LegalizeCommission Delegated Regulation (EU) 2021/805 of 8 March 2021 amending Annex II to Regulation (EU) 2019/6 of the European Parliament and of the Council (Text with EEA relevance)
This is the act as published. Later amendments are not folded into the text below: each one is a separate act in this repository and an entry in this law's history.
Information on the mechanism of action of the active substance(s) shall be provided, together with information on primary and secondary pharmacodynamic effects in order to assist in the understanding of any adverse effects in the animal studies. Detailed reporting of pharmacodynamic properties relating to the therapeutic effect shall be reported in Part 4A of the dossier.
IIIa.3A2.2. Pharmacokinetics
Data on the fate of the active substance and its metabolites in laboratory animals shall be provided, covering absorption, distribution, metabolism and excretion (ADME). The data shall be related to the dose/effect findings in the pharmacological and toxicological studies, to determine adequate exposure.
IIIa.3A3. Toxicology
| (1) | The documentation on toxicology shall follow the guidance published by the Agency on the general approach to testing and guidance on particular studies. This guidance includes toxicological data required for the establishment of user safety, and the assessment of adverse effects in target animals and the environment. | |
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| (2) | Toxicity studies shall be conducted with the active substance(s), not with the formulated product, unless specifically required otherwise. | |
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| (3) | Animal studies shall be conducted in established strains of laboratory animals for which (preferably) historical data are available. |
IIIa.3A3.1. Single-dose toxicity
Single-dose toxicity studies may be used to predict:
- (a) the possible effects of acute overdose in the target species;
- (b) the possible effects of accidental administration to humans;
- (c) the doses which may usefully be employed in the repeat dose studies.
Single-dose toxicity studies shall reveal the acute toxic effects of the substance and the time course for their onset and remission.
The studies to be carried out shall be selected with a view to providing information on user safety, for example, if substantial exposure by inhalation or dermal contact of the user of the veterinary medicinal product is anticipated, those routes of exposure shall be studied.
IIIa.3A3.2. Repeat-dose toxicity
Repeat-dose toxicity tests are intended to reveal any physiological and/or pathological changes induced by repeated administration of the active substance or combination of active substances under examination, and to determine how those changes are related to dosage.
A repeat-dose toxicity study in one species of experimental animal shall normally be sufficient. This study may be replaced by a study conducted in the target animal. The frequency and route of administration, and the duration of the study shall be chosen having regard to the proposed conditions of clinical use and/or user exposure. The applicant shall give his reasons for the extent and duration of the studies and the dosages chosen.
IIIa.3A3.3. Tolerance in the target species
A summary shall be provided of any signs of intolerance which have been observed during studies conducted, usually with the final formulation, in the target species in accordance with the requirements of Part IIIa.4A4 (target animal safety). The studies concerned, the dosages at which the intolerance occurred, and the species and breeds concerned shall be identified. Details of any unexpected physiological changes shall also be provided. The full reports of those studies shall be included in Part 4 of the dossier.
IIIa.3A3.4. Reproductive toxicity including developmental toxicity
| (1) | Study of the effects on reproduction For products intended for use in breeding animals, reproductive safety studies in line with VICH GL43 shall be provided. Reproduction toxicity studies in laboratory animals are not expected for the evaluation of effects on the user. | |
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| (2) | Study of developmental toxicity For the evaluation of effects in the target animal species, developmental toxicity studies are not required for products intended only for use in non-breeding animals. For other products a study of developmental toxicity shall be performed in at least one species, which may be the target species. For the evaluation of user safety, standard developmental toxicity testing in accordance with standard tests based on established guidance (including VICH GL32 and OECD tests) shall be performed in all cases where significant user exposure may be expected. |
IIIa.3A3.5. Genotoxicity
Tests for genotoxic potential shall be performed, unless otherwise justified, to reveal changes which a substance may cause in the genetic material of cells. Any substance intended to be included in a veterinary medicinal product for the first time shall be assessed for genotoxic properties.
A standard battery of genotoxicity tests in accordance with standard tests based on established guidance (including VICH GL23 and OECD tests) shall usually be carried out on the active substance(s).
IIIa.3A3.6. Carcinogenicity
The decision on whether carcinogenicity testing is required shall take into account the results of genotoxicity tests, structure-activity relationships and the findings in repeat dose toxicity tests that may demonstrate the potential for hyper-/neo-plastic changes.
Any known species specificity of the mechanism of toxicity shall be considered, as well as any differences in metabolism between the test species, target animal species, and human beings.
Carcinogenicity testing shall be conducted in accordance with standard tests based on established guidance (including VICH GL28 and OECD tests).
IIIa.3A3.7. Exceptions
Where a veterinary medicinal product is intended for topical use, systemic absorption shall be investigated in the target animal species. If it is proved that systemic absorption is negligible, the repeated dose toxicity tests, the tests for developmental toxicity and the carcinogenicity tests may be omitted, unless:
- (a) under the intended conditions of use, oral ingestion of the veterinary medicinal product by the animal is to be expected, or
- (b) under the intended conditions of use, oral exposure of the user of the veterinary medicinal product is to be expected.
IIIa.3A4. Other requirements
IIIa.3A4.1. Special studies
For particular groups of substances, or if the effects observed during repeated dose studies in animals include changes indicative of, for example, immunogenicity, immunotoxicity, neurotoxicity or endocrine dysfunction, further testing shall be required, for example, sensitisation studies or delayed neurotoxicity tests. Depending on the nature of the product, it may be necessary to conduct additional studies to assess the underlying mechanism of the toxic effect or the irritation potential.
For products for which there may be exposure to skin and eyes, irritation and sensitisation studies shall be provided. Those studies shall usually be conducted with the final formulation.
The state of scientific knowledge and established guidance shall be taken into account when designing such studies and evaluating their results.
IIIa.3A4.2. Observations in humans
Information shall be provided on whether the pharmacologically active substances of the veterinary medicinal product are used as medicinal products in human therapy; if this the case, a compilation shall be made from published studies of all the effects observed (including adverse reactions) in humans and of their cause, to the extent that they may be important for the assessment of the safety of the veterinary medicinal product, where constituents of the veterinary medicinal products are themselves not used or are no longer used as medicinal products in human therapy for safety reasons, they shall be stated if publicly available.
