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Application News Figure 1. ICPMS-2030 Elemental Analysis: ICPMS-2030 Validation of quantitative method for determination of elemental impurities in pharmaceutical products following USP 232/233 on ICPMS-2030 No. AD-0189 Overview The 24 elemental impurities defined in USP<232> in three generic drug products were quantitatively determined on ICPMS-2030. A simple ICP-MS method that employs a single collision mode for all targeted elements is optimised and used. The sample preparation and method validation follow the USP<233> procedure strictly including both limit procedures and quantitative procedures. 1. Introduction Elemental impurities in pharmaceutical products are of great concerns for both manufactures and consumers due to their impact on patient safety, drug shelf life and thus drug efficacy. In January 2018, new USP guidelines for elemental impurities was implemented to replace USP <231> - Heavy Metal Limit Test. The over 100-year-old colorimetric method is considered not quantitative and inadequate to determine the toxicity of individual metal contaminations [3]. After being harmonized to ICH Q3D, USP<232> defines 24 targeted elements and the Permitted Daily Exposure (PDE) based on each impurity’s toxicity and their possibility of contamination in drug manufacturing process [1]. The new USP<233> specifies ICPOES and ICPMS as the recommended measuring techniques [2]. For samples required strong acid digestion, USP<233> recommends to use closed vessel to minimize the loss of volatile impurities such as mercury and lead in sample preparation. Table 1. Analytical conditions and parameters of ICPMS-2030 Raymond Li , Zhaoqi Zhan 2. Experimental Closed vessel microwave digestion is regarded as a universal digestion method that can prevent sample loss of volatile elements. Digested samples were diluted to 100mL with ultrapure DI water to give a dilution factor of 250x. All samples were in a matrix of 2% HNO3 and 0.5% HCl. Sc, Y and Bi were added as internal standards at a final concentration of 100 μg/L each with internal standards online addition kit. Parameter Setting RF Frequency Power 1.20 kW Sampling Depth 5.0 mm Plasma Gas Ar 8.0 L/min Auxiliary Gas Ar 1.10 L/min Carrier Gas Ar 0.70 L/min Torch Mini-Torch, ICPMS Nebulizer Nebulizer, 07UES Chamber Cyclone Chamber Chamber Temperature 5 º C No. of Scans 10 times Cell Gas (He) 6.0 mL/min Cell Voltage -21.0 V Energy Filter 7.0 V Solvent Rinse Time 10 sec (Low), 30 sec (High) Sample Rinse Time 30 sec (Low), 40 sec (High) Microwave Oven Model Milestone Ethos Easy Mixed Acid Recipe Acid Volume (mL) HNO3 2 HCl 0.5 H2O2 0.5 DI Water 3 Digestion Program Step Time (min) Ramp to 220 º C 20 Hold at 220 º C 20 Cool down to room Temperature 30 Table 2. Microwave digestion protocol 2.1 Sample Preparation Three pharmaceutical products in various forms are obtained in their original packaging. Drug 1 Capsule, Antibacterial Drug 2 Tablet, Pain and fever treatment Drug 3 Liquid, Cough suppressant Weighted sample (approximately 0.4g) was transferred into the vessel of microwave digestion system (Milestone Ethos Easy). Concentrated strong acids, hydrogen dioxide in ultrapure grade and DI water were added into each vessel shown in Table 2.
Application News No. AD-0189 Linear calibrations were achieved for all 24 target elements with r shown in Table 3. Calibration curves of Class 1 elements (As, Cd, Hg and Pb) and Class 2 (Co, Ni and V) which is mandatory for oral drug products were shown in Figure 2. Cr has the highest concentration range among the impurity elements. Good linearity of Cr calibration was also shown in Figure 2. 2.2 Analytical conditions An Shimadzu ICPMS-2030 (Figure 1) coupled with autosampler AS-10 was used. A universal He collision mode on ICPMS-2030 was used to reduce or eliminate polyatomic interferences. The detailed instrument configurations and the optimized operating parameters are summarized in Table 1. 