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Class Element Oral Preparations µg/day Injected Preparations µg/day Inhaled Preparations µg/day Class Element Oral Preparations µg/day Injected Preparations µg/day Inhaled Preparations µg/day 1 As 15 15 2 2B Pt 100 10 1 Cd 5 2 2 Se 150 80 130 Hg 30 3 1 Rh 100 10 1 Pb 5 5 5 Ru 100 10 1 2A Co 50 5 3 Tl 8 8 8 Ni 200 20 5 3 Ba 1400 700 300 V 100 10 1 Cr 11000 1100 3 2B Ag 150 10 7 Cu 3000 300 30 Au 100 100 1 Li 550 250 25 Ir 100 10 1 Mo 3000 1500 10 Os 100 10 1 Sb 1200 90 20 Pd 100 10 1 Sn 6000 600 60 Application News No.J119 Inductively Coupled Plasma Mass Spectrometry Analysis of ICH Q3D Guideline for Elemental Impurities in Drug Products Using ICPMS-2030 LAAN-A-CP-E032 p Outline of ICH Q3D Guideline for Elemental Impurities in Drug Products The ICH Q3D Guideline for Elemental Impurities sets permitted daily exposures (PDEs) for 24 elemental metal impurities of which toxicity is a concern, including the so-called big four (lead (Pb), cadmium (Cd), mercury (Hg), and arsenic (As)), and residual catalyst metals that are added intentionally during active pharmaceutical ingredient synthesis. Table 1 shows the ICH Q3D guideline of PDE for elemental impurities. The PDE levels shown for metal impurities must be converted to concentrations in order to evaluate the presence of metal impurities in drug products and their components. We describe an example of analysis of 24 elements included in the ICH Q3D guideline using inductively coupled plasma mass spectrometry. p Sample ・Tablet (daily dose: 1 tablet [0.2 g]) p Sample Preparation After placing one tablet (daily dose: one tablet [0.20 g]), hydrochloric acid 0.5 mL, and nitric acid 5 mL in a quartz decomposition vessel, decomposition was performed using a microwave sample pretreatment system. After decomposition, hydrochloric acid 0.1 mL was added, the mixture was made up to 20 mL with pure water, and this solution was used for analysis (100-fold dilution). At this point, Sc, Ga, Y, and Te internal standard elements were added (as an analytical solution concentration of 10 μg/L). After decomposition treatment of a sample, the elements to be measured were added to the sample to create a spike-and- recovery test solution. p Instrument and Analytical Conditions Shimadzu's ICPMS-2030 inductively coupled plasma mass spectrometer was used for analysis. Analytical conditions are shown in Table 2. In addition to being highly sensitive, the ICPMS-2030 uses a helium gas collision system that greatly reduces the spectral interference caused by argon and chlorine. Use of Eco mode and a mini-torch drastically reduces running costs associated with gas usage, compared to previous ICP-MS systems. Table 1 Permitted Daily Exposure Levels for Elemental Impurities in ICH Q3D

Application News No. © Shimadzu Corporation, 2016 For Research Use Only. Not for use in diagnostic procedures. This publication may contain references to products that are not available in your country. Please contact us to check the availability of these products in your country. The content of this publication shall not be reproduced, altered or sold for any commercial purpose without the written approval of Shimadzu. Company names, product/service names and logos used in this publication are trademarks and trade names of Shimadzu Corporation or its affiliates, whether or not they are used with trademark symbol “TM” or “®”. Third-party trademarks and trade names may be used in this publication to refer to either the entities or their products/services. Shimadzu disclaims any proprietary interest in trademarks and trade names other than its own. The information contained herein is provided to you "as is" without warranty of any kind including without limitation warranties as to its accuracy or completeness. Shimadzu does not assume any responsibility or liability for any damage, whether direct or indirect, relating to the use of this publication. This publication is based upon the information available to Shimadzu on or before the date of publication, and subject to change without notice. www.shimadzu.com/an/ J119 First Edition: Sep. 2016 Instrument : ICPMS-2030 High-frequency output : 1.2 kW Plasma gas ﬂowrate : 8.0 L/min Auxiliary gas ﬂowrate : 1.1 L/min Carrier gas ﬂowrate : 0.60 L/min Sample introduction : Nebulizer 10 Chamber : Cyclone chamber (electronic cooling) Plasma torch : Mini-torch Collision gas : He Table 2 Analytical Conditions Q Analysis Quantitative analysis and spike and recovery testing were performed for 24 elements included in ICH Q3D guideline. Analyses were performed by the calibration curve method and internal standard method. Q Analytical Results Table 3 shows the analytical results for tablet preparations. Good spike and recovery results were obtained for all samples. Detection limits converted into sample concentrations also met all permitted concentration levels. Q Conclusions We successfully and accurately analyzed 24 elements included in the ICH Q3D guideline in a short period of time using the ICPMS-2030. [References] ・Guideline for Elemental Impurities in Drug Products (PFSB/ELD Notiﬁcation No. 4, September 30, 2015) [In Japanese] ・ICH Q3D Guideline for Elemental Impurities (December 16, 2014) ・General Tests, Supplement Ⅰto the Japanese Pharmacopoeia Sixteenth Edition Table 3 Analytical Results for Tablet Preparations Element Oral Preparation PDE *1 Permitted Concentration *2 Detection Limit Converted for Tablet Preparations (3 σ) Measured Result (in Tablet Preparation) Spiked Concentration (in Tablet Preparation) Spike and Recovery (%) µg µg/g µg/g µg/g µg/g % Ag 150 750 0.001 N.D. 0.1 107 As 15 75 0.002 N.D. 0.2 101 Au 100 500 0.001 N.D. 0.2 91 Ba 1400 7000 0.002 0.013 0.2 96 Cd 5 25 0.003 N.D. 0.2 96 Co 50 250 0.0006 N.D. 0.4 101 Cr 11000 55000 0.003 0.017 0.4 104 Cu 3000 15000 0.04 0.15 0.4 102 Hg 30 150 0.006 N.D. 0.2 100 Ir 100 500 0.0005 N.D. 0.2 98 Li 550 2750 0.01 N.D. 0.2 93 Mo 3000 15000 0.001 N.D. 0.2 107 Ni 200 1000 0.003 0.156 0.4 101 Os 100 500 0.007 N.D. 0.2 92 Pb 5 25 0.001 0.003 0.2 105 Pd 100 500 0.006 N.D. 0.2 104 Pt 100 500 0.003 N.D. 0.2 99 Rh 100 500 0.0008 0.003 0.2 101 Ru 100 500 0.002 N.D. 0.2 98 Sb 1200 6000 0.0009 0.007 0.2 98 Se 150 750 0.01 N.D. 0.2 98 Sn 6000 30000 0.002 N.D. 0.2 98 Tl 8 40 0.0005 N.D. 0.2 103 V 100 500 0.002 N.D. 0.4 100 *1: Permitted concentration: PDE level based on a daily intake of 0.2 g, which refers to a permitted concentration for oral preparations. *2: Detection limit converted for tablet preparations (3 σ): Detection limit in measured solution (3 σ) × Dilution ratio (100) N.D.: Not detected