common name (DCI);
- the name of the International Union of Pure and Applied Chemistry (UICPA);
the Chemical Abstract Service (CAS) number;
- Therapeutic, pharmacological and chemical classification;
synonyms and abbreviations;
the structural formula;
the molecular formula;
- molecular weight;
the degree of purity;
the qualitative and quantitative composition of impurities;
• description of physical properties;
- the melting point;
the boiling point;
– vapour pressure;
- solubility in water and organic solvents expressed in g/l, indicating temperature;
- density;
– the refractory, rotational spectrum, etc.;
– the formula of the product.
2. Pharmacology
Pharmacologic studies are of paramount importance as they help to better understand the mechanisms responsible for the therapeutic effect of the veterinary drug. This is why these studies in experimental animal species and in destination animal species are included in the fourth part.
In addition, pharmacological studies may also participate in the understanding of toxicological phenomena. In addition, the pharmacological effects that appear in the absence of a toxic response, or at a dose below the toxic dose, are considered when assessing the safety of a veterinary drug.
This is why safety documentation is always preceded by a detailed description of the pharmacological research carried out on laboratory animals and all relevant observations made during clinical studies of the destination animal.
2. Pharmacodynamics
Information should be provided on the mechanism of action of the active substance(s), as well as data on primary and secondary pharmacodynamic effects to allow a better understanding of adverse effects in animal studies.
2. 2. Pharmacokinetics
Data should be provided on the fate of the active substance and its metabolites in the species used for toxicological studies, including absorption, distribution, metabolism and excretion (ADME). The data is correlated with the conclusions on the dose-effect ratio of pharmacological and toxicological studies to determine the appropriate levels of exposure. In Part IV, a comparison should be included with pharmacokinetic data from the studies of target species (Part IV, Chapter I, Section A. 2, below), to assess the relevance of the results obtained in the toxicity studies for target species.
3. Toxicology
Toxicology documentation is consistent with existing guidelines for the general test approach and guidance for specific studies. These guidelines include:
1. The basic tests required for all new veterinary drugs to be used in food-producing animals, with a view to assessing the safety of residues in foods intended for human consumption.
2. Additional tests may be required due to specific toxicological concerns such as those associated with the structure, class and mode of action of the active substance(s).
3. Special tests that may contribute to the interpretation of the data obtained during base tests or additional tests.
Studies are conducted on the active substance(s) and not on the formulated product. When studies of the formulated product are necessary, this is specified below.
3. 1. Single administration toxicity
Single administration toxicity studies can be used to predict:
- the potential effects of acute overdose on destination species;
the possible effects of an accidental administration to man;
– the doses it can be useful to use in repetitive administration toxicity studies.
Single administration toxicity studies provide information on the effects of acute toxicity of the substance, as well as on the time lapse prior to the occurrence and mitigation.
The studies to be conducted are selected to provide information on user safety; Thus, if it is anticipated that a man may be exposed to significant quantities of the veterinary drug by inhalation or by skin contact, the routes of exposure in question are studied.
3. 2. Recurrent administration toxicity
The purpose of the repetitive toxicity tests is to highlight the physiological and/or pathological changes resulting from the repeated administrations of the active substance or association of active substances and to establish the conditions for the appearance of these alterations according to the dosage.
In the case of veterinary substances or drugs exclusively intended for non-food-producing animals, it is normally sufficient to carry out a repetitive toxicity study on a laboratory animal species. This study can be replaced by a study on the destination animal. The choice of frequency and route of administration as well as the duration of the study takes into account the clinical conditions proposed. The experimenter justifies the extent and duration of the tests and the doses chosen.
In the case of veterinary substances or drugs intended to be used in food-producing animals, toxicity tests by repetitive administration (90 days) are carried out on a rodent species and on a non- rodent species, to identify target organs and toxicological limits and to determine the appropriate species and doses to be used in chronic toxicity tests, where applicable.
The experimenter justifies the choice of species taking into account the state of scientific knowledge regarding the metabolism of the product in the animal and in man. The test substance is administered orally.
The experimenter clearly indicates the reasons for selecting the mode and frequency of the administrations as well as the duration of the tests.
The highest dose is normally chosen to show adverse effects. The lowest doses should not produce any signs of toxicity.
The assessment of toxic effects is based on the examination of behaviour, growth, blood formula and physiological tests, particularly those related to excretor organs, as well as on the basis of necropsic reports accompanied by histological data associated with it. The type and extent of each examination category is selected based on the animal species used and the state of scientific knowledge.
In the case of new associations of substances already known and studied according to the provisions of this Order or Directive, repetitive administration tests may, on justification by the experimenter, be simplified in an adequate manner, except in the case where toxicity tests have revealed potential or new toxic effects.
3. 3. Tolerance in the destination animal
A summary of all signs of intolerance observed during the studies, generally with the final formulation, in the destination animal, should be provided in accordance with the requirements set out in Part IV, Chapter I, Section B, below. Studies, doses for which intolerance is manifested and the species and races concerned are identified. Any unforeseen physiological alteration is also the subject of a detailed description. The full reports of these studies are included in the fourth part.
3. 4. Reproductive toxicity,
including development toxicity
3. 4. 1. Study of reproductive effects
The purpose of this study is to identify possible alterations of the male or female reproductive function or adverse effects on the offspring due to the administration of the veterinary drug or the substance under study.
In the case of pharmacologically active substances or veterinary medicines for food-producing animals, the study of reproductive consequences is carried out in the form of a multi-generation reproduction study to detect possible effects on mammal reproduction. These effects relate to male and female fertility, mating, design, implantation, ability to carry out a term gestation, parturition, lactation, survival, growth and development of the progeny of birth to withdrawal, sexual maturity and subsequent reproductive function of descendants to adulthood. At least three different doses should be used. The highest dose is normally chosen to show adverse effects.
The lowest doses should not produce any signs of toxicity.
3. 4. 2. Study of Toxicity for Development
In the case of pharmacologically active substances or veterinary drugs for feed-producing animals, developmental toxicity studies are conducted. These studies are intended to detect possible adverse effects on the gravid female and on the development of the embryo and fetus as a result of an exposure of the female, from the implantation to the day before the scheduled basing date, to the gestation period. Adverse effects are considered: increased toxicity compared to that observed in non-grave females, embryo-fetal death, altered fetal growth and structural changes in fetus. A development toxicity study is performed in rats. Based on the results, it may be necessary to conduct a study on a second species in accordance with the guidelines in force.
In the case of pharmacologically active substances or drugs not intended for feed-producing animals, a development toxicity study is carried out on at least one species that can be the destination animal if the product is intended for females that could be used for livestock. However, in cases where the use of the veterinary drug would result in a significant exposure of users, standard development toxicity studies are conducted.
3. 5. Genetoxicity
Studies of genotoxic potential need to be carried out in order to highlight changes that a substance may cause in the genetic material of cells. It is necessary to assess the genotoxic properties of any substance intended to be included for the first time in a veterinary drug.
A standard battery of in vitro and in vivo genotoxicity studies is normally conducted on the active substance(s), in accordance with the guidelines in force. In some cases, it may also be necessary to study one or more metabolites found in the form of residues in foodstuffs.
3. 6. Cancerogen
The decision to conduct cancer studies is based on the results of genotoxicity studies, structural-activity reports and the conclusions of systemic toxicity studies that may be relevant to the longer-term studies of neoplastic lesions.
Any known species of the toxicity mechanism should be considered, as well as any differences in the metabolism between species used for studies, animal species of destination and human beings.
When cancer studies are needed, a two-year rat study and a 18-month mouse study are usually required. Subject to appropriate scientific justification, cancer studies may be conducted on a single rodent species, preferably the rat.
3. 7. Derogations
In case a veterinary drug is intended for topical use, systemic absorption is studied in the destination animal. If it is proven that systemic absorption is negligible, re-administered toxicity studies, reproductive function toxicity studies and cancer studies may be removed, except in the case where, under recommended conditions of use:
- oral ingestion of the veterinary drug by the animal is predictable;
― or an exposure of the veterinary drug user by other routes than the skin track is predictable;
― or the active substance or its metabolites are likely to pass into food from the treated animal.
4. Other requirements
4. 1. Special studies
For specific groups of substances or where the effects observed in the animal during re-administered toxicity studies include symptomatic impairments, such as immunotoxicity, neurotoxicity or endocrine dysfunction, additional tests are required, such as awareness studies or delayed neurotoxicity tests. Depending on the nature of the product, additional studies may be required to assess the underlying mechanism of the toxic effect or the potential for irritation. These studies are usually conducted on final formulation.
The development of such studies and the analysis of results takes into account the state of scientific knowledge and the guidelines in force.
4. 2. Microbiological properties of residues
4. 2. Possible effects on human intestinal flora
The potential microbiological risk to which residues of antimicrobial products expose human intestinal flora, taking into account the guidelines in force, should be studied.
4. 2. 2. Possible effects on micro-organisms used
in the industrial transformation of foodstuffs
In some cases, experiments may be required to determine whether microbiologically active residues may interfere in the technological processes used for industrial food processing.
4. 3. Observations in man
The file contains information on whether the pharmacologically active substances of the veterinary drug are used as medicines in human medicine; if this is the case, it is necessary to report all the observed effects (including adverse effects) on humans and their cause, to the extent that they may be of importance to the assessment of the safety of the veterinary drug, including, where appropriate, the published study findings; where substances contained in the veterinary drug are not or are no longer used as a medicine in human medicine, the reasons should be given.
