Desenvolvimento de método por ICP-MS utilizando AQbD para determinação de impurezas elementares em soluções injetáveis

Abstract

The presence of elemental impurities (EI) in medicines, such as heavy metals, represents a risk to human health due to their high toxicity even at low concentrations, and to ensure patient safety, it is essential to carry out a rigorous assessment of these contaminants. The international guideline ICH Q3D (International Council for Harmonisation Guideline Q3D: Guideline for Elemental Impurities) establishes PDE (Permitted Daily Exposure) limits based on toxicological data and the route of drug administration. In addition, chapters of the USP (United States Pharmacopeia) describe modern analytical techniques, such as ICP-MS (Inductively Coupled Plasma Mass Spectrometry) and ICP OES (Inductively Coupled Plasma Optical Emission Spectrometry), which allow for the detection and quantification of these impurities with high sensitivity, constituting an effective quality control system. In view of the need to identify and control inorganic contaminants originating from raw materials, manufacturing processes, equipment, and packaging in the final product, this work aims to develop a safe and validated analytical method using ICP-MS, through AQbD (Analytical Quality by Design), for the determination of the 24 elemental impurities controlled by the guideline in injectable-matrix pharmaceuticals. To achieve this objective, the ATP (Analytical Target Profile) was defined as a method capable of quantifying IE in injectable solutions, with an average and individual recovery percentage between 70 and 150%, RSD ≤ 20%, discovery curve scanning coefficient ≥ 0.99, and a detection limit greater than 0.2 J μg/L. If the method is capable of quantifying the element at concentrations equal to or lower than 30% of “J”, it may, in some cases, even eliminate the need for continuous monitoring. Next, a cause-and-effect (Ishikawa) diagram was developed with the aim of identifying the potential critical method parameters of the analytical procedure. These parameters were subsequently classified according to their risk using the FMEA (Failure Mode and Effects Analysis) tool, resulting in the selection of four experimental factors with the greatest potential impact on the analytical response: nebulizer gas flow (L/min), plasma power (W), acidity of the diluent solution (% HNO₃), and sample dilution factor. These factors were evaluated at three coded levels (–1, 0, +1), following an experimental design based on a CCD (Central Composite Design), implemented using the statistical software Minitab. The study generated a total of 155 experiments, aiming to model and understand variations in the analytical response resulting from intentional changes in the selected parameters. This approach sought to define the method’s MODR (Method Operable Design Region), within which analytical performance meets the criteria established in the ATP, ensuring robustness, precision, and reliability throughout the method’s lifecycle. The results obtained showed recovery values consistent with the applied spiking levels, falling close to the upper limit of the specification range (100%). Given the robustness, consistency, and analytical performance observed, it was concluded that the parameters defined in the DoE (Design of Experiments) are suitable for adoption as the definitive method, both for constructing analytical calibration curves and for sample preparation, ensuring reliability and reproducibility in subsequent processes.