IIIa.3A4.3. Development of resistance and related risk in humans
The data requirements mentioned in this point are related to antibacterial substances and may not be applicable to other types of antimicrobial (namely antivirals, antifungals and antiprotozoals); for substances other than antibacterial for which the existence of antimicrobial resistance is well established, the same requirements may be followed, where applicable.
Data on the potential emergence of resistant bacteria or resistance determinants of relevance for human health which are associated with the use of veterinary medicinal products are necessary. The mechanism of the development and selection of such resistance is particularly important in this regard. Where necessary, measures to limit resistance development from the intended use of the veterinary medicinal product shall be proposed.
Resistance data relevant for clinical use of the product in target animals shall be addressed in accordance with Part IIIa.4A2. Where relevant, cross reference shall be made to the data set out in Part IIIa.4A2.
| (1) | For food-producing animals the risk assessment shall address: (a) the identification of resistant bacteria or resistance determinants that could be associated with human illness (zoonotic and/or commensal bacteria) and are selected by the use of the antimicrobial veterinary medicinal product in target animals (hazard identification); (b) the probability of release of the identified hazard(s) from the target animal species as a result of the use of the veterinary medicinal product under consideration; (c) the probability of subsequent human exposure to the identified hazard(s) via the foodborne route or through direct contact, and the resulting consequences (adverse health effects) to human health. Guidance is available in VICH GL27 and EU GLs. | |
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| (2) | For companion animals, consideration of risk to human or public health shall address: (a) the identification of resistant bacteria or resistance determinants that could be associated with human illness and are selected by the use of the antimicrobial veterinary medicinal product in target animals; (b) an estimate of exposure of zoonotic and commensal bacteria in the target animal species based on the conditions of use of the veterinary medicinal product under consideration; (c) consideration of subsequent human exposure to AMR, and the resulting consequences to human health. | |
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| (3) | Resistance in the environment shall be addressed. |
IIIa.3A5. User safety
The user safety section shall include an assessment of the effects found in Part IIIa.3A to IIIa.3A4 and relate this to the type and extent of human exposure to the product with a view to formulating appropriate user warnings and other risk management measures.
User safety shall be addressed in accordance with CVMP guidelines.
IIIa.3A6. Environmental risk assessment
IIIa.3A6.1. Environmental risk assessment of veterinary medicinal products not containing or consisting of genetically modified organisms
| (1) | An environmental risk assessment shall be performed to assess the potential harmful effects, which the use of the veterinary medicinal product may cause to the environment and to identify the risk of such effects. The assessment shall also identify any precautionary measures which may be necessary to reduce such risk. | |
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| (2) | This assessment consists of two phases. The first phase of the assessment shall always be performed. The details of the assessment shall be provided in accordance with guidance published by the Agency. It shall indicate the potential exposure of the environment to the product and the level of risk associated with any such exposure taking into account in particular the following items: (a) the target animal species, and the proposed pattern of use; (b) the method of administration, in particular the likely extent to which the product will enter directly into environmental systems; (c) the possible excretion of the product, its active substances or relevant metabolites into the environment by treated animals; persistence in such excreta; (d) the disposal of unused veterinary medicinal product or other waste product. | |
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| (3) | In the second phase, further specific investigation of the fate and effects of the product on particular ecosystems shall be conducted, in accordance with guidance published by the Agency. The extent of exposure of the product to the environment, and the available information about the physical/chemical, pharmacological and/or toxicological properties of the substance(s) concerned, including metabolites in case of an identified risk, which has been obtained during the conduct of the other tests and trials required by this Regulation, shall be taken into consideration. For products intended for food producing species persistent, bioaccumulative and toxic (PBT) or very persistent and very bioaccumulative (vPvB) substances shall be classified according to the criteria in Annex XIII to the REACH Regulation and assessed in accordance with the guidance for PBT and vPvB assessment of substances in veterinary medicines published by the Agency |
IIIa.3A6.2. Environmental risk assessment for veterinary medicinal products containing or consisting of genetically modified organisms
| (1) | In the case of a veterinary medicinal product containing or consisting of genetically modified organisms the application shall also be accompanied by the documents required under Article 2 and Part C of Directive 2001/18/EC. | |
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| (2) | Potential adverse effects on human health and the environment, which may occur through gene transfer from GMOs to other organisms or arise from genetic modifications, shall be accurately assessed on a case-by-case basis. The objective of such an environmental risk assessment is to identify and evaluate potential direct and indirect, immediate or delayed adverse effects of the GMO on human health and the environment (including plants and animals) and shall be carried out in accordance with the principles of Annex II to Directive 2001/18/EC. |
IIIa.3B. Residue tests
| (1) | For the purposes of this point, the definitions of Regulation (EC) No 470/2009 shall apply. | |
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| (2) | The purpose of studying the depletion of residues from the edible tissues or from eggs, milk and honey (wax if appropriate) derived from treated animals is to determine under what conditions and to what extent residues may persist in foodstuffs produced from those animals. In addition, the studies shall enable the determination of a withdrawal period. | |
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| (3) | In the case of veterinary medicinal products intended for use in food-producing animals, the residue documentation shall show: (a) to what extent, and for how long, residues of the veterinary medicinal product or its metabolites persist in the edible tissues of the treated animal or in milk, eggs and/or honey (wax if appropriate) obtained therefrom; (b) that in order to prevent any risk to the health of the consumer of foodstuffs from treated animals, it is possible to establish realistic withdrawal periods which may be observed under practical farming conditions; (c) that the analytical method(s) used in the residue depletion study are sufficiently validated to provide the necessary reassurance that the residues data submitted are suitable as the basis for a withdrawal period. |
IIIa.3B1. Identification of the product
An identification of the veterinary medicinal product(s) used in the testing shall be provided, including:
- (a) composition;
- (b) the physical and chemical (potency and purity) test results for the relevant batch(es);
- (c) batch identification.