4. 4. Development of resistance
In the case of veterinary drugs, it is necessary to provide data on the emergence of resistant bacteria that may have an impact on human health. The mechanism for developing such resistance is particularly important in this regard. Where appropriate, measures to limit the development of resistance related to the intended use of the veterinary drug are proposed.
Resistance of interest in clinical use of the product is treated in accordance with the requirements of Part IV below. Where appropriate, reference should be made to the data in Part IV.
5. User security
This section includes a review of the effects observed in the previous sections and links them to the type and extent of human exposure to the product, for the formulation of appropriate warnings to the user and other risk management measures.
6. Environmental risk assessment submitted by veterinary drugs that do not contain genetically modified organisms or do not consist of such organisms
An environmental risk assessment is required to assess the potential adverse effects that the use of the veterinary drug may have on the environment and to identify the risks associated with these effects. The evaluation also looks for all job precautions that can reduce these risks.
This evaluation is normally conducted in two stages. The first step in the evaluation is mandatory in all cases. Details of the evaluation should be provided in accordance with the guidelines in force. The assessment should indicate the potential exposure of the environment to the product and the level of risk associated with this exposure, taking into account the following aspects:
- the animal species of destination and the proposed method of employment;
― the mode of administration, including the possibility that the product passes directly into ecosystems;
- the possible excretion of the product, its active substances or its appropriate metabolites in the environment by treated animals; their persistence in these excretions;
the disposal of unused veterinary drugs or other wastes.
In the second phase, specific additional research is required with respect to the fate and effects of the product on specific ecosystems, in accordance with the guidelines in force.For this purpose, consideration should be given to the importance of exposure of the environment to the product, as well as information on the physico-chemical, pharmacological and/or toxicological properties of the course(s) identified, including metabolic risks,
Chapter II
Presentation of information
and documents
The safety test kit includes:
an index of all studies in the file;
a statement confirming that all known data of the applicant at the time of the application, whether favourable or unfavourable, are included;
- a justification for omission of a type of study;
– an explanation for inclusion of another type of study;
– a presentation of the contribution that a study prior to studies conducted in accordance with good laboratory practices (BPL) can make to the overall risk assessment.
Each study report includes:
a copy of the study plan (protocol);
a declaration of compliance with good laboratory practices, if applicable;
a description of the methods, equipment and equipment used;
a description and justification of the test system;
- a description of the results obtained, sufficiently detailed to allow the critical appraisal of these results, regardless of the interpretation given by the author;
a statistical analysis of results, if any;
- a review of results, with comments on doses with and without observed effect, as well as any unusual findings;
a detailed description and a thorough analysis of the results of the study on the safety profile of the active substance and their relevance to the assessment of the hazards that these residues may pose to humans.
B. ∙ STUDY
Chapter I
Conduct of tests
1. Introduction
For the purposes of this annex, the definitions contained in Regulation No. 470 / 2009 / EC of the European Parliament and the Council apply.
The purpose of the study of residue depletion is to determine under what conditions and to what extent residues in edible tissues or in eggs, milk or honey from treated animals can persist in foods produced from these animals. In addition, studies will need to determine a waiting time.
In the case of veterinary drugs for food-producing animals, documentation on residues highlights:
1. To what extent and for how long the residues of veterinary drugs or their metabolites persist in the tissues of treated animals intended for human consumption or in the milk, eggs or honey that come from them.
2. Whether it is possible to define realistic waiting times, which can be met in practical conditions and which may deviate any risk to the health of the consumer of food from a treated animal or any disadvantage in the industrial processing of foodstuffs.
3. That the analytical method(s) used in the study of residue depletion have been sufficiently validated to ensure that the data submitted on residues is an adequate basis for the determination of the waiting time.
2. Metabolic and kinetic residues
2. Pharmacokinetics
(absorption, distribution, metabolism, excretion)
A summary of pharmacokinetic data referring to pharmacokinetic studies in the species of destination, presented in Part IV, should be provided. It is not necessary to provide the entire study report.
The pharmacokinetic study of veterinary drug residues is intended to assess absorption, distribution, metabolism and excretion of the product in the species of destination.
The finished product or preparation having comparable characteristics in terms of bioavailability is administered to the destination animal at the recommended maximum dose.
The extent of the absorption of the veterinary drug according to the method of administration is the subject of a detailed description. While it has been shown that systemic absorption of products for topical application is negligible, further studies on residues are not required.
The distribution of the veterinary drug in the organism of the destination animal is described; the possibility of fixation to plasma proteins or passage into milk or eggs as well as accumulation of lipophilic compounds is studied.
The routes of excretion of the product by the destination animal are described. The main metabolites are identified and characterized.
2. 2. Depletion of residues
The purpose of this study is to measure the rate of residue loss in the destination animal after the last administration of the drug is to determine the waiting time.
The residue content is determined to a sufficient number of points in time after the last administration of the veterinary drug to the test animal, applying validated analytical methods; the operating mode and the reliability and sensitivity of the method used are indicated.
3. Residue Analysis Method
Details of the analytical methods or methods used in the residue removal studies(s) and the validation procedure should be described.
The following characteristics of the method are indicated:
specificity;
accuracy;
precision;
detection limit;
- limit of quantification;
― practicability and applicability in normal laboratory conditions;
- sensitivity to interference;
– stability of the residues found.
The appropriateness of the use of the proposed analytical method is appreciated in the light of the state of scientific and technical knowledge at the time of filing the file.
The analysis method is presented in an internationally recognized format.
Chapter II
Presentation of information
and documents
1. Product identification
The veterinary product(s) used during the study are described including:
composition;
- the results of the physical and chemical testing of the batch(s) concerned;
― the identification of the lot;
– the relationship with the finished product;
- specific activity and isotopic purity of marked substances;
– the position of atoms marked in the molecule.
2. Residue Study Record
The residue study file includes:
an index of all studies in the file;
a statement confirming that all known data of the applicant at the time of the application, whether favourable or unfavourable, are included;
- a justification for omission of a type of study;
– an explanation for inclusion of another type of study;
– a presentation of the contribution that a study prior to the studies conducted in accordance with the LPG can make to the overall risk assessment;
– a proposal for waiting time.
3. Study reports
Each study report includes:
a copy of the study plan (protocol);
a declaration of compliance with good laboratory practices, if applicable;
a description of the methods, equipment and equipment used;
- a description of the results obtained, sufficiently detailed to allow the critical appraisal of these results, regardless of the interpretation given by the author;
a statistical analysis of results, if any;
- a review of results;
– an objective review of the results obtained, followed by proposals for waiting times to ensure that foodstuffs from treated animals do not contain residues that may constitute a danger to the consumer.
PART IV
PRECLINICAL AND CLINICAL TESTS
Information and documents relating to pre-clinical and clinical trials that are attached to applications for market authorization pursuant to 2° of Article R. 5141-16 of the Public Health Code or the third dash of Article 12, paragraph 3, of the Directive are presented in accordance with the following requirements.
Chapter I
Preclinical requirements
Preclinical studies are required to establish pharmacological activity and product tolerance.
A. ― PHARMACOLOGY
A. 1. Pharmacodynamics
The pharmacodynamic effects of the active substance(s) included in the veterinary drug are characterized.
First, it is necessary to adequately describe the mechanism of action and the pharmacological effects that are at the basis of the recommended practical applications, by expressing the results in quantitative form (e.g., by means of dose-effect curves, time-effect, or other) and, as far as possible, in comparison with a substance whose activity is well known. If an active substance is presented as having superior efficiency, the difference is demonstrated and statistically significant.
There is then a need to provide an overall pharmacological assessment of the active substance, specifically targeting the possibility of side effects. In general, effects should be studied on the main organic functions.
It is necessary to examine any potential impact of other product characteristics (such as route of administration or formulation) on the pharmacological activity of the active substance.
The research is all the more advanced as the recommended dose is closer to the dose likely to produce adverse effects.
Experimental techniques, when not usual, are described to allow their reproducibility and the experimenter demonstrates their validity. Experimental data are presented in a clear manner and, for some types of tests, their statistical significance is provided.
Unless appropriate, any quantitative change in effects due to repetitive administration is also considered.
Fixed associations of substances can come from either pharmacological data or clinical indications. In the first case, pharmacodynamic and/or pharmacokinetic studies must highlight the interactions that make the association itself recommendable for clinical use. In the second case, when the scientific justification of the drug association is provided by clinical experimentation, it is necessary to investigate whether the expected effects of the association can be highlighted in the animal and to control at least the importance of the adverse effects. If an association contains a new active substance, the latter must have been thoroughly investigated.
A. 2. Development of resistance
Where applicable, there is a need to provide clinically relevant data for veterinary drugs with respect to the possible occurrence of resistant organisms. The development mechanism of this resistance is particularly important in this regard. The applicant is responsible for proposing measures to limit the development of resistance related to the intended use of the veterinary drug.
Where applicable, references are made to the data in Part Three.
A. 3. Pharmacokinetics
For new active substances, it is necessary, as part of the assessment of the clinical safety and efficacy of the veterinary drug, to have basic pharmacokinetic data.
The objectives of pharmacokinetic studies in the animal species of destination can be classified according to their membership in three main areas:
(i) Descriptive pharmacokinetic studies that allow the determination of fundamental parameters;
(ii) The use of these parameters to study the relationship between the dosage regime, the evolution of plasma concentration and tissue concentration over time, and the pharmacological, therapeutic or toxic effects;
(iii) Where applicable, the comparison of kinetics between different species of destination and the search for differences between potential species that affect the safety of the destination animal and the effectiveness of the veterinary drug.
Pharmacokinetic studies in the species of destination are, in principle, necessary to complete pharmacodynamic studies and contribute to the determination of effective dosage regimes (way and administration site, dose, frequency, number of administrations, etc.). Additional pharmacokinetic studies may be necessary to determine dosage regimes based on certain population parameters.
