Comprehensive Quality Control of the ITG 68Ge/68Ga Generator and Synthesis of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for Clinical Imaging

A good-manufacturing-practices (GMP) Ge-68/Ga-68 generator that uses modified dodecyl-3,4,5-trihydroxybenzoate hydrophobically bound to a octadecyl silica resin (C-18) as an adsorbent has been developed that allows for dilute HCl (0.05N) to efficiently elute metal-impurity-free Ga-68(3+) ready for peptide labeling. We characterized the performance of this generator system over a year in conjunction with the production of Ga-68-labeled DOTATOC and Glu-NH-CO-NH-Lys(Ahx)-HBED-CC (PSMA-HBED-CC) intended for clinical studies and established protocols for batch release. Methods: A 2,040-MBq self-shielded Ge-68/Ga-68 generator provided metal-free (GaCl3)-Ga-68 ready for peptide labeling in the fluidic labeling module after elution with 4 mL of 0.05N HCl. The compact system was readily housed in a laminar flow cabinet allowing an ISO class-5 environment. Ga-68 labeling of peptides using GMP kits was performed in 15-20 min, and the total production time was 45-50 min. Batch release quality control specifications were established to meet investigational new drug submission and institutional review board approval standards. Results: Over a period of 12 mo, Ga-68 elution yields from the generator averaged 80% (range, 72.0%-95.1%), and Ge-68 breakthrough was less than 0.006%, initially decreasing with time to 0.001% (expressed as pertentage of Ge-68 activity present in the generator at the time of elution), a unique characteristic of this generator. The radiochemical purity of both Ga-68-DOTATOC and Ga-68-PSMA-HBED-CC determined by high-performance liquid chromatography analysis was greater than 98%, with a minimum specific activity of 12.6 and 42 GBq/pmol, respectively. The radionuclidic (Ge-68) impurity was 0.00001% or less (under the detection limit). Final sterile, pyrogen-free formulation was provided in physiologic saline with 5%-7% ethanol. Conclusion: The GMP-certified Ge-68/Ga-68 generator system was studied for a year. The generator system is contained within the fluidic labeling module, and it is compact, self-shielded, and easy to operate using simple manual techniques. The system provides radiolabeled peptides with high (>98%) radiochemical purity and greater than 80% radiochemical yield. The Ge-68 levels in the final drug products were under the detection limits at all times. Ga-68-DOTATOC and Ga-68-PSMA-HBED-CC investigational radiopharmaceuticals are currently being studied clinically under investigational new drug (IND) applications submitted to the U.S. Food and Drug Administration.