IIIa.3B2. Depletion of residues
| (1) | The purpose of these studies, which measure the rate at which residues deplete in the target animal after the last administration of the veterinary medicinal product, is to permit the determination of withdrawal periods necessary to ensure that no residues which might constitute a hazard for consumers are present in foodstuffs obtained from treated animals. | |
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| (2) | The current status of the maximum residue limits for the components of the veterinary medicinal product in the relevant target species shall be reported. | |
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| (3) | The levels of residues present shall be determined at a sufficient number of time points after the test animals have received the final dose of the veterinary medicinal product. The studies in mammals and birds shall be performed according to VICH GL48 and other relevant guidelines. Residue studies in honey shall be performed according to VICH GL56 and depletion studies in aquatic species according to VICH GL57. | |
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| (4) | Based on the evaluation, the rationale for the proposed withdrawal period shall be addressed. |
IIIa.3B3. Residue analytical method
| (1) | The residue depletion study (studies), the analytical method(s) and its (their) validation shall be performed in accordance with VICH GL49. | |
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| (2) | The suitability of the analytical method proposed shall be evaluated with regard to the state of scientific and technical knowledge at the time the application is submitted. |
IIIa.4. Part 4: Efficacy documentation (pre-clinical studies and clinical trial(s))
IIIa.4A. Pre-clinical studies
Pre-clinical studies aim to investigate the target animal safety and efficacy of the product and are required to establish the pharmacological activity, pharmacokinetic properties, dose and dosing interval, resistance (if applicable) and the target animal tolerance of the product.
IIIa.4A1. Pharmacology
IIIa.4A1.1. Pharmacodynamics
| (1) | The pharmacodynamic effects of the active substance(s) included in the veterinary medicinal product shall be characterised. | |
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| (2) | The mode of action and the pharmacological effects on which the recommended application in practice is based shall be adequately described, including secondary effects (if any). In general, the effects on the main body functions shall be investigated. The results shall be expressed in quantitative terms (using, for example, dose-effect curves, time-effect curves, etc.) and, wherever possible, in comparison with a substance the activity of which is well known. Where a higher activity is being claimed for an active substance, the difference shall be demonstrated and shown to be statistically significant. | |
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| (3) | Any effect of the other characteristics of the products (such as the route of administration or formulation) on the pharmacological activity of the active substance shall be investigated. | |
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| (4) | The experimental techniques, unless they are standard procedures, shall be described in such detail as to allow them to be reproduced, and their validity to be established. The experimental results shall be set out clearly and the outcome of any statistical comparisons presented. | |
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| (5) | Unless adequate reasons are given to the contrary, any quantitative modification of responses resulting from repeated administration of the substance shall also be investigated. |
IIIa.4A1.2. Pharmacokinetics
| (1) | Basic pharmacokinetic data on the active substance are required in the context of assessment of the target animal safety and efficacy of the veterinary medicinal product in the target species, particularly if this concerns a new substance or formulation. | |
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| (2) | The objectives of pharmacokinetic studies in the target animal species may be divided into four main areas: (a) to describe the basic pharmacokinetic characteristics (namely absorption, distribution, metabolism and excretion) of the active substance in the formulation; (b) to investigate the relationships between dosage regimen, plasma and tissue concentration over time and pharmacological, therapeutic or toxic effects; (c) where appropriate, to compare pharmacokinetic parameters between different target species and to explore possible species differences having an impact on target animal safety and efficacy of the veterinary medicinal product; (d) where appropriate, to compare bioavailability to support bridging of safety and efficacy information between different products, pharmaceutical forms, strengths or routes of administration, or to compare the impact of changes in manufacturing or composition, including pilot and final formulations. | |
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| (3) | In the target animal species, pharmacokinetic studies are, as a rule, necessary as a complement to the pharmacodynamic studies to support the establishment of safe and effective dosage regimens (route and site of administration, dose, dosing interval, number of administrations, etc.). Additional pharmacokinetic studies may be required to establish dosage regimens according to certain population variables. | |
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| (4) | Where pharmacokinetic studies have been submitted under Part 3 of the dossier, cross-reference to such studies may be made. | |
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| (5) | For fixed combinations, please refer to Section IV. |
IIIa.4A2. Development of resistance and related risk in animals
| (1) | For relevant biological veterinary medicinal products (for example, substances with antimicrobial and antiparasitic activity), information on current resistance (if applicable) and on the potential emergence of resistance of clinical relevance for the claimed indication in the target animal species shall be provided. Where possible, information on the resistance mechanism(s), the molecular genetic basis of resistance, and the rate of transfer of resistance determinants shall be presented. Whenever relevant, information on co-resistance and cross-resistance shall be presented. Measures to limit resistance development in organisms of clinical relevance for the intended use of the veterinary medicinal product shall be proposed by the applicant. | |
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| (2) | Resistance relevant for risks to humans shall be addressed in Part 3 of the dossier. Where relevant, cross-reference shall be made to data set out in Part 3 of the dossier. |
IIIa.4A3. Dose determination and confirmation
| (1) | Appropriate data shall be provided to justify the proposed dose, dosing interval, duration of treatment and any re-treatment interval. | |
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| (2) | For studies conducted under field conditions, relevant information shall be provided as outlined under clinical studies. |
IIIa.4A4. Tolerance in the target animal species
| (1) | The local and systemic tolerance of the veterinary medicinal product shall be investigated in the target animal species. The purpose of target animal safety studies is to characterise signs of intolerance and to establish an adequate margin of safety using the recommended route(s) of administration. This may be achieved by increasing the dose and/or the duration of treatment. | |
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| (2) | The study report(s) shall contain details of all expected pharmacological effects and all adverse reactions. The conduct of target animal safety studies shall be in accordance with VICH and relevant guidance published by the Agency. Other pre-clinical studies and clinical studies, along with relevant information from the published literature may also provide information on safety in the target species. |
IIIa.4B. Clinical trials
IIIa.4B1. General principles
| (1) | Clinical trials shall be designed, carried out and reported taking into account VICH and relevant guidance published by the Agency. Data stemming from clinical trials conducted outside the Union may be taken into consideration for the assessment of an application for a marketing authorisation only, if the data are sufficiently representative of the Union situation. | |
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| (2) | Experimental data such as exploratory/pilot trials, or results from non-experimental approaches shall be confirmed by data obtained under normal field conditions, unless otherwise justified. | |
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| (3) | The purpose of clinical trials is to examine under field conditions the target animal safety and efficacy of a veterinary medicinal product under normal conditions of animal husbandry and/or as part of good veterinary practice. They shall demonstrate the effect of the veterinary medicinal product after administration to the intended target species using the proposed dosage regimen and the proposed route(s) of administration. The trial design shall aim to support the indications and take into account any contra-indications according to species, age, breed and sex, directions for use of the veterinary medicinal product as well as any adverse reactions which it may have. | |
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| (4) | All veterinary clinical trials shall be conducted in accordance with a detailed trial protocol. For formulations intended for use in veterinary clinical trials in the Union, the words “for veterinary clinical trial use only” shall appear prominently and indelibly on the labelling. | |
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| (5) | Unless otherwise justified, clinical trials shall be carried out with control animals (controlled clinical trials). The efficacy results obtained with the new product shall be compared with those from the target animal species that have received a veterinary medicinal product authorised in the Union that has demonstrated an acceptable level of efficacy and been approved for the proposed indication(s) for use in the same target animal species, or a placebo or no treatment. All the results obtained, whether positive or negative, shall be reported. | |
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| (6) | Established statistical principles in accordance with the relevant guidance published by the Agency shall be used in protocol design, analysis and evaluation of clinical trials, unless otherwise justified. |
IIIa.4B2. Documentation
The dossier on efficacy shall include all pre-clinical and clinical documentation, whether favourable or unfavourable to the veterinary medicinal products, in order to enable an objective overall assessment of the benefit/risk balance of the product.
