Radiopharmaceutical Quality Control Considerations for Accelerator-Produced Actinium Therapies

Abstract

Background: Alpha-particle-emitting radiotherapies are of great interest for the treatment of disseminated cancer. Actinium-225 (²²⁵Ac) produces four α-particles through its decay and is among the most attractive radionuclides for use in targeted radiotherapy applications. However, supply issues for this isotope have limited availability and increased cost for research and translation. Efforts have focused on accelerator-based methods that produce ²²⁵Ac in addition to long-lived ²²⁷Ac. Objective: The authors investigated the impact of ²²⁵Ac/²²⁷Ac material in the radiolabeling and radiopharmaceutical quality control evaluation of a DOTA chelate-conjugated peptide under good manufacturing practices. The authors use an automated module under identical conditions with either generator or accelerator-produced actinium radiolabeling. Methods: The authors have performed characterization of the radiolabeled products, including thin-layer chromatography, high-pressure liquid chromatography, gamma counting, and high-energy resolution gamma spectroscopy. Results: Peptide was radiolabeled and assessed at >95% radiochemical purity with high yields for generator produced ²²⁵Ac. The radiolabeling results produced material with subtle but detectable differences when using ²²⁵Ac/²²⁷Ac. Gamma spectroscopy was able to identify peptide initially labeled with ²²⁷Th, and at 100 d for quantification of ²²⁵Ac-bearing peptide. Conclusion: Peptides produced using ²²⁵Ac/²²⁷Ac material may be suitable for translation, but raise new issues that include processing times, logistics, and contaminant detection.

Keywords: accelerator; actinium; generator; translation.

FIG. 1.

Automated Radiosynthesis Module and Conditions. (A) A software-controlled automated procedure was used to ²²⁵Ac-radiolabel the precursor peptide, under GMP conditions in a radiopharmacy hot cell. (B) Schematic representation of the conditions and fluid controls. (C) Radiolabeling schema for the DOTA-conjugated peptide. GMP, good manufacturing practice.

FIG. 2.

Radiochemical Purity Analysis. (A) Radio-instant thin-layer (radio-iTLC) chromatography of ^225/227Ac radiolabeled peptide migrated by DTPA (50 mM). (B) Control radio-iTLC of source ^225/227Ac material under identical conditions. Peak analysis results show >99% radiochemical yield by radio-iTLC of (A). (C) UV-chromatogram from HPLC of the peptide postradiolabeling; DOTA-conjugated radiolabeled peptide peak at 11.7 min is detected. (D) Gamma counting of the HPLC fractionated samples, using an open, 15–800 keV, energy window. Free ions, noncomplexed, ions are detected in fractions 3–4, while the majority of the activity is associated with peptide at 12 mL. Calculation of radiochemical yield by gamma counted HPLC fractions was RCP = 94.2%. HPLC, high-pressure liquid chromatography.

FIG. 3.

Gamma Spectroscopy of HPLC-Purified Peptide. (A) At day 2 postradiolabeling (day of patient injection) the gamma ray lines from ²²⁵Ac and daughters ²²¹Fr and ²¹³Bi are prominent. (B) Magnification of dashed region; presence of ²²⁷Th associated with the radiolabeled peptide. (C) The same fraction evaluated at day 82 and (D) day 100 postradiolabeling. The ²²⁵Ac contribution to the spectra has diminished, while ²²⁷Ac-daughters emissions have reached equilibrium.