Section IIIa

Requirements for Biological Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products.

The following requirements shall apply to biological veterinary medicinal products except immunological products or where otherwise set out in Section IV.

The Secretary of State may waive individual requirements in this part where the applicant demonstrates that it is scientifically justified and based on the specific properties of the biological product. For particular substances, safety data in addition to the requirements listed in this Section may be required depending on the nature of the product.

IIIa.1. Part 1: Summary of the dossier

Please refer to Section I.

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

IIIa.2A. Product description

IIIa.2A.1. Qualitative and quantitative composition

  • (1.) The qualitative and quantitative composition of the biological veterinary medicinal product shall be stated. This section shall include information regarding:

    • (a) the active substance(s).
    • (b) the constituent(s) of the excipients, whatever their nature or the quantity used, including adjuvants, preservatives, stabilisers, thickeners, emulsifiers, colouring matter, flavouring and aromatic substances, markers, etc.
    • (c) the composition, that is to say, list of all components of the dosage form and their amount on a per-unit basis (including overages, if any), the function of the components, and a reference to their quality standards (for example, compendial monographs or manufacturer’s specifications).
    • (d) accompanying reconstitution solvent(s).
    • (e) the type of container and its closure used for the dosage form and for any accompanying reconstitution solvents and devices, if applicable. If the device is not delivered together with the biological veterinary medicinal product, relevant information about the device shall be provided.

  • (2.) In order to give the quantitative composition of all the active substances and excipients of the veterinary medicinal products, it is necessary, depending on the pharmaceutical form concerned, to specify the mass, or the number of units of biological activity, either per dosage-unit or per unit of mass or volume, of each active substance and excipient.

  • (3.) Where possible, biological activity per units of mass or volume shall be indicated. Where an international unit of biological activity has been defined, this shall be used, unless otherwise justified. Where no international unit has been defined, the units of biological activity shall be expressed in such a way as to provide unambiguous information on the activity of the substances by using, where applicable, the European Pharmacopoeia Units. Where relevant to composition should be given in terms of minimum and maximum quantities.

  • (4.) The “usual terminology” to be used in describing the constituents of biological veterinary medicinal products notwithstanding the application of the other provisions of Schedule 1 para 2, shall mean:

    • (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

IIIa.2A.2. Product development

An explanation shall be provided including but not 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 the 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 microbiological characteristics (microbiological purity and antimicrobial activity) and usage instructions
  • (e) the possible further packaging, outer packaging, if relevant
  • (f) the proposed pack sizes related to the proposed route of administration, the posology and the target species
  • (g) any overage(s) in the formulation to guarantee minimum potency at end of shelf life with justification
  • (h) the selection of the manufacturing process of the active substance and the finished product
  • (i) 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
  • (j) when a dosing device is provided with the finished product, the accuracy of the doses(s) shall be demonstrated
  • (k) when an accompanying test is recommended to be used with the finished product (e.g. a diagnostic test), relevant information about the test shall be provided
  • (l) This explanation shall be supported by scientific data on product development

IIIa.2A.3. Characterisation

IIIa.2A.3.1. Elucidation of structure and other characteristics

  1. Characterisation of a biotechnological or biological substance (which includes the determination of physicochemical properties, biological activity, immuno-chemical properties, purity and impurities) by appropriate techniques is necessary to allow a suitable specification to be established. Reference to literature data only is not acceptable, unless otherwise justified by prior knowledge from similar molecules for modifications where there is no safety concern. Adequate characterisation shall be performed in the development phase and, where necessary, following significant process changes.

  2. All relevant information available on the primary, secondary and higher-order structure including post- translational (for example, glycoforms) and other modifications of the active substance shall be provided.

  3. Details shall be provided on the biological activity (namely the specific ability or capacity of a product to achieve a defined biological effect). Usually, the biological activity shall be determined or evaluated using an appropriate, reliable and qualified method. Lack of such an assay shall be justified. It is recognised that the extent of characterisation data will increase during development.

  4. The rationale for selection of the methods used for characterisation shall be provided and their suitability shall be justified.

