Compounding of [177Lu]Lu-PSMA-I&T using USP grade solvents in the radiopharmacy: experience in Quebec City

Introduction: Objectives: Radiolabeling with ¹⁷⁷Lu is usually performed using solvents and reagents of trace metal quality, including ultra-pure water for preparation of solutions and buffers, as well as pH-modifying additives.¹ On the other hand, USP- and GMP-grade materials are favored by regulators for the preparations that will be administered to humans. These, however, are normally not tested or certified for traces of metals. In a context of a typical nuclear medicine department that often is not equipped with the full suite of specialized instrumentation and chemistry expertise to prepare and quality-control radiopharmaceuticals from chemical grade materials, a kit-like protocol using commercially available approved excipients could be useful and could expand patients' access to the investigational drugs radiolabeled with ¹⁷⁷Lu. This project investigates the use of commercially available USP grade sterile water for injection and USP grade sterile sodium acetate injection in the preparation of [¹⁷⁷Lu]Lu-PSMA-I&T, a DOTA-like conjugated peptide.

Methods: Methods: Commercially available USP grade solutions were used as received. The bioactive precursor, PSMA-I&T (in the form of trifluoroacetic acid (TFA) salt or as acetate), was of GMP grade and provided with a certificate of analysis. The radionuclide was supplied as [¹⁷⁷Lu]LuCl₃(c.a or n.c.a) in 0.04 N HCl solution of GMP quality with specific activity ranging from 880 to 3984 GBq/mg Lu but typically 1050-1250 GBq/mg Lu. All consumables (syringes, needles, vials, etc.) were purchased sterile. Radiopharmaceutical preparation was performed manually in aseptic manner in a biosafety cabinet (ISO 5 clean air). A molar ratio of PSMA-I&T to LuCl₃ ("cold" mass) was at least 2:1. The precursors (PSMA-I&T, [¹⁷⁷Lu]LuCl₃) and diluents (water for injection, 4M sodium acetate solution for injection) were combined in a vial affording a solution of pH~5, which was then heated at 98°C for 30 min. The radiochemical purity was determined using thin-layer chromatography (iTLC-SG glass microfiber paper impregnated with silica gel developed in methanol:1M ammonium acetate (1:1 v/v) and TLC silica gel plates developed in 0.1M sodium citrate). The chromatograms were visualized with AR-2000 TLC reader. The final volume was adjusted with USP-grade 0.9% saline and sterilized by filtration.

Results: Results: Over 20 multi-dose preparations were performed in 2021. Typically, ~30 GBq [¹⁷⁷Lu]LuCl₃ was used for radiolabeling. At least two-fold molar excess of the precursor PSMA-I&T over the lutetium mass was essential to drive the reaction to completion. The radiolabeling efficiency exceeded 95% in all cases. On average, the radiochemical purity of the final product was greater than 97%. All formulated batches met internally established quality specifications. It should be noted that PSMA-I&T precursor as TFA salt was easily soluble in water or diluted HCl. In contrast, lyophilized PSMA-I&T acetate was poorly soluble in water and dissolved much better in sodium acetate buffer.

Conclusions: Conclusions: [¹⁷⁷Lu]Lu-PSMA-I&T can be easily prepared in a typical nuclear medicine department using commonly available excipients such as USP grade water for injection and USP grade sodium acetate injection suggesting that intrinsic concentration of metals in these commercially available liquids is well tolerated by the radiolabeling reaction at tested conditions. A standard operating procedure was developed to facilitate the preparation of [¹⁷⁷Lu]Lu-PSMA-I&T by nuclear medicine technologists.