When pharmacokinetic studies have been submitted in Part III, reference should be made to this.
In the case of new associations of substances already known and studied according to the provisions of this Order or Directive, pharmacokinetic research concerning the fixed association is not required if the administration of active substances in the form of a fixed association does not alter their pharmacokinetic properties may be justified.
Bioavailability should be assessed to determine bioequivalence:
when a new formula of a veterinary drug is compared to the existing formula;
― when it is necessary to compare a new method or a new route of administration with that already established.
B. ― TOLERANCE TO THE ANIMAL OF DESTINATION
The local tolerance and systemic tolerance of the veterinary drug should be studied in the destination animal. The purpose of these studies is to characterize the signs of intolerance and establish an adequate margin of security using the recommended route(s). It is possible to achieve this by increasing the therapeutic dose and/or duration of treatment. The experiment report includes detailed information on all expected pharmacological effects and adverse effects.
Chapter II
Clinical requirements
1. General principles
The purpose of clinical trials is to identify or mitigate the effects of the veterinary drug administered under the recommended dosage regime and route of administration and to specify its indications and counter-indications, depending on the species, age, race and sex of the animal and according to the terms and conditions of use and possible adverse effects of this veterinary drug.
Experimental data is confirmed by data obtained under normal terrain conditions.
Unless justified, clinical trials are conducted using control animals (controlled clinical trials).
The efficacy data obtained are compared with those for target species that have received a veterinary drug authorized in the European Union for the same indications of use in the same target species, or placebo, or have not been subjected to any treatment. All results, whether positive or negative, are indicated.
Unless justified, there is a need to use statistical principles established for the design of the protocol, for the analysis and evaluation of clinical trials.
In the case of a veterinary drug primarily intended to be used to improve performance, particular attention should be paid to:
1. The yield of the animal product;
2.The quality of the animal product (organoleptic, nutritional, hygienic and technological)
3. To the food value and animal growth of the species of destination;
4.To the general health of the animals of the species of destination.
2. Conduct of clinical trials
All veterinary clinical trials are conducted in accordance with a detailed test protocol.
Unless otherwise justified, field clinical trials are conducted in accordance with established principles of good clinical practice.
Before any trial on the ground begins, the informed consent of the owner or owner of the animals used for the test is given in writing and documented. In particular, the owner of the animal receives written information on the consequences of participation in the test, including how to eliminate the treated animal or the removal of food from that animal. A copy of this notification, countersigned and dated by the owner of the animal, is attached to the test documentation.
Unless the field trial is conducted in blind, the labelling provisions for veterinary clinical trials apply.
Chapter III
Information and documents
All documents relating to preclinical and clinical trials and/or test results, whether favourable or unfavourable to the veterinary drug, should be included in the efficacy file, in order to allow an objective overall assessment of the risk/benefit ratio of the product.
1. Preclinical test results
Information on results should be provided to the extent possible:
(a) Tests showing pharmacological actions;
(b) Tests showing the pharmacodynamic mechanisms responsible for the therapeutic effect;
(c) Tests showing the main pharmacokinetic profile;
(d) Tests demonstrating safety in the destination animal;
(e) Tests for the study of resistance development.
Any unexpected results appearing during the trial are described in detail.
In addition, all pre-clinical studies include the following information:
(a) A summary;
(b) A detailed experimental protocol with a description of the methods, apparatus and material used, specifying the species, age, weight, sex, number, race or lineage of animals, animal identification, dose, and path and pattern of administration;
(c) Statistical analysis of results, if applicable;
(d) An objective review of the results obtained, leading to conclusions on the efficacy and safety of the veterinary drug.
If a part or all of this data fails, a justification is provided.
2. Results of clinical trials
All information is provided by each experimenter by means of clinical observation sheets, individual for individual and collective treatments for collective treatments.
The information provided is as follows:
(a) Name, address, function and titles of the responsible experimenter;
(b) Place and date of treatment; name and address of the owner or owner of animals;
(c) Detailed description of the clinical trial protocol including a description of the methods used, including for randomization and blind trials, and specifying the path of administration, the pattern of administration, the dosage, identification, species, race or lineage, age, weight and sex of the animal, as well as the physiological status of the animals tested;
(d) Mode of management and feeding of animals with indication of the composition of foods and the nature and quantity of any food additives;
(e) Anamnesis as complete as possible, including the emergence and evolution of any intercurrent disease;
(f) Diagnosis and means to establish it;
(g) Clinical signs, if possible according to conventional criteria;
(h) Accurate description of the preparation of the veterinary drug used for the clinical trial and the results of the physical and chemical tests of the affected batch(s);
(i) Dosage of the veterinary drug, mode, route and frequency of administration and, if applicable, precautions taken during the administration (injection duration, etc.);
(j) Duration of treatment and subsequent observation period;
(k) Any clarification of other veterinary medicines administered during the examination period shall be prior to, or parallel to the test product and, in this case, on any possible interactions found;
(l) All clinical trial results, including a complete description of the results based on the criteria and efficacy parameters specified in the clinical trial protocol and the results of statistical analysis, if applicable;
(m) Any information on unexpected events, whether harmful or not, as well as the measures taken accordingly; the relationship of cause to effect is studied if possible;
(n) Impact on animal performance, if applicable;
(o) Effects on the quality of foodstuffs from treated animals, particularly in the case of veterinary drugs intended for use as performance ameliorators;
(p) Conclusion on safety and efficacy in each individual case or synthesis in terms of frequency or other appropriate variables in case of specific mass processing.
If one or more of the information mentioned in points a to p fails, a justification is provided.
The holder of the veterinary drug marketing authorization shall make all necessary arrangements to ensure that the original documents used as the basis for the information provided for at least five years after the suspension or termination of the operation of the authorization.
Clinical observations are summarized by summarizing the trials and their results, including:
(a) The number of animal witnesses and treated individually or collectively with species, race or lineage, age and sex of the animal;
(b) The number of animals on which the tests were interrupted before the end and the reasons for this interruption;
(c) For control animals, specify whether these:
― did not receive any treatment;
or received a placebo;
or have received another veterinary drug authorized in the European Union for the same indications of use in the same target species;
or received the active substance studied in a different formulation or by a different pathway;
(d) The frequency of adverse effects observed;
(e) Observations on the impact on animal performance, if any;
(f) Details on the subjects in which the risks may be of particular importance due to their age, livestock or feeding, their destination or whose physiological or pathological status is to be considered;
(g) Statistical evaluation of results.
Finally, the investigator points out general conclusions on the effectiveness and safety of the veterinary drug under the conditions of intended use, and in particular provides any information on indications and contraindications, dosage and average duration of the treatment, as well as, where applicable, on interactions with other veterinary drugs or food additives, particular precautions of employment and clinical signs of overdose have been observed.
For drugs containing a fixed association of active substances, the investigator also highlights conclusions on the safety and efficacy of the product, by comparing with the independent administration of the active substances concerned.
PART II
IMPLEMENTATION
IMMUNOLOGICAL VETURNS
Without prejudice to the specific provisions of Community legislation relating to the control and eradication of certain infectious animal diseases, the following provisions apply to immunological veterinary drugs, except where the products are intended to be used in particular species or according to specific indications, as defined in headings III and IV and in the applicable guidelines.
PART I
SUMMARY OF THE WORKSHOP
A. ― ADMINISTRATIVE INFORMATION
1. General information
The immunological veterinary drug that is the subject of the application is identified by its name and by the name of the active substance(s) as well as by biological activity, content or title, pharmaceutical form, path and, where applicable, the method of administration and a description of the final presentation of the product, including the external packaging, labelling and notice. Solvents can be packed with vaccine bottles or separately.
Information on solvents required to prepare the final vaccine should be included in the file. An immunological veterinary drug is considered a unique product, even when it is necessary to use multiple solvents to develop different formulations of the finished product, which may be administered according to different pathways or modes.
The name and address of the applicant are mentioned as well as the name and address of the manufacturers and premises where the various stages of manufacture and control are taking place (including the manufacturer(s) of the active substance(s), and, where applicable, the name and address of the importer.
The applicant specifies the number and titles of the documentation volumes provided in support of the application and, where applicable, mentions the nature of the samples provided.
Copies of a document showing that the manufacturer (s) is authorized to produce immunological veterinary drugs in accordance with section L. 5142-2 or section 44 of the directive should be attached to the administrative information. In addition, it is necessary to provide a list of organisms handled at the production site.
The applicant is responsible for submitting a list of countries where authorization has been granted and a list of countries where a request has been submitted.
2. Information on pharmacovigilance
The applicant presents the pharmacovigilance system of the relevant veterinary drug or the company responsible for marketing.
The description of the pharmacovigilance system provides an overview of the general organization adopted by the licensee of the marketing authorization for personnel, data collection and storage tools, the quality management system applied to this field and the use of subcontracting. It specifies the geographical location of the sites involved in this system in the European Union and, possibly, the location of subcontractors and the contractual relationship between the holder and subcontractors.
The information provided under pharmacovigilance is prepared and presented in accordance with volume 9B published in the Regulation of Drugs in the European Union (Guidelines of pharmacovigilance for veterinary medicinal products for veterinary use).
2. Information about the person
Veterinary Pharmacovigilance
This section includes:
- the name, first name and contact information of the person responsible for veterinary pharmacovigilance;
a summary of his curriculum vitae;
― a summary of his worksheet or postcard;
― the description of the pleading procedure in the event of the absence of the person responsible for veterinary pharmacovigilance;
an attestation, signed by the holder of the marketing authorization and by the person responsible for veterinary pharmacovigilance, certifying the availability of the person responsible for veterinary pharmacovigilance and the provision of the means necessary for the collection and notification of any adverse effects occurring either in the European Union or in a third country.
