A “wet chemistry” approach for isolation of ²¹¹At from an irradiated bismuth target is described. The approach involves five steps: (1) dissolution of bismuth target in conc. HNO₃; (2) removal of the HNO₃ by distillation; (3) dissolution of residue in 8 M HCl; (4) extraction of ²¹¹At from 8 M HCl into DIPE; and (5) extraction of ²¹¹At from DIPE into NaOH. Results from 55 “optimized” ²¹¹At isolation runs gave recovery yields of approximately 78% after decay and attenuation corrections. An attenuation-corrected average of 26 ± 3 mCi in the target provided isolated (actual) yields of 16 ± 3 mCi of ²¹¹At. A sixth step, used for purification of ²¹¹At from trace metals, was evaluated in seven runs. In those runs, isolated ²¹¹At was distilled under reductive conditions to provide an average 71 ± 8% recovery. RadioHPLC analyses of the isolated ²¹¹At solutions, both initial and after distillation, were obtained to examine the ²¹¹At species present. The primary species of ²¹¹At present was astatide, but astatate and unidentified species were also observed. Studies to determine the effect of bismuth attenuation on ²¹¹At were conducted to estimate an attenuation factor (~1.33) for adjustment of ²¹¹At readings in the bismuth target.

The objective of this study was to translate reaction conditions and quality control methods used for production of an astatine-211(²¹¹At)-labeled anti-CD45 monoclonal antibody (MAb) conjugate, ²¹¹At-BC8-B10, from the laboratory setting to cGMP production. Five separate materials were produced in the preparation of ²¹¹At-BC8-B10: (1) p-isothiocyanato-phenethyl-closo-decaborate(2-) (B10-NCS), (2) anti-CD45 MAb, BC8, (3) BC8-B10 MAb conjugate, (4) [²¹¹At]NaAt, and (5) ²¹¹At-BC8-B10. The ²¹¹At-labeling reagent, B10-NCS, was synthesized as previously reported. BC8 was produced, then conjugated with B10-NCS under cGMP conditions to form BC8-B10. [²¹¹At]NaAt was produced by α-irradiation of Bi targets, followed by isolation of the ²¹¹At using a “wet chemistry” method. The clinical product, ²¹¹At-BC8-B10, was prepared by reacting [²¹¹At]NaAt with BC8-B10 in NH₄OAc buffer (pH 5.5) for 2 min at room temperature, followed by size-exclusion chromatography purification. Quality control tests conducted on the ²¹¹At-BC8-B10 included evaluations for purity and identity, as well as pyrogen and sterility tests. Stability of the ²¹¹At-BC8-B10 in 25 mg/mL sodium ascorbate solution was evaluated at 1, 2, 4, 6 and 21 h post isolation. For qualification, three consecutive ²¹¹At-BC8-B10 clinical preparations were successfully conducted in the cGMP suite, and an additional cGMP clinical preparation was carried out to validate each step required to deliver ²¹¹At-BC8-B10 to a patient. These cGMP preparations provided 0.80–1.28 Gbq (21.5–34.5 mCi) of ²¹¹At-BC8-B10 with radiochemical purity of >97%. The preparations were found to be sterile and have a pyrogen level 95% for up to 21 h at room temperature. The experiments conducted have defined conditions for translation of ²¹¹At-BC8-B10 production from the laboratory to cGMP suite. This study has allowed the initiation of a phase I/II clinical trial using ²¹¹At-BC8-B10 (NCT03128034).