IIIa.4B2.1. Results of pre-clinical studies
Wherever possible, particulars shall be given of the results of:
- (a) tests demonstrating pharmacological activity;
- (b) tests demonstrating the pharmacodynamic mechanisms underlying the therapeutic effect;
- (c) tests demonstrating the main pharmacokinetic profile;
- (d) tests demonstrating target animal safety;
- (e) tests to determine and confirm the dose (including dose interval, duration of treatment and any re-treatment interval);
- (f) tests and investigations on resistance, if applicable.
In the case where unexpected results occur during the course of the tests, those results shall be sufficiently detailed. Additionally, the following particulars shall be provided in all pre-clinical study reports.
- (a) a summary;
- (b) a study protocol;
- (c) a detailed description of the objectives, design and conduct to include methods, apparatus and materials used, details such as species, age, weight, sex, number, breed or strain of animals, identification of animals, dose, route and schedule of administration;
- (d) a statistical analysis of the results;
- (e) an objective discussion of the results obtained, leading to conclusions on the efficacy and target animal safety of the veterinary medicinal product.
Omission of any of those data shall be justified.
IIIa.4B2.2. Results of clinical trials
All the particulars shall be supplied by each of the investigators on individual record sheets in the case of individual treatment and collective record sheets in the case of collective treatment.
The marketing authorisation holder shall make all necessary arrangements to ensure that the original documents, which formed the basis of the data supplied, are kept for at least five years after the veterinary medicinal product is no longer authorised.
In respect of each clinical trial, the clinical observations shall be summarised in a synopsis of the trials and the results thereof, indicating in particular:
- (a) the number of control and test animals treated either individually or collectively, with a breakdown according to species, breed or strain, age and sex;
- (b) the number of animals withdrawn prematurely from the trials and the reasons for such withdrawal;
- (c) in the case of control animals, whether they have:
- (i) received no treatment;
- (ii) received a placebo;
- (iii) received another veterinary medicinal product authorised in the Union that has demonstrated an acceptable level of efficacy and been approved for the proposed indication(s) for use in the same target animal species; or
- (iv) received the same active substance under investigation in a different formulation or by a different route;
- (d) the frequency of observed adverse reactions;
- (e) observations as to the effect on animal performance, if appropriate;
- (f) details concerning test animals which may be at increased risk owing to their age, their mode of rearing or feeding, or the purpose for which they are intended, or animals the physiological or pathological condition of which requires special consideration;
- (g) a statistical evaluation of the results.
The main investigator shall draw general conclusions on the efficacy and target animal safety of the veterinary medicinal product under the proposed conditions of use, and in particular any information relating to indications and contraindications, dosage and average duration of treatment and, where appropriate, any interactions observed with other veterinary medicinal products or feed additives as well as any special precautions to be taken during treatment and the clinical signs of overdoseage, when observed.
SECTION IIIb
REQUIREMENTS FOR IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS
The following requirements shall apply to immunological veterinary medicinal products as defined in Article 4(5), except where otherwise set out in Section IV.
IIIb.1. Part 1: Summary of the dossier
Please refer to Section I.