2. 2. Organizational information
Diagrams are provided to present synthetically:
― the organization of the pharmacovigilance system of the licensee of marketing authorization with the positioning of the person responsible for veterinary pharmacovigilance in the general flow of the licensee and, where applicable, the various sites where veterinary pharmacovigilance operations are taking place;
- the circuit of declarations of any origin (from the declarant to the transmission to the authorities).
In the case of the use of subcontractors, the relevant information is indicated in item 2-5.
2. 3. Information on procedures
Pharmacovigilance operations or activities are subject to procedures, work instructions. The applicant shall provide a list of the written procedures available, upon request, within 48 hours.
The areas covered by the documents include:
― the activities of the person responsible for veterinary pharmacovigilance, its suppleance;
― collection, processing (data);
- the follow-up of statements;
- the detection of duplicates;
- monitoring of the transmission of serious cases within fifteen days;
e-submission of statements;
- updated periodic security reports;
- pharmacovigilance activities applicable to all drugs;
– the detection signal and the day before;
― the assessment of the profit-risk ratio;
― the information of the competent authorities and health professionals of any change in the risk-benefit ratio of veterinary drugs, etc;
― the interaction between the safety profile of veterinary drugs and quality defects;
― responses to requests for information from the competent authorities;
- the management of the crisis situation;
- the administration and use of databases or other recording systems;
- the internal audit of the pharmacovigilance system;
- training;
- archiving.
2. 4. Information on databases
This section includes a list of databases dedicated to the collection of pharmacovigilance declarations with their brief functional description, specifying the location of the centralized database.
The latter covers, inter alia, the following operations: the collection, monitoring, processing of security information received from different origins, the development of updated periodic security reports, the detection of signals, the codification of clinical signs, the monitoring and sorting of adverse effects, the functionality to generate files compatible with the electronic submission of adverse reaction reports to competent national authorities, etc.
2. 5. Information on subcontractors
The main contracts of subcontracting for the conduct of the various activities of pharmacovigilance, the nature of the agreements reached between the market authorization holder and the marketing structures and their respective responsibilities for pharmacovigilance activities are described.
In case of specific subcontracting related to a veterinary drug, they are summarized in a specific addendum to the veterinary drug.
2. 6. Training information
A brief description of the organization of the training provided to pharmacovigilance staff is given. The structures responsible for updating staff records, monitoring training, curriculum vitae, job descriptions and functions are appointed.
2. 7. Information on documentation
The main sites where different types of pharmacovigilance documentation are retained are described.
2. 8. Quality assurance information
The quality assurance system of the marketing authorization holder is described by specifying the organization of activities, the responsibilities for pharmacovigilance operations, documentation and the conduct of corrective and preventive actions.
Responsibilities for the audit of the pharmacovigilance system, including subcontractors, are also specified.
B. ― SUMMARY OF PRODUCT FEATURES,
AND NOTICE
The applicant proposes a summary of the product characteristics, in accordance with section R. 5141-15 of the Public Health Code or section 14 of the directive.
A proposal for a text for the labelling of primary conditioning and outer packaging should be provided in accordance with sections R. 5141-73 to R. 5141-75 of the Public Health Code or title V of the Directive, as well as a notice when required under section R. 5141-76 of the same Code or section 61 of the Directive. In addition, the applicant is responsible for providing one or more specimens of the final presentation(s) of the veterinary drug, in French or, where applicable, in one or more other official languages of the European Union.
C. ∙ DETAILLED AND CRITICAL SUMMARY
Each detailed and critical summary referred to in 2° of section R. 5141-16 of the Public Health Code or in the second paragraph of section 12, paragraph 3, of the directive is based on the state of scientific knowledge at the time of filing of the application. It contains an assessment of the various controls and tests, which constitute the marketing authorization file, and addresses all relevant issues for the evaluation of the quality, safety and effectiveness of the immunological veterinary drug. It provides detailed results of the controls and tests performed and accurate bibliographic references.
All important data are summarized in the annex to detailed and critical summaries and, to the extent possible, presented as tables or charts. Detailed and critical summaries contain specific references to information in the main documentation.
Detailed and critical summaries are signed, dated and accompanied by information on the author's titles, training and professional experience. The author's professional links with the applicant are indicated.
PART II
CHEMICAL DATA, PHARMACEUTIQUES
AND BIOLOGICAL / MICROBIOLOGICAL (QUALITY)
All test procedures meet the criteria for analysis and quality control of raw materials and finished product and are validated. The results of the validation studies are provided. The particular material that could be used is the subject of a sufficient description with a possible supporting schema. If necessary, the formula of laboratory reagents is supplemented by the manufacturing method.
For test procedures in the European Pharmacopoeia or in the pharmacopoeia of a Member State, this description may be replaced by a specific reference to the pharmacopoeia in question. Where applicable, the chemical and biological references of the European Pharmacopoeia should be used. If other preparations and other reference standards are used, they are identified and described in detail.
A. ― QUALITATIVE COMPOSITIONS
AND QUANTITATIVE OF COMPOSANTS
1. Quality composition
"Qualitative composition" of all components of the immunological veterinary drug means the designation or description:
- the active substance(s);
- components of adjuvants;
- the component(s) of the excipients, regardless of the nature or quantity implemented, including the preservatives, stabilizers, emulsifiers, dyes, taste correctors, flavourings, markers, etc.;
– elements of pharmaceutical forming intended to be administered to animals. These indications are supplemented by any useful information on primary conditioning and, possibly, its closure, on devices with which the immunological veterinary drug is used or administered and which will be delivered with the drug. If the device is not issued with the immunological veterinary drug, it is necessary to provide relevant information on this device, when necessary for the evaluation of the product.
2. Common terms
By "usual terms" to designate the components of the immunological veterinary drug, it must be understood, without prejudice to the application of the other details provided in section 3 R. 5141-14 of the Public Health Code or paragraph 3 (c) of section 12 of the Directive:
- for products in the European Pharmacopoeia or, if not, in the pharmacopoeia of a Member State, the principal name retained by the monograph concerned, obligatory for all substances of this type, with reference to this pharmacopoeia;
- for other products, the international common name recommended by the World Health Organization, may be accompanied by another common name or, if not, by the exact scientific name. Products without international common name or exact scientific designation are designated by the indication of origin and method of obtaining, supplemented, if any, by any useful clarification. For coloring materials, the designation by the number "E" that is assigned to them by Directive 2009 / 35 / EC of the European Parliament and of the Council of 23 April 2009 on substances that can be added to drugs for their coloring and Annex I of Directive 94 / 36 / This is mentioned.
3. Quantitative composition
To give the "quantitative composition" of the active substances of the veterinary immunological drug, it is necessary to indicate, if possible, the number of organisms, the specific protein content, the mass, the number of international units (UI) or biological activity units, either per unit of take, or per unit of volume, of each active substance and, with respect to the adjuvant and components of the excipients, the mass or
When an international biological activity unit has been defined, it should be used.
The biological activity units that have not been published are expressed in such a way as to unequivocally inform the activity of the substance, for example by mentioning the immunological effect on which the dosage assessment method is based.
4. Product development
The choice of composition, components and primary conditioning is explained. This explanation is justified by scientific data on product development. Overdose in manufacturing and its justification are indicated.
B. ― FABRICATION MODE DESCRIPTION
The description of the manufacturing method attached to the application for authorization, pursuant to the 2° of section R. 5141-16 of the Public Health Code or the point d of paragraph 3 of section 12 of the directive, is set out in such a way as to give a satisfactory idea of the nature of the operations being carried out.
To this end, it shall include:
― the mention of the various manufacturing steps (including the production of the antigen and purification procedures) to assess the reproducibility of the manufacturing method and the risks of adverse effects associated with the finished product, such as microbiological contamination; proof of the validation of key steps, as well as of the entire production process, along with the results obtained in three consecutive batches manufactured using the method described;
- in case of continuous manufacture, any information on the guarantees of homogeneity and consistency of all finished product lots;
- a listing of all substances used at various stages, including those that cannot be found during manufacturing;
a detailed description of the production of the mixture, with quantitative indication of all the products used;
- the designation of the manufacturing stages to which sample samples are collected for the controls being produced.
C. ∙ PRODUCTION AND CONTROL
OF THE FIRST
For the purposes of this section, all components used in the production of the immunological veterinary drug must be understood by "the raw materials". Crop circles consisting of several components used for the production of the active substance are considered to be a single raw material. However, the qualitative and quantitative composition of any culture environment should be presented, since the authorities consider that this information is relevant to determining the quality of the finished product and the risks that could result. In the case of the use of animal materials for the preparation of these crop circles, the animal species and the tissue used should be indicated.
The file includes specifications, information on the tests to be carried out for the quality control of all batches of raw material and the results obtained on a batch for all components used and is presented in accordance with the provisions listed below.
1. Substances listed in pharmacopoeia
The monographs of the European Pharmacopoeia are required for all the raw materials contained therein. For other products, each Member State may impose, for the manufactures carried out in its territory, respect for its national pharmacopoeia. The conformity of components to the requirements of the European Pharmacopoeia or the pharmacopoeia of a Member State is sufficient for the application of the provisions of the 7th of Article R. 5141-16 of the Public Health Code or of Article 12, paragraph 3, of the Directive. In this case, the description of analytical methods may be replaced by the detailed reference to the pharmacopoeia in question.
