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8.2 PYROGEN TEST

8.2 PYROGEN TEST

      Materials intended for parenteral use should be free from undue amounts of pyrogenic substances. The pyrogen test is designed to limit to an acceptable level of the risks of febrile reaction in the patient to the administration, by injection, of the product concerned. The test involves measuring the rise in temperature of rabbits following the intravenous injection of a test solution. The dose specific for the test is usually related to that generally given to the patient, but for practical reasons, it does not exceed 10 ml per kg of body weight of the test animal, injected intravenously within a period of not more than 10 minutes. For products that require preliminary preparation or are subject to special conditions of administration, additional directions given in the individual monograph are to be followed.

Test Animals

      Use healthy, adult rabbits weighing not less than 1.5 kg. House the rabbits individually in an area of uniform temperature between 20º and 24º and free from disturbances likely to excite them. The temperature varies not more than ±3º from the selected temperature. The animals are given ad libitum water and food, commonly used for laboratory animals. Not more than seven days before using a rabbit that has not previously been used for a pyrogen test, perform a sham test to condition the animal by conducting a training exercise as described under Procedure, omitting the injection.

      Do not use animals for pyrogen tests more frequently than once every 72 hours. After a pyrogen test in the course of which a rabbit’s temperature has risen by 0.5º or more, or after a rabbit has been given a test substance that was adjudged pyrogenic, at least 2 weeks must be allowed to elapse before the animal is used again.

Temperature Recording

      Use an accurate temperature-sensing device such as a clinical thermometer, or thermistor probes or similar probes that have been calibrated to assure an accuracy of ±0.1º and have been tested to determine that a maximum reading is reached in less than 5 minutes. Insert the temperature-sensing probe into the rectum of the test rabbit to a depth of 7.5 to 9 cm, and, after a period of time not less than that previously determined as sufficient, record the rabbit’s body temperature.

Apparatus and Diluents

      Render the syringes, needles and glassware free from pyrogens by heating at 250º for not less than 30 minutes or at 200º for not less than 1 hour or by any other suitable method. Treat all diluents and solutions for washing and rinsing of devices or parenteral injection assemblies in a manner that will assure that they are sterile and pyrogen-free. Periodically perform control pyrogen tests on representative portions of the diluents and solutions for washing or rinsing of the apparatus.

Procedure

      Perform the test using three rabbits in a separate area designated solely for pyrogen testing and under environmental conditions similar to those under which the animals are housed and free from disturbances likely to excite them. Food is withheld from the rabbits overnight until the end of the test, and water withheld during the test. The animals should be placed under the conditions of the test at least 1 hour before the injection. If the temperature-sensing device is to remain inserted throughout the sensing period, restrain the rabbit in such a way that allows it to assume a natural resting position.

      Not more than 30 minutes prior to the injection of the test dose, determine the “control temperature” of each rabbit: this is the base for the determination of any temperature increase resulting from the injection of a test solution. In any one group of test rabbits, use only those rabbits whose control temperatures do not vary by more than 1º from each other, and do not use any rabbit having temperature exceeding 39.8º.

      Unless otherwise specified in the individual monograph, inject into an ear vein of each of three rabbits 10 ml of the test solution per kg of body weight, completing each injection within 10 minutes after start of administration. The test solution is either the product, constituted if necessary as directed in the labelling, or the material under test treated as directed in the individual monograph and injected in the dose specified the rein. For pyrogen testing of devices or injection assemblies, use washings or rinsings of the surfaces that come in contact with the parenterally administered material or with the injection site or internal tissues of the patient. Assure that all test solutions are protected from contamination. Perform the injection after warming the test solution to a temperature of 37º±2º. Record the temperature at 30-minute intervals between 1 and 3 hours subsequent to the injection.

Test Interpretation and Retest

      Consider any temperature decreases as zero rise. If no rabbit shows an individual rise in temperature of 0.5º or more above its respective control temperature, the tested material meets the requirements for the absence of pyrogens. If any rabbit shows an individual temperature rise of 0.5º or more, continue the test using five other rabbits. If not more than three of the eight rabbits show individual rises in temperature of 0.5º or more and if the sum of the eight individual maximum temperature rises does not exceed 3.3º, the tested material under examination meets the requirements for the absence of pyrogens.

APPENDICES • 8.2 PYROGEN TEST
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หมายเหตุ / Note : TP II 2011 PAGE 521-522