IIIb.2. Part 2: Quality documentation (physicochemical, biological and microbiological information)
IIIb.2.A. Product description
IIIb.2A1. Qualitative and quantitative composition
| (1) | Qualitative composition of all the constituents of the immunological veterinary medicinal product shall mean the designation or description of: (a) the active substance(s); (b) the constituents of the adjuvants; (c) the constituent(s) of other excipients, whatever their nature or the quantity used, including preservatives, stabilisers, colouring matter, flavouring and aromatic substances, markers, etc. (d) accompanying reconstitution solvents. | |
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| (2) | Those data in point (1) shall be supplemented by any relevant data concerning the immediate packaging and if relevant the outer packaging and, where appropriate, its manner of closure, together with details of devices with which the immunological veterinary medicinal product will be used or administered and which will be delivered with the medicinal product. If the device is not delivered together with the immunological veterinary medicinal product, relevant information about the device shall be provided, where necessary for the assessment of the product. | |
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| (3) | The usual terminology to be used in describing the constituents of immunological veterinary medicinal products, notwithstanding the application of the other provisions of Article 8, means: (a) in respect of substances which appear in the European Pharmacopoeia or, failing this, in the pharmacopoeia of one of the Member States, the main title of the monograph in question, which will be obligatory for all such substances, with reference to the pharmacopoeia concerned; (b) in respect of other substances, the INN recommended by the WHO, which may be accompanied by another non-proprietary name or, failing these, the exact scientific designation; substances not having an international non-proprietary name or an exact scientific designation shall be described by a statement of how and from what they were prepared, supplemented, where appropriate, by any other relevant details; (c) in respect of colouring matter designation by the “E” code assigned to them in Directive 2009/35/EC. | |
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| (4) | In order to give the quantitative composition of the active substances of an immunological veterinary medicinal product, it is necessary to specify whenever possible the number of organisms, the specific protein content, the mass, the number of International Units (IU) or units of biological activity, either per dosage-unit or volume, and with regard to the adjuvant and to the constituents of the excipients, the mass or the volume of each of them, with due allowance for the details provided in Part IIb.2B. | |
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| (5) | Where an international unit of biological activity has been defined, this shall be used. | |
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| (6) | The units of biological activity for which no published data exist shall be expressed in such a way as to provide unambiguous information on the activity of the ingredients, for example, by stating the amount as determined by titration or potency testing of the final product. | |
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| (7) | The composition shall be given in terms of minimum quantities and, if appropriate, with maximum quantities. |
IIIb.2A2. Product development
| (1) | Explanation shall be provided with regard to, but may not be limited to: (a) the choice of composition and the choice of the constituents, in particular relative to their intended functions and their respective concentrations; (b) the inclusion of a preservative in the composition shall be justified; (c) the immediate packaging and the suitability of the container and its closure system used for the storage and use of the finished product. A study of the interaction between finished product and the primary packaging shall be submitted wherever the risk of such interaction is regarded as possible, especially where injectable preparations are concerned; (d) the possible further packaging, outer packaging if relevant; (e) the proposed pack sizes related to the proposed route of administration, the posology and the target species; (f) any overage(s) in the formulation to guarantee minimum potency/antigen content at end of shelf life with justification; (g) the selection of the manufacturing process of the active substance and the finished product; (h) differences between the manufacturing process(es) used to produce batches used in clinical trials and the process described in the application for marketing authorisation shall be discussed; (i) when an accompanying test is recommended to be used with the finished product (e.g. diagnostic test), relevant information about the test shall be provided. | |
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| (2) | This explanation shall be supported by scientific data on product development. |
IIIb.2B. Description of the manufacturing method
| (1) | The description of the manufacturing method accompanying the application for marketing authorisation pursuant to Article 8 shall be drafted in such a way as to give an adequate description of the nature of the operations employed, including the identification of the key stages in the production process. | |
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| (2) | The description of the manufacturing process shall include at least: (a) the various stages of manufacture (including production of the antigen and purification procedures) accompanied by a process flow chart so that an assessment may be made of the reproducibility of the manufacturing procedure and of the risks of adverse effects on the finished products, such as microbiological contamination; (b) in the case of continuous manufacture, full details concerning precautions taken to ensure the homogeneity and consistency of each batch of the finished product. Information on how a batch is defined and on the proposed commercial batch size(s) shall be provided; (c) listing of all the substances at the appropriate steps where they are used, including those which cannot be recovered in the course of manufacturing; (d) the details of the blending, with the quantitative particulars of all the substances used, including an example for a representative production batch; (e) list of in-process controls including the stage of manufacture at which they are conducted; (f) for sterile products, where non-pharmacopoeial sterilisation conditions are used, details of the sterilisation processes and/or aseptic procedures used. | |
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| (3) | Validation of all the methods of control used in the manufacturing process shall be described, documented and the results provided, unless otherwise justified. The validation of key stages in the production process shall be demonstrated and the validation of the production process as a whole shall be demonstrated with provision of results of three consecutive batches produced using the method described. |
IIIb.2C. Production and control of starting materials
| (1) | For the purposes of this Part, “starting materials” means all components used in the production of the immunological veterinary medicinal product. | |
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| (2) | Commercially available ready-to-use adjuvant systems designated by a brand name as well as culture media used for production of the active substance consisting of several components shall be regarded as one starting material. Nevertheless, the qualitative and quantitative composition shall be presented insofar as the authorities consider that this information is relevant to the quality of the finished product and any risks that might be posed. | |
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| (3) | If materials of animal origin are used for preparation of those culture media or adjuvant systems, the animal species and the tissue used have to be included and compliance with the relevant monographs including general monographs and general chapters of the European Pharmacopoeia shall be demonstrated. | |
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| (4) | The applicant shall supply documentation to demonstrate that the starting materials, including seed materials, cell seeds, batches of serum and other material originating from animal species relevant for the transmission of TSE and the manufacturing of the veterinary medicinal product is in compliance with the requirements of the Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products, as well as with the requirements of the corresponding monograph of the European Pharmacopoeia. Certificates of Suitability issued by the European Directorate for the Quality of Medicines and HealthCare, with reference to the relevant monograph of the European Pharmacopoeia, may be used to demonstrate compliance. | |
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| (5) | The dossier shall include the specifications, information on the tests to be conducted for the quality control of all batches of starting materials and results for a batch for all components used and shall be submitted in accordance with the requirements of this Part. | |
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| (6) | Certificates of analysis shall be presented for the starting materials in order to demonstrate compliance with the defined specification. | |
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| (7) | Colouring matter shall, in all cases, satisfy the requirements of Directive 2009/35/EC. | |
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| (8) | The use of antibiotics during production and the inclusion of preservatives in the composition of the finished product shall be justified and in compliance with the European Pharmacopoeia. | |
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| (9) | For novel excipients, that is to say excipient(s) used for the first time in the Union in a veterinary medicinal product or by a new route of administration, details of manufacture, characterisation, and controls, with cross references to supporting safety data, both clinical and non- clinical, shall be provided. For colouring matters the declarations of compliance as mentioned under Part II.2C2, points (3) and (4) shall be considered sufficient. |
IIIb.2C1. Starting materials listed in pharmacopoeias
| (1) | The monographs of the European Pharmacopoeia shall be applicable to all starting materials appearing in it, unless proper justification is provided. | |
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| (2) | In respect of other substances, each Member State may require observance of its own national pharmacopoeia with regard to products manufactured in its territory. | |
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| (3) | The description of the analytical methods may be replaced by a detailed reference to the pharmacopoeia in question. | |
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| (4) | The routine tests carried out on each batch of starting materials shall be as stated in the application for marketing authorisation. If tests other than those mentioned in the pharmacopoeia are used, proof shall be supplied that the starting materials meet the quality requirements of that pharmacopoeia. | |