Coloring materials meet the requirements of Directive 2009 / 35 / EC of the European Parliament and of the Council of 23 April 2009 on substances that can be added to drugs for their colouring. The routine tests to be performed on each batch of raw material are reported in the application for marketing authorization. If other tests than those mentioned in the pharmacopoeia are used, evidence must be provided that the raw materials meet the quality requirements of this pharmacopoeia.
In the event that a specification or other provisions of a monograph of the European Pharmacopoeia or the pharmacopoeia of a Member State would not be sufficient to guarantee the quality of the product, the competent authorities may require the applicant to be allowed to place more appropriate specifications on the market. The authorities responsible for the pharmacopoeia in question are informed of the alleged insufficiency.
Where a raw material is not described in the European Pharmacopoeia or in the pharmacopoeia of a Member State, the reference to a monograph of a pharmacopoeia of a third country may be accepted; in this case, the applicant shall submit a copy of the monograph accompanied, if necessary, by the validation of the analytical procedures contained in that monograph and, where appropriate, a translation.
When materials of animal origin are used, they must comply with the provisions of the relevant monographs, including the general monographs and general chapters of the European Pharmacopoeia. Tests and controls are adapted to the raw material. It is up to the applicant to provide documentation demonstrating that the raw materials and the manufacture of the veterinary drug meet the requirements of the explanatory note regarding the reduction of the risk of transmission of agents of animal spongiform encephalopathies by human and veterinary drugs, as well as the requirements of the corresponding monograph of the European Pharmacopoeia. Certificates of conformity issued by the European Directorate of the Quality of Medicines, together with a reference to the European Pharmacopoeia monograph, may be used to prove compliance.
2. Substances not listed in a pharmacopoeia
2. Organic raw materials
These products must be monographed.
Vaccine production is based, if possible, on a seed lot system and on defined cell banks. For the production of immunological veterinary medicines consisting of serums, the origin, general health and immunological status of producing animals are indicated and defined mixtures of raw materials are used.
The origin, including the geographic region, and the history of raw materials are described and documented.
For raw materials derived from genetic engineering, this information is sufficiently detailed, particularly with regard to the description of the cells or starting strains, the construction of the expression vector (name, origin, function of the replicon, biological regulator [s] of the proponent and other elements involved in the regulation), the control of the DNA or RNA sequence actually inserted, the oligonuclear sequences of the plasmid vector intracell
Stem material, including cell banks and crude serum for the production of aniserum, is subject to identification tests and contamination by foreign agents is sought.
Information is provided on all substances of biological origin used at any stage of the manufacturing process. This information includes:
a detailed description of the origin of raw materials;
- a detailed description of any treatment, purification and inactivation implemented, together with data concerning the validation of the processes used and the controls being produced;
– a detailed description of all contamination search tests carried out on each product batch.
If the presence of foreign agents is detected or suspected, the material in question is excluded or used only in exceptional circumstances in which the subsequent processing of the product ensures the removal or inactivation of contaminant agents. This removal or inactivation is demonstrated.
If cell banks are used, it must be demonstrated that cellular characteristics have not undergone any alteration to the largest number of passages used for production.
For attenuated live vaccines, evidence of the stability of seed mitigation features is required.
It is necessary to provide evidence that the stem material, cell banks, serum lots and other animal-based materials that play a role in the transmission of ESTs are in accordance with the explanatory note on reducing the risk of transmission of agents of spongiform animal encephalopathies by human and veterinary drugs, as well as the corresponding monograph of the European Pharmacopoeia.
Certificates of conformity issued by the European Directorate of Quality of Medicines, with a reference to the European Pharmacopoeia monograph, may be used to prove compliance.
Samples of the raw biological material or reagents are, if any, provided to the French Food Safety Agency to allow testing.
2. 2. Non-organic raw materials
Non-organic raw materials are the subject of a monograph covering each of the following headings:
- the name of the raw material meeting the requirements of section A, item 2, supplemented by the synonyms either commercial or scientific;
― the description of the raw material in accordance with the one used for the writing of a monograph of the European Pharmacopoeia;
the function of the raw material;
― identification methods;
– any particular precaution that may be necessary to keep the raw material and, if necessary, the shelf life.
D. ∙ FABRICATION ASSESSMENT
1. The file includes information on controls on intermediate products, to ensure consistency in manufacturing and finished product.
2. For inactivated or detoxified vaccines, inactivation and detoxification are controlled during each production operation as quickly as possible after the end of the inactivation or detoxification process and after neutralization, if any, but before the next production step.
E. ∙ FINI PRODUCT CONTROL
For all controls, finished product analysis methods are described in a sufficiently detailed way for quality assessment.
The file includes information on the controls performed on the finished product. Where appropriate monographs exist, if the methods and test limits are not those in the European Pharmacopoeia or, failing that, in the pharmacopoeia of a Member State, evidence should be provided that the finished product in the pharmaceutical form in question meets the quality requirements of that pharmacopoeia, if controlled in accordance with these monographs. The application for marketing authorization contains a list of tests carried out on representative samples of each finished product lot. The frequency at which the tests that are not performed on each lot is indicated. The limits to liberation are indicated.
Where applicable, chemical and biological references of the European Pharmacopoeia are used. If other preparations and other reference standards are used, they are identified and described in detail.
1. General characteristics of the finished product
The controls of the general characteristics, whenever possible, relate to the determination of the mean masses and maximal deviations, mechanical, physical, or chemical tests and physical characteristics, such as density, pH, viscosity, etc. For each of these characteristics, specifications with the appropriate confidence interval are defined, in each particular case, by the applicant.
2. Identification of the active substance(s)
Whenever necessary, a specific identification test is performed.
3. Title or content of lots
The quantification of the active substance in each batch must be carried out in order to demonstrate that its content or title ensures that it is safe and effective.
4. Identification and dosage of adjuvants
As long as analytical methods are available, the quantity, nature and components of the adjuvant in the finished product are verified.
5. Identification and dosage of excipient components
To the extent necessary, the components of the excipient are, at a minimum, the subject of identification.
The Conservatives are required to be tested "lower and higher limits". Any other component of the excipient likely to cause an adverse reaction is mandatoryly subjected to a "upper limit" test.
6. Safety tests
Regardless of the results of the tests submitted in accordance with Part 3 of this title (Safety Season), information on batch safety testing should be provided. These controls are, preferably, overdose studies performed at least on one of the most sensitive species of destination using the route of administration for which the risk is highest. The routine conduct of batch safety tests may not be required in the interest of animal welfare, where a sufficient number of consecutive batches have been produced and have been deemed to be in compliance with the test requirements.
7. Sterility and purity tests
Tests to highlight the absence of contamination by foreign agents or other products are carried out, depending on the nature of the immunological veterinary drug, method and conditions of manufacture. If the number of routine tests for each lot is less than that required by the European Pharmacopoeia, the tests carried out are critical to certifying compliance with the monograph. Evidence should be provided that the immunological veterinary drug would meet the requirements if it were subjected to all the tests required by the monograph.
8. Residual humidity
Residual moisture is controlled in each lot of lyophilized product.
9. Inactivation
For inactivated vaccines, inactivation is verified in the final primary conditioning of the product, unless such tests were conducted at an advanced stage of manufacture.
F. ∙ OLTS CONFORMITY
In order to ensure a constant quality of the product from one batch to another and to prove compliance with the specifications, a complete protocol should be provided for three consecutive batches and the results of all tests carried out during production and the finished product.
G. ∙ STABILITY TESTS
The information and documents attached to the application for authorization under the 5th and 7th of Article R. 5141-16 of the Public Health Code or points f and i of Article 12, paragraph 3, of the Directive shall be submitted in accordance with the requirements listed below.
The applicant is required to describe the research that determined the proposed shelf life. This research is always real-time studies; In addition, a sufficient number of lots produced according to the process described as well as products retained in the final primary packaging(s); these studies include biological and physico-chemical stability tests.
The conclusions contain the results of the analyses justifying the proposed shelf life under all proposed conservation conditions.
In the case of products administered in foods, it is also necessary to provide information on the shelf life of the product at the different stages of the mixture, which is carried out in accordance with the recommended method of use.
When a finished product is to be reconstituted before administration or is administered (dilute) in drinking water, the proposed shelf life for the reconstituted product should be specified in the recommended method of use. Data should be submitted in support of the proposed shelf life for the reconstituted product.
Stability data for drug associations can be used as preliminary data for derivatives containing one or more identical components.
The proposed shelf life is justified.
The effectiveness of any conservation system used is demonstrated.
Information on the effectiveness of preservatives present in other immunological veterinary drugs produced by the same manufacturer may be sufficient.
H. ― OTHER INFORMATION
Information on the quality of the immunological veterinary drug not covered by the previous sections may be included in the file.
PART III
INNOCUITY TESTS
A. ∙ GENERAL INTRODUCTION AND IMPLEMENTATION
Safety tests indicate the potential risks associated with the immunological veterinary drug under the proposed conditions of use in the animal: these risks are assessed against the potential benefits of the drug.
For immunological veterinary drugs made up of living organisms, including organisms transmitted by vaccinated animals, it is necessary to assess the potential risk to which non-immunized animals belonging to the same species or any other species likely to be exposed to the organisms in question.
Safety studies are conducted on the species of destination. The dose used corresponds to the recommended quantity of product and the lot used for safety testing shall be taken from one or more batches produced in accordance with the manufacturing process described in the second part of the application for authorization.
For immunological veterinary drugs containing a living organism, the dose used in laboratory tests described in sections B1 and B2 corresponds to the amount of product with the highest title. If necessary, the concentration of the antigen can be adapted to obtain the required dose. For inactivated vaccines, the dose used corresponds to the recommended amount and the highest antigen content, except for justification.
