Multi-curie production of gallium-68 on a biomedical cyclotron and automated radiolabelling of PSMA-11 and DOTATATE

Abstract

Background With increasing clinical demand for gallium-68, commercial germanium-68/gallium-68 ([68Ge]Ge/[68Ga]Ga) generators are incapable of supplying sufficient amounts of the short-lived daughter isotope. In this study, we demonstrate a high-yield, automated method for producing multi-Curie levels of [68Ga]GaCl3 from solid zinc-68 targets and subsequent labelling to produce clinical-grade [68Ga]Ga-PSMA-11 and [68Ga]Ga-DOTATATE. Results Enriched zinc-68 targets were irradiated at up to 80 µA with 13 MeV protons for 120 min; repeatedly producing up to 194 GBq (5.24 Ci) of purified gallium-68 in the form of [68Ga]GaCl3 at the end of purification (EOP) from an expected > 370 GBq (> 10 Ci) at end of bombardment. A fully automated dissolution/separation process was completed in 35 min. Isolated product was analysed according to the Ph. Eur. monograph for accelerator produced [68Ga]GaCl3 and found to comply with all specifications. In every instance, the radiochemical purity exceeded 99.9% and importantly, the radionuclidic purity was sufficient to allow for a shelf-life of up to 7 h based on this metric alone. Fully automated production of up to 72.2 GBq [68Ga]Ga-PSMA-11 was performed, providing a product with high radiochemical purity (> 98.2%) and very high apparent molar activities of up to 722 MBq/nmol. Further, manual radiolabelling of up to 3.2 GBq DOTATATE was performed in high yields (> 95%) and with apparent molar activities (9–25 MBq/nmol) sufficient for clinical use. Conclusions We have developed a high-yielding, automated method for the production of very high amounts of [68Ga]GaCl3, sufficient to supply proximal radiopharmacies. The reported method led to record-high purified gallium-68 activities (194 GBq at end of purification) and subsequent labelling of PSMA-11 and DOTATATE. The process was highly automated from irradiation through to formulation of the product, and as such comprised a high level of radiation protection. The quality control results obtained for both [68Ga]GaCl3 for radiolabelling and [68Ga]Ga-PSMA-11 are promising for clinical use.

Development of [225Ac]Ac-PSMA-I&T for Targeted Alpha Therapy According to GMP Guidelines for Treatment of mCRPC

“…The validation of the used equipment (dose calibrator, radio-(i)TLC, HPGe-detector, gamma counter, and HPLC) and related quality control techniques were based upon the European Association of Nuclear Medicine (EANM) guidelines [ 32 ] and in accordance with Good Manufacturing Practice (GMP) guidelines [ 33 ]. From the output of the analytical techniques (radio-(i)TLC and HPGe-detector), the radiochemical yield (RCY) was calculated, which is defined as the ratio (%) between labeled [ 225 Ac]Ac-PSMA-I&T and free Ac-225 and/or [ 225 Ac]Ac-DTPA (total Ac-225 activity).…”

[68Ga]Ga-PSMA-11: The First FDA-Approved 68Ga-Radiopharmaceutical for PET Imaging of Prostate Cancer

“…Using a liquid target of up to 9.85 GBq of 68 Ga might be achievable, while using a solid target, it might be up to 194 GBq [ 38 ]. Recent studies have also evaluated the production of 68 Ga-labeled tracers (e.g., [ 68 Ga]Ga-PSMA-11) with cyclotron-produced 68 Ga and obtained approximately 1.65 GBq of end product (liquid target production [ 39 ]) and up to 72.2 GBq of end product (solid target production [ 40 ]), respectively. The recognition of the cyclotron production of 68 Ga as an accepted manufacturing route is further demonstrated by the recent release of the European Pharmacopoeia monograph “Gallium ( 68 Ga) chloride (accelerator-produced) solution for radiolabeling” (01/2021:3109) [ 41 ] and by the FDA approval of the production of [ 68 Ga]Ga-PSMA-11 using cyclotron-produced 68 Ga at UCSF.…”

Aktuelle radiopharmazeutische Entwicklungen für die theranostische Anwendung

“…Hierbei ist zu beachten, dass sich bei einer Radiomarkierung mit Fluor-18 statt mit Gallium-68 die pharmakologischen Eigenschaften der resultierenden diagnostischen und therapeutischen Radioliganden möglichst ähnlich sein sollten, um das Theranostik-Prinzip nutzen zu können [17]. Am Zyklotron produziertes Gallium-68 kann inzwischen in großen Mengen für die Herstellung von Radiopharmaka verwendet werden [18,19]. COOH 68 Ga/ 177 Lu ▶ Abb.…”