Evaluation of the Efficacy and Safety of the ITM 68Ge/68Ga Generator After its Recommended Shelf-life

Tossaporn  Sriprapa; Thanete  Doungta; Nopparath Sakulsamart; Nilmanee  Taweewatthanasopon; Lanyawat  Madputeh; Pitima  Ragchana; Napamon  Sritongkul; Malulee  Tantawiroon; Somlak  Kongmuang; Benjapa  Khiewvan; Shuichi Shiratori

doi:10.33192/smj.v75i10.264289

Authors

Tossaporn Sriprapa Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
Thanete Doungta Thailand Institute of Nuclear Technology, Bangkok 10900, Thailand
Nopparath Sakulsamart Bachelor of Pharmacy, Department of Pharmacy, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
Nilmanee Taweewatthanasopon Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
Lanyawat Madputeh Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
Pitima Ragchana Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
Napamon Sritongkul Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
Malulee Tantawiroon Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
Somlak Kongmuang Department of Pharmaceutical Technology, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand
Benjapa Khiewvan Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
Shuichi Shiratori Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand

DOI:

https://doi.org/10.33192/smj.v75i10.264289

Keywords:

68Ge/68Ga Generator, 68Ge Breakthrough, 68Ge/68Ga Generator impurities, Gallium-68, 68Ge/68Ga Generator shelf-life

Abstract

Objective: ⁶⁸Ga can be routinely produced by a ⁶⁸Ge/⁶⁸Ga generator without the need for a cyclotron. It is recommended to replace the ⁶⁸Ge/⁶⁸Ga generator after 250 elutions or 12 months of shelf-life whichever endpoint is reached first. However, a ⁶⁸Ge/⁶⁸Ga generator that has gone past its recommended lifespan can still be further used as a ⁶⁸Ga source for ⁶⁸Ga-labeled radiopharmaceuticals for use in animal experiments. To ensure the quality of ⁶⁸Ga eluates, we aimed to evaluate the efficacy and safety of the ITM (Isotope Technologies München) ⁶⁸Ge/⁶⁸Ga generator in our institute after its recommended shelf-life.

Materials and Methods: A 21-month-old ITM ⁶⁸Ge/⁶⁸Ga generator was eluted using 4.0 ml of 0.05 M HCl. The ⁶⁸Ga elution yields were calculated, and ⁶⁸Ge breakthrough was measured at least 48 h after elution in an aliquot amount using a multichannel analyzer (MCA) with a high-purity germanium probe. Metal impurities in the ⁶⁸Ga eluates were analyzed by ICP-MS.

Results: The elution yield of ⁶⁸Ga was 35.2 ± 8.1%; n = 5 (decay corrected). ⁶⁸Ge breakthrough from the ITM ⁶⁸Ge/⁶⁸Ga generator was below the detectable level. The average amounts of the metallic ions ⁵⁷Fe, ⁶⁶Zn, ²⁰³Pb, ⁶⁰Ni, and ⁶³Cu were 18.60, 9.86, 2.42, 0.52, and 0.47 µg/GBq, respectively.

Conclusion: The ITM ⁶⁸Ge/⁶⁸Ga generator demonstrated consistent and reliable ⁶⁸Ga elution profiles with an absence of either ⁶⁸Ge breakthrough or other metal contaminants in the eluent samples as verified by the manufacturer. The use of the ITM ⁶⁸Ge/⁶⁸Ga generator could be extended past its recommended shelf-life to prepare ⁶⁸Ga radiopharmaceuticals that are considered safe and suitable for use in animal experimentation and other applications.

References

Sarko D, Eisenhut M, Haberkorn U, Mier W. Bifunctional chelators in the design and application of radiopharmaceuticals for oncological diseases. Curr Med Chem. 2012;19(17):2667-88.

Schuhmacher J, Zhang H, Doll J, Mäcke HR, Matys R, Hauser H, et al. GRP receptor-targeted PET of a rat pancreas carcinoma xenograft in nude mice with a 68Ga-labeled bombesin(6-14) analog. J Nucl Med. 2005;46(4):691-9.

Jeong JM, Hong MK, Chang YS, Lee Y-S, Kim YJ, Cheon GJ, et al. Preparation of a promising angiogenesis PET imaging agent: 68Ga-labeled c(RGDyK)-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid and feasibility studies in mice. J Nucl Med. 2008;49(5):830.

Mier W, Hoffend J, Krämer S, Schuhmacher J, Hull WE, Eisenhut M, et al. Conjugation of DOTA Using Isolated Phenolic Active Esters: The Labeling and Biodistribution of Albumin as Blood Pool Marker. Bioconjug Chem. 2005;16(1):237-40.

Hoffend J, Mier W, Schuhmacher J, Schmidt K, Dimitrakopoulou-Strauss A, Strauss LG, et al. Gallium-68-DOTA-albumin as a PET blood-pool marker: experimental evaluation in vivo. Nucl Med Biol. 2005;32(3):287-92.

Baum RP, Prasad V, Müller D, Schuchardt C, Orlova A, Wennborg A, et al. Molecular imaging of HER2-expressing malignant tumors in breast cancer patients using synthetic 111In- or 68Ga-labeled affibody molecules. J Nucl Med. 2010;51(6):892-7.

Werner RA, Bluemel C, Allen-Auerbach MS, Higuchi T, Herrmann K. 68Gallium- and 90Yttrium-/ 177Lutetium: "theranostic twins" for diagnosis and treatment of NETs. Ann Nucl Med. 2015;29(1):1-7.

Eiber M, Weirich G, Holzapfel K, Souvatzoglou M, Haller B, Rauscher I, et al. Simultaneous (68)Ga-PSMA HBED-CC PET/MRI Improves the Localization of Primary Prostate Cancer. Eur Urol. 2016;70(5):829-36.

