Pharmaceutical Manufacturing Handbook: Production and

92 RADIOPHARMACEUTICAL MANUFACTURING
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 fi lter methods. It is a great advantage to incubate only the fi lters instead of the
radioactive solutions.
The test is performed according to the Ph.Eur/USP monograph on Sterility tests
[13, 14] , but with an important modifi cation. Small batch sizes, typical for radiopharmaceuticals,
make it necessary to use smaller test volumes than required in the
monographs. Also the risk for radiation exposure supports this modifi cation.
All radiopharmaceuticals for human administration are required to be pyrogen
free. Also the tests for apyrogenicity must be modifi ed 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 diffi cult 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.
However, even the LAL test may be too time consuming for the very short lived
PET radiopharmaceuticals. Hence, less time consuming methods are in progress and
will probably improve this situation. Meanwhile, it is accepted that the test for apyrogenicity,
like the sterility test is for most radiopharmaceuticals, is fi nished after
release of the most short lived radiopharmaceuticals.
Bubble Point Testing of Filters Parenteral radiopharmaceuticals that are not terminally
sterilized must undergo a sterile fi ltration process as part of the aseptic
production procedure. Although the supplier certifi es the fi lters used, they must be
checked for integrity after use to assure that there has been no leakage during the
fi ltration. The integrity of the fi lter may be demonstrated by bubble point testing . In
this test, the fi lter is placed and monitored under controlled pressure. When the test
is done on wet fi lters, the pressure needed to push gas through the fi lter is defi ned
as the bubble point. A fi lter with given pore width has a corresponding bubble point
value. Most frequently, sterile fi ltration is performed by 0.22 - μ m fi lters; hence the
bubble point is about 3 – 4 bars. However, the fi lter supplier should specify the bubble
point valid for a specifi c fi lter.
Since this is an in - process test, special caution must be given to radiation protection.
The test equipment should be placed within a closed and shielded unit and a
system should be in place to collect any radioactive spill from the test.
When the fi lter integrity test fails, the sterile fi ltration process must be rejected.
Visual Inspection of Finished Product As part of the quality control, all parenterals
will be subject to an inspection for the possible content of particles. Visual
inspection of radiopharmaceuticals is more complicated than for other pharmaceuticals,
as radiation protection guidelines strongly discourage any direct eye contact
with radioactive sources. Normally, the visual inspection of a radiopharmaceutical
is performed by placing the vial on a rotating station connected to a camera. The
station is properly shielded, and the operators can study the solution on a distant
screen.