Appendix XV K (Vet) 3. Evaluation of Safety of each Batch of Immunosera for Veterinary Use
Definition of abnormal reactions
During development studies, the type and degree of reactions expected after administration of the immunoserum are defined in the light of safety testing. This definition of normal or abnormal local and systemic reactions is then used as part of the operation procedure for the batch safety test to evaluate acceptable and unacceptable reactions.
Amount to be administered in the test
In the tests, ‘dose’ means the quantity of the immunoserum to be recommended for use and containing the titre or potency within the limits specified for production batches. The amount to be administered in the test is usually defined in a number of doses.
Route of administration
The immunoserum is administered by a recommended route. In principle, preference should be given to the application route with the higher possibility to detect reactions.
Target animal species and category of animals
Use animals of the most sensitive species and of the minimum age recommended for administration of the immunoserum, unless otherwise justified and authorised.
Animal numbers
The number of animals to be used for the test is prescribed in the general monograph Immunosera for veterinary use (0030).
Identification of animals
Unless otherwise justified and authorised, all animals are marked in a suitable way to ensure individual documentation of data for the whole observation period.
Observation period
Where objective criteria such as body temperature are to be recorded as described below, the animals are examined and observed for at least 3 days prior to administration of the immunoserum. After administration of the immunoserum, the animals are observed and examined at least once every day for a period of at least 14 days for signs of local and systemic reactions. On the day of administration of the immunoserum, at least 1 additional inspection is necessary after 4 h or at intervals as specified in the monograph. Where there is a 2nd administration of the immunoserum the period usually ends 14 days after the 2nd administration.
Local and systemic reactions
Animals showing severe abnormal local or systemic reactions are euthanised. All dead animals undergo a post-mortem with macroscopic examination. Additional microscopic and microbiological investigations may be indicated.
The animals are observed and examined for signs of local and systemic reactions. Where it is known to be a useful indicator, other criteria are recorded, such as body temperature, body mass, other performance measurements and food intake.
Local reactions As far as appropriate and possible, the size and persistence of any local reaction (including incidence of painful reactions) and the proportion of animals showing local reactions are recorded.
Systemic reactions Body temperature and, if appropriate, body mass are documented as general indicators of systemic effects of administration of the immunoserum. In addition, all clinical signs are recorded.
Body temperature For mammals, the studies include measurement of body temperature during the observation period. The body temperatures are recorded beginning at least 3 days before administration of the immunoserum, at the time of administration, 4 h after and at suitable intervals. The body temperature before administration of the immunoserum has to be within the physiological range. At least for immunosera where a significant increase in body temperature may be expected or where an increase in body temperature is specified in an individual monograph, it is recommended to use the mean temperature of the days before administration of the immunoserum (e.g. day -3 to day 0) as the baseline temperature to have clear guidance for evaluation of the test.
Body mass and food intake Where it is known to be a reliable and useful indicator of safety, for example in young growing animals, the body mass is measured and documented shortly before administration of the immunoserum and during the observation period. The food intake is monitored and documented as an indicator of the effect of administering the immunoserum. In most cases, it will be sufficient to record the daily ration has been consumed or partly or wholly rejected but, in some cases it may be necessary to record the actual weight of food consumed, if this is a relevant indicator of the safety of the immunoserum.
Clinical signs All expected and unexpected clinical signs of a general nature are recorded, including changes in health status and behaviour changes.
Score sheets The score sheets are prepared for each immunoserum in the light of expected signs. All parameters and data are recorded in score sheets. The score sheets contain general parameters but are also adapted for each kind of immunoserum to list clinical signs that might be more evident for a given immunoserum.
Criteria for repeating the test
If an abnormal sign occurs, the responsible veterinarian determines, based on post-mortem examination if necessary, whether this was due to the immunoserum or not. If it is not clear what caused the abnormal sign or where an animal is withdrawn for reasons unrelated to the immunoserum, the test may be repeated. If in the 2nd test there is the same abnormal sign as in the 1st test, the immunoserum does not comply with the test. Any treatment administered to an animal during the observation period is recorded. If the treatment may interfere with the test, the test is invalid.