Process validation, cGMP production, dosimetry, and toxicity studies of the CAIX imaging agent [(111)In]XYIMSR-01 for phase I regulatory approval

INTRODUCTION: [(111)In]XYIMSR-01 is a promising single-photon emission computed tomography (SPECT) imaging agent for identification of tumors that overexpress carbonic anhydrase IX. To translate [(111)In]XYIMSR-01 to phase I trials, we performed animal toxicity and dosimetry studies, determined the maximum dose for human use, and completed the chemistry, manufacturing and controls component of a standard regulatory application. METHODS: The production process, quality control testing, stability studies, and specifications for sterile drug product release were based on United States Pharmacopeia chapters and , FDA 21 CFR part 212. Toxicity was evaluated by using non-radioactive [(113/115)In]XYIMSR-01 according to 21 CFR part 58 guidelines. OLINDA/EXM was used to calculate the maximum single dose for human studies. RESULTS: Three process validation runs at starting radioactivities of ~ 800 MBq were completed with a minimum concentration of 407 MBq/mL and radiochemical purity of ≥ 99 % at the end-of-synthesis. A single intravenous dose of 55 μg/mL of [(113/115)In]XYIMSR-01 was well-tolerated in male and female Sprague-Dawley rats. The calculated maximum single dose for human injection from dosimetry studies was 390.35 MBq of [(111)In]XYIMSR-01. CONCLUSION: We have completed toxicity and dosimetry studies as well as validated a manufacturing process to test [(111)In]XYIMSR-01 in a phase I clinical trial.