QC evaluation of 62Cu bis(thiosemicarbazone) instant synthesis kits for PET imaging

Abstract

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Objectives: Lyophilized kit formulations for facile clinical synthesis of 62Cu-PTSM, 62Cu-ETS, and 62Cu-ATSM have been developed by Proportional Technologies (PTI). This work seeks to 1) Demonstrate large lot GMP production of the lyophilized kits. 2) Establish release specifications and testing methods to evaluate API dose uniformity and purity, verify sterility and apyrogenicity, and demonstrate high radiochemical labeling yield upon addition of generator produced 62Cu.

Methods: Aqueous solutions of the three ligands were prepared with 20 mg/mL excipient and sterile filtered. The solutions were then shipped to a vendor for sterile lyophilization. One mL aliquots of each solution were lyophilized in individual 5 mL serum vials and sealed under N2. Following return of the kits, routine quality control assays were performed on 2% of each lot, including dose uniformity, identity, purity, pyrogenicity, and sterility. Radiochemical 62Cu labeling yield was also evaluated, and kit-produced complex identities were confirmed using HPLC comparison to the cold copper complexes.

Results: Recently, 800 – 900 unit batches of all three ligand kits were produced under GMP conditions. All three batches exhibited negative sterility and endotoxin tests and >95% radiochemical labeling. Purity of the API remained comparable (93 – 98%) to the raw ligands prior to lyophilization. Trace metal contamination in the kits (primarily Zn) did not affect radiochemical labeling yields due to the extremely high Cu complex formation constant compared to Zn.

Conclusions: The PTI-developed lyophilized bis(thiosemicarbazone) kits are readily produced under GMP conditions. In combination with the PTI 62Cu microgenerator, the kits provide a convenient and reliable means for instant clinical site synthesis of 62Cu complexes for use in PET imaging.