Determination of 226Ra in 225Ac Active Pharmaceutical Ingredients by ICP-QQQ-MS

Growing demand for 225Ac-radiopharmaceuticals in targeted α therapy (TAT) has led to the development of new and diverse 225Ac manufacturing processes. While this has augmented global 225Ac supply, it has also created a need for common analytical methods to ensure 225Ac active pharmaceutical ingredients (APIs) meet uniform expectations for safety and efficacy. A particular challenge is the measurement of long-lived radionuclidic impurities (e.g., 227Ac, 226Ra, or 229Th). Many of the common radiometric techniques for radiopharmaceutical quality control suffer from poor sensitivity and long measurement times when applied to long-lived radionuclides. Mass spectrometry presents an attractive alternative owing to greater sensitivity for long-lived radionuclides and faster sample measurement. Several new 225Ac manufacturing processes use the long-lived radionuclide 226Ra as a starting material. This work reports a method for the determination of 226Ra in 225Ac APIs using triple quadrupole inductively coupled plasma mass spectrometry (ICP-QQQ-MS). The sensitivity and interference formation characteristics of multiple instrument modes (STD, KED, O2) were evaluated to identify the best configuration for 226Ra determination. The polyatomic ion 225Ac1H+ was identified as an interference at m/z = 226 in both STD mode and KED mode, however, the use of O2 as a reaction gas effectively removed this interference. Thus, the measurement of 226Ra at m/z = 226 → 226 in O2 reaction mode provided the best combination of sensitivity and specificity. This methodology was evaluated against appropriate criteria for accuracy, precision, specificity, linearity, and lower range limits. Accuracy and precision were evaluated by spike recovery studies using 226Ra spiked 225Ac API solutions. Spike recoveries were 85–114% for samples with 0.0500 to 0.997 ng L –1 of 226Ra. Repeatability (n = 6, one analysis) and intermediate precision (n = 12, two analyses) were evaluated by replicate determinations of 226Ra spiked samples (0.499 ng L–1) giving RSDs of 3.8% and 6.5%, respectively. The instrumental detection limit and quantitation limit were estimated to be 0.010 ng L–1 (0.36 Bq L–1) and 0.030 ng L–1 (1.1 Bq L–1), respectively. The proposed methodology allows for rapid, sensitive determination of 226Ra in 225Ac APIs. Implementation into 225Ac manufacturing processes will support high standards of product safety and efficacy.