Abstract
242092
Introduction: Medical isotope production within the framework of current Good Manufacturing Practice (cGMP) has primarily been steered by a Quality by Testing approach. However, this conventional strategy can lead to product variability and potential batch failure, leading to a disruption in the medical isotope supply chain. In the recent past, failures of this nature have been detrimental to the Nuclear Medicine Industry. To address these challenges, the industry continues to transition towards a Quality by Design (QbD) philosophy. This framework emphasizes developing a design space through thorough understanding and control of manufacturing process variability. One such tool to understand this variability is through Design of Experiments (DoEs), which allows one to thoroughly explore process parameters and their potential interplay as well as overall effect on product quality.
In the irradiation phase of isotope production, multiple complex factors are at play, and applying DoEs at this stage of isotope production presents unique challenges due to the technical complexity and high costs. This paper proposes an innovative solution: the adoption of theoretical DoEs to effectively evaluate critical irradiation parameters.
Methods: The creation of accelerator-derived medical isotopes involves a dynamic interplay between the characteristics of the particle beam (energy and current) and the target material. This interaction leads to multiple, competing nuclear reactions, the yields and purity of which are determined by the excitation functions representing the nuclear reaction cross-sections. These functions are instrumental in estimating the production efficiency of specific radionuclides and the level of radioimpurities present. Because such a multitude of factors are at play, and the interplay between these parameters can be challenging to test, theoretical DoEs can play an integral role in understanding how irradiation parameters impact medical isotope product quality.
Results: One such instance of this irradiation parameter interplay is in the production of Germanium-68 (Ge-68) derived from Gallium-Nickel (GaNi) targets. The intricate nature of this process necessitates meticulous control over several irradiation parameters, which can significantly influence the Critical Quality Attributes (CQAs) such as radionuclidic purity. In this instance, following a theoretical DoE can aid in establishing the critical irradiation parameters.
Following this approach for Ge-68 first requires a model to be built based on physics principles that will then enable theoretical multivariate experiments to be performed. Once the model is developed the interactions between the substrate and irradiation parameters, directly affecting the quality of the final product can be continuously modeled and subsequently refined using experimental data, enhancing its accuracy in predicting product and impurity yields.
The Pareto plot produced after following this DoE approach allow us to visually identify the important effects and compare the relative magnitude of the various effects. For the production of Ge-68 from Gallium, the largest effect on radionuclidic purity is the time period between EOB and Calibration (G). This methodology underscores its effectiveness in refining control strategies for irradiation inputs, propelling advancements in medical isotope production.
Conclusions: The implementation of DoEs, particularly in selecting target materials and determining irradiation parameters, is essential yet can be neglected due to perceived complexities and costs. These stages, however, are critical for establishing a robust and high-quality manufacturing process, significantly impacting CQAs. By synergizing theoretical and experimental data, this approach can be integral to the design process of medical isotope manufacturing leading to more reliable medical isotope production.
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