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| (5) | In cases where a specification or other provisions contained in a monograph of the European Pharmacopoeia or in the pharmacopoeia of a Member State might be insufficient to ensure the quality of the substance, the competent authorities may request more appropriate specifications from the applicant for marketing authorisation. The alleged insufficiency shall be reported to the authorities responsible for the pharmacopoeia in question. |
IIIb.2C2. Starting materials not listed in a pharmacopoeia
IIIb.2C2.1. Starting materials of biological origin
| (1) | The description shall be given in the form of a monograph. | |
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| (2) | Vaccine production shall be based on a seed lot system and on established cell seeds, whenever possible. For the production of immunological veterinary medicinal products consisting of serum, the origin, general health and immunological status of the producing animals shall be indicated and defined pools of source materials shall be used. | |
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| (3) | The origin, including geographical region, and history of starting materials shall be described and documented. | |
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| (4) | For genetically engineered starting materials this information shall include details such as the description of the starting cells or strains, the construction of the expression vector (name, origin, function of the replicon, promoter enhancer and other regulator elements), control of the sequence of DNA or RNA effectively inserted, oligonucleotide sequences of plasmid vector in cells, plasmid used for cotransfection, added or deleted genes, biological properties of the final construct and the genes expressed, copy number and genetic stability. | |
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| (5) | In the case of veterinary medicinal products containing or consisting of genetically modified organisms (GMO), the quality part of the application shall also be accompanied by the documents required in accordance with Directive 2001/18/EC. | |
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| (6) | Seed materials, including cell seeds and raw serum for anti-serum production shall be tested for identity and the absence of extraneous agents shall be demonstrated according to the European Pharmacopoeia. | |
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| (7) | Information shall be provided on all substances of biological origin used at any stage in the manufacturing procedure. The information shall include: (a) details of the source of the materials; (b) details of any processing, purification and inactivation applied, with data on the validation of those processes and controls during production; (c) details of any tests for contamination carried out on each batch of the substance. | |
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| (8) | If the presence of extraneous agents is detected or suspected, the corresponding material shall be discarded or processed to reduce the risk of presence with a validated treatment. If after treatment presence is detected or suspected, the corresponding material shall be used only when further processing of the product ensures their elimination and/or inactivation; elimination and/or inactivation of such extraneous agents shall be demonstrated. | |
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| (9) | When cell seeds are used, the cell characteristics shall be shown to have remained unchanged up to the highest passage level used for the production. | |
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| (10) | For live attenuated vaccines, confirmation of the stability of the attenuation characteristics of the seed shall be provided. Unless a specific characteristic is associated with the attenuation (e.g. genetic marker, thermal stability), this is typically achieved through absence of reversion to virulence in the target animal species. | |
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| (11) | When required, samples of the biological starting material or reagents used in the testing procedures shall be provided to enable the competent authority to arrange for check tests to be carried out. |
IIIb.2C2.2. Starting materials of non-biological origin
The description shall be given in the form of a monograph under the following headings:
- (a) the name of the starting material meeting the requirements of point (3) of Part IIIb.2A1. shall be supplemented by any trade or scientific synonyms;
- (b) the description of the starting material, set down in a form similar to that used in a descriptive item in the European Pharmacopoeia;
- (c) the function of the starting material;
- (d) methods of identification;
- (e) any special precautions which may be necessary during storage of the starting material and, if necessary, its storage life shall be given.
IIIb.2D. Control tests during the manufacturing process
| (1) | The dossier shall include particulars relating to the control tests, which are carried out on intermediate stages of manufacture with a view to verifying the consistency of the manufacturing process and the final product. Specifications shall be set for each control test and the analytical methods shall be described. Validation of the control tests for parameters considered critical to the manufacturing process shall be provided unless otherwise justified. | |
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| (2) | For inactivated or detoxified vaccines, inactivation or detoxification shall be tested during each production run as soon as possible after the end of the inactivation or detoxification process and after neutralisation if this occurs, but before the next step of production. | |
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| (3) | In accordance with the provisions of Directive 2010/63/EU and the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes, tests shall be carried out in such a way as to use the minimum number of animals and to cause the least pain, suffering, distress or lasting harm. If available, an alternative in vitro test shall be used when this leads to replacement or reduction of animal use or reduction of suffering. |
IIIb.2E. Control tests on the finished product
| (1) | For all tests, the description of the techniques for analysing the finished product shall be set out in sufficient detail for a quality assessment. | |
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| (2) | Where appropriate monographs exist, if test procedures and limits other than those mentioned in the monographs of the European Pharmacopoeia, or failing this, in the pharmacopoeia of a Member State, are used, proof shall be supplied that the finished product would, if tested in accordance with those monographs, meet the quality requirements of that pharmacopoeia for the pharmaceutical form concerned. The application for marketing authorisation shall list those tests, which are carried out on representative samples of each batch of finished product. The frequency of the tests carried out on the final bulk vaccine instead of on the batch or batches prepared from it, shall be stated. Release limits shall be indicated and justified. Validation of the control tests carried out on the finished product shall be provided. | |
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| (3) | Information regarding the establishment and replacement of reference material shall be provided. If more than one reference standard has been used, a qualification history shall be provided describing how the relationship between the different standards was maintained. | |
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| (4) | Where available, chemical and biological reference material of the European Pharmacopoeia shall be used. If other reference preparations and standards are used, they shall be identified and described in detail. | |
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| (5) | In accordance with the provisions of Directive 2010/63/EU and the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes, tests shall be carried out in such a way as to use the minimum number of animals and to cause the least pain, suffering, distress or lasting harm. If available, an alternative in vitro test shall be used when this leads to replacement or reduction of animal use or reduction of suffering. | |
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| (6) | General characteristics of the finished product The tests of general characteristics shall, wherever applicable, relate to the appearance and to physical or chemical tests, such as, conductivity, pH, viscosity, etc. For each of those characteristics, specifications, with appropriate acceptance limits, shall be established by the applicant. | |
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| (7) | Identification of active substance(s) Where necessary, a specific test for identification shall be carried out. When appropriate, the identification test may be combined with the batch titre or potency test. | |
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| (8) | Batch titre or potency A quantification of the active substance shall be carried out on each batch to show that each batch will contain the appropriate potency or titre to ensure its safety and efficacy. | |
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| (9) | Identification and assay of adjuvants The quantity and nature of the adjuvant and its components shall be verified on the finished product, unless otherwise justified. | |
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| (10) | Identification and assay of excipient components Insofar as is necessary, the excipient(s) shall be subject at least to identification tests. An upper and lower limit test shall be obligatory in respect of preserving agents. An upper limit test for any other excipient components liable to give rise to an adverse reaction shall be obligatory. | |
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| (11) | Sterility and purity test Freedom from extraneous agents (bacteria, mycoplasma, fungi and bacterial endotoxin when relevant) shall be demonstrated for parenterally administered products in compliance with the European Pharmacopoeia. For non-liquid, non-parenterally administered products, where adequately justified, compliance to a maximum bioburden limit instead of sterility test may be acceptable. Appropriate tests to demonstrate the absence of contamination by extraneous agents or other substances, shall be carried out according to the nature of the immunological veterinary medicinal product, the method and the conditions of manufacture. A risk-based approach to demonstrate the absence of extraneous agents as described in the European Pharmacopoeia shall be used. | |
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| (12) | Residual humidity Each batch of lyophilised product shall be tested for residual humidity. | |
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| (13) | Filling volume Appropriate tests to demonstrate the correct filling volume shall be carried out. |
IIIb.2F. Batch-to-batch consistency
In order to ensure that quality of the product is consistent from batch to batch and to demonstrate conformity with specifications a full protocol of three consecutive batches representative of the routine production giving the results for all tests performed during production and on the finished product shall be provided. Consistency data obtained from combined products may be used for derivative products containing one or more of the same components.
