Production of [211At]NaAt solution under GMP compliance for investigator-initiated clinical trial
Sadahiro Naka, Kazuhiro Ooe, Yoshifumi Shirakami, Kenta Kurimoto, Toshihiro Sakai, Kazuhiro Takahashi, Atsushi Toyoshima, Yang Wang, Hiromitsu Haba, Hiroki Kato, Noriyuki Tomiyama, Tadashi Watabe
Abstract
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 At]NaAt 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 At]NaAt solution. According to the 3-lot tests, decay collected radioactivity and radiochemical yield of [ 211 At]NaAt were 78.8 ± 6.0 MBq and 40 ± 3%, respectively. The radiochemical purity of [ 211 At]At − 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 At]NaAt 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 At]NaAt solution met all quality standards. Conclusions We successfully established a stable method of [ 211 At]NaAt solution that can be administered to humans intravenously as an investigational product.