{"id":1589,"date":"2025-06-03T15:08:54","date_gmt":"2025-06-03T08:08:54","guid":{"rendered":"https:\/\/htiscientific.vn\/?p=1589"},"modified":"2025-06-03T17:00:25","modified_gmt":"2025-06-03T10:00:25","slug":"thu-nghiem-va-tham-dinh-tap-chat-trong-duoc-pham-theo-ich-q3d-va-usp-su-dung-nexion-1100-icp-ms","status":"publish","type":"post","link":"https:\/\/htiscientific.vn\/en\/thu-nghiem-va-tham-dinh-tap-chat-trong-duoc-pham-theo-ich-q3d-va-usp-su-dung-nexion-1100-icp-ms\/","title":{"rendered":"Testing and Validation of Elemental Impurities in Pharmaceutical Products According to ICH Q3D and USP \/ Using the NexION 1100 ICP-MS"},"content":{"rendered":"

In 2018, the United States Pharmacopeia (USP) in General Chapters 1 and 2 updated the list of elements and maximum permissible daily exposure (PDE) values of elemental impurities in drugs, pharmaceutical substances, and raw materials. The USP is now aligned with the International Council for Harmonization (ICH) Q3D (R2) Step 5, the latest version of which was adopted in 2022.<\/span><\/p>\n

Chapter specifies the list of elements and their maximum permissible daily exposure (PDE) values according to the modes of administration: oral, parenteral (intravenous injection) and inhalation drugs. Chapter details the sample preparation, analytical procedures, and quality control validation protocols for the analysis of elements specified in Chapter . The (ICH) Q3D (R2) Step 5 guidelines apply to the same group of pharma products and drug substances with the addition of limits for elemental impurities delivered via the cutaneous and transcutaneous route. It is a riskbased testing protocol for the assessment of the potential presence of toxic elements.<\/span><\/p>\n

USP suggests adaptability of both ICP-OES and ICP-MS technologies for impurities analysis. However, the choice of technology depends on the permitted daily exposure (PDE), dosage forms and amount of daily dosage. ICP-OES has the sensitivity and linear dynamic range to handle some oral drug products; however, for the lowest limits of detection and widest linear range of calibrations, ICP-MS is the ideal technique.<\/span><\/p>\n

In Table 1, the regulated elements and PDE limits from ICH Q3D are shown according to the routes of drug administration. They are divided in three classes (1, 2A\/2B and 3), according to toxicity and likelihood of their occurrence in the drug products. For example, Class 1 and 2A, at a minimum, must be included in the risk assessment in all categories of drug products.<\/span><\/p>\n

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B\u1ea3ng 1:\u00a0Harmonized List of Elements and Established PDEs for Elemental Impurities<\/span>\u00a0<\/em><\/span><\/p>\n

When the PDE values expressed in \u00b5g\/day are changed to \u00b5g\/g or \u00b5g\/L based on a maximum daily dose, they are called Target Limits or Permitted Concentration. After a dilution factor is taken into account, they become J values that are calculated as follows:<\/span><\/p>\n

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PerkinElmer offers a USP\/ICH kit4 that, among other components, includes a J Calculator for accurate calculation of J values of elemental impurities, making standard preparation and method development much easier. This study focuses on the practical benefits of the NexION\u00ae 1100 ICP-MS5 for the determination of a group of toxicologically relevant elements in a large volume of parenteral (LVP) pharmaceutical products. It gives an overview of the USP methodology, with particular emphasis on the impurity levels and the recommended analytical procedures. Figures of merit for the system, based on the USP validation protocol for the method, are presented.<\/span><\/p>\n

Experimental<\/strong><\/span><\/p>\n

Sample Preparation<\/strong><\/span><\/p>\n

A high-purity NaCl solution (seaBlank, 10-11% NaCl, Elemental Scientific Inc., Omaha, Nebraska, USA) was used to prepare the simulated large volume parenteral (LVP) saline solutions (0.9% NaCl) by an 11-fold dilution into a solution made of 2% HNO3 and 2% HCl. The simulated LVP saline solution thus prepared were further diluted 2-fold with the 2% HNO3 and 2% HCl solution into a final salinity of 0.45% before analysis. The USP requires the instrument calibration based on a minimum of two standards (0.5J and 1.5J). Pharmaceutical companies often use 0.3J as risk assessment. In extreme cases, if the sample contains an equal amount of J, samples spiked 1.5J will result in a concentration of 2.5J. Therefore, the low standard includes 0.3J and the high standard reaches 3J. Calibration standard concentrations are shown in Table 2.<\/span><\/p>\n

