In-house GMP manufacturing of [211At]PSMA-5 solution using an automated synthesizer for investigator-initiated clinical trials

Introduction: The prostate-specific membrane antigen (PSMA) is a major target for the theranostics in prostate cancer. Recently, [211At]PSMA-5, an alpha-therapy drug developed at Osaka University that targets PSMA, has shown excellent tumor growth inhibition in a mouse model of prostate cancer with minimal side effects in normal organs, and is expected to be a new targeted alpha therapy, especially metastatic castration-resistant prostate cancer (1). We optimized the synthesis procedure and confirmed its quality for scale-up production with automated synthesizer of [211At]PSMA-5 for investigator-initiated clinical trials.

Methods: ²¹¹At was produced with the nuclear reaction of ²⁰⁹Bi(⁴He, 2n) using AVF Cyclotron at RIKEN or Research Center for Nuclear Physics, Osaka University. ²¹¹At in irradiated Bi target was purified by an automated dry distillation apparatus installed at the GMP manufacturing facility of Osaka University Hospital. The procedure for recovery of purified ²¹¹At from the trap tube to the reaction vessel was investigated. In the synthesis of [²¹¹At]PSMA-5, the reaction vessel was changed from a 1.5 mL fluoropolymer tube to a 10 mL glass vial to increase the total volume of the reaction solution in order to shift from manual synthesis to an automated synthesizer, and the labeling rate and residual radioactivity in the reaction vessel were checked. The reaction solution was purified with an HLB cartridge and collected through a Millex GV filter as a 15 mL solution. Using an optimized synthesis procedure, four lots of [²¹¹At]PSMA-5 were synthesized (two times by each target) and evaluated for quality as sterile injectable drugs. In addition, the stability of [²¹¹At]PSMA-5 in the final formulation solution after 6 hours of synthesis was checked.

Results: More than 90 % of the purified ²¹¹At was recovered by allowing 700 μL mL of 7 % sodium bicarbonate injection solution to keep for 5 min into the trap tube. Using a glass vial as the reaction vessel, the labeling rate of [²¹¹At]PSMA-5 was over 70% in a 45-minute reaction at 95°C with 1 mL of reaction solution (700 μL of ²¹¹At soluton, 10 µL of 1 mg/mL PSMA-5 precursor and 290 µL of 0.1 M potassium iodide a.q. solution), and the residual radioactivity in the reaction vessel was less than 5 %. [²¹¹At]PSMA-5 produced by the synthesizer under optimized conditions was obtained in 28±3% of radiochemical yield (after decay collection) within 2.5 hours synthesis time. The radiochemical purity was 95±1% at the end of synthesis and still over 90% after 6 hours of synthesis. All other quality test items were also confirmed to meet the specification criteria of [²¹¹At]PSMA-5 solution.

Conclusions: [²¹¹At]PSMA-5 solution was obtained using an automated synthesizer with sufficient radio chemical yield and quality under GMP compliance for investigator-initiated clinical trials.