The Current Status of the Production and Supply of Gallium-68

The interest in Gallium-68 (⁶⁸Ga) has increased tremendously in the recent past due to (1) it becoming a routinely used radioisotope in clinical positron emission tomography (PET) imaging facilities around the world, and (2) its coordination chemistry applies to the development of ¹⁷⁷Lu-labeled theranostic agents. For example, ⁶⁸Ga-labeled somatostatin receptor-specific peptides, DOTA-TATE (NETSPOT) and DOTA-TOC in the United States and DOTA-TOC (SomaKit) in the European Union, are being used successfully for neuroendocrine tumor imaging. In addition, worldwide clinical trials with ⁶⁸Ga-labeled Prostate-Specific Membrane Antigen (PSMA) target-specific ligands, PSMA-11 and PSMA-617, are ongoing for prostate cancer imaging. ^1,2 The objective of the present report is to summarize the background and the current status of the production and supply of ⁶⁸Ga.

As a history and background, Mendeleev, in 1871, predicted an unknown element, eka-aluminum, in his periodic table and believed that it would be directly below aluminum with 68 atomic mass. ³ Four years later, Boisbaudran discovered Ga element from the observation of two violet lines in the spectrum of a material separated from zinc blend. ⁴ Ga was named from the Latin word Gallia for Gaul, the native place of Boisbaudran in France. Electropositive Ga, with the most common and stable oxidation state of +3, 47–62 pm ionic radius, and sluggish water-exchange rate, belongs to group 13 of the periodic table of the elements. Due to high charge density, Ga³⁺ is highly acidic with a pK_a of 2.6 and is easily hydrolyzed to Ga(OH) _n (where n = 1–4) under even acidic conditions. All of the hydrolyzed species, except Ga(OH)₄ ⁻, are insoluble in the aqueous medium. Due to the strong affinity of Ga³⁺ for hydroxide, it tends to demetallate from its complexes to form soluble Ga(OH)₄ ⁻ and has a strong binding affinity toward transferrin. ⁵

The design of a Ga-based imaging pharmaceutical involves using a bifunctional chelating agent that (1) is capable of keeping the metal bound to a chelator in the in vivo environment, and (2) conjugates to a receptor-specific biomolecule. Generally, acyclic (HBED-CC)* and macrocyclic polyaminocarboxylates (NOTA and DOTA)* chelating agents have been found to form thermodynamically stable and kinetically inert metal chelates. ⁵ These properties led to the development of ⁶⁸Ga-labeled DOTA-TATE, DOTA-TOC, PSMA-11, and PSMA-617 as commercial and potential PET imaging pharmaceuticals, respectively.

Ga has two naturally occurring stable isotopes, ⁶⁹Ga and ⁷¹Ga, with 60.11% and 39.89% natural abundance, respectively. Three Ga radionuclides are available for the radiolabeling of biomolecules as potential imaging pharmaceuticals. ⁶⁶Ga (t _1/2 = 9.49 h, β⁺ 56.5%, E_{β+, max} 4.15 MeV; electron capture [EC] 43.5%, E_γ, _max 4.0 MeV) and ⁶⁸Ga (t _1/2 = 67.71 min, β⁺ 89%, E_{β+, max} 1.9 MeV; EC 11%, E_{γ max} 4.0 MeV) decay by positron emission and consequently are suitable for PET imaging. ⁶⁷Ga (t _1/2 = 78.3 h, γ 37%, 93.3 keV; γ 24.4%, 184.6 keV, γ 16.6%, 300.2 keV) decays by gamma-emission and is used as a SPECT (single-photon emission computed tomography) imaging agent. ⁶⁶Ga is an attractive radionuclide, due to its longer half-life than ⁶⁸Ga, for evaluation of biomolecules with slow clearance rate as imaging pharmaceuticals; however, limited research is conducted related to its production and use as a potential PET imaging pharmaceutical. ⁶ This is due to its high positron energy, which lowers the resolution of images and has the potential to give high radiation dose to patients as it emits multiple γ rays with energies above 1 MeV. ⁶⁸Ga radioisotope is a pure orbital EC decay product of germanium-68 (⁶⁸Ge) isotope (a long-lived radioisotope with t _1/2 = 270.9 d), which is produced by the proton bombardment of ⁶⁹Ga, via a p,2n nuclear reaction. ⁶⁷Ga citrate is used worldwide in the detection of tumors and infections in various inflammatory diseases. It also has the potential to become a therapeutic agent in the future due to the emission of Auger electrons.

