Applying quality by design principles to the small-scale preparation of the bone-targeting therapeutic radiopharmaceutical rhenium-188-HEDP

Introduction Rhenium-188-HEDP (¹⁸⁸Re-HEDP) is a therapeutic radiopharmaceutical for treatment of osteoblastic bone metastases. No standard procedure for the preparation of this radiopharmaceutical is available. Preparation conditions may influence the quality and in vivo behaviour of this product. In this study we investigate the effect of critical process parameters on product quality and stability of ¹⁸⁸Re-HEDP. Methods A stepwise approach was used, based on the quality by design (QbD) concept of the ICH Q8 (Pharmaceutical Development) guideline. Potential critical process conditions were identified. Variables tested were the elution volume, the freshness of the eluate, the reaction temperature and time, and the stability of the product upon dilution and storage. The impact of each variable on radiochemical purity was investigated. The acceptable ranges were established by boundary testing. Results With 2 ml eluate, adequate radiochemical purity and stability were found. Nine ml eluate yielded a product that was less stable. Using eluate stored for 24 h resulted in acceptable radiochemical purity. Complexation for 30 min at room temperature, at 60 °C and at 100 °C generated appropriate and stable products. A complexation time of 10 min at 90 °C was too short, whereas heating 60 min resulted in products that passed quality control and were stable. Diluting the end product and storage at 32.5 °C resulted in notable decomposition. Conclusion Two boundary tests, an elution volume of 9 ml and a heating time of 10 min, yielded products of inadequate quality or stability. The product was found to be instable after dilution or when stored above room temperature. Our findings show that our previously developed preparation method falls well within the proven acceptable ranges. Applying QbD principles is feasible and worthwhile for the small-scale preparation of radiopharmaceuticals.