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) 68Ge/⁶⁸Ga 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 ⁶⁸Ga³⁺ ready for peptide labeling. We characterized the performance of this generator system over a year in conjunction with the production of ⁶⁸Ga-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 68Ge/⁶⁸Ga generator provided metal-free ⁶⁸GaCl₃ 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. ⁶⁸Ga 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, ⁶⁸Ga elution yields from the generator averaged 80% (range, 72.0%-95.1%), and 68Ge breakthrough was less than 0.006%, initially decreasing with time to 0.001% (expressed as percentage of 68Ge activity present in the generator at the time of elution), a unique characteristic of this generator. The radiochemical purity of both ⁶⁸Ga-DOTATOC and ⁶⁸Ga-PSMA-HBED-CC determined by highperformance liquid chromatography analysis was greater than 98%, with aminimumspecific activity of 12.6 and 42 GBq/μmol, respectively. The radionuclidic (68Ge) 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 68Ge/⁶⁸Ga 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 68Ge levels in the final drug products were under the detection limits at all times. ⁶⁸Ga-DOTATOC and ⁶⁸Ga-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.