Production of the [62Cu]Cu-ETS radiopharmaceutical using the ITG iQS®Fluidic Labeling Module as a manual synthesis platform.

1164 Objectives: To develop and validate an approach to on-demand synthesis of generator-based 62Cu-radiopharmaceuticals using a commercially available synthesis module. Methods: The required 62Zn2+(~7.4 GBq/shipment) was obtained from Zevacor, Inc. (Noblesville, IN) in ~2 mL dilute HCl. This was adjusted to 2M HCl with concentrated ultrapure HCl, and 62Zn/62Cu generators constructed by passing that 62Zn2+solution through a lead-shielded 3 x 50-mm glass column of Dowex®1x8 (200-400 mesh) ion exchange resin. The generator was then switched to the desired eluent of 0.2M HCl:1.8M NaCl. At ~60-minutes after that initial loading and flushing, the generator was eluted in 0.5-mL fractions to confirm its elution profile. The 62Cu-generator was then connected to the standard sterile plumbing pathway of an ITG iQS®Fluidic Labeling Module, attaching the generator outlet to the synthesis system in the same fashion as one would attach an ITG 68Ga generator for 68Ga radiopharmaceutical synthesis. Thus configured, the ITG Fluidic Module essentially recapitulates the configuration of a previously designed system for [62Cu]Cu-PTSM synthesis (CJ Mathias, WH Margenau, JW Brodack, MJ Welch, MA Green, Appl Radiat Isot 42:317-320; 1991). [62Cu]Cu-ETS was prepared by loading the Fluidic Module plumbing system with 1.5-3.0 µg H2ETS [ethylglyoxal bis(thiosemicarbazone)] in 0.2-mL ethanol, and 0.4 mL USP Sodium Acetate for Injection (2M), followed by elution of the 62Cu-generator with 2-mL 0.2M HCl:1.8M NaCl. This was quickly followed by a sequential flush from the reagent addition port (labeled “Peptide Syringe” on the apparatus) with 5-mL air, 1-mL sterile water, and 2 x 5-mL air to effect complete reagent transfer to the room temperature reaction vial. To mix the reactor contents, 2 x 5-mL air was then pushed through the dip tube of the reactor from the “Cartridge Syringe” position of the Fluidic Module, followed by an additional 5-mL sterile water and 2 x 5-mL air. The valves were then repositioned to allow product transfer to a conditioned C18 SepPak Light® solid-phase extraction cartridge by syringe pressurization of the reactor headspace, collecting that SepPak eluate as waste. The SepPak was then washed with 5-mL sterile saline, followed by air. Finally, the [62Cu]Cu-ETS product was recovered by elution of the C18 SepPak with 0.75-mL ethanol, followed by 1.0-mL sterile saline to rinse the lines. The resulting solution of [62Cu]Cu-ETS was then diluted with an additional 9-mL sterile saline, and filtered through a sterile 0.2-µm PVDF filter to yield final product. Quality control for the first [62Cu]Cu-ETS product batch of the day consisted of TLC assessment of radiochemical purity (silica gel plate and/or ITLC-SA strip eluted with ethanol); confirmation of the bubble point of the filtration unit; measurement of final product pH; measurement of bacterial endotoxin levels in the final product; assessment of 62Zn-breakthrough; and a retrospective USP sterility test. Results: Synthesis of the [62Cu]Cu-ETS radiopharmaceutical was reliably and conveniently effected through use of the ITG iQS®Fluidic Module. In three process validation runs, radiochemical purity of the [62Cu]Cu-ETS product averaged 97.7 ± 0.8%, with product 62Zn-breakthrough levels of 6.9 x 10-7± 5.6 x 10-7% (decay-corrected to start-of-elution). The final product solutions were sterile, pH 5, and had endotoxin levels <5.00 EU/mL (the detection limit of the test). Conclusions: With its sterile plumbing pathway comprised of medical-grade components, this manually operated synthesis apparatus can serve as a convenient platform for synthesis of 62Cu-radiopharmaceuticals. Support for this work was provided by R01 CA202695.