⁶⁸Ga is currently produced using ⁶⁸Ge/⁶⁸Ga generator systems in the clinical and research environments. Current commercially available generators contain ⁶⁸Ge adsorbed onto a solid chromatographic support, although the first generator, “a positron cow” by Gleason, was based on a liquid/liquid extraction technique. ⁷ Numerous researchers were involved in the development of ⁶⁸Ge/⁶⁸Ga generators with various solid supports, organic resins, ⁸ and nano-zirconia and modified polymer solid support. ⁹ Progress in the development of ⁶⁸Ge/⁶⁸Ga generators was slow after the late seventies due to (1) inadequate design of the generators, and (2) rapid development of new classes of ^99mTc and ¹⁸ F-labeled imaging pharmaceuticals.

However, the pioneering achievement of Russian radiochemists resulted in the development of a new ⁶⁸Ge/⁶⁸Ga generator, which became commercially available in the early years of the 21st century. Since then, several ⁶⁸Ge/⁶⁸Ga generators have become available for research and the manufacture of clinical-grade imaging pharmaceuticals. For example, titanium dioxide-based IGG100 (Eckert & Ziegler), Galli EO (IRE Elit), Obninsk (Cyclotron Co. Ltd.), tin dioxide-based iThemba (iThemba Labs), and dodecyl gallate-modified silica-based ITG (ITG) are supplied for research use. Two TiO₂-based ⁶⁸Ge/⁶⁸Ga generators, Gallia Pharm (Eckert & Ziegler) and Galli Ad (IRE Elit) with open drug master files with the Food and Drug Administration (FDA) are available for human clinical use. The eluted [⁶⁸Ga]GaCl₃, from these generators, meets European Pharmacopeia's specifications. The commercial generators are supplied with 10–100 mCi capacity, have very low ⁶⁸Ge-breakthrough (<0.001%–0.005% depending on the supplier), very low metal/chemical impurities, and are eluted with 0.05–0.6 M HCl. Claimed elution yields and shelf-lives are 60%–80% and 6–12 months or 250–400 elutions, respectively. ^10,11 Fifty and ninety percent of ⁶⁸Ga radioactivity is regenerated in 68 min and 4 h, respectively, for the next elution of the generator. The cost of the generators is high and varies depending on the supplier and/or the grade. Until recently, the supply of ⁶⁸Ge/⁶⁸Ga generators, specifically the good manufacturing practices (GMP) grade, had a long lead time to acquire (up to 18 months). Recently, the situation related to the supply of ⁶⁸Ga generators has improved (lead time being ∼3 months) due to the availability of an alternate supplier for a GMP-grade generator and increased production capacity of the original supplier. It is anticipated that there may be ⁶⁸Ge/⁶⁸Ga generator production and supply issues again in the future when there will be increasing demand for PET imaging, particularly when PSMA imaging agents are approved and become reimbursable.

Production of ⁶⁸Ga radionuclide using cyclotrons has been proposed by the researchers as an alternative to ⁶⁸Ge/⁶⁸Ga generators due to (1) limited supply of ⁶⁸Ga each day, (2) the recurring replacement cost per year due to a shelf-life of 9–12 months, (3) the challenging and expensive disposal of radioactive waste of spent generators, which creates a need for long-term storage, and (4) high price of the generators is due to limited supply of ⁶⁸Ge. ⁶⁸Ge can be produced in a high-energy accelerator using a variety of potential nuclear reactions. Some of the potential nuclear reactions are ⁶⁹Ga (p,2n)⁶⁸Ge, ^natGa(p,xn)⁶⁸Ge where x = 2 and 4, ^natGe(p,pxn)⁶⁸Ge, ⁶⁹Ga(d,3n)⁶⁸Ge, ⁶⁶Zn(α,2n)⁶⁸Ge, and ^66,67,68Zn( ³ He,xn)⁶⁸Ge where x = 1–3. There are a limited number of worldwide sites (Cyclotron Co., iThemba Laboratories, Brookhaven National Laboratory, Los Alamos National Laboratory, Institute of Nuclear Physics, Institute for Nuclear Research, and Orsay) for production of ⁶⁸Ge. ⁶⁸Ge is currently being produced by 60–640-h-long proton (20 to ∼60 MeV energy and 40–125 μA current) bombardment of Ga targets on various metallic backings. Typical yields are in the 9.2–32 Ci/Ah range. ¹²

Proton bombardment of enriched ⁶⁸Zn target by a cyclotron produces ⁶⁸Ga by the ⁶⁸Zn(p,n)⁶⁸Ga nuclear reaction in the 11–14 MeV energy range. For high-purity ⁶⁸Ga production, the proton beam energy must be optimized due to the threshold energy for producing ⁶⁷Ga from competing ⁶⁸Zn(p,2n)⁶⁷Ga reaction being 12 MeV.