IIIa.2A.3.2. Impurities

  1. Process-related impurities (for example, host cell proteins, host cell DNA, media residues, column leachables) and product-related impurities (for example, precursors, cleaved forms, degradation products, aggregates) shall be addressed. Quantitative information on impurities shall be provided including maximum amount for the highest dose. For certain process-related impurities (for example, antifoam agents), an estimation of clearance may be justified.

  2. In the case that only qualitative data are provided for certain impurities, this shall be justified.

IIIa.2B. Description of the manufacturing method

  • (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.

  • (2.) The name(s) and address(es) and responsibilities of each manufacturer, including contractors, and each proposed production site or facility involved in manufacture, testing and batch release shall be provided.

  • (3.) The description of the manufacturing process shall include at least:

    • (a) the various stages of manufacture, including production of the active substance and description of the purification steps
    • (b) a process flow chart of all successive steps shall be given so that an assessment can be made of the reproducibility of the manufacturing procedure and of the risks of adverse effects on the finished products, such as microbiological contamination
    • (c) 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
    • (d) listing of all the substances at the appropriate steps where they are used, including those which cannot be recovered in the course of manufacturing
    • (e) the details of the blending, with the quantitative particulars of all the substances used, including an example for a representative production batch
    • (f) list of in-process controls including the stage of manufacture at which they are conducted and acceptance criteria
    • (g) for sterile products, where non-pharmacopoeial sterilisation conditions are used, details of the sterilisation processes and/or aseptic procedures used

  • (4.) Description, documentation, and results of the validation and/or evaluation studies shall be provided for critical steps or critical assays used in the manufacturing process (for example, validation of the sterilisation process or aseptic processing or filling) 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.

IIIa.2C. Production and control of starting materials

  1. For the purposes of this point “starting materials” means all components, including the active substances used in the production of the biological veterinary medicinal product. Culture media used for production of the active substances shall be regarded as one starting material.

  2. The qualitative and quantitative composition shall be presented insofar as the Secretary of State consider that this information is relevant to the quality of the finished product and any risks that might be posed.

  3. If materials of animal origin are used for preparation of those culture media, 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 or the British Pharmacopoeia shall be demonstrated.

  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.

  5. 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.

  6. 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 from a batch of all components used and shall be submitted in accordance with the following provisions.

  7. Certificates of Analysis shall be presented for the starting materials in order to demonstrate compliance with the defined specification.

  8. Colouring matter shall in all cases satisfy the requirements of Directive 2009/35/EC.

  9. The use of antibiotics during production and preservatives shall be in compliance with the European Pharmacopoeia.

  10. For novel excipients – 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.

IIIa.2C.1. Starting materials listed in pharmacopoeias

  1. The monographs of the European Pharmacopoeia or British Pharmacopoeia shall be applicable to all starting materials appearing in it, unless adequate justification is provided.

  2. Non applicable.

  3. The description of the analytical methods may be replaced by a detailed reference to the pharmacopoeia in question.

  4. The routine tests carried out on each batch of starting materials shall be as stated in the application for marketing uthorization. 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.

  5. 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 Secretary of State 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.

IIIIa.2C.2. Starting materials not listed in a pharmacopoeia

IIIa.2C.2.1. Starting materials of biological origin

  1. Where source materials such as microorganisms, tissues of either plant or animal origin, cells or fluids (including blood) of human or animal origin or biotechnological cell constructs are used in the manufacture of veterinary medicinal products, the origin, including geographical region, and history of starting materials shall be described and documented. The origin, general health and immunological status of animals used for production shall be indicated and defined pools of source materials shall be used.

  2. Freedom from extraneous agents (bacteria, mycoplasma, fungi and viruses) shall be demonstrated in compliance with the European Pharmacopoeia or British Pharmacopoeia for seed materials, including cell seeds and pools of serum and, whenever possible, the source materials from which they are derived.

  3. Information shall be provided on all substances of biological origin used at any stage in the manufacturing procedure. The information shall include the manufacturing strategy, purification and inactivation procedures with their validation and all in-process control procedures designed to ensure the quality, safety and batch to batch consistency of the finished product as well as details of any tests for contamination carried out on each batch of the substance. Any special precautions which may be necessary during storage of the starting material and, if necessary, its storage life shall be given.

  4. When starting materials of animal or human origin are used, the measures used to ensure freedom from extraneous agents shall be described. 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.