IIIb.2G. Stability tests
| (1) | Stability tests cover stability of the active substance and the finished product, including solvent(s), if relevant. | |
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| (2) | A description shall be given of the tests undertaken to support the shelf life, the recommended storage conditions and the specifications at the end of the shelf life proposed for the active substance and the finished product. Those tests shall always be real-time studies. If intermediate products obtained at various stages of the manufacturing process are stored, the intended conditions and duration of storage shall be adequately justified on the basis of the stability data available. | |
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| (3) | Stability tests for the finished product shall be carried out on not fewer than three representative batches produced according to the described production process and on products stored in the final container(s); those tests include biological and physicochemical stability tests carried out at regular intervals, for the finished product until 3 months beyond the claimed end of the shelf life. | |
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| (4) | The conclusions shall contain the results of analyses, justifying the proposed shelf life under all proposed storage conditions. The results obtained during the stability study shall be taken into account when defining appropriate formulation and release specifications to ensure the conformity of the product with the claimed shelf life | |
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| (5) | In the case of products administered in feed, information shall also be given as necessary on the shelf life of the product, at the different stages of mixing, when mixed in accordance with the recommended instructions. | |
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| (6) | Where a finished product requires reconstitution prior to administration or is administered in drinking water, details of the proposed shelf life are required for the product reconstituted as recommended. Data in support of the proposed shelf life for the reconstituted product shall be submitted. | |
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| (7) | Stability data obtained from combined products may be used where adequately justified for derivative products containing one or more of the same components. | |
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| (8) | In the case of multi-dose containers, where relevant, stability data shall be presented to justify a shelf life for the product after it has been broached or opened for the first time and an in-use shelf-life specification shall be defined. | |
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| (9) | The efficacy of any preservative system shall be demonstrated. | |
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| (10) | Information on the efficacy of preservatives in other similar immunological veterinary medicinal products from the same manufacturer may be sufficient. | |
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| (11) | If active substances are stored, the intended conditions and duration of storage shall be defined on the basis of stability data. Those data may be obtained either through testing of the active substances themselves or through appropriate testing of the finished product. |
IIIb.2H. Other information
Information relating to the quality of the immunological veterinary medicinal product not covered by this Section may be included in the dossier.
IIIb.3. **Part 3: Safety documentation (safety and residues
tests)**
IIIb.3A. General requirements
| (1) | The safety documentation shall be adequate for the assessment of: (a) the safety of the immunological veterinary medicinal product when administered to the target species and any undesirable effects which may occur under the proposed conditions of use; those undesirable effects shall be evaluated in relation to potential benefits of the product; (b) the potential harmful effects to man of residues of the veterinary medicinal product or substance in foodstuffs obtained from treated animals; (c) the potential risks which may result from the exposure of human beings to the veterinary medicinal product, for example, during its administration to the animal; (d) the potential risks to the environment resulting from the use of the veterinary medicinal product. | |
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| (2) | Pre-clinical studies shall be carried out in compliance with good laboratory practice (GLP) requirements. Non-GLP studies may be accepted for non-target species studies as well as studies evaluating immunological, biological or genetic properties of the vaccine strains, under adequately controlled conditions. Other deviations shall be justified. | |
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| (3) | All safety trials shall be conducted in accordance with a fully considered detailed protocol, which shall be recorded in writing prior to commencement of the trial. The welfare of the trial animals shall be subject to veterinary supervision and shall be taken fully into consideration during the elaboration of any trial protocol and throughout the conduct of the trial. | |
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| (4) | Pre-established systematic written procedures for the organisation, conduct, data collection, documentation and verification of safety trials shall be required. | |
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| (5) | Clinical trials (field trials) shall be conducted in compliance with established principles of good clinical practice (GCP). Deviations shall be justified. | |
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| (6) | The safety studies shall be in line with the relevant European Pharmacopeia requirements. Deviations shall be justified. | |
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| (7) | The safety studies shall be carried out in the target species. The dose to be used shall be the quantity of the product to be recommended for use and the batch used for safety testing shall be taken from a batch or batches produced according to the manufacturing process described in Part 2 of the application. | |
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| (8) | For laboratory tests described in Sections B.1, B.2 and B.3, the dose of the veterinary medicinal product shall contain the maximum titre, antigen content or potency. If necessary, the concentration of the antigen may be adjusted to achieve the required dose. | |
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| (9) | The safety of an immunological veterinary medicinal product shall be demonstrated for each category of target animal species in which its use is recommended, by each recommended route and method of administration and using the proposed schedule of administration. A worst-case scenario for route and method of administration may be used if scientifically justified. | |
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| (10) | In the case of immunological veterinary medicinal products consisting of live organisms, special requirements are included under B.6. | |
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| (11) | The particulars and documents which shall accompany the application for marketing authorisation shall be submitted in accordance with the requirements for pre-clinical studies and clinical trials described in Parts IIIb.4B, point (4), and IIIb.4C, point (3).. |
IIIb.3B. Pre-clinical studies