Prasad V, Steffen IG, Diederichs G, Makowski MR, Wust P, Brenner W. Biodistribution of [(68)Ga]PSMA-HBED-CC in Patients with Prostate Cancer: Characterization of Uptake in Normal Organs and Tumour Lesions. Mol Imaging Biol. 2016;18(3):428-36.

Cytawa W, Seitz AK, Kircher S, Fukushima K, Tran-Gia J, Schirbel A, et al. (68)Ga-PSMA I&T PET/CT for primary staging of prostate cancer. Eur J Nucl Med Mol Imaging. 2020;47(1):168-77.

Derlin T, Weiberg D, von Klot C, Wester HJ, Henkenberens C, Ross TL, et al. (68)Ga-PSMA I&T PET/CT for assessment of prostate cancer: evaluation of image quality after forced diuresis and delayed imaging. Eur Radiol. 2016;26(12):4345-53.

Antunes P, Ginj M, Zhang H, Waser B, Baum RP, Reubi JC, et al. Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals? Eur J Nucl Med Mol Imaging. 2007;34(7):982-93.

Reubi JC, Schär JC, Waser B, Wenger S, Heppeler A, Schmitt JS, et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27(3):273-82.

Hofmann M, Maecke H, Börner R, Weckesser E, Schöffski P, Oei L, et al. Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data. Eur J Nucl Med. 2001;28(12):1751-7.

Kowalski J, Henze M, Schuhmacher J, Mäcke HR, Hofmann M, Haberkorn U. Evaluation of positron emission tomography imaging using [68Ga]-DOTA-D Phe(1)-Tyr(3)-Octreotide in comparison to [111In]-DTPAOC SPECT. First results in patients with neuroendocrine tumors. Mol Imaging Biol. 2003;5(1):42-8.

Wild D, Mäcke HR, Waser B, Reubi JC, Ginj M, Rasch H, et al. 68Ga-DOTANOC: a first compound for PET imaging with high affinity for somatostatin receptor subtypes 2 and 5. Eur J Nucl Med Mol Imaging. 2005;32(6):724.

Wild D, Schmitt JS, Ginj M, Mäcke HR, Bernard BF, Krenning E, et al. DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals. Eur J Nucl Med Mol Imaging. 2003;30(10):1338-47.

Kratochwil C, Flechsig P, Lindner T, Abderrahim L, Altmann A, Mier W, et al. (68)Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer. J Nucl Med. 2019;60(6):801-5.

Spreckelmeyer S, Balzer M, Poetzsch S, Brenner W. Fully-automated production of [68Ga]Ga-FAPI-46 for clinical application. EJNMMI Radiopharmacy and Chemistry. 2020;5(1):31.

Lin M, Waligorski GJ, Lepera CG. Production of curie quantities of (68)Ga with a medical cyclotron via the (68)Zn(p,n)(68)Ga reaction. Appl Radiat Isot. 2018;133:1-3.

Rodnick ME, Sollert C, Stark D, Clark M, Katsifis A, Hockley BG, et al. Cyclotron-based production of (68)Ga, [(68)Ga]GaCl(3), and [(68)Ga]Ga-PSMA-11 from a liquid target. EJNMMI Radiopharm Chem. 2020;5(1):25.

Velikyan I. 68Ga-Based radiopharmaceuticals: production and application relationship. Molecules. 2015;20(7):12913-43.

Romero E, Martínez A, Oteo M, Ibañez M, Santos M, Morcillo MÁ. Development and long-term evaluation of a new 68Ge/68Ga generator based on nano-SnO2 for PET imaging. Sci Rep. 2020;10(1):12756.

https://rusatom-energy.com/media/rosatom-news/rosatom-facility-gains-record-revenues-from-stable-isotopes-sales/

M. Harfensteller, R. Henkelmann, J. Moreno, O. Leib, T. August, O. Buck, T. Nikula. Gallium-68 a candidate for use in clinical routine. February 3, 2010, CERN.

Eppard E, Loktionova NS, Rösch F. Quantitative online isolation of68Ge from68Ge/68Ga generator eluates for purification and immediate quality control of breakthrough. Appl Radiat Isot 2013;82:45-48.

Chakravarty R, Chakraborty S, Ram R, Vatsa R, Bhusari P, Shukla J, et al. Detailed evaluation of different (68)Ge/(68)Ga generators: an attempt toward achieving efficient (68)Ga radiopharmacy. J Labelled Comp Radiopharm. 2016;59(3):87-94.

Uğur A, Yaylali O, Yüksel D. Examination of metallic impurities of 68Ge/68Ga generators used for radioactive labeling of peptides in clinical PET applications. Nucl Med Commun. 2021;42(1):81-85.

Amor-Coarasa A, Kelly JM, Gruca M, Nikolopoulou A, Vallabhajosula S, Babich JW. Continuation of comprehensive quality control of the itG 68Ge/68Ga generator and production of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for clinical research studies. Nucl Med Biol. 2017;53:37-39.

Asti M, De Pietri G, Fraternali A, Grassi E, Sghedoni R, Fioroni F, et al. Validation of 68Ge/68Ga generator processing by chemical purification for routine clinical application of 68Ga-DOTATOC. Nucl Med Biol. 2008;35:721-4.

Amor-Coarasa A, Milera A, Carvajal D, Gulec S, McGoron AJ. Lyophilized Kit for the Preparation of the PET Perfusion Agent [(68)Ga]-MAA. Int J Mol Imaging. 2014;2014:269365.

Lückerath K, Stuparu AD, Wei L, Kim W, Radu CG, Mona CE, et al. Detection Threshold and Reproducibility of 68Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer. J Nucl Med. 2018;59(9):1392-7.