Abstract
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Objectives: Due to recently increasing divergent regulatory requirements on PET manufacturers under 21 CFR 212 and nuclear pharmacy practice under state board of pharmacy/ USP <825>, our goal was to evaluate impact of incorporating a fill line into the 18F-Fludeoxyglucose (18F-FDG) manufacturing process to prepare multiple multidose vials from a single master product vial. The master product vial and the multidose vials are currently prepared in the same clean room and in the same ISO 5 dispensing hot cell. This process change would eliminate two separate processes under two different regulatory agencies (FDA and Board of Pharmacy) which are becoming increasing difficult to comply with the two different sets of standards.
Methods: We have been manufacturing 18F-FDG on the GE FASTlab synthesizer unit using the FDG Citrate cassette since 2011 when our ANDA was filed. Our manufacturing process concludes after the sterile filtration of the drug product into a 50 mL sterile vial and samples are drawn for sterility and quality control testing. Post manufacturing, under the practice of pharmacy, we divide the drug product into three to four multidose vials for use in the clinical nuclear medicine department’s Intego PET infusion system. One to two of the multidose vials are diluted with 10 mL 0.9% Sodium Chloride to accommodate concentration and dose volume requirements of the Intego system. To streamline the process, we sought to incorporate a fill line within the manufacturing process to prepare multidose vials, thus eliminating two separate processes regulated under two different agencies. 18F-FDG validation runs were completed on the GE FASTlab synthesis unit as described above. All sterile processing and vial preparation were performed in a Capintec ISO 5 isolator/dispensing hot cell. Environmental monitoring and personal monitoring were performed during all sterile processes. The fill line consists of five 18F-FDG sub-vials from the 18F-FDG master product vial (MPV) manufacturing runs. Two different manufactures of both the 50 mL sterile vials for master product vials and 30 mL evacuated vials for sub-vial preparation were used to evaluate potential variables. Vials A-C were prepared with 5 mLs of 18F-FDG neat. Vials D and E were prepared with 10 mLs of Rotem FDG diluent (0.45% sodium chloride with sodium citrate) followed by the addition of 5 mLs of 18F-FDG. Sterility testing was completed on the MPV, vial A, vial E and the remaining Rotem diluent post manipulations, within 30 hours of EOS per USP <71>. Quality control was completed on the MPV, vial A and vial E per ANDA/USP test specifications. Sterility and stability testing were conducted on the MPV, vial A and vial E 14 hours post EOS per ANDA/USP specifications.
Results: All quality control testing of the MPV, vial A and vial E meet specifications at initial testing and the stability time point. Radiochemical purity remained consistent among all samples tested. An increase in pH from 6 to 6.5 was observed in 18F-FDG final product vials containing Rotem 0.45% Sodium chloride with sodium Citrate FDG diluent. No variables were found based on manufacture of vials used. Environmental and personnel monitoring met specifications per FDA/USP limits. Sterility testing of all samples inoculated passed sterility testing by not showing any growth after 14 days per USP <71>.
Conclusions: Based on quality control and sterility data incorporating a multidose vial fill line into the manufacturing process of 18F-FDG does not impact the quality or sterility of the 18F-FDG drug product. By incorporating the multidose vial preparation into a manufacturing fill line the need for two separate processes is eliminated, potentially reducing regulatory oversight to a single regulatory agency, the FDA.
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