2.3 Calibration standards Calibration standards were prepared in accordance with USP<233> with the calibration standard at 0.5J, 1.0J and 2.0J in Table 3. J value is the concentration (target limit) of element(s) and is calculated from PDE for oral administration defined in USP<232>. The diluted drug samples were measured using an external calibration approach against calibration solutions with the same matrix (in 2% HNO3 and 0.5% HCl) as the prepared samples. Element USP/ICH Class Isotope used *PDE (Oral) (μg/day) 0.5J^ value (μg/L) 1.0J value (μg/L) 2.0J value (μg/L) r Cd 1 111 5 2.5 5 10 1.00000 Pb 1 206 5 2.5 5 10 0.99999 As (Inorg.) 1 75 15 7.5 15 30 0.99998 Hg (Inorg.) 1 202 30 15 30 60 0.99995 Co 2A 59 50 25 50 100 0.99999 V 2A 51 100 50 100 200 1.00000 Ni 2A 62 200 100 200 400 0.99999 Tl 2B 205 8 4 8 16 0.99995 Au 2B 197 100 50 100 200 0.99993 Pd 2B 105 100 50 100 200 0.99980 Ir 2B 193 100 50 100 200 0.99996 Os 2B 188 100 50 100 200 0.99965 Rh 2B 103 100 50 100 200 0.99999 Ru 2B 101 100 50 100 200 0.99991 Pt 2B 194 100 50 100 200 0.99943 Se 2B 78 150 75 150 300 0.99997 Ag 2B 107 150 75 150 300 0.99963 Li 3 7 550 275 550 1100 0.99940 Sb 3 121 1200 600 1200 2400 1.00000 Ba 3 137 1400 700 1400 2800 0.99904 Mo 3 97 3000 1500 3000 6000 0.99997 Cu 3 63 3000 1500 3000 6000 0.99999 Sn 3 118 6000 3000 6000 12000 1.00000 Cr 3 52 11000 5500 11000 22000 0.99998 * PDE (Oral) is Permitted Daily Exposure limit for oral administration drugs defined in USP<232> ^ J value is calculated from J=PDE/(Dilution Factor*Max. Daily Dose) assuming maximum daily dose is 4g per day and DF is 250 in this analysis. Figure 2. Calibration curves of Class 1 elements (As, Cd, Hg and Pb), Class 2A elements (Co, Ni, V) and Cr. 3. Results and Discussion 0 25 Concentration (ug/L) 0 5 10 15 20 25 30 Intensity As 75 (DBG) 0 5 10 Concentration (ug/L) 0 1 2 3 4 5 Intensity Cd 111 (DBG) 0 25 50 Concentration (ug/L) 0.0 2.5 5.0 Intensity Hg 202 (DBG) 0 5 10 Concentration (ug/L) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Intensity Pb 206 (DBG) 0 50 100 Concentration (ug/L) 0 250 500 750 1000 Intensity Co 59 (DBG) 0 250 Concentration (ug/L) 0 50 100 150 200 250 Intensity Ni 62 (DBG) 0 100 200 Concentration (ug/L) 0 250 500 750 Intensity V 51 (DBG) 0 10000 20000 Concentration (ug/L) 0 25000 50000 75000 100000 125000 Intensity Cr 52 (DBG) As 75 Cd 111 Co 59 V 51 Hg 202 Ni 62 Pb 206 Cr 52 3.1 Calibration linearity Table 3. PDEs of classified elemental impurities, calibration standards and correlation coefficients
Application News Element Drug 1 (μg/L) Drug 2 (μg/L) Drug 3 (μg/L) LOD (μg/L) LOQ (μg/L) J value (μg/L) Cd N.D. N.D. N.D. 0.003 0.010 5 Pb N.D. N.D. N.D. 0.002 0.007 5 As N.D. N.D. N.D. 0.009 0.030 15 Hg N.D. N.D. N.D. 0.010 0.032 30 Co <LOQ N.D. <LOQ 0.002 0.008 50 V 0.28 0.16 0.29 0.015 0.050 100 Ni 0.21 0.54 N.D. 0.058 0.193 200 Tl N.D. N.D. N.D. 0.002 0.008 8 Au N.D. N.D. N.D. 0.133 0.439 100 Pd N.D. N.D. 0.31 0.098 0.327 100 Ir N.D. N.D. N.D. 0.002 0.006 100 Os N.D. N.D. 0.09 0.024 0.079 100 Rh N.D. N.D. N.D. 0.000 0.001 100 Ru N.D. N.D. N.D. 0.001 0.003 100 Pt N.D. N.D. N.D. 0.001 0.003 100 Se N.D. N.D. 0.14 0.075 0.250 150 Ag N.D. N.D. N.D. 0.025 0.070 150 Li N.D. N.D. N.D. 7.620 25.40 550 Sb 0.91 N.D. N.D. 0.278 0.928 1200 Ba N.D. N.D. N.D. 0.021 0.069 1400 Mo N.D. N.D. N.D. 0.039 0.131 3000 Cu N.D. N.D. N.D. 0.187 0.624 3000 Sn N.D. N.D. N.D. 0.216 0.721 6000 Cr N.D. N.D. N.D. 0.043 0.145 11000 Table 4. Concentrations of 24 elemental impurity in three digested drug sample solutions. 3.3 Method Validation The established method was validated following the procedures described in USP<233> for ICP-MS using drug sample 2. The results were summarized in Table 5. •System suitability: Drift was measured by comparing standard solution at 2.0J before and after sample analysis. The drift results of all target elements were less than 5% which was well below suitability criteria (≤20% for each element). 