Section IIIb
Requirements for Immunological Veterinary Medicinal Products.
The following requirements shall apply to immunological veterinary medicinal products, except where otherwise set out in Section IV.
Please refer to Section I.
IIIb.2A.1. Qualitative and quantitative composition
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(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 Schedule 1, means:
- (a) in respect of substances which appear in the European Pharmacopoeia or, failing this, in the British Pharmacopoeia, 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.2A.2. Product development
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(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.
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(1) The description of the manufacturing method accompanying the application for marketing authorisation pursuant to Schedule 1 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.
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(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 Great Britain 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.2C.1. Starting materials listed in pharmacopoeias
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(1) The monographs of the European Pharmacopoeia or British Pharmacopoeia shall be applicable to all starting materials appearing in it, unless proper justification is provided.
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(2) The description of the analytical methods may be replaced by a detailed reference to the pharmacopoeia in question.
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(3) 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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(4) In cases where a specification or other provisions contained in a monograph of the European Pharmacopoeia or in the British Pharmacopoeia 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.2C.2. Starting materials not listed in a pharmacopoeia
IIIb.2C.2.1. Starting materials of biological origin
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(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 the GMO Deliberate Release Regulations.
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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 or British 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.2C.2.2. 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 or British 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
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(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 the Animals (Scientific Procedures) Act 1986 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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(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 British Pharmacopoeia, 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 or British 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 the Animals (Scientific Procedures) Act 1986 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.
- (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 or British 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 or British 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.
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.
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(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.
Information relating to the quality of the immunological veterinary medicinal product not covered by this Section may be included in the dossier.
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(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 or British Pharmacopoeia 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).
- (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.
- (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.
- (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.
- (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
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(7) 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.
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(8) 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.
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(9) 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.
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(10) 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.
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(11) 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.
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(12) 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 Committee for Medicinal Products for Veterinary Use (CVMP) guidelines .
- (13) 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.
Unless otherwise justified, results from pre-clinical studies shall be supplemented with data from clinical trials, using batches representative of the manufacturing process described in the marketing authorisation application. Both safety and efficacy may be investigated in the same clinical trials.
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(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 VICH GL6. 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 route and method of administration, in particular the likely extent to which the product will enter directly into the environmental system
- (c) the possible excretion or secretion of the product, its active substances into the environment by treated animals, persistence in such excreta or secreta
- (d) the disposal of unused or waste product
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(3) In the case of live vaccine strains which may be zoonotic, the risk to humans shall be assessed.
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(4) Where the conclusions of the first phase indicate a relevant potential risk for the environment of the product, the applicant shall proceed to the second phase and evaluate the potential risk(s) that the veterinary medicinal product might pose to the environment. Where necessary, further investigations on the impact of the product (soil, water, air, aquatic systems, non-target organisms) shall be carried out.
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(5) For DNA vaccines, a specific safety concern is the potential risk of migration of the DNA to gonadal tissues and potential DNA transfer into germ line cells of vaccinated male and female animals and thus potential transmission to offspring. The applicant shall evaluate and discuss potential risk(s) such immunological veterinary medicinal products might pose on human health and the environment (including plants and animals). If potential risk(s) are identified, investigations on the impact of the vaccine depending on its use in companion animals or in food producing animals shall be carried out to provide information on this point.
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(1) In the case of veterinary medicinal products containing or consisting of genetically modified organisms (GMOs) the application shall also be accompanied by the documents required under the GMO Deliberate Release Regulations.
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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 the GMO deliberate Release Regulations.
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(1) For immunological veterinary medicinal products, it will normally not be necessary to undertake a study of residues.
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(2) Where antibiotics, adjuvants, preservatives or any other excipient are used in the manufacture of immunological veterinary medicinal products intended for food producing animals and/or are included in the final formulation, consideration shall be given to the possibility of consumer exposure to residues in foodstuffs derived from treated animals and compliance with MRLs legislation. Consumer safety implications arising from their potential presence in the finished product shall be addressed.
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(3) In the case of live vaccines for well-established zoonotic diseases, in addition to the studies of dissemination, the determination of residual vaccine organisms at the injection site may be required. If necessary, the effects of such residues shall be investigated.
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(4) A proposal for a withdrawal period shall be made and its adequacy shall be discussed in relation to any residue studies which have been undertaken.
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(1) The following general requirements shall be complied with:
- (a) the efficacy studies shall be in line with the general European Pharmacopeia or British Pharmacopoeia requirements; Deviations shall be justified
- (b) the primary parameter on which determination of efficacy is based needs to be defined by the investigator at the time of study design and shall not be changed after the study is completed
- (c) the planned statistical analysis shall be described in detail in the study protocols
- (d) the choice of antigens or vaccine strains shall be justified on the basis of epizoological data
- (e) efficacy trials carried out in the laboratory shall be controlled trials, including untreated control animals unless this is not justified for animal welfare reasons and efficacy can be otherwise demonstrated
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(2) In general, pre-clinical studies shall be supported by trials carried out in field conditions.
When pre-clinical studies fully support the claims made in the summary of product characteristics, trials carried out in field conditions are not required.
Unless otherwise justified, results from pre-clinical studies shall be supplemented with data from clinical trials, using batches representative of the manufacturing process described in the marketing authorisation application. Both safety and efficacy may be investigated in the same clinical trials.
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(3) All trials shall be described in sufficient detail so as to be properly assessed by the competent authorities. The validity of all techniques used in the trial shall be demonstrated.
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(4) All results obtained, whether favourable or unfavourable, shall be reported:
- (a) The efficacy 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. Unless otherwise justified, the onset and duration of immunity shall be established and supported by data from trials.