Safety documentation is used to assess human hazards that may possibly be associated with exposure to the veterinary drug, for example at the time of administration to the animal.
B. ― LABORATORY TESTS
1. Safety of dose administration
The immunological veterinary drug is administered at the recommended dose and by each of the recommended routes of administration to animals belonging to all species and categories to which it is intended, including animals with minimal age of administration. Animals are kept in observation and signs of local or systemic reaction are sought. Careful observations, both macroscopic and microscopic, of the area where the injection was carried out, if any, are made after the animal's death. Other objective criteria, such as rectal temperature and performance measurement, are recorded.
Animals are kept in observation and are subject to examinations until no reaction is more predictable, but the period of observation and examination should last at least 14 days after the administration.
This study may be part of the repetitive administration required under item 3 or may be omitted if the results of the overdose study required under item 2 have not revealed any signs of local or systemic reaction.
2. Safety of overdose administration
Only live immunological veterinary drugs are subjected to overdose testing.
An overdose of immunological veterinary drug is administered by each route of administration recommended to animals belonging to the most sensitive categories of target species, unless the choice of the most sensitive pathways among several similar routes of administration is justified. For injected veterinary immunological drugs, doses as well as pathways of administration are selected based on the maximum volume that can be administered on a single injection area. Animals are kept in observation and signs of local or systemic reaction are sought for at least fourteen days after administration.
Other criteria, such as rectal temperature and performance measurement, are recorded.
Careful observations, both at the macroscopic and microscopic scale, of the area where the injection was carried out, if any, are made after the animal's death if this was not done in accordance with point 1.
3. Safety of repeated dose administration
For immunological veterinary drugs to be administered on several occasions, as part of a basic vaccination plan, a study of the repeated administration of a dose is necessary to highlight any adverse effects resulting from such administration. These tests are performed on the most sensitive categories of target species (such as certain strains or age groups) using the recommended pathway.
Animals are kept in observation and signs of local or systemic reaction are sought for at least fourteen days after the last administration. Other objective criteria, such as rectal temperature and performance measurement, are recorded.
4. Study of reproductive function
A reproductive function study is considered whenever some data suggests that the raw material from which the product originates may present a risk factor. The reproductive function is studied in the male and in the female gravel and non-grave using the recommended dose and the most sensitive route of administration. In addition, consideration should be given to the adverse effects on the offspring as well as to the teratogenic and abortive effects.
These studies may be part of the safety studies described in items 1, 2 and 3 or field studies referred to in section C.
5. Review of immunological functions
If the immunological veterinary drug in question may have a harmful effect on the immune response of the vaccinated animal or its offspring, appropriate tests should be conducted on immunological functions.
6. Specific requirements for live vaccines
6. 1. Diffusibility of vaccine strain
The diffusibility of the vaccine strain by an animal vaccinated with non-immunized animals in the destination species is studied using the recommended route of administration with which the risk of diffusibility is highest. In addition, it may be necessary to study the diffusibility of the strain to animal species to which the drug is not intended but which may be susceptible to a live vaccine.
6. 2. Dissemination in the body of the vaccinated animal
The presence of the vaccine strain is, as the case may be, sought in feces, urine, milk, eggs, as well as in nasal and oral secretions, among others. In addition, studies may be required on the spread of the strain in the animal's body by insisting on places where the replication of the body is preferably performed. For live vaccines intended to control zoonoses within the meaning of Directive 2003 / 99 / EC of the European Parliament and the Council for food-producing animals, these studies particularly take into account the persistence of the body on the injection area.
6. 3. Reversion to attenuated vaccine virulence
Reversion to virulence on the primary seed lot should be studied. If the primary seed lot is not available in sufficient quantity, a lot of work seed should be studied corresponding to the lowest number of passages. The use of a different number of passages is justified. The initial vaccination is performed by choosing the route of administration for which the probability of a reversion to virulence is the strongest. Successive passages must be carried out in five groups of target animals, unless a larger number of passages are justified or the organism does not disappear from the animals tested earlier. When the body does not have the ability to respond adequately, it is necessary to make as many passages as possible in the target species.
6. 4. Biological properties of vaccine strain
Other tests may be necessary to determine as precisely as possible the intrinsic biological properties of the vaccine strain (e.g. neurotropism).
5. Recombination or genomic rearrangement of strains
The likelihood of recombination or genomic re-arrangement with strains on the ground or with other strains is examined.
7. User security
This section includes a review of the effects observed in the previous sections and links them to the type and extent of human exposure to the product for the formulation of appropriate warnings to the user and other risk management measures.
8. Residual study
It is generally not necessary to study residues in the case of immunological veterinary drugs.
However, when adjuvants or preservatives enter the manufacture of the drugs in question, it is necessary to take into account that any residue may persist in food. The effects of such residues are, if any, studied.
A waiting time is proposed, whose merit is appreciated in relation to all studies on residues.
9. Interactions
If there is a declaration of compatibility with other immunological veterinary drugs in the summary of product characteristics, it is necessary to examine the safety of the association. Any other known interaction with veterinary drugs is described.
C. ∙ TERRAIN STUDIES
Unless warranted, laboratory research should be supplemented by data from field studies, using lots produced in accordance with the manufacturing process described in the application for marketing authorization. Safety and effectiveness are studied in the same field studies.
D. ∙ RISK ASSESSMENT
FOR ENVIRONMENT
The environmental risk assessment has as a double objective the assessment of the potential adverse effects of the product on the environment and the search for all precautions of employment that can reduce these risks.
This evaluation is normally conducted in two stages. The first step in the evaluation is mandatory in all cases. Details of the evaluation should be provided in accordance with the guidelines in force. The potential exposure of the environment to the product and the level of risk associated with such exposure should be indicated, with particular attention to:
- the species of destination and the proposed method of employment;
― the mode of administration, including the possibility that the product passes directly into ecosystems;
- the possible excretion of the product and its substances active in the environment by treated animals; their persistence in excretions;
disposal of waste or unused products.
In the case of live vaccine strains likely to be zoonotic, human risk is assessed.
If the findings of the first step reveal a possible exposure of the environment to the product, the applicant proceeds to the second stage in which it assesses the potential or potential risks that the veterinary drug may pose to the environment. Whenever necessary, further research is carried out on the impact of the product (soil, water, air, aquatic systems, organisms to which the drug is not intended).
PART IV
EFFICIENCY TESTS
Chapter I
1. General principles
The purpose of the tests described in this part is to demonstrate or confirm the effectiveness of the immunological veterinary drug. All claims submitted by the applicant regarding the properties, effects and use of the drug are supported by the results of the specific tests mentioned in the application for marketing authorization.
2. Conduct of tests
All efficiency tests are carried out in accordance with a detailed protocol that has been thoroughly considered. This protocol is recorded in writing before the trial begins. The well-being of tested animals is subject to veterinary control and is taken into account in the development of any experimental protocol as well as throughout the conduct of testing.
Written, pre-established and applied in a systematic manner to the organization and conduct of the tests, to the collection of data, documentation and verification of efficiency tests are required.
Unless otherwise justified, field trials are conducted in accordance with the principles of good clinical practice.
Before any trial on the ground begins, the informed consent of the owner or owner of the animals used for the test is given in writing and documented. In particular, the owner or owner of the animal receives written information on the consequences of participation in the test, including how to eliminate the treated animal or the removal of food from that animal. A copy of this notification, countersigned and dated by the owner or owner of the animal, is attached to the test documentation.
Unless the field trial is conducted in blind, the labelling provisions for veterinary clinical trials apply.
Chapter II
A. ― GENERAL EXIGENCES
1. The choice of antigens or vaccine strains is justified by epizoological data.
2. Laboratory efficacy tests are controlled tests, involving untreated control animals, unless this is justified for animal welfare reasons and the efficacy can be demonstrated otherwise.
In general, tests conducted under conditions of use, including untreated control animals, are presented in support of laboratory tests.
All tests are described in a sufficiently detailed manner to be reproducible in controlled tests, performed at the request of the French Food Safety Agency. The investigator demonstrates the validity of all methods used.
All results obtained are recorded, whether favourable or unfavourable to the applicant.
3. The effectiveness of an immunological veterinary drug is proven for each target category that is recommended for vaccination and for each recommended route of administration by applying the recommended plan of administration. Where applicable, the influence of natural antibodies and maternal antibodies on the effectiveness of a vaccine is appropriately appreciated. Unless justified, the beginning and duration of immunity are established and supported by tests.
4. For multiple and combined immunological veterinary drugs, the effectiveness of each component is demonstrated. If it is recommended to administer the drug in combination with another veterinary drug, or at the same time, they must be proved compatibility.
5. Whenever a drug is part of a vaccination plan recommended by the applicant, it is necessary to demonstrate the activating or amplifying effect or the contribution of the immunological veterinary drug to the effectiveness of the plan as a whole.
6. The dose used corresponds to the recommended quantity of product and the lot used for efficiency testing is taken from one or more batches produced in accordance with the manufacturing process described in the second part of the application for authorization.
7. If there is a declaration of compatibility with other immunological drugs in the summary of product characteristics, it is necessary to examine the effectiveness of the association. Any other known interaction with other veterinary drugs is described. A concurrent or simultaneous use may be permitted, provided that it is supported by appropriate studies.
8. For immunological veterinary drugs administered to animals for diagnostic purposes, the applicant indicates how reactions to the product should be interpreted.
9. With regard to vaccines designed to distinguish vaccine animals from infected animals (vaccins markers) and for which claims of efficacy are based on in vitro diagnostic tests, sufficient data should be provided on these tests to allow an adequate assessment of the claims related to the properties of markers.
