The pyrogen test is designed to limit to an acceptable level 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 and is designed for products that can be tolerated by the test rabbit in a dose not to exceed 10 mL per kg 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, follow the additional directions given in the individual monograph or, in the case of antibiotics or biologics, the additional directions given in the federal regulations
APPARATUS AND DILUENTS
Render the syringes, needles, and glassware free from pyrogens by heating at 250° for not less than 30 minutes 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. Where Sodium Chloride Injection is
specified as a diluent, use Injection containing 0.9 percent of NaCl.
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 ±0.1° 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 not less than 7.5 cm, and, after a period of time not less than that previously determined as sufficient, record the rabbit’s body
Use healthy, mature rabbits. House the rabbits individually in an area of uniform temperature between 20° and 23° and free from disturbances likely to excite them. The temperature varies not more than ±3° from the selected temperature. Before using a rabbit for the first time in a pyrogen test, condition it not more than seven days before use by a sham test that includes all of the steps as directed under Procedure except injection. Do not use a rabbit for pyrogen testing more frequently than once every 48 hours, nor prior to 2 weeks following a maximum rise of its temperature of 0.6° or more while being subjected to the pyrogen test, or following its having been
given a test specimen that was adjudged pyrogenic.
Perform the test 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. Withhold all food from the rabbits used during the period of the test. Access to water is allowed at all times, but may be restricted during the test. If rectal temperature-measuring probes remain inserted throughout the testing period, restrain the rabbits with light-fitting neck stocks that allow the rabbits to assume a natural resting posture. 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 1° from each other, and do not use any rabbit having a temperature exceeding 39.8°.
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 labeling, or the material under test treated as directed in the individual monograph and injected in the dose specified therein. 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 37 ± 2°. Record the temperature at 30-minute intervals between 1 and 3 hours subsequent to the
TEST INTERPRETATION AND CONTINUATION
Consider any temperature decreases as zero rise. If no rabbit shows an individual rise in
temperature of 0.5° or more above its respective control temperature, the product meets the requirements for the absence of pyrogens. If any rabbit shows an individual temperature rise of 0.5° or more, continue the test using five other rabbits. If not more than three of the eight rabbits show individual rises in temperature of 0.5° or more and if the sum of the eight individual maximum
temperature rises does not exceed 3.3°, the material under examination meets the requirements for the absence of pyrogens.
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