The calibration standards were prepared by diluting commercial multi-element and single-element standards (see Consumables Used table) to concentrations based on PDEs, dilution factor of 2, and 2 L\/day dose of saline solution samples. Internal standards consist of 1000 ppb Ge, 20 ppb Tb, and 20 ppb Bi in 2% HNO3 and 2% HCl and were mixed online with the blanks, standards and samples.<\/span><\/p>\n

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Table\u00a0<\/span>2. PDEs (\u00b5g\/day) and Calibration Standard Concentrations (\u00b5g\/L) for LVP Saline Solution<\/span><\/em><\/span><\/p>\n

Instrumental<\/strong><\/span><\/p>\n

A NexION 1100 ICP-MS (PerkinElmer, Shelton, Connecticut, USA) was used for the analysis of LVP saline samples in accordance with USP Chapters \/ and ICH Q3D. The NexION with patented ion optics design \u2014 the Triple Cone Interface-Quadrupole Ion Deflector combination and the quadrupole-based Universal Cell \u2014 combines the simplicity and convenience of a traditional collision cell with exceptional detection limits. In this application, helium was used as a collision gas for the measurement of all elements using Collision (KED) mode.<\/span><\/p>\n

The cell gas flows were optimized for the best detection limits following the instrument operation manual.6 A default RPq (cell rejection parameter) was used for all the analytes to simplify method development. The elements, their isotopes, and helium (He) gas flows used for the analysis are listed in Table 3.<\/span><\/p>\n

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B\u1ea3ng 3. Method Setup and Linearity<\/span><\/em><\/span><\/p>\n

All Matrix Solution (AMS) with a flow of argon into the spray chamber neck, usually used for high-TDS samples, was applied here to stabilize signal, and afforded an additional 2-fold dilution.<\/span><\/p>\n

C\u00e1c th\u00f4ng s\u1ed1 v\u1eadn h\u00e0nh thi\u1ebft b\u1ecb \u0111\u01b0\u1ee3c hi\u1ec3n th\u1ecb trong B\u1ea3ng 4. Trong ch\u1ebf \u0111\u1ed9 va ch\u1ea1m (KED), t\u1ef7 l\u1ec7\u00a035<\/sup>Cl16<\/sup>O\/59<\/sup>The instrument operating parameters are shown in Table 4. In Collision (KED) mode, the ratio of 35Cl16O\/59Co is typically 0.5%. For V analysis of a LVP saline sample, 35Cl16O+\/59Co+ should be adjusted to less than 0.3%. Newly cleaned cones need to be conditioned prior to sample analysis. In this method, the cones were conditioned by aspirating 0.45% NaCl in 2% HNO3 and 2% HCl and monitoring the internal standards until the signals stabilized. The system was then washed by aspirating ultrapure water followed by 2% HNO3 and 2% HCl before starting the sample runs.\u00a035<\/sup>Cl16<\/sup>O+ \/59<\/sup>Co+ c\u1ea7n \u0111\u01b0\u1ee3c \u0111i\u1ec1u ch\u1ec9nh xu\u1ed1ng d\u01b0\u1edbi 0,3%. C\u00e1c cone m\u1edbi \u0111\u01b0\u1ee3c l\u00e0m s\u1ea1ch c\u1ea7n \u0111\u01b0\u1ee3c \u0111i\u1ec1u ch\u1ec9nh tr\u01b0\u1edbc khi ph\u00e2n t\u00edch m\u1eabu. Trong ph\u01b0\u01a1ng ph\u00e1p n\u00e0y, c\u00e1c cone \u0111\u01b0\u1ee3c \u0111i\u1ec1u ch\u1ec9nh b\u1eb1ng c\u00e1ch h\u00fat 0,45% NaCl trong 2% HNO3 v\u00e0 2% HCl v\u00e0 theo d\u00f5i c\u00e1c n\u1ed9i chu\u1ea9n cho \u0111\u1ebfn khi t\u00edn hi\u1ec7u \u1ed5n \u0111\u1ecbnh. H\u1ec7 th\u1ed1ng sau \u0111\u00f3 \u0111\u01b0\u1ee3c r\u1eeda b\u1eb1ng c\u00e1ch h\u00fat n\u01b0\u1edbc si\u00eau tinh khi\u1ebft, sau \u0111\u00f3 l\u00e0 dung d\u1ecbch 2% HNO3 v\u00e0 2% HCl tr\u01b0\u1edbc khi b\u1eaft \u0111\u1ea7u c\u00e1c l\u1ea7n ch\u1ea1y m\u1eabu.<\/span><\/p>\n

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B\u1ea3ng 4. Instrumental Parameters for LVP Saline Solution<\/span><\/em><\/span><\/p>\n

Results<\/strong><\/span><\/p>\n

The USP 7 and define several QA\/QC protocols to test and validate for method development. They include:<\/p>\n