- (b) The influence of passively acquired maternally derived antibodies on the efficacy of vaccines when administered to animals at an age at which maternally acquired immunity is still present shall be adequately evaluated, if appropriate.
- (c) The efficacy of each of the components of multivalent and combined immunological veterinary medicinal products shall be demonstrated. If the product is recommended for administration in combination with or at the same time as another veterinary medicinal product, to the efficacy of the association shall be demonstrated by appropriate studies. Any known interactions with any other veterinary medicinal products shall be described.
- (d) Whenever a product forms part of a vaccination scheme recommended by the applicant, the priming or booster effect or the contribution of the veterinary immunological product to the efficacy of the scheme as a whole shall be demonstrated.
- (e) The dose to be used shall be the quantity of the product to be recommended for use and the batch used for efficacy testing shall be taken from a batch or batches produced according to the manufacturing process described in Part 2 of the application.
- (f) For diagnostic immunological veterinary medicinal products administered to animals, the applicant shall indicate how reactions to the product are to be interpreted.
- (g) For vaccines intended to allow a distinction between vaccinated and infected animals (marker vaccines), where the efficacy claim is reliant on in vitro diagnostic tests, sufficient data on the diagnostic tests shall be provided to allow adequate assessment of the claims related to the marker properties.
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(1) In principle, demonstration of efficacy shall be undertaken under well-controlled laboratory conditions by challenge after administration of the immunological veterinary medicinal product to the target animal under the recommended conditions of use. Insofar as possible, the conditions under which the challenge is carried out shall reflect the natural conditions for infection. Details of the challenge strain and its relevance shall be provided.
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(2) For live vaccines, the product used for efficacy testing shall be taken from a batch or batches containing the minimum titre or potency. For other products, product from batches containing the minimum active content or potency expected at the end of the period of validity shall be used, unless otherwise justified.
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(3)If possible, the immune mechanism (cell-mediated/humoral, local/general classes of immunoglobulin) which is initiated after the administration of the immunological veterinary medicinal product to target animals by the recommended route of administration shall be specified and documented.
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(4) The following shall be provided for all pre-clinical studies:
- (a) a summary
- (b) the name of the body having carried out the studies
- (c) a detailed experimental protocol giving a description of the methods, apparatus and materials used, details such as species or breed of animals, categories of animals, where they were obtained, their identification and number, the conditions under which they were housed and fed (stating, inter alia, whether they were free from any specified pathogens and/or specified antibodies, the nature and quantity of any additives contained in the feed), dose, route, schedule and dates of administration, a description and a justification of the statistical methods used
- (d) in the case of control animals, whether they received a placebo or no treatment
- (e) in the case of treated animals and, where appropriate, whether they received the test product or another product authorised in Great Britain
- (f) all general and individual observations and results obtained (with averages and standard deviations), whether favourable or unfavourable. The data shall be described in sufficient detail to allow the results to be critically evaluated independently of their interpretation by the author. The individual data shall be presented in tabular form. By way of explanation and illustration, the results may be accompanied by reproductions of recordings, photomicrographs, etc
- (g) the nature, frequency and duration of observed adverse reactions
- (h) the number of animals withdrawn prematurely from the studies and reasons for such withdrawal
- (i) a statistical analysis of the results, where such is called for by the test programme, and variance within the data
- (j) occurrence and course of any intercurrent disease
- (k) all details concerning veterinary medicinal products (other than the product under study), the administration of which was necessary during the course of the study
- (l) any other observations and deviations from the protocol and possible impact on the results
- (m) an objective discussion of the results obtained, leading to conclusions on the safety and efficacy of the product
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(1) Unless otherwise justified, results from pre-clinical studies shall be supplemented with data from field trials, using batches representative of the manufacturing process described in the marketing authorisation application. Both safety and efficacy may be investigated in the same field trial.
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(2) Where pre-clinical studies cannot be supportive of efficacy, the performance of field trials alone may be acceptable.
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(3) Particulars concerning field trials shall be sufficiently detailed to enable an objective judgement to be made. They shall include the following:
- (a) a summary
- (b) a statement of compliance with good clinical practice
- (c) name, address, function and qualifications of the investigator in charge
- (d) place and date of administration, identity code that may be linked to the name and address of the owner of the animal(s)
- (e) details of the trial protocol, giving a description of the methods, apparatus and materials used, details such as the route and method of administration, the schedule of administration, the dose, the categories of animals, the duration of observation, the serological response and other investigations carried out on the animals after administration
- (f) in the case of control animals, whether they received a placebo, a competitor product or no treatment
- (g) identification of the treated and control animals (collective or individual, as appropriate), such as species, breeds or strains, age, weight, sex, physiological status;
- (h) a brief description of the method of rearing and feeding, stating the nature and quantity of any additives contained in the feed
- (i) all the particulars on observations, performances and results (with averages and standard deviation); individual data shall be indicated when tests and measurements on individuals have been carried out
- (j) a statistical analysis of the results, where such is called for by the test programme, and variance within the data
- (k) all observations and results of the trials, whether favourable or unfavourable, with a full statement of the observations and the results of the objective tests of activity required to evaluate the product; the techniques used shall be specified and the significance of any variations in the results explained
- (l) effects on the animals’ performance
- (m) the number of animals withdrawn prematurely from the trials and reasons for such withdrawal
- (n) the nature, frequency and duration of observed adverse reactions
- (o) occurrence and course of any intercurrent disease
- (p) all details concerning veterinary medicinal products (other than the product under study) which have been administered either prior to or concurrently with the test product or during the observation period; details of any interactions observed
- (q) any other observations and deviations for the protocol and possible impact on the results
- (r) an objective discussion of the results obtained, leading to conclusions on the safety and efficacy of the product