B. ― LABORATORY TESTS
1. The efficacy of the drug is in principle demonstrated in well-defined laboratory conditions, by performing a provocative test after administration of the immunological veterinary drug under the recommended conditions of use. To the extent possible, the conditions under which provocation is carried out must reproduce the natural conditions of infection. Details should be provided on the strain used for provocation and its relevance.
For live vaccines, it is necessary, except for justification, to use lots with the lowest content or title. For other products, it is necessary to use, unless otherwise justified, lots with the lowest active content.
2. If possible, the type of immune response (to cellular / humoral, local / general, immunoglobulin class) induced by the administration of the immunological veterinary drug to the destination animal by the recommended administration is indicated and documented.
C. ∙ TERRAIN STUDIES
1. Unless warranted, laboratory research should be supplemented by data from field studies using representative batches of the manufacturing process described in the application for marketing authorization. Safety and effectiveness are studied in the same field studies.
2. When laboratory tests do not reveal the efficacy of the product, the only field test drive may be acceptable.
PART II
INFORMATION AND DOCUMENTS
A. ∙ INTRODUCTION
The safety and effectiveness studies file includes an introduction to locate the subject and specifying the controls performed in accordance with the third and fourth sections, followed by a summary with detailed bibliographic references. This summary contains an objective review of all the results obtained and results in a conclusion on the safety and effectiveness of the immunological veterinary drug. If one of the listed controls or tests fails, a justification is provided.
B. ● LABORATORY STUDY
For any study, we must present:
1. A summary.
2. The name of the body that conducted the study.
3. A detailed experimental protocol with the description of the methods used, the apparatus and the material used, the species, the race or the lineage of the animals, their category and origin, their identification and number, the environmental and feeding conditions adopted by specifying, among other things, whether they are free from specific pathogens and/or specific antibodies, the nature and quantity of the additives contained in the schedule
4. For control animals, it is necessary to specify whether they have received placebo treatment or not.
5. For treated animals, if any, if they have received the test drug or other medicine authorized in the European Union.
6. All general or individual information and results obtained (with averages and standard deviations), favourable and unfavourable. The data are sufficiently detailed to allow the critical evaluation of the results, regardless of the interpretation given by the author. The raw data are presented in the form of tables.For example, the results can be accompanied by documents reproducing the recordings, microphotographs, etc.
7. The nature, frequency and duration of the adverse effects observed.
8. The number of animals on which the tests were interrupted before the end and the reasons for this interruption.
9. A statistical analysis of results, when required by the test program, and variance between data.
10.The occurrence and evolution of possible intercurrent diseases.
11. All details on veterinary drugs (other than those tested), administered during the examination period.
12. An objective review of the results obtained, leading to conclusions regarding the safety and efficacy of the drug.
C. ∙ TERRAIN STUDIES
Information on field studies is sufficiently detailed to make an objective judgment. They include:
1. A summary.
2. The name, address, function and qualifications of the responsible investigator.
3. The place and date of processing, an identification code that may be related to the name and address of the owner or owner of the animal(s).
4. A detailed experimental protocol with the description of the methods used, the equipment and equipment used, the path, the schema and the dose of administration, the categories of animals, the duration of the observation period, the serologic response and other tests performed on animals after the administration.
5. For control animals, it is necessary to specify whether they have received placebo treatment or not.
6. Identification of treated animals and witnesses (collective or individual, as appropriate) with species, race or lineage, age, weight, sex and physiological status.
7. A brief description of the livestock and feed mode, indicating the nature and quantity of the additives contained in the food.
8. Information on clinical observations, performance or results (with averages and standard deviations); where individual controls and measurements have been performed, individual results are indicated.
9. All clinical observations and results of studies, favourable or unfavourable, with full mention of clinical observations and objective results of activity required to assess the drug; the methods followed are indicated and the meaning of the various deviations observed.
10. Impact on animal performance.
11. The number of animals on which the tests were interrupted before the end and the reasons for this interruption.
12. The nature, frequency and duration of the adverse effects observed.
13. The appearance and evolution of possible intercurrent diseases.
14. Any clarification of veterinary drugs (other than the one studied), administered either beforehand or in parallel to the product tested or during the observation period; a detailed description of any observed interaction.
15. An objective review of the results obtained, leading to conclusions regarding the safety and efficacy of the drug.
PART SIXTH
BIBLIOGRAPHIC REFERENCES
The bibliographic references cited in the summary referred to in the first part are the subject of a detailed list and copies are provided.
PART III
SPECIFIC REQUIREMENTS
AUTHORIZATION OF MISE ON MARKET
1. Generic veterinary drugs
Applications based on 1° of article R. 5141-20 of the Public Health Code (general veterinary medicine as defined in 8° of Article L. 5141-2 of the Public Health Code) or section 13 of the directive contain the data described in the first and second parts of Title I of this Annex, an environmental risk assessment, as well as the data confirming that the drug has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference veterinary drug and those showing bioequivalence with the reference veterinary drug. If the reference veterinary drug is a biological medicine, the documentation requirements referred to in paragraph 2 for similar veterinary medicines should be met.
For generic veterinary drugs, detailed and critical safety and security summaries are specifically focused on:
― motives to invoke essential similarity;
a summary of the impurities in batches of the active substance(s) and of the impurities of the finished drug (and, if applicable, the decomposition products forming during storage) whose use is proposed in the product intended to be marketed, as well as an assessment of these impurities;
an assessment of bioequivalence studies or an explanation of why the studies were not conducted in accordance with the guidelines in force;
― where appropriate, additional data to demonstrate the equivalence of the safety and efficacy properties of different salts, esters or derivatives of an authorized active substance are provided by the applicant; these data include evidence that there is no change in the pharmacokinetic or pharmacodynamic properties of the therapeutic fraction or its toxicity, which can influence the safety-effectiveness profile.
Each feature invoked in the summary of the characteristics of the product that is not known or deducted from the properties of the drug or its therapeutic class is discussed in the detailed non-clinical summaries and shown by the published literature or additional studies.
For generic veterinary drugs intended for intramuscular, subcutaneous or transdermal administration, the following additional data should be provided:
evidence of the equivalence or non-depletion of residues from the administration site reported by appropriate studies;
- proof of tolerance in the destination animal at the administration site, which can be reported by appropriate studies.
2. Similar veterinary drugs
In accordance with article R. 5141-20 of the Public Health Code or section 13, paragraph 4, of the Directive, where a biological veterinary drug, similar to a reference biological veterinary drug, does not meet the conditions in the definition of the generic drug, the information to be provided is not limited to the first and second parts ( Pharmaceutical, Chemical and Biological data), supplemented by bioavailability and bioavailability data. In this case, additional data should be provided, particularly on the safety and effectiveness of the product:
- the nature and quantity of additional data (i.e. toxicological data and other safety studies, and appropriate clinical studies) determined on a case-by-case basis, in accordance with the corresponding scientific guidelines;
― the necessary studies due to the diversity of biological veterinary drugs, determined by the French Food Safety Agency and planned in the third and fourth parts, taking into consideration the specific characteristic of each veterinary biologic drug considered isolated.
The general principles to be applied are addressed in a guideline that will be adopted by the European Medicines Agency, taking into account the characteristics of the biological drug concerned. When the reference biological veterinary drug has more than one indication, the efficacy and safety of the drug presented as similar are justified or, if necessary, demonstrated separately for each of the indications claimed.
3. Proper veterinary use
For medications where the active substance(s) has a "definite veterinary use" as referred to in 1° of article R. 5141-18 of the Public Health Code or referred to in Article 13 bis of the Directive and having recognized effectiveness and an acceptable level of security, the following specific rules apply.
The applicant shall submit the first and second parts, as described in Title I of this annex.
For the third and fourth parts, a detailed scientific bibliography covers all aspects related to safety and effectiveness.
The following specific rules apply to demonstrate the well-established veterinary use:
3. 1. The factors to be considered to demonstrate that the veterinary use of drug components is well established are:
(a) The duration of use of an active substance;
(b) Quantitative aspects of the use of the active substance;
(c) The degree of scientific interest in the use of the active substance (reflected in the published scientific literature);
(d) Coherence of scientific assessments.
Different times may be required to demonstrate the well-established use of different substances. In any event, the time taken to demonstrate that the veterinary use of a component of a drug is well established, however, may not be less than ten years counted from the first systematic and documented use of that substance as a veterinary drug in the European Union.
3. 2. The documentation submitted by the applicant covers all aspects of the assessment of the safety and/or efficacy of the product for the proposed indication in the species of destination, applying the recommended route of administration and dosage. It includes a review of the corresponding literature or refers to it, and takes into account pre-marketing and post-marketing studies and published scientific literature referring to the experiment in the form of epidemiological surveys, in particular comparative epidemiological surveys.
All documents, both favourable and unfavourable, are communicated. With respect to the provisions relating to "properly established veterinary use", it is especially necessary to specify that bibliographic references from other sources of evidence (post-marketing studies, epidemiological studies, etc.), and not only data relating to testing and controls, may constitute valid evidence of the safety and effectiveness of a product, provided that the use of such sources of information is explained and explained.
3. 3. There is a need to specifically monitor missing data and explain why it is possible to support that an acceptable level of safety and/or efficiency can be guaranteed, even in the absence of some studies.
3. 4. Detailed and critical summaries of safety or efficiency explain the relevance of all the data provided that relate to a product different from the one that will be marketed. It is considered whether the product studied may be considered similar to the product for which a marketing authorization application was made despite existing differences.
