Comprehensive quality control of the ITG 68Ge/68Ga generator and synthesis of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for clinical imaging

Alejandro Amor-Coarasa, Megan Schoendorf, Marian Meckel, Shankar Vallabhajosula, John W. Babich

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1402-1405
Number of pages4
JournalJournal of Nuclear Medicine
Volume57
Issue number9
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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Quality Control
Peptides
Limit of Detection
Investigational New Drug Application
Metals
Investigational Drugs
Pyrogens
Radiopharmaceuticals
Research Ethics Committees
United States Food and Drug Administration
Carbon Monoxide
Liquid Chromatography
Silicon Dioxide
Ethanol
N,N'-bis(2-hydroxy-5-(ethylene-beta-carboxy)benzyl)ethylenediamine N,N'-diacetic acid
Ga(III)-DOTATOC
Pharmaceutical Preparations

Keywords

  • Ga generator
  • Ga-dotatoc quality control
  • Ga-PSMA-HBED-CC

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Comprehensive quality control of the ITG 68Ge/68Ga generator and synthesis of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for clinical imaging. / Amor-Coarasa, Alejandro; Schoendorf, Megan; Meckel, Marian; Vallabhajosula, Shankar; Babich, John W.

In: Journal of Nuclear Medicine, Vol. 57, No. 9, 01.09.2016, p. 1402-1405.

Research output: Contribution to journalArticle

Amor-Coarasa, Alejandro ; Schoendorf, Megan ; Meckel, Marian ; Vallabhajosula, Shankar ; Babich, John W. / Comprehensive quality control of the ITG 68Ge/68Ga generator and synthesis of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for clinical imaging. In: Journal of Nuclear Medicine. 2016 ; Vol. 57, No. 9. pp. 1402-1405.
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abstract = "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.",
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AU - Schoendorf, Megan

AU - Meckel, Marian

AU - Vallabhajosula, Shankar

AU - Babich, John W.

PY - 2016/9/1

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N2 - 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.

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KW - Ga-dotatoc quality control

KW - Ga-PSMA-HBED-CC

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