3.2 Quantitative sample results The results of impurity elements in three drugs determined are summarized in Table 4. The targeted elements were either not detected or well below the calculated limits (J values) in accordance to oral PDEs. It is worth to note that the LODs and LOQs of the method are far below the J values indicating the capability of ICPMS in trace contamination detection. •Accuracy : Accuracy test was performed by spiking samples at 0.5J and 1.5J. Spike recoveries were 88- 114% and 81-115%, respectively. The acceptance range is 70%-150%. •Precision : Repeatability was evaluated by analyzing 6 replicates of sample 2 spiked at 1.0J. Ruggedness was evaluated by analyzing samples in a different day. The RSD% of both days for all 24 elements were below 2.5% which was far less than the required 20% criteria. •Detectability : Detectability was confirmed by comparing sample spiked at 0.8J and 1.0J. The calculated ratios were from 0.61 to 0.87 which was in agreement with USP <233> requirement of less than 1 No. AD-0189 N.D. means not detected
Application News No. AD-0189 www.shimadzu.com/an/ Shimadzu Corporation SHIMADZU (Asia Pacific) Pte. Ltd 79 Science Park Drive, #02-01/08 Cintech IV, Singapore 118264, www.shimadzu.com.sg ; Tel: +65-6778 6280 Fax: +65-6778 2050 For Research Use Only. Not for use in diagnostic procedures. Contents and/or instrumentations in this application may not available in some countries under each regulation. Please contact the local representatives in details. Copyright © 2019 SHIMADZU (Asia Pacific) Pte. Ltd. All rights reserved. No part of this document may be reproduced in any form or by any means without permission in writing from SHIMADZU (Asia Pacific) Pte. Ltd. Elements Drift % Std. at 2.0J Repeatability 1.0J, n=6, RSD%, Day 1 Repeatability 1.0J, n=6, RSD% Day2 0.5J spike recovery 1.5J spike recovery Detectability 0.8J/1.0J Cd -2.8% 1.48 1.34 105% 97% 79% Pb -1.0% 0.21 1.36 111% 96% 79% As -2.6% 1.47 0.49 97% 99% 79% Hg -2.3% 0.48 1.18 98% 95% 79% Co -3.7% 1.03 0.44 100% 97% 80% V -2.5% 1.03 0.71 99% 97% 79% Ni -3.0% 0.92 0.59 98% 97% 80% Tl -1.0% 0.63 1.17 95% 94% 79% Au -1.9% 0.47 1.99 114% 111% 61% Pd -3.8% 1.73 0.78 98% 79% 84% Ir -2.5% 0.37 1.77 99% 96% 79% Os -2.6% 0.32 1.57 88% 81% 80% Rh -2.9% 1.46 0.95 98% 111% 78% Ru -3.6% 1.58 1.14 99% 97% 80% Pt -2.0% 0.55 1.78 96% 83% 79% Se -2.0% 1.04 1.49 103% 102% 80% Ag 0.6% 1.49 0.22 105% 100% 87% Li -3.8% 2.37 1.50 105% 91% 78% Sb -0.8% 0.78 0.78 101% 101% 79% Ba -2.8% 1.18 0.82 97% 115% 79% Mo -4.0% 1.15 0.72 99% 99% 79% Cu -4.2% 1.28 0.26 98% 103% 83% Sn -2.5% 0.77 0.92 101% 101% 79% Cr -3.6% 0.98 0.45 100% 99% 79% Table 5. Method validation results according to USP<233>. • Specificity : Mass peak profiles were examined to ensure that each target element is free of interference from other elements and matrix components. Peak profile of As, Cd and Hg of the blank matrix used for sample preparation and calibration standards are shown in Figure 3. Figure 3. Mass peaks profiles of As75, Cd111 and Hg202 of calibration standards and blank matrix. 4. Conclusions Targeted elemental impurities in three drug products were analysed following new USP <232>/<233> using ICPMS-2030. The method was validated following the procedures defined by USP<233> and combined with microwave digestion for sample preparation. Excellent calibration linearity, repeatability and low drift were achieved for all 24 elements. Low LODs and LOQs were achieved as compared to the J values for all 24 elements. The simple method that using only He collision mode can reduce the time to shift between different mode and thus improve the throughput for routine trace elemental impurity analysis in pharmaceutical product. References: [1] USP General Chapter <232> Elemental Impurities – Limits, USP 40- NF 35, 2017 [2] USP General Chapter <233> Elemental Impurities – Procedures, USP 38- NF 33, 2015 [3] Wang T.; Wu J.; Hartman R.; Jia X.; Egan RS, A multi- element ICP-MS survey method as an alternative to the heavy metals limit test for pharmaceutical materials. J. Pharm. Biomed. Anal. 2000, 23(5), 867-890. Third-party trademarks and trade names may be used in this publication to refer to either the entities or their products/services, whether or not they are used with trademark symbol “ TM” or “ Ⓡ”.
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