Ethanol-Based Post-processing of Generator-Derived ⁶⁸Ga Toward Kit-Type Preparation of ⁶⁸Ga-Radiopharmaceuticals

Abstract

Post-processing by means of a cation-exchanger-based protocol is an efficient strategy for purification and concentration of generator-derived 68 Ga. It ensures the removal of 68 Ge before 68 Ga-radiopharmaceutical preparation and high labeling yields of 68 Ga-labeled radiopharmaceuticals for routine medical application. Methods: In an effort to overcome the problem associated with acetone in the currently applied method, we have investigated the feasibility of replacing it with ethanol. The purification of 68 Ga from coeluted metallic impurities ( 68 Ge 41 , Fe 31 , Zn 21 , and Ti 41 ) on various cation-exchange columns has been investigated with a variety of post-processing solutions. As a proof of principle, the post-processed 68 Ga was used to radiolabel DOTATOC in combination with high-purity water and various buffer solutions. Results: An effective protocol for the processing of generator-produced 68 Ga on the basis of cation-exchange chromatography using EtOH/HCl medium has been developed. Up to 95% of the initially eluted 68 Ga activity can be collected in a 1-mL fraction of 90% EtOH/0.9N HCl after removal of 68 Ge-breakthrough in a washing step. The post-processed eluate has been used to radiolabel DOTATOC in yields of approximately 97% ± 0.25% at 80°C in 5 min. Conclusion: The described novel protocol improves the radiolabeling efficiency and efficacy of DOTATOC, providing yields of greater than 99% (decay-corrected). As a result, further purification to separate the desired product from uncomplexed 68 Ga is not necessary. The developed post-processing and labeling protocols permit reliable and high-yield preparation of injectable 68 Ga-DOTATOC (or other 68 Ga-labeled radiopharmaceuticals) that are suitable for routine application. It is possible to incorporate this protocol into existing automated modules.

Experience in production of 68Ga-DOTA-NOC for clinical use under an Expanded Access IND

“…We employed fractionated elution of the EZAG generator system to minimize introduction of trace metals into the [ 68 Ga]Ga-DOTA-NOC reaction mixture, allowing labeling with consistently high yields while avoiding pre-synthesis clean-up of the generator eluate (Di Pierro, et al, 2008;Schultz, et al, 2013;Eppard, et al, 2014)]. Specifically, after discarding the generator void volume, we collected the next ~1.8-mL of EZAG generator eluate for synthesis, transferring 1.5-mL of that volume to the reaction mixture, and using the remainder for the regulatory-mandated half-life measurement (performed during the synthesis heating period), plus a subsequent measure of the level of 68 Ge breakthrough that was present in the reaction mixture.…”

Optimization of Labeling PSMAHBED with Ethanol-Postprocessed 68Ga and Its Quality Control Systems

“…68 Ga obtained from a 1.1-GBq 68 Ge/ 68 Ga generator (IGG100; Eckert & Ziegler Strahlen-und Medizintechnik AG) with a TiO 2 matrix was eluted with 0.1N HCl and postprocessed with ethanol/HCl solution according to a method described in the literature (13,15). PSMA HBED was labeled by adding aliquots (5, 10, 15 mL 5 5, 10, 15 mg 5 5.28, 10.56, 15.84 nmol) of a PSMA HBED stock solution (1 mg/mL) to mixtures of postprocessed 68 Ga eluate (800 mL) and 1 M NaOAc solution (1.6 mL, pH 7), which corresponds to an ethanol content of 33 vol% of the crude reaction solution using the small radiolabeling synthesizer Modular-Lab eazy (Eckert & Ziegler Strahlen-und Medizintechnik AG) and a temperature of 110°C.…”

“…The initial method pioneered by Zhernosekov et al using acetone/hydrochloric acid solutions provides high recovery of 68 Ga and complete removal of 68 Ge, as well as a decrease in acidity, volume, and other metallic impurities (13). A suitable and efficient variation is cation-exchange-based postprocessing using ethanol/hydrochloric acid medium (15). It equally allows concentration of 68 Ga generator eluate, removal of metal impurities, and quantitative removal of 68 Ge breakthrough, ensuring that the final injectable radiopharmaceutical fulfills regulatory requirements relating to 68 Ge content.…”

“…Several methods have been developed for purification of 68 Ga eluate to fulfill regulatory requirements (13)(14)(15). Initial publications on 68 Ga-PSMA HBED used crude 68 Ga generator eluate for 68 Ga labeling of PSMA and highperformance liquid chromatography (HPLC) for quality control.…”

Radiolabeling of DOTA-like conjugated peptides with generator-produced 68Ga and using NaCl-based cationic elution method

“…The resulting final product acetone concentrations are found to be well within regulatory limits for release. Labeling procedures using ethanol instead of acetone have also been published 9,10 . Because of the high concentration of ethanol in the radiopharmaceutical product, the determination of ethanol content is required in many countries.…”