  5. 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.

  6. 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.

  7. 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.

  8. When required, samples of the biological starting material or reagents used in the testing procedures shall be provided to enable the Secretary of State to arrange for check tests to be carried out.

IIIa.2C.2.2.  Starting materials of non-biological origin

1.  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 IIIa.2A1(4) 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 the British Pharmacoepia
  • (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

IIIa.2D. Control tests during the manufacturing process

  1. The dossier shall include particulars relating to the in-process control tests, which are carried out on intermediate stages of manufacture with a view to verify 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 shall be provided, unless otherwise justified.

  2. The specification for the batch(es) of active substance shall define acceptance criteria together with the tests used to exert sufficient control of the quality of the active substance. A test for biological activity shall be included unless otherwise justified. Upper limits, taking into account safety considerations, shall be set for the impurities. Microbiological quality for the active substance shall be specified. Freedom from extraneous agents (bacteria, mycoplasma, fungi and viruses) shall be demonstrated according to the European Pharmacopoeia.

  3. In accordance with 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.

IIIa.2E. Control tests on the finished product

IIIa.2E.1 Finish product specification

For all tests, the description of the techniques for analysing the finished product shall be set out in sufficient detail for quality assessment.

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 must 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 instead of on the batch or batches prepared from it, shall be stated, if applicable. The frequency of the tests which are not carried out routinely shall be justified. Acceptance criteria for release shall be indicated and justified. Validation of the control tests carried out on the finished product shall be provided.

Upper limits, taking into account safety considerations, shall be set for the impurities.

IIIa.2E.2 Method descriptions and validation of release tests

  • (1.) General characteristics

The tests of general characteristics shall, wherever applicable, relate to the appearance of the finished product and to physical or chemical tests, such as, pH, osmolality, etc. For each of those characteristics, specifications, with appropriate confidence limits, shall be established by the applicant in each particular case.

  • (2.) Identification and potency test

Where necessary, a specific test for identification of the active substance shall be carried out. When appropriate, the identification test may be combined with the potency test.

An activity test or test for quantification of the active substance or test to quantitatively measure the functionality (biological activity/functional effect) which is linked to relevant biological properties shall be implemented to show that each batch will contain the appropriate potency to ensure its safety and efficacy.

A biological assay shall be obligatory when physicochemical methods does not provide adequate information on the quality of the product. Such an assay shall, whenever possible, include reference materials and statistical analysis allowing calculation of confidence limits. Where those tests may not be carried out on the finished product, they may be performed at an intermediate stage, as late as possible in the manufacturing process.

Where degradation occurs during manufacture of the finished product, the maximum acceptable levels of individual and total degradation products immediately following manufacture shall be indicated.

  • (3.) 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. If applicable, the quantity and nature of the adjuvant and its components shall be verified on the finished product, unless otherwise justified.

  • (4.) Sterility and purity tests

Freedom from extraneous agents (bacteria, mycoplasma, fungi and bacterial endotoxin when relevant) shall be demonstrated in compliance with the European Pharmacopoeia. Appropriate tests to demonstrate the absence of contamination by other substances, shall be carried out according to the nature of the biological veterinary medicinal product, the method and the conditions of manufacture. If fewer tests than required by the relevant European Pharmacopoeia are routinely employed for each batch, the tests carried out shall be critical to the compliance with the monograph. Proof shall be supplied that the biological veterinary medicinal product would meet the requirements, if fully tested according to the monograph.

  • (5.) Residual humidity

Each batch of lyophilised product or tablet shall be tested for residual humidity and suitable minimum and maximum acceptance criteria should be set.

  • (6.) Filling volume

Appropriate tests to demonstrate the correct filling volume shall be carried out.

IIIa.2E.3. Reference standards or materials

Information regarding the manufacturing process used to establish the reference material shall be provided. If more than one reference standard has been used for a particular test during product development, a qualification history shall be provided describing how the relationship between the different standards was maintained.

If other reference preparations and standards than those of the European Pharmacopoeia or British Pharmacopoeia are used, they shall be identified and described in detail. Information on maintenance, monitoring, replacement and how continuity is ensured for reference materials should be provided.

