Development of separation technology for the removal of radium-223 from targeted thorium conjugate formulations. Part II: purification of targeted thorium conjugates on cation exchange columns

摘要

Tumor targeting pharmaceuticals will play a crucial role in future pharma pipelines. The targeted thorium conjugate (TTC) therapeutic platform could provide real benefit to patients, whereby targeting moieties like monoclonal antibodies are radiolabelled with the alpha-emitting radionuclide thorium-227 (Th-227, t(1/2) = 18.7 days). A potential problem could be the accumulation of the long-lived daughter nuclide radium-223 (Ra-223, t(1/2) = 11.4 days) in the drug product during manufacturing and distribution. Therefore, the level of Ra-223 must be standardized before administration to the patient. The focus in this study has been the removal of Ra-223, as the other progenies will have a very limited stay in the formulation. In this study, the purification of TTCs labeled with decayed Th-227 has been explored. Columns packed with a strong cation exchange resin have been used to sequester Ra-223. The separation of TTC from Ra-223 has been evaluated as influenced by both formulation and process parameters with a design of experiments (DOE) study; including citrate or acetate buffer, pH, buffer concentration, presence or absence of pABA+DTA, resin amount and sodium chloride concentration. The aim was to achieve a separation with high sorption of Ra-223 and accompanying low TTC sorption. The results were analyzed by multivariate analysis. Four regression models of TTC and Ra-223 sorption from citrate and acetate buffered formulations were developed. The predictive accuracy of sorption in the four statistical models was given by standard deviations and confidence intervals. The TTC sorption in citrate and acetate buffered formulations was affected by the identical variables and the variation in TTC sorption was comparable for the two models. However, the DOE variables had a significantly stronger impact on the Ra-223 sorption in citrate buffered formulations than the Ra-223 sorption in acetate buffer. An optimal separation with a TTC sorption below 25% and Ra-223 sorption above 90% can be achieved in both citrate and acetate buffered formulations. Stability studies of radiochemical purity (RCP) indicated that the measured Th-227 values may be partly due to free Th-227 and not TTC, but the results indicate that TTC stability may be controlled by optimizing formulation parameters. Hence, the sorption data and the regression models presented must be reviewed and further explored with regard to what is known about the stability of the TTC in the different buffered formulations.