Tb-DOTATOC Production Using a Fully Automated Disposable Cassette System: A First Step Toward the Introduction of Tb into the Clinic.

Tb is an interesting radionuclide for application in the treatment of neuroendocrine neoplasms' small metastases and single cancer cells because of its conversion and Auger-electron emission. Tb has coordination chemistry similar to that of Lu; therefore, like Lu, it can stably radiolabel DOTATOC, one of the leading peptides used for the treatment of neuroendocrine neoplasms. However, Tb is a recently developed radionuclide that has not yet been specified for clinical use. Therefore, the aim of the current work was to characterize and specify Tb and to develop a protocol for the synthesis and quality control of Tb-DOTATOC with a fully automated process conforming to good-manufacturing-practice guidelines, in view of its clinical use. Tb, produced by neutron irradiation of Gd in high-flux reactors followed by radiochemical separation from its target material, was characterized regarding its radionuclidic purity, chemical purity, endotoxin level, and radiochemical purity (RCP) in analogy to what is described in the European Pharmacopoeia for no-carrier-added Lu. In addition, Tb was introduced into a fully automated cassette-module synthesis to produce Tb-DOTATOC, as used for Lu-DOTATOC. The quality and stability of the produced radiopharmaceutical in terms of identity, RCP, and ethanol and endotoxin content were assessed by means of high-performance liquid chromatography, gas chromatography, and an endotoxin test, respectively. Tb produced under the described conditions showed, as the no-carrier-added Lu, a pH of 1-2, radionuclidic purity and RCP of more than 99.9%, and an endotoxin level below the permitted range (175 IU/mL), indicating its appropriate quality for clinical use. In addition, an efficient and robust procedure for the automated production and quality control of Tb-DOTATOC with clinically applicable specifications and activity levels, that is, 1.0-7.4 GBq in 20 mL, was developed. The radiopharmaceutical's quality control was also developed using chromatographic methods, which confirmed the product's stability (RCP ≥ 95%) over 24 h. The current study demonstrated that Tb has appropriate features for clinical use. The developed synthesis protocol guarantees high yields and safe preparation of injectable Tb-DOTATOC. The investigated approach could be translated to other DOTA-derivatized peptides; thus, Tb could be successfully applied in clinical practice for radionuclide therapy.