IIIa.2F. Batch-to-batch consistency

IIIa.2F.1. Active substance

In order to ensure that quality of the active substance is consistent from batch to batch and to demonstrate conformity with specifications data from representative batches shall be provided.

IIIa.2F.2. Finished product

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 shall be provided.

IIIa.2G. Stability tests

  1. Stability tests cover stability of the active substance and the finished product, including solvent(s), if relevant. If active substance(s) are stored, the intended conditions and duration of storage shall be defined on the basis of stability data; they may be obtained either through testing of the active substances themselves or through appropriate testing of the finished product.

  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 by the applicant. Those tests shall always be real-time studies; they 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 the claimed end of the shelf life.

  3. 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. The interval between testing should be justified and shown to be suitable depending on the nature of the product.

  4. 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.

  5. 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.

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

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

  8. Stability data obtained from combined products may be used where adequately justified for derivative products containing one or more of the same components.

  9. The efficacy of any preservative system shall be demonstrated. Information on the efficacy of preservatives in other similar biological veterinary medicinal products from the same manufacturer may be sufficient.

IIIa.2H. Other information

Information relating to the quality of the biological veterinary medicinal product not covered by Part IIIa.2 to IIIa2G may be included in the dossier.

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

  • (1.) Each study report shall include:

    • (a) a copy of the study plan (protocol) *(b) a statement of compliance with good laboratory practice, where applicable
    • (c) a description of the methods, apparatus and materials used
    • (d) a description and justification of the test system
    • (e) a description of the results obtained, in sufficient detail to allow the results to be critically evaluated independently of their interpretation by the author
    • (f) a statistical analysis of the results where appropriate
    • (g) a discussion of the results, with comment on observed and no-observed-effect levels, and on any unusual findings
    • (h) the name of the laboratory
    • (i) the name of the study director
    • (j) signature and date
    • (k) place and period of time during which the study was undertaken
    • (l) key for abbreviations and codes, irrespective of whether they are internationally accepted or not
    • (m) description of mathematical and statistical procedures

  • (2.) Published studies may be accepted if they contain a sufficient amount of data and sufficient details to allow an independent assessment. The experimental techniques shall be described in such detail as to allow them to be reproduced, and the investigator shall establish their validity. Summaries of studies for which detailed reports are not available shall not be accepted as valid documentation. To address certain safety requirements reference may be made to EPMAR when the substance has been previously evaluated for the establishment of MRLs. Where reference to EPMARs is made there is no need to submit studies already evaluated as part of the MRL evaluation; only new studies not available for the MRL assessment shall be provided. If the route of exposure (for example, for the user) is not identical to the route used in accordance with Regulation (EU) 2018/78, new studies may be necessary.

IIIa.3A. Safety tests

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

    • (a) the potential toxicity of the veterinary medicinal product and any dangerous or undesirable effects in target species which may occur under the proposed conditions of use
    • (b) the potential risks which may result from the exposure of human beings to the veterinary medicinal product, for example, during its administration to the animal
    • (c) the potential risks to the environment resulting from the use of the veterinary medicinal product

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

  • (3.) An excipient used for the first time in a veterinary medicinal product in Great Britain or by a new means of administration shall be treated like an active substance. Since substances falling into this category may not always allow for conventional pharmacology or toxicology studies to be considered relevant for the evaluation of their hazards to humans, target animals or the environment, a more flexible approach may be taken

  • (4.) All sections listed in Part IIIa.3A shall be addressed. Depending on the nature of the product, certain sections may not be relevant and studies may be omitted, where justified.

IIIa.3A.1. Precise identification of the product and of its active substance(s):

  • (a) international non-proprietary name (INN)
  • (b) International Union of Pure and Applied Chemistry Name (IUPAC)
  • (c) Chemical Abstract Service (CAS) number
  • (d) therapeutic, pharmacological and chemical classification
  • (e) synonyms and abbreviations
  • (f) structural formula
  • (g) molecular formula
  • (h) molecular weight
  • (i) degree of impurity
  • (j) qualitative and quantitative composition of impurities
  • (k) description of physical properties:
    • appearance
    • melting point
    • boiling point
    • vapour pressure
    • pH value
    • solubility in water and organic solvents expressed in g/l, with indication of temperature
    • octanol/water partition (Pow)
    • density
    • particle size distribution
  • (l) formulation of the product

IIIa.3A.2. Pharmacology

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

  2. Pharmacological studies may also assist in the understanding of toxicological phenomena. Where a veterinary medicinal product produces pharmacological effects in the absence of a toxic response, or at doses lower than those required to elicit toxicity, those pharmacological effects shall be taken into account during the evaluation of the safety of the veterinary medicinal product.

