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) (68)Ge/(68)Ga 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 (68)Ga(3+) ready for peptide labeling. We characterized the performance of this generator system over a year in conjunction with the production of (68)Ga-labeled DOTATOC and Glu-NH-CO-NH-Lys(Ahx)-HBED-CC (PSMA-HBED-CC) intended for clinical studies and established protocols for batch release.



A 2,040-MBq self-shielded (68)Ge/(68)Ga generator provided metal-free (68)GaCl3 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. (68)Ga 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.



Over a period of 12 mo, (68)Ga elution yields from the generator averaged 80% (range, 72.0%-95.1%), and (68)Ge breakthrough was less than 0.006%, initially decreasing with time to 0.001% (expressed as percentage of (68)Ge activity present in the generator at the time of elution), a unique characteristic of this generator. The radiochemical purity of both (68)Ga-DOTATOC and (68)Ga-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/μmol, respectively. The radionuclidic ((68)Ge) impurity was 0.00001% or less (under the detection limit). Final sterile, pyrogen-free formulation was provided in physiologic saline with 5%-7% ethanol.



The GMP-certified (68)Ge/(68)Ga 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 (68)Ge levels in the final drug products were under the detection limits at all times. (68)Ga-DOTATOC and (68)Ga-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.
Department of Radiology, Weill Cornell Medicine, New York, New York; and.
Alejandro
A
Amor-Coarasa
Department of Radiology, Weill Cornell Medicine, New York, New York; and.
Megan
M
Schoendorf
Isotope Technologies Garching GmbH, Garching, Germany.
Marian
M
Meckel
Department of Radiology, Weill Cornell Medicine, New York, New York; and.
Shankar
S
Vallabhajosula
Department of Radiology, Weill Cornell Medicine, New York, New York; and job2060@med.cornell.edu.
John W
JW
Babich
D004340:Drug Contamination / Q000517:prevention & control; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis / Q000592:standards; D004867:Equipment Design; D019544:Equipment Failure Analysis; D005709:Gallium Isotopes; D005710:Gallium Radioisotopes; D007553:Isotope Labeling / Q000295:instrumentation / Q000592:standards; D009518:New York; D015282:Octreotide / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis / Q000592:standards; D009842:Oligopeptides / Q000032:analysis / Q000138:chemical synthesis* / Q000592:standards*; D009942:Organometallic Compounds / Q000032:analysis / Q000138:chemical synthesis* / Q000592:standards*; D011786:Quality Control; D011876:Radionuclide Generators / Q000295:instrumentation* / Q000592:standards*
C499142:Ga(III)-DOTATOC; D005709:Gallium Isotopes; D005710:Gallium Radioisotopes; D009842:Oligopeptides; D009942:Organometallic Compounds; C000718244:gallium 68 PSMA-11; D004492:Edetic Acid; D015282:Octreotide
68Ga generator; 68Ga-DOTATOC; 68Ga-PSMA-HBED-CC; quality control