The Coalition for PET Drug Approval continues to pose questions to the FDA regarding compliance with 21 CFR 212. When feedback is received, those questions and answers will be posted here.
Below are questions with responses developed based on feedback received from the FDA:
1. USP Sterility mentions the use of several microbes and fungi to be tested under aerobic and anaerobic conditions. In a recent webinar offered through the FDA, during the question and answer session, the use of just one microbe was mentioned. If this is correct, which microbe would it be, i.e., E. Coli or something else? What exactly is an anaerobic incubator? After inoculation of our FTM and TSB Hungate media tubes, the environment inside the tube is considered anaerobic. In that case, how does one make a sealed Hungate tube aerobic? In the past, all tubes were inoculated and either stored at room temperature or placed in the incubator for the 14 day period. Are we going to be required to do something different?
For ready to use media from a qualified commercial supplier, the use of one of the aerobic species for TSB and one of the anaerobic species fro FTM is recommended. Species listed in USP Sterility Tests may be used. An anaerobic incubator is unnecessary if the FTM is handled properly. FTM should remain anoxic below the surface of the medium. USP recommends FTM is incubated at 30-35*C, and that TSB is incubated at 20-25*C. The incubation practices should conform to USP .
2. The intention of the promotion testing and/or operator simulation is to prove that the media being used actually grows organisms or replicates the operator qualification for manipulation of sterile products by using a positive control. It was mentioned on one of the slides that once vendor qualification was accomplished by completing three batches, that the sterility test or environmental monitoring media test could be done periodically. The sterility test must be done for each batch of PET drug product, it is unclear what was meant by “sterility test” on that slide. Furthermore, the same slide mentioned to test one batch “periodically” (e.g. quarterly) to see that you actually get a positive growth test.
Could the quarterly test be done in conjunction with an operator qualification if it just happens that both fall close to each other (within a couple of weeks) on the calendar? Is it acceptable if the Microbiology Department in the hospital completese this testing on our behalf? In this case, the Microbiology Department is equipped to handle inoculation of organisms into our sterile media and they have these microorganisms on hand and it is not desireable to introduce these microorganisms into the Radiopharmacy.
When media are purchased “ready-to-use” from a commercial vendor, the first three batches should be tested for growth promotion as part of the vendor qualification. Commercially prepared media used in the sterility test should be used within the label’s shelf life, stored according to the label’s recommendations, and one batch should be tested for growth promotion periodically (e.g. quarterly).
The periodic growth promotion testing could be performed in conjunction with an operator qualification as long as their timing is close. If this is the case, a positive control should be prepared by inoculating a separate vial from te same batch of media used for the media fill. This will also serve as a growth promotion test. The microbiology department within your hospital is an acceptable laboratory to perform this testing.
3. If, for example, the next quarter arrivesm, and you still have the same lots of FTM and TSB in your inventory, is it still necessary to replicate the test on the existing lot or can you wait until your existing lot is consumed, a new vendor lot arrives, and you proceed to test the new lot?
Only the first batch/lot fo the medium that arrives in the next quarter needs to be growth promotion tested, unless last quarter’s medium has not been stored according to the manufacturer’s recommendations. If the previous quarter’s medium has been stored according to the manufacturer’s recommendation and hasn’t reached expiry, that batch/lot may continue to be used.
4. Does the 100 mol bulk vial of TSB that we use in our operator qualifications for sterile manipulation also have to be tested for growth promotion. If it does, could we only do this procedure when we get a new vendor lot in inventory?
A positive control should be included in each media fill, prepared by inoculationga separate vial from the same batch/lot of medium used for the media fill. This will aslo serve as a growth promotion test for that lot of medium. If the medium used to prepare the media fill’s positive control provides acceptable growth promotion test results, then this may also serve to fulfill the requirement of periodic (e.g., quarterly) growth promotion testing.