  3. The safety documentation shall always be preceded by details of pharmacological investigations undertaken in laboratory animals and all relevant information observed during clinical studies in the target animal.

IIIa.3A.2.1. Pharmacodynamics

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.3A.2.2. 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.

Where toxicological studies conducted in laboratory animals are not relevant to the substance under evaluation, data from target animal studies and data relevant to humans must be provided.

IIIa.3A.3. Toxicology

  1. The documentation on toxicology shall follow the guidance in VICH GL6 and GL 33 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.

  2. Toxicity studies shall be conducted with the active substance(s), not with the formulated product, unless specifically required otherwise.

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

  4. In all cases, data relevant to the evaluation of toxicological safety in both the target species and in humans must be provided.

  5. Any divergence from established guidance must be scientifically justified.

IIIa.3A.3.1. 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.3A.3.2. 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.3A.3.3. 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.3A.3.4. 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.

  • (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.3A.3.5. 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.3A.3.6. 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.3A.3.7. 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.3A.4. Other requirements

IIIa.3A.4.1. 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.3A.4.2. 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.

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

  • (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

  • (3.) Resistance in the environment shall be addressed.

IIIa.3A.5. 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 Committee for Medicinal Products for Veterinary Use (CVMP) guidelines.

IIIa.3A.6. Environmental risk assessment

IIIa.3A.6.1. 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.

  • (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 method of administration, in particular the likely extent to which the product will enter directly into environmental systems
    • (c) the possible excretion of the product, its active substances or relevant metabolites into the environment by treated animals; persistence in such excreta
    • (d) the disposal of unused veterinary medicinal product or other waste product

  • (3.) In the second phase, further specific investigation of the fate and effects of the product on particular ecosystems shall be conducted, in accordance with VICH GL 38. 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

IIIa.3A.6.2. 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 the GMO deliberate Release Regulations.

  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.

IIIa.3B. Residue tests

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

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

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

    • (a) to what extent, and for how long, residues of the veterinary medicinal product or its metabolites persist in the edible tissues of the treated animal or in milk, eggs and/or honey (wax if appropriate) obtained therefrom
    • (b) that in order to prevent any risk to the health of the consumer of foodstuffs from treated animals, it is possible to establish realistic withdrawal periods which may be observed under practical farming conditions
    • (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.3B.1.  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.3B.2. 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.

  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.

  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.

  4. Based on the evaluation, the rationale for the proposed withdrawal period shall be addressed.

IIIa.3B.3. 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.

  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.4A.1. Pharmacology

IIIa.4A.1.1. Pharmacodynamics

  1. The pharmacodynamic effects of the active substance(s) included in the veterinary medicinal product shall be characterised.

  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.

  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.

  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.

  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.4A.1.2. 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.

  • (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

  • (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.

  • (4.) Where pharmacokinetic studies have been submitted under Part 3 of the dossier, cross-reference to such studies may be made.

  • (5.) For fixed combinations, please refer to Section IV.

  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.

  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.4A.3. 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.

  2. For studies conducted under field conditions, relevant information shall be provided as outlined under clinical studies.

IIIa.4A.4. 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.

  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. 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.4B.1. General principles

  1. Clinical trials shall be designed, carried out and reported taking into account VICH GL9. Data stemming from clinical trials conducted outside Great Britain may be taken into consideration for the assessment of an application for a marketing authorisation only, if the data are sufficiently representative of Great Britain.

  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.

  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.

  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 Great Britain, the words “for veterinary clinical trial use only” shall appear prominently and indelibly on the labelling.

  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 Great Britain 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.

  6. Established statistical principles in accordance with VICH Gl9 shall be used in protocol design, analysis and evaluation of clinical trials, unless otherwise justified.

IIIa.4B.2. 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.4B.2.1. 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.4B.2.2. 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 Great Britain 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.