Production of 211AtNaAt solution under GMP compliance for investigator-initiated clinical trial

Abstract Background The alpha emitter astatine-211 ( 211 At) is garnering attention as a novel targeted alpha therapy for patients with refractory thyroid cancer resistant to conventional therapy using beta emitter radioiodine ( 131 I). Herein, we aimed to establish a robust method for the manufacturing and quality control of 211 AtNaAt solution for intravenous administration under the good manufacturing practice guidelines for investigational products to conduct an investigator-initiated clinical trial. Results 211 At was separated and purified via dry distillation using irradiated Bi plates containing 211 At obtained by the nuclear reaction of 209 Bi( 4 He, 2n) 211 At. After purification, the 211 At trapped in the cold trap was collected in a reaction vessel using 15 mL recovery solution (1% ascorbic acid and 2.3% sodium hydrogen carbonate). After stirring the 211 At solution for 1 h inside a closed system, the reaction solution was passed through a sterile 0.22 μm filter placed in a Grade A controlled area and collected in a product vial to prepare the 211 AtNaAt solution. According to the 3-lot tests, decay collected radioactivity and radiochemical yield of 211 AtNaAt were 78.8 ± 6.0 MBq and 40 ± 3%, respectively. The radiochemical purity of 211 AtAt − obtained via ion-pair chromatography at the end of synthesis (EOS) was 97 ± 1%, and remained > 96% 6 h after EOS; it was detected at a retention time (RT) 3.2–3.3 min + RT of I − . LC-MS analysis indicated that this principal peak corresponded with an astatide ion (m/z = 210.988046). In gamma-ray spectrometry, the 211 At-related peaks were identified (X-ray: 76.9, 79.3, 89.3, 89.8, and 92.3 keV; γ-ray: 569.7 and 687.0 keV), whereas the peak at 245.31 keV derived from 210 At was not detected during the 22 h continuous measurement. The target material, Bi, was below the 9 ng/mL detection limit in all lots of the finished product. The pH of the 211 AtNaAt solution was 7.9–8.6; the concentration of ascorbic acid was 9–10 mg/mL. Other quality control tests, including endotoxin and sterility tests, confirmed that the 211 AtNaAt solution met all quality standards. Conclusions We successfully established a stable method of 211 AtNaAt solution that can be administered to humans intravenously as an investigational product.