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

中文翻译：

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符合 GMP 要求的 [211At]NaAt 溶液的生产，用于研究者发起的临床试验

α 发射体砹-211 (211At) 作为一种新型靶向 α 疗法而受到关注，该疗法适用于对使用 β 发射体放射性碘 (131I) 的常规疗法产生耐药性的难治性甲状腺癌患者。在此，我们的目标是根据研究产品的良好生产规范指南，建立一种用于静脉注射的[211At]NaAt溶液的生产和质量控制的稳健方法，以进行研究者发起的临床试验。使用由 209Bi(4He, 2n)211At 的核反应获得的含有 211At 的辐照 Bi 板，通过干蒸馏分离和纯化 211At。纯化后，使用15mL回收溶液(1％抗坏血酸和2.3％碳酸氢钠)将冷阱中捕获的211At收集到反应容器中。在密闭系统内搅拌 211At 溶液 1 h 后，将反应溶液通过置于 A 级控制区域的无菌 0.22 μm 过滤器，并收集在产品瓶中以制备[211At]NaAt 溶液。根据3批测试，衰变收集的[211At]NaAt放射性和放射化学产率分别为78.8±6.0MBq和40±3%。在合成结束 (EOS) 时通过离子对色谱获得的 [211At]At− 的放射化学纯度为 97 ± 1%，并在 EOS 后 6 小时保持 > 96%；它是在保留时间 (RT) 3.2–3.3 分钟 + I− 的 RT 处检测到的。 LC-MS 分析表明该主峰对应于砹离子 (m/z = 210.988046)。在伽马射线光谱测定中，识别出与 211At 相关的峰（X 射线：76.9、79.3、89.3、89.8 和 92.3 keV；γ 射线：569.7 和 687.0 keV），而源自 210At 的 245.31 keV 处的峰为22小时连续测量中未检测到。所有批次成品中的目标材料 Bi 均低于 9 ng/mL 检测限。 [211At]NaAt溶液的pH值为7.9–8.6；抗坏血酸的浓度为 9–10 mg/mL。其他质量控制测试，包括内毒素和无菌测试，证实 [211At]NaAt 溶液符合所有质量标准。我们成功建立了一种稳定的 [211At]NaAt 溶液方法，可以作为研究产品静脉注射给人类。