177Lu-ITG-PSMA-1: Development of a fully automatized in-hospital production

J. Delage, J. Costes, K. Casagrande, T. Baumgartner, J. Caputo, J. De Figueiredo, O. Fabre, P. Houlmann, F. Sadeghipour
HU de Lausanne, Suisse

Introduction
177Lu-ITG-PSMA-1 is a beta particle-emitting radioactive therapeutic agent indicated for the treatment of progressive, metastatic, castration-resistant prostate cancer (CRPCa) in adult male patients whose disease expresses prostate-specific membrane antigen (PSMA). The substance is characterized by high selectivity and specificity to PSMA, which is overexpressed in CRPCa patients.
177Lu-ITG-PSMA-1 is produced by a complexation reaction of the radiometal 177Lu non carrier added and the peptide ITG-PSMA-1. The aim of our work was to develop and automate this synthesis in order to produce this new radiotracer in our hospital.

Material and method
We developed a fully automated process on a Mini Aio Trasis synthezisor. The complexation reaction was performed in acetate buffer at pH 4-5 and with thermal heating (90°C for 25 min) of 115 µg ITG-PSMA-1 and 4.0 – 8.0 GBq of 177Lu . At the end of the incubation, the drug substance is eluted through a sterile filter into the product vial. Then, NaCl 0,9% is added to the product vial to dilute the solution.
Regarding the quality control, the radiochemical purity (RCP) of 177Lu-ITG-PSMA-1 was determined by radio-HPLC and calculated by the following equation: RCP (%) = 100 – (177LuCl3 (%) + other impurities (%)). The radiochemical stability was demonstrated by measuring RCP until 24h post-production. UV HPLC was used to confirm the identity of 177Lu-ITG-PSMA-1 using a non-radioactive standard and quantified the amount of ITG-PSMA-1 injected to the patient. The concentration of ascorbate in the drug product, which should be ≥ 7 mg/mL. was measured with a semi quantitative method. Due to the long half life of 177Lu, sterility tests were achieved with simulated labelling. Sterility endotoxin tests were performed in accordance to Ph. Eur. An automated filter integrity test was performed on the final sterile filter.

Results
The three validation batches of 177Lu- ITG-PSMA-1 were synthetized with an activity of 7.75 ± 0.31 GBq. The application volume was from 18 mL to 20 mL. The RCP was 96.9 ± 0.25 %. The 177LuCl3 impurity was quantified and the results obtained were respectively 0.4, 0.2 and 0.3%. Based on the stability data, a shelf life of 6h was defined. The concentration of ascorbate met the specification. The retention time comparison between the standard and 177Lu-ITG-PSMA-1 was inferior to 30s. The maximum amount of ITG-PSMA-1 injected, including inactive metallic complex, was inferior to 6 µg/mL. The bubble point test was superior to 3 bars for each batch. The drug products were sterile and endotoxin free.

Discussion
The automatized production of 177Lu- ITG-PSMA-1 was successfully implemented in our hospital. The reproductibility, the cost and the availability of this in house production allows to increase the access of the patient with CRPa to this innovative therapeutic radiopharmaceutical in our hospital.

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