Production of [211At]NaAt solution under GMP compliance for investigator-initiated clinical trial

Abstract

Background

The alpha emitter astatine-211 (²¹¹At) is garnering attention as a novel targeted alpha therapy for patients with refractory thyroid cancer resistant to conventional therapy using beta emitter radioiodine (¹³¹I). Herein, we aimed to establish a robust method for the manufacturing and quality control of [²¹¹At]NaAt solution for intravenous administration under the good manufacturing practice guidelines for investigational products to conduct an investigator-initiated clinical trial.

Results

²¹¹At was separated and purified via dry distillation using irradiated Bi plates containing ²¹¹At obtained by the nuclear reaction of ²⁰⁹Bi(⁴He, 2n)²¹¹At. After purification, the ²¹¹At 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 ²¹¹At 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 [²¹¹At]NaAt solution. According to the 3-lot tests, decay collected radioactivity and radiochemical yield of [²¹¹At]NaAt were 78.8 ± 6.0 MBq and 40 ± 3%, respectively. The radiochemical purity of [²¹¹At]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 ²¹¹At-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 ²¹⁰At 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 [²¹¹At]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 [²¹¹At]NaAt solution met all quality standards.

Conclusions

We successfully established a stable method of [²¹¹At]NaAt solution that can be administered to humans intravenously as an investigational product.