1. Radiopharmaceutical Production FDG Production Problems Troubleshooting STOP

2. Table of Contents 1.No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer 2.Partial transfer of F-18Partial transfer of F-18 3.Fluorine-18 not released from the resin columnFluorine-18 not released from the resin column 4.No trapping of tetraacetate on C-18 columnNo trapping of tetraacetate on C-18 column 5.Final product not delivered into vialFinal product not delivered into vial 6.Product purity is low due to unhydrolyzed tetraacetateProduct purity is low due to unhydrolyzed tetraacetate 7.Mechanical problemsMechanical problems 8.Software problemsSoftware problems 9.Human errorsHuman errors 10.Sterile filtration failure and recoverySterile filtration failure and recovery 11.Pyrogen test failurePyrogen test failure 12.Ionization chamber failureIonization chamber failure STOP

3. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP [ 18 O]H 2 O Delivery Source of problem Problem Symptom or description Potential Solution(s) TransferNo delivery of irradiated water from the target after irradiation Check for delivery path, maybe it was delivered into a different hot cell? Check for clogged transfer frit at the target Transfer lines itself can be clogged after using them for a few weeks/month

4. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP [ 18 O]H 2 O Delivery Source of problem Problem Symptom or description Potential Solution(s) TransferNo delivery of irradiated water from the target after irradiation He bottle for transfer is empty (you would be surprised how often this happened in the beginning) Check that the water target was actually loaded with O-18 water X

5. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP [ 18 O]H 2 O Delivery Source of problem Problem Symptom or description Potential Solution(s) TransferOnly parts of the irradiated water are delivered Check for leaks in the transfer line Check for the target filler system, especially after a few years of heavy use they need high maintenance Check to see if the water broke up during transfer (significant residual activity in the transfer line). If so depressurize the line and slowly pressurize again

6. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP No 18 F - Trapping Source of problem Problem Symptom or description Potential Solution(s) Trapping of 18 F No trapping of the [ 18 F]fluoride on the ion exchange cartridge in the module Forgot to condition the ion exchange cartridge before installation In the last months/past year the quality of the cartridges are questionable, so even correctly conditioned cartridges failed

7. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP Source of problem Problem Symptom or description Potential Solution(s) Release of 18 F No transfer of the [ 18 F]fluoride from the ion exchange cartridge into the reactor Forget to install eluant vial at the module (it is a little bit out of the way and tends to be forgotten) Pinch valves at the eluant block tend to fail after a few weeks of use without maintenance Eluant leaks out The concentration of the carbonate solution is incorrect or has lost strength over time 18 F - Release

8. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP Tetraacetate Separation Source of problem Problem Symptom or description Potential Solution(s) Trapping of tetraacetate Low trapping efficiency of the un-hydrolysed labeled acetylated compound (2- [ 18 F]fluoro-1,3,4,6- tetra-O-acetyl-D- glucose) on the reverse phase cartridge from WATERS. In the last months/past year the quality of the reverse phase cartridge (Sep-Pak Plus C18) from WATERS are questionable Incorrect acetonitrile to water ratio when applied to seppak STOP

9. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP No FDG Delivery Source of problem Problem Symptom or description Potential Solution(s) Final Product Delivery Final Product does not arrive in the multi- injection vial Forgot to install the sterile filter at the final product vial If the product is transferred from the production hot cell into the dispensing hot cell the wrong transfer line is hooked up to the final product vial in the dispensing cell STOP

10. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP No FDG Delivery Source of problem Problem Symptom or description Potential Solution(s) Final Product Delivery Final Product does not arrive in the multi- injection vial Vent needle is inserted too deep into the product vial, so FDG solution can spray out of the vent Final purification cartridges not conditioned or installed properly STOP

11. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP FDG Purity Problems Source of problem Problem Symptom or description Potential Solution(s) Product purity Product is not completely hydrolyzed Acid concentration was too low Vessel was not up to temperature during hydrolysis step

12. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP Mechanical Problems Source of problem Problem Symptom or description Potential Solution(s) Mechanical Problems Slow transfer of reagents Replace frits, back flush valves, look for crimped lines Loss of vacuumChange damaged/broken lines

13. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP Software Problems Source of problem Problem Symptom or description Potential Solution(s) Software Problems Valve did not open during the run Set appropriate conditions (temperature. Pressure) and open the valve manually Reactor heater did not respond Set appropriate temperature and turn on heater manually

14. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP Human Errors Source of problem Problem Symptom or description Potential Solution(s) Human error System not pressurizedOpen valve on the He cylinder Run failed due to precursor not being transferred into reactor Observe the video monitor at critical times Run failed due to wrong position of F-18 trap and purification column Be alert when doing synthesis Forgot to dissolve triflate, used only acetonitrile Follow the procedures exactly as written

15. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP Sterile Filtration Failure Syringe Filter Integrity Test Conduct the integrity test for the filter used to filter the final product into the MIV. If the test fails, indicating that filter is not intact at the time of testing, the product can be re-filtered into a new set sterile MIV, and delivered to the PET. Additional Sterile MIV If there is another identical sterile setup available from a later run, this may be used after changing the label to indicate the correct delivery number. Otherwise, a new sterile setup must be prepared using the standard sterile setup technique. The product must be drawn up from the original MIV using a sterile needle and syringe, and filtered as usual into the new MIV. The new filter must be integrity tested before delivery can be made.

16. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP Pyrogen test failure Positive Pyrogen Tests If the sample showed positive results for pyrogen on the 20 minute PTS test at maximum allowable dilution, this is a serious matter and NO deliveries can be made for humans until the problem is resolved. If a radiotracer has failed to pass the two consecutive tests, then a sample must be sent to AppTec (Commercial Testing Company) for pyrogen testing. Responsible Physician Notification In all cases, the responsible physician should be informed, so appropriate notations can be made in the subject’s file.

17. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP Capintec Failure High Background If background activity exceeds normal background limits, then check for radioactivity in the hood and remove or shield appropriately. Re-check background. Contaminated Capintec If no radioactivity is found in the area then check for contamination of the chamber liners and/or dipper. Replace if contaminated and re-check background. Capintec Problems If normal background cannot be established with either procedure above then the chamber must be re-calibrated, repaired or replaced. Noisy response A noisy response is defined as abnormal fluctuations in displayed numbers with or without radioactivity. Check that the proper isotope selection button is depressed. Depress the button then release and repeat several times to confirm position. Check cable connections from chamber to display. Repeat daily check if noise is eliminated to assure proper operation.

18. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP Capintec Failure No Capintec response If no numbers are displayed then check power connections, circuit breaker and main power switch on display unit. A circuit breaker may be reset only one time to restore power. If numbers appear, but do not change after a known change in radiation levels, then confirm radioactivity levels with another device (e.g. frisker) and re-check cables and isotope selection button. Malfunction during Synthesis Most often the problems above will be detected during the daily performance check when there is time to carry out corrective actions and re-check instrument performance. If there is a malfunction during synthesis and the corrective actions listed above are not possible then: –Alternate Ion Chamber- If the final product assay chamber malfunctions then the radioactivity of the product may be measured in another calibrated chamber in the laboratory. Confirm that the chamber has been properly calibrated before use and document in the batch record.

19. Radiopharmaceutical Production No Fluorine-18 transferred to synthesizerNo Fluorine-18 transferred to synthesizer Partial transfer of F-18 Fluorine-18 not released from the resin column No trapping of tetraacetate on C-18 column Final product not delivered into vial Product purity is low due to unhydrolyzed tetraacetate Mechanical problems Software problems Human errors Sterile filtration failure and recovery Pyrogen test failure Ionization chamber failure STOP Summary There are several problems which can occur during the production and delivery of the fluoride There are other problems that may occur during the production Some of these problems can be anticipated and corrective actions taken if the corrective actions are planned and documented in advance.

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