The safety tests shall show the potential risks from the immunological veterinary medicinal product, which may occur under the proposed conditions of use in animals: these shall be evaluated in relation to the potential benefits of the product.
Where immunological veterinary medicinal products consist of live organisms, especially those, which could be shed by vaccinated animals, the potential risk to unvaccinated animals of the same or of any other potentially exposed species shall be evaluated.
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.
In the case of an immunological veterinary medicinal products containing a live organism, the dose to be used in the laboratory tests described in Sections B.1 and B.2 shall be the quantity of the product containing the maximum titre. If necessary the concentration of the antigen may be adjusted to achieve the required dose. For inactivated vaccines the dose to be used shall be that quantity recommended for use containing the maximum antigen content unless justified.
The safety documentation shall be used for assessment of 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.
The immunological veterinary medicinal product shall be administered at the recommended dose and by each recommended route of administration to animals of each species and category in which it is intended for use, including animals of the minimum age of administration. The animals shall be observed and examined for signs of systemic and local reactions. Where appropriate, these 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.
The animals shall be observed and examined until reactions may no longer be expected, but in all cases, the observation and examination period shall be at least 14 days after administration.
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 signs of systemic or local reactions.
Only live immunological veterinary medicinal products require overdose testing.
An overdose of the immunological veterinary medicinal product shall be administered by each recommended route(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) 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 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, these studies shall include detailed post-mortem macroscopic and microscopic examinations of the injection site if this has not been done under point 1.
In the case of immunological veterinary medicinal products to be administered more than once, as part of the basic vaccination scheme, a study of the repeated administration of one dose shall be required to reveal any adverse effects induced by such administration. These tests shall be carried out on the most sensitive categories of the target species (such as certain breeds, age groups), using each recommended route of administration.
The animals shall be observed and examined 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.
Examination of reproductive performance shall be considered 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 of administration. In addition, harmful effects on the progeny, as well as teratogenic and abortifacient effects, shall be investigated.
These studies may form part of the safety studies described in points 1, 2, 3 or of the field studies provided for in Section C.
Where the immunological veterinary medicinal product might adversely affect the immune response of the vaccinated animal or of its progeny, suitable tests on the immunological functions shall be carried out.
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.
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(1) to be used for food producing animals, these studies must shall take particularly into account the persistence of the organism at the injection site.
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 of administration most likely to lead to 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.
Other tests may be necessary to determine as precisely as possible the intrinsic biological properties of the vaccine strain (e.g. neurotropism).
The probability of recombination or genomic reassortment with field or other strains shall be discussed.
This section shall include a discussion of the effects found in the preceding sections, which shall 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.
For immunological veterinary medicinal products, it will normally not be necessary to undertake a study of residues. However, where adjuvants and/or preservatives are used in the manufacture of immunological veterinary medicinal products, consideration shall be given to the possibility of any residue remaining in the foodstuffs. If necessary, the effects of such residues shall be investigated.
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.
If there is a compatibility statement with other veterinary immunological 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 justified, results from laboratory studies shall be supplemented with data from field studies, using batches according to the manufacturing process described in the marketing authorisation application. Both safety and efficacy may be investigated in the same field studies.
The purpose of the environmental risk assessment is to assess the potential harmful effects, which the use of the product may cause to the environment and to identify any precautionary measures, which may be necessary to reduce such risks.
This assessment shall normally be conducted in two phases. The first phase of the assessment shall always be performed. The details of the assessment shall be provided in accordance with established guidance. 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:
the target animal species and the proposed pattern of use,
the method of administration, in particular the likely extent to which the product will enter directly into the environmental system,
the possible excretion of the product, its active substances into the environment by treated animals, persistence in such excreta,
the disposal of unused or waste product.
In the case of live vaccine strains which may be zoonotic, the risk to humans shall be assessed.
Where the conclusions of the first phase indicate potential exposure of the environment to 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.
In the case of veterinary medicinal products containing or consisting of genetically modified organisms the application shall also be accompanied by the documents required under Article 2 and Part C of Directive 2001/18/EC.”