3. 5.The post-marketing experience collected with other products containing the same components is of particular importance and applicants must focus on this aspect.
4. Veterinary drugs containing an association
of active substances
In the case of applications based on 2° of section R. 5141-18 of the Public Health Code or section 13 ter of the directive, a record must be provided for the drug containing an association of active substances that includes the first, second, third and fourth parts. It is not necessary to submit studies on the safety and efficacy of each active substance. However, it is possible to include information on each substance taken in isolation in the application for a fixed association. The presentation of data on each active substance taken in isolation, together with the necessary safety studies for the user, residue removal studies and clinical studies on the fixed association, may be considered sufficient to justify the omission of data on the association, for reasons of animal welfare and to avoid unnecessary experimentation on animals, unless there is a need to suspect an interaction leading to increased toxicity. Where applicable, information on manufacturing sites and the safety assessment of the substances resulting from this association should be provided.
5. Requests with consent of the licensee
of marketing authorization
Applications based on the 4th of section R. 5141-20 of the Public Health Code or on section 13 quater of the directive include the data described in Part I of this Schedule, and the document attesting to the availability of data from parties 2, 3 and 4 by the licensee of the marketing authorization of the reference veterinary drug. In this case, it is not necessary to provide detailed and critical summaries on quality, safety and effectiveness.
6. Documentation for authorisation applications
in exceptional circumstances
6. General provisions
A marketing authorization may be granted subject to certain specific obligations made to the applicant to present specific elements, including the safety and effectiveness of the veterinary drug, when pursuant to 6° and 9° of section R. 5141-20 of the Public Health Code or in accordance with section 26(3) of the Directive the applicant may demonstrate that it is not in a position to provide complete data on the quantification of the active substance
The essential requirements for all applications referred to in this paragraph (in the area of safety or efficiency) are specified on a case-by-case basis by the Director of the French Food Safety Agency on the basis of recommendations made by guidelines.
6. 2. Immunological drugs
Without prejudice to the above provisions, the data to be provided for an immunological drug are:
For the second part:
- the qualitative and quantitative composition of the immunological drug including excipients, specifying whether the active ingredient is alive or not, and whether the product contains an adjuvant;
― the name and address of establishments that carry out manufacturing and import operations if the manufacturer is in a third country. For establishments located abroad, where applicable, opening permits and certificates of good manufacturing practices;
a summary description of the manufacturing process;
- the list of controls for potential contaminant agents (agents sought: viral, bacterial, fungal, mycoplasmic, possibly parasitic, and mention of the techniques used) conducted on all raw materials of biological origin and the corresponding acceptability standards, along with the corresponding test certificates;
- a description of the safety and activity controls conducted on the finished product and the corresponding acceptability standards, along with a certification from the manufacturer certifying that the controls comply with the established standards. In particular, the manufacturer compares the conformity of the immunological product to the monograph of the European Pharmacopoeia, where applicable, and possibly justifies the non-compliance with this monograph.
For the third part:
- laboratory demonstration of safety after administration of a dose or overdose and, if necessary, a study of reproductive function and an examination of immunological functions;
- in the case of an immunological substance containing at least one living organism, a study to assess the diffusibility and stability (reversion to virulence state) of the strain used as a vaccine;
– data in laboratory or field of efficiency.
7. Joint marketing authorization applications
Mixed market authorization applications are applications for which the third or fourth part of the file includes safety and effectiveness studies conducted by the applicant and bibliographic references. All other parts conform to the structure described in the first and second parts of Part I of this Annex. The French Food Safety Agency accepts on a case-by-case basis the format submitted by the applicant.
8. Application for marketing authorization for species or indications of minor importance referred to in Article 7 R. 5141-20
For applications involving an animal species or indications representing limited market niches, in addition to the adjustments provided for in Part I and Part II, Part I, Part II, Part III and Part IV of the file may be reduced, as appropriate, in accordance with the provisions of the scientific guidelines adopted by the European Agency.
9. Application for marketing authorization for veterinary medicines for aquarium fish, apartment birds, passenger pigeons, terrarium animals, small rodents, furets and pet rabbits exclusively mentioned in the 8th article R. 5141-20 of the Public Health Code
For applications made under section R. 5141-20 of the Public Health Code, Parts I and II are incorporated in accordance with Part I of this annex.
In the case of active substances whose use is well established, Parts III and IV are based on reports of qualified experts in accordance with the first paragraph of Article R. 5141-23 of the same Code.
The toxicity data for the user are particularly detailed.
PART IV
EXIGENCES RELATING TO THE AUTHORIZATION OF IMPLEMENTATION ON THE MARKET OF PARTICULATED VETUREMENT
This title sets out the specific requirements for veterinary drugs identified according to the active substance they contain.
1. Veterinary immunological drugs
A. ― PERMANENT REPRESENTATIVE
For certain specific immunological veterinary drugs and by derogation from the provisions of Part II, Part II, Section C, on active substances, the concept of a permanent record of immunizing antigen is introduced.
For the purposes of this annex, a permanent record of the antigen immunizing a stand-alone part of the application file for authorization to market a vaccine, which contains all relevant information regarding the quality of each active ingredient in this veterinary drug. The autonomous part may be common to one or more monovalent and/or combined vaccines submitted by the same applicant or licensee of the marketing authorization.
Scientific guidelines for the filing and evaluation of the permanent vaccine antigen file will be adopted by the European Medicines Agency. The filing of this type of file includes an application established in accordance with Article R. 5141-14 of the Public Health Code and the relevant documentation referred to in 2°, 6° and 7° of Article R. 5141-16 of the same Code. This file and the evaluation also adhere to the guidelines published by the Commission in Regulation of Drugs in the European Union, Volume 6 B, Notice to Applicants.
B. ∙ DOSSIER MULTISOUCHES
For some immunological veterinary drugs (ephen fever, avian influenza and caarrhal fever) and by derogation from the provisions of Part II, Part II, Section C, on active substances, the concept of multi-layer case is introduced.
A multi-layer file means a single file containing the relevant data required for a unique and in-depth scientific assessment of the various options for strains / stem associations, with a view to permitting vaccines against viruses with antigenic variability.
Scientific guidelines on the filing and evaluation of multi-layer records will be adopted by the European Medicines Agency. The filing of this type of file includes an application established in accordance with Article R. 5141-14 of the Public Health Code and the relevant documentation referred to in 2°, 6° and 7° of Article R. 5141-16 of the same Code. This file and the evaluation also adhere to the guidelines published by the Commission in Regulation of Drugs in the European Union, Volume 6 B, Notice to Applicants.
4. Veterinary homeopathic drugs
This section sets out the specific provisions for the application of Part I, Part II and Part III, applicable to veterinary homeopathic drugs as defined in Article L. 5141-2 of the Public Health Code.
For the second part:
The provisions of Part Two apply to documents submitted in accordance withArticle R. 5141-64 of the Public Health Code or section 18 of the Directive for the Simplified Registration of Veterinary Homeopathic Drugs referred to inArticle L. 5141-9 of the Public Health Code or section 17, paragraph 1, of the directive, and documents for the authorization of veterinary homeopathic drugs referred to in the 5th of section R. 5141-20 of the same code or section 19, paragraph 1, of the directive, with the following modifications.
(a) Terminology:
The Latin name of the homeopathic strain described in the application file for marketing authorization corresponds to the Latin title of the European Pharmacopoeia or, if not, the pharmacopoeia of a Member State. Where applicable, the traditional names or names used in each Member State shall be provided.
(b) Control of raw materials:
The information and documents accompanying the application and related to raw materials, i.e. all the materials used, including starting materials and intermediate materials up to the final dilution that must be incorporated in the finished veterinary homeopathic medicine, are supplemented by additional data on the homeopathic strain.
The general quality requirements apply to all raw materials as well as to the intermediate stages of the manufacturing process to the final dilution intended to be incorporated into the finished homeopathic product. When a toxic component is present, it should be checked if possible in the final dilution.
However, if this is not possible due to the significant dilution, the toxic component is controlled at an earlier stage. Each stage of the manufacturing process from the raw materials to the final dilution intended to be incorporated into the finished product is described in a complete manner.
In the case where dilutions occur, these dilution steps are carried out in accordance with the homeopathic manufacturing methods described in the European Pharmacopoeia monograph or, if not, in the pharmacopoeia of a Member State.
(c) Finished product control:
The general quality requirements apply to finished veterinary homeopathic drugs. An exception is duly justified by the applicant.
The identification and dosage of all components with toxic risk are performed. If it can be justified that identification and/or dosage of all components with toxic risk are not possible, for example because of their dilution in the finished product, the quality is demonstrated by a complete validation of the manufacturing and dilution process.
(d) Stability tests:
The stability of the finished product is demonstrated. The stability data of homeopathic strains are generally transposable to dilutions or triturations obtained from these strains. If no identification or dosing of the active substance is possible due to the degree of dilution, the stability data of the pharmaceutical form are taken into account.
For the third part:
The provisions of the third part apply to the simplified registration of veterinary homeopathic drugs referred to in section L. 5141-9 of the Public Health Code or section 17, paragraph 1, of the directive with the following specification, without prejudice to the provisions of Regulation No. 470 / 2009 / EC concerning substances included in homeopathic strains intended to be administered to feed animal species.
Any missing information is justified and it is necessary to explain, for example, why it is possible to support that an acceptable level of security can be guaranteed, even in the absence of certain studies.
Done in Paris, September 1, 2009.
Minister of Health and Sports,
For the Minister and by delegation:
Deputy Executive Director
health,
S. Delaporte
Minister of Food,
agriculture and fisheries,
For the Minister and by delegation:
Director General
food,
P. Briand
