Radiopharmaceuticals, pyrogen test

Sterility and Pyrogen Testing Sterility indicates the absence of any viable bacteria or microorganisms in a radiopharmaceutical preparation. Hence, sterility testing is performed to prove that radiopharmaceuticals are essentially free of viable microorganism. The test for microbial contamination of these products is best carried out with filter methods. It is a great advantage to incubate only the filters instead of the radioactive solutions. 

Whereas readers are referred to these specific documents for details available on the Web site http //www.fda.gov/cder/fdama, some of the specifics are briefly mentioned here. The essence of this guidance emphasizes the importance of the overall quality assurance in manufacturing a PET radiopharmaceutical. All equipment and measurements used in the manufacture must be validated. The areas and hoods in which PET radiopharmaceuticals are manufactured must be run in a sterile condition. The personnel responsible for the manufacture must be well trained in the methodology, and an appropriate number of personnel are required in a production laboratory. Each step of the production must be verified and records must be maintained. The sterility and pyrogen testing of the finished product must be performed by appropriate methods. If a PET radiopharmaceutical is to be commercially distributed, appropriate containers and techniques must be adopted for safe shipments. 

All radiopharmaceuticals for human administration are required to be pyrogen free. Also the tests for apyrogenicity must be modified when applied for these products. The classical rabbit test for pyrogens was never a convenient test for parenteral radiopharmaceuticals. Practical problems due to radioactive rabbits and the need for larger test volumes made this a difficult task. Today, the Limulus amebocyte test (LAL) is the method of choice and has been accepted by the Ph. monographs for many years. This test is normally done within an hour, compared to several days for the rabbit test. 

Cooper, J.F. Hochstein, D.H. Seligmann, E.B. The limulus test for endotoxin (Pyrogen) in radiopharmaceuticals and biologicals. Bull. Parent. Drug Assoc. 1972, 26, 153-162. 

Tests for pyrogens include a rabbit test, in which rabbits are administered with the radiopharmaceutical and their rectal temperatures are monitored. From the rise in temperature in the rabbits, pyrogenicity of a sample is determined. However, a simpler and quicker method is the so-called limsulus amebocyte lysate (LAL) test, also called the bacterial endotoxin test (BET). In this test, the lysate of amebocytes from the blood of the horseshoe crab (Limulus polyphemus) is mixed with the sample and incubated at 37° C. An opaque gel is formed within 15-60 min depending on the concentration of pyrogens. 

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