The pioneering work ¹³ involving ∼14 MeV and 20 μA proton irradiation of 1.7 M solution of ⁶⁸Zinc nitrate in 0.2 N nitric acid, in a liquid target, for 30 min, followed by cation-exchange column purification produced 1.925 GBq ⁶⁸Ga with 5.20–6.27 GBq/μg molar activity. Furthermore, a 45 μA proton beam energy irradiation of 30 mg/mL ⁶⁸Zn(NO₃)₂ solution for 45 min yielded 6 GBq of ⁶⁸Ga. A production of 40 GBq of ⁶⁸Ga was anticipated by optimization of concentration and beam parameters. ¹⁴ The highest cyclotron production yield of ⁶⁸Ga (9.85 GBq) was achieved by 60 min of 45 μA proton beam energy irradiation of 1.42 M ⁶⁸Zn(NO₃)₂ solution in 1.42 M HNO₃, ¹⁵ although some studies have shown limited production of 2.5–4.3 GBq ⁶⁸Ga. ^16,17

Numerous studies involving electrodeposited ⁶⁸Zn on copper, platinum, and silver targets have been reported in the past. ^{18 –22} The targets were irradiated by protons at 30–150 μA current and 12–15 MeV incident beam energy. It was reported in 2009 that up to 189 GBq of ⁶⁸Ga (end of beam, EOB) can be produced by 150 μA current and 15 MeV energy proton beam bombardment of ⁶⁸Zn electrodeposited on copper target for 0.25 h. ¹⁸ Lower amounts of ⁶⁸Ga, 6.3–60.9 GBq (EOB), were produced by irradiating ⁶⁸Zn/platinum targets with 30–35 μA current and 14.5 MeV energy beam for 8.5 to 60 min. ^20,21 More recent studies used ⁶⁸Zn deposited on silver targets and an ARTMS Quantum irradiation system for the production of ⁶⁸Ga. The EOB ⁶⁸Ga and end of separation (EOS) [⁶⁸Ga]GaCl₃ yields exceeded 140 and 70 GBq, respectively, when the target was irradiated for 105 min with 40 μA current and 13 MeV energy beam, leading to the production of curie quantities of the ⁶⁸Ga-labeled HBED-CC. ²¹ A most recent study, under similar conditions except increasing the beam current to 80 μA and irradiation time to 120 min led to the production of increased amounts of ⁶⁸Ga, >370 GBq (EOB) and 194 GBq (EOS).

From the results presented above, as expected, it can be concluded that solid targets produce higher amounts of ⁶⁸Ga than liquid targets. On the contrary, the ⁶⁸Ge/⁶⁸Ga generators produce a limited amount of radioactivity, typically 2.7 GBq ⁶⁸Ga per elution, and they are successfully used in the clinical environment. Multiple elutions per day are possible from the generators providing additional amounts of radioactivity and improved radionuclide quality. A comparison of maximum radioactivity produced by the three methods is given in Table 1.

While ⁶⁸Ge/⁶⁸Ga generators are successfully being used in the clinical environment, for example, the use of a generator for radiolabeling of imaging tracers such as DOTA-TATE is now simple and requires a relatively inexpensive automatic synthesizer and a shielded hood. However, each generator can only produce a sufficient amount of ⁶⁸Ga each day for a limited number of patients. For a larger patient population, cyclotron production of ⁶⁸Ga, using a solid or a liquid target, is a more attractive choice, which requires (1) a major capital investment in the cyclotron facility or availability of spare capacity in the existing facility, (2) working with complex targets, (3) the need for enriched material, (4) development of rapid, reliable, and robust processes, (4) the need for purification steps before the final radiolabeling step, and (4) the approval by the regulatory agencies. The major advantage of cyclotrom methods is that no Ge breakthrough exists. In summary, the three ⁶⁸Ga production methods are important, however, the choices between the three methods in the clinical environment can be made based on the patient needs, available resources, and the regulatory status of the method.