A "dose on demand" Biomarker Generator for automated production of [(18)F]F(-) and [(18)F]FDG.

The University of Oklahoma-College of Pharmacy has installed the first Biomarker Generator (BG75) comprising a self-shielded 7.5-MeV proton beam positive ion cyclotron and an aseptic automated chemistry production and quality control module for production of [(18)F]F(-) and clinical [(18)F]FDG. Performance, reliability, and safety of the system for the production of "dose on demand" were tested over several months. No-carrier-added [(18)F]F(-) was obtained through the (18)O(p,n)(18)F nuclear reaction by irradiation (20-40 min) of a >95% enriched [(18)O]H2O target (280 μl) with a 7.5-MeV proton beam (3.5-5.0 μA). Automated quality control tests were performed on each dose. The HPLC-based analytical methods were validated against USP methods of quality control. [(18)F]FDG produced by BG75 was tested in a mouse tumor model implanted with H441 human lung adenocarcinoma cells. After initial installment and optimization, the [(18)F]F(-) production has been consistent since March 2011 with a maximum production of 400 to 450 mCi in a day. The average yield is 0.61 mCi/min and 0.92 mCi/min at 3.8 µA and 5 µA, respectively. The current target window has held up for over 25 weeks against >400 bombardment cycles. [(18)F]FDG production has been consistent since June 2012 with an average of six doses/day in an automated synthesis mode (RCY≈50%). The release criteria included USP-specified limits for pH, residual solvents (acetonitrile/ethanol), kryptofix, radiochemical purity/identity, and filter integrity test. The entire automated operation generated minimal radiation exposure hazard to the operator and environment. As expected, [(18)F]FDG produced by BG75 was found to delineate tumor volume in a mouse model of xenograft tumor. In summary, production and quality control of "[(18)F]FDG dose on demand" have been accomplished in an automated and safe manner by the first Biomarker Generator. The implementation of a cGMP quality system is under way towards the ANDA submission and first clinical use of [(18)F]FDG produced by BG75.