| (1) | Safety of the administration of one dose The immunological veterinary medicinal product shall be administered at the recommended dose and by each recommended route and method of administration to animals of each species and each relevant category (e.g. minimum age, pregnant animals, as appropriate) in which it is intended for use. The animals shall be observed and examined daily for signs of systemic and local reactions until reactions may no longer be expected, but in all cases, at least 14 days after administration. Where appropriate, those studies shall include detailed post-mortem macroscopic and microscopic examinations of the injection site. Other objective criteria shall be recorded, such as rectal temperature and performance measurements. This study may be part of the repeated dose study required under point 3 or omitted if the results of the overdose study required under point 2 have revealed no major signs of systemic or local reactions. If omitted, the systemic or local reactions seen in the overdose study shall be taken as the basis for describing safety of the product in the Summary of Product Characteristics. | |
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| (2) | Safety of one administration of an overdose Only live immunological veterinary medicinal products require overdose testing. An overdose of the immunological veterinary medicinal product, normally consisting of ten doses, shall be administered by each recommended route(s) and method(s) of administration to animals of the most sensitive categories of the target species, unless the selection of the most sensitive of several similar routes is justified. In the case of immunological veterinary medicinal products administered by injection, the doses and route(s) and method(s) of administration shall be chosen to take account of the maximum volume, which can be administered at any one single injection site. The animals shall be observed and examined daily for at least 14 days after administration for signs of systemic and local reactions. Other criteria shall be recorded, such as rectal temperature and performance measurements. Where appropriate, those studies shall include detailed post-mortem macroscopic and microscopic examinations of the injection site if this has not been done under point 1. | |
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| (3) | Safety of the repeated administration of one dose In the case of immunological veterinary medicinal products to be administered more than once, as part of the basic administration scheme, a study of the repeated administration of one dose shall be required to reveal any adverse effects induced by such administration. The test shall be carried out on the most sensitive categories of the target species (such as certain breeds, age groups), using each recommended route and method of administration. The number of administrations shall not be less than the maximum number recommended; for vaccines, this shall take account of the number of administrations for primary vaccination and the first re-vaccination. The interval between administrations may be shorter than the one claimed in the Summary of Product Characteristics. The chosen interval shall be justified with respect to the proposed conditions of use. The animals shall be observed and examined daily for at least 14 days after the last administration for signs of systemic and local reactions. Other objective criteria shall be recorded, such as rectal temperature and performance measurements. | |
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| (4) | Examination of reproductive performance Examination of reproductive performance shall be considered when the immunological veterinary product is intended for use or may be used in pregnant animals or laying birds and when data suggest that the starting material from which the product is derived may be a potential risk factor. Reproductive performance of males and non-pregnant and pregnant females shall be investigated with the recommended dose and by the most sensitive route and method of administration. For immunological veterinary medicinal products that are recommended for use in pregnant animals, examination of the reproductive performance shall address safety of administration during the entire gestation period or during specific period of gestation taking into account the intended use of the product. The observation period shall be extended to parturition to investigate possible harmful effects on the progeny, including teratogenic and abortifacient effects. Those studies may form part of the safety studies described in points 1, 2, 3 or of the field trials provided for in Section IIIb.3C. | |
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| (5) | Examination of immunological functions Where the immunological veterinary medicinal product might adversely affect the immune response of the vaccinated animal or of its progeny, suitable tests on immunological function shall be carried out. | |
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| (6) | Special requirements for live vaccines |
(1) Spread of the vaccine strain
Spread of the vaccine strain from vaccinated to unvaccinated target animals shall be investigated, using the recommended route of administration most likely to result in the spread. Moreover, it may be necessary to investigate the spread to non-target animal species which could be highly susceptible to a live vaccine strain. An assessment of the number of animal-to-animal passages likely to occur under normal conditions of use and potential consequences shall be provided.
(2) Dissemination in the vaccinated animal
Faeces, urine, milk, eggs, oral, nasal and other secretions shall be tested for the presence of the organism as appropriate. Moreover, studies may be required of the dissemination of the vaccine strain in the body, with particular attention being paid to the predilection sites for replication of the organism. In the case of live vaccines for zoonoses within the meaning of Directive 2003/99/EC of the European Parliament and of the Council to be used for food producing animals, those studies shall take particularly into account the persistence of the organism at the injection site.
(3) Increase in virulence
Increase in or reversion to virulence shall be investigated with the master seed. If the master seed is not available in sufficient quantity the lowest passage seed used for the production shall be examined. Use of another passage option shall be justified. The initial vaccination shall be carried out using the route and method of administration most likely to lead to an increase in virulence indicative of reversion to virulence. Serial passages shall be made in target animals through five groups of animals, unless there is justification to make more passages or the organism disappears from the test animals sooner. Where the organism fails to replicate adequately, as many passages as possible shall be carried out in the target species.
(4) Biological properties of the vaccine strain
Other tests may be necessary to determine as precisely as possible the intrinsic biological properties of the vaccine strain (e.g. neurotropism).
For vaccines containing live genetically modified organism(s), where the product of a foreign gene is incorporated into the strain as a structural protein, the risk of changing the tropism or virulence of the strain shall be addressed and, where necessary, specific tests shall be conducted.
(5) Recombination or genomic reassortment of strains
The probability of recombination or genomic reassortment with field or other strains shall be evaluated and the consequences of such events discussed.
| (7) | User safety This section shall include a discussion of the effects found in Part IIIb.3A to IIIb.3B and relate those effects to the type and extent of human exposure to the product with a view to formulating appropriate user warnings and other risk management measures. User safety shall be addressed in accordance with relevant guidance published by the Agency. | |
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| (8) | Interactions If there is a compatibility statement with other veterinary medicinal products in the summary of product characteristics the safety of the association shall be investigated. Any other known interactions with veterinary medicinal products shall be described. |
IIIb.3C. Clinical trials
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