Abstract
1059
Objectives: Due to the use of the positron emitter 68Ga in radiopharmaceuticals for the diagnosis of malignant tumors using PET / CT, the global demand for 68Ge/68Ga generators increased rapidly. Approved generators cannot meet this demand due to the low number of manufacturing sites, which results in delivery times of one year or more. Hospitals with pronounced patient care with 68Ga labeled radiopharmaceuticals are forced to use unauthorized 68Ge/68Ga generators under a temporary agreement of their authorities. Therefore the maximum of 68Ge breakthrough and the concentration on foreign ions of the generator eluate must be tested regularly to meet the pharmaceutical specifications. Here we present methods for performing the pharmaceutically required tests, which can be easily included in the routine clinical production of 68Ga labeled radiopharmaceuticals.
Methods: For each production of 68Ga labeled PSMA-11 or DOTATOC the 68Ga activity of up to three 68Ge/68Ga generators from ITG and Eckert & Ziegler were used. The collected eluates of the generators were passed through an SCX cartridge (conditioned with 5M HCl and 10 ml of water) using a synthesis module (Scintomics / Eckert & Ziegler Pharmtracer). The 68Ga remained on the SCX-cartridge was eluted with 0.5 ml of concentrated hydrochloric NaCl solution into the reaction vessel containing the reaction buffer and the corresponding precursor (PSMA-11 or DOTATOC). After the labeling (5-7 min), the reaction mixture was diluted with 3 mL of water for injection and sterile filtered. Samples for quality control (ITLC-SG, pH, radionuclidic purity / 68Ge breakthrough, endotoxin test, sterility test) were taken. After 72 h the 68Ge breakthrough in the final product was determined by an HPGe detector (full decay of 68Ga). During the incoming control of the 68Ge/68Ga generators, the concentration of iron and zinc ions in the generator eluate was determined by colorimetrical tests (Iron Test, Zinc Test Merckmillipore) to meet Ph.Eur.-Requirements.
Results: Colorimetric metal ion concentration tests are extremely inexpensive as well as accurate in comparison to the alternative to the Ph. Eur. recommended determination by atomic absorption spectroscopy (AAS). The specifications for zinc and iron (maximum of 10 μg per GBq) were easily met by ITG and E&Z generators and could be determined to be < 1 μg iron and zinc / GBq 68Ga, respectively. The 68Ge breakthrough in the generator eluate of the ITG-generator was higher than the Ph. Eur. prescribed 0.001%, which renders the need for advanced procedures for removal of 68Ge impurities. The SCX purification which was carried out prior to the radiolabeling reduced the 68Ge concentration significantly. Therefore the limit value for 68Ge of 0.001 % in the final product could be achieved routinely. Despite the use of multiple older generators with a correspondingly lower amount of 68Ga activity and higher 68Ge content, parallel elution and use of the described procedure provided a sufficient amount of 68Ga for the synthesis of radiopharmaceuticals.
Conclusions: These results demonstrate that patient care with 68Ga-radiopharmaceuticals can be ensured in compliance with GMP guidelines by using non-approved generators (under a temporary agreement of the authorities), despite the current shortage of approved 68Ge/68Ga generators. Incoming control procedures in addition to post-processing of the generator eluate using SCX pre-purification are suitable to meet Ph. Eur. Requirements (68Ge breakthrough).