Radiopharmaceutical Production FDG Production Problems Troubleshooting STOP Table
Radiopharmaceutical Production FDG Production Problems Troubleshooting STOP
Table of Contents 1. 2. 3. 4. 5. 6. No 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 7. Mechanical problems 8. Software problems 9. Human errors 10. Sterile filtration failure and recovery 11. Pyrogen test failure 12. Ionization chamber failure STOP
Radiopharmaceutical Production No 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 Symptom or problem description Transfer Potential Solution(s) No delivery of irradiated Check for delivery water from the target path, maybe it was after irradiation 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
Radiopharmaceutical Production No 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 Problem Potential Solution(s) of Symptom problem or description Transfer No 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) X Check that the water target was actually loaded with O-18 water
Radiopharmaceutical Production No 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) Transfer Only 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
No 18 F- Trapping Radiopharmaceutical Production No 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 Symptom or problem description Potential Solution(s) Trapping of 18 F Forgot to condition the ion exchange cartridge before installation No trapping of the [18 F]fluoride on the ion exchange cartridge in the module In the last months/past year the quality of the cartridges are questionable, so even correctly conditioned cartridges failed
18 FRadiopharmaceutical Production No 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 Release Source Problem Symptom Potential Solution(s) of or description problem Release of 18 F No transfer of the Forget to install eluant vial [18 F]fluoride from at the module (it is a the ion exchange little bit out of the way cartridge into the and tends to be reactor 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
Tetraacetate Separation Radiopharmaceutical Production No 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 Potential Solution(s) description Trapping of Low trapping efficiency tetraacetate 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 C 18) from WATERS are questionable Incorrect acetonitrile to water ratio when applied to seppak STOP
No FDG Delivery Radiopharmaceutical Production No 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 Symptom or problem description Potential Solution(s) Final Product Delivery Forgot to install the sterile filter at the final product vial Final Product does not arrive in the multiinjection 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
No FDG Delivery Radiopharmaceutical Production No 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 Symptom or problem description Potential Solution(s) Final Product Delivery Vent needle is inserted too deep into the product vial, so FDG solution can spray out Final Product does not arrive in the multiinjection vial of the vent Final purification cartridges not conditioned or installed properly STOP
FDG Purity Problems Radiopharmaceutical Production No 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 Symptom or problem description Potential Solution(s) Product purity Acid concentration was too low Product is not completely hydrolyzed Vessel was not up to temperature during hydrolysis step
Mechanical Problems Radiopharmaceutical Production No 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 Mechanical Slow transfer of Problems reagents Loss of vacuum Potential Solution(s) Replace frits, back flush valves, look for crimped lines Change damaged/broken lines
Software Problems Radiopharmaceutical Production No 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 Symptom or problem 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
Human Errors Radiopharmaceutical Production No 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 Symptom or problem description Human error Potential Solution(s) System not pressurized Open 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 Be alert when doing position of F-18 trap synthesis and purification column Forgot to dissolve triflate, used only acetonitrile Follow the procedures exactly as written
Sterile Filtration Failure Radiopharmaceutical Production No 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 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.
Pyrogen test failure Radiopharmaceutical Production No 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 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 App. Tec (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.
Capintec Failure Radiopharmaceutical Production No 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 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 properation.
Capintec Failure Radiopharmaceutical Production No 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 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.
Summary Radiopharmaceutical Production No 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 • 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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