Analysis by ICP Atomic Emission Spectrometry in Accordance with the ICH Q3D Guideline for Elemental Impurities

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At the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), a variety of guidelines were created and harmonized through three-party cooperation between Japan, the United States and Europe. The guideline for elemental impurities is under review as "ICH Q3D". In this guideline, the permitted daily exposure (PDE) was established for 24 elemental impurities for which toxicity is a concern. They include lead (Pb), cadmium (Cd), mercury (Hg), and arsenic (As), the "big four", as well as residual catalytic metals added intentionally in the synthesis of a drug substance.
An ICP atomic emission spectrometer enables quick and easy analysis of multiple elements. The Shimadzu ICPE-9820 multitype ICP atomic emission spectrometer can perform a batch analysis of these target elements.

Sample Pretreatment

An analysis was performed on an eye drop solution and on tablets (daily intake: 1 tablet (0.2 g)). Nitric acid and hydrochloric acid were added to the eye drop sample, and it was diluted 5 times with pure water to obtain the measurement solution. Two of the tablets were dissolved with nitric acid and hydrochloric acid using a microwave digestion system. The sample was filled up 20mL for the measurement solution (50 times dilution).

Analysis and Results

The Shimadzu ICPE-9820 multitype ICP atomic emission spectrometer was used as the analysis system. The ICPE-9820 is equipped with an Echelle spectrometer and a CCD detector, so the instrument is capable of simultaneously analyzing all elements and all wavelengths. This enables high-throughput measurements even when there are many target elements and samples. In addition, the instrument is equipped with a mini torch and a vacuum spectrometer, substantially reducing the running costs for gas in comparison to other ICP instruments.
In this measurement, quantitative analysis and additive recovery tests were performed on 24 elements cited in the ICH Q3D by the calibration curve method – internal standard method. Table 1 shows the analysis results for the eye drop solution, and Table 2 shows the analysis results for the tablets. Favorable results were obtained for the additive recovery rates for both samples (columns marked with *1 in Tables 1 and 2). In addition, the detection limits calculated from the concentrations in the samples (columns marked with *2 in Tables 1 and 2) sufficiently satisfied the permitted concentrations (columns marked with *3 in Tables 1 and 2).
The definitions for the terms, permitted concentration, concentration after treatment, additive concentration, converted detection limit, and <DL in Tables 1 and 2 are shown below Table 2.

Table 1: Analysis Results for the Eye Drop Solution

Element Name Parenteral
PDE		 *3 Permitted Concentration Concentration
After Treatment		 Additive Concentration Measurement Value
(In the Tablet)		 *1 Additive
Recovery Rate		 *2 Converted Detection Limit
in the Tablet (3σ)
μg μg/mL μg/mL μg/mL μg/mL % μg/mL
As 15 15 3 1 ＜DL 104 0.04
Cd 2 2 0.4 0.4 ＜DL 101 0.0006
Hg 3 3 0.6 0.3 ＜DL 105 0.007
Pb 5 5 1 0.3 ＜DL 102 0.01
Co 5 5 1 0.3 ＜DL 95 0.001
Ni 20 20 4 0.5 ＜DL 104 0.003
V 10 10 2 0.5 ＜DL 98 0.0008
Ag 10 10 2 0.5 ＜DL 104 0.0008
Au 100 100 20 0.5 ＜DL 99 0.006
Ir 10 10 2 0.5 ＜DL 101 0.01
Os 10 10 2 0.5 ＜DL 103 0.006
Pd 10 10 2 0.5 ＜DL 102 0.004
Pt 10 10 2 0.5 ＜DL 99 0.02
Se 80 80 16 0.5 ＜DL 103 0.02
Rh 10 10 2 0.5 ＜DL 95 0.007
Ru 10 10 2 0.5 ＜DL 103 0.003
Tl 8 8 1.6 0.5 ＜DL 95 0.02
Ba 700 700 140 0.5 ＜DL 96 0.0006
Cr 1100 1100 220 0.5 ＜DL 97 0.002
Cu 300 300 60 0.5 ＜DL 96 0.002
Li 250 250 50 0.5 ＜DL 99 0.01
Mo 1500 1500 300 0.5 ＜DL 100 0.003
Sb 90 90 18 0.5 ＜DL 103 0.010
Sn 600 600 120 0.5 ＜DL 100 0.01

Table 2: Analysis Results for the Tablet

Element Name Oral
PDE		 *3 Permitted Concentration Concentration
After Treatment		 Additive Concentration Measurement Value
(In the Tablet)		 *1 Additive
Recovery Rate		 *2 Converted Detection
Limit for the Tablet (3σ)
μg μg/g μg/mL μg/mL μg/g % μg/g
As 15 75 1.5 0.5 ＜DL 107 0.5
Cd 5 25 0.5 0.1 ＜DL 100 0.007
Hg 30 150 3 1 ＜DL 101 0.1
Pb 5 25 0.5 0.1 ＜DL 98 0.07
Co 50 250 5 1 ＜DL 101 0.01
Ni 200 1000 20 1 0.1 100 0.03
V 100 500 10 1 ＜DL 103 0.01
Ag 150 750 15 1 ＜DL 104 0.02
Au 100 500 10 1 ＜DL 105 0.03
Ir 100 500 10 1 ＜DL 100 0.09
Os 100 500 10 1 ＜DL 85 0.04
Pd 100 500 10 1 ＜DL 106 0.05
Pt 1000 5000 100 1 ＜DL 102 0.3
Se 150 750 15 1 ＜DL 108 0.3
Rh 100 500 10 1 ＜DL 101 0.1
Ru 100 500 10 1 ＜DL 100 0.03
Tl 8 40 0.8 0.1 ＜DL 103 0.2
Ba 1400 7000 140 1 ＜DL 102 0.003
Cr 11000 55000 1100 1 ＜DL 101 0.02
Cu 3000 15000 300 1 ＜DL 105 0.05
Li 550 2750 55 1 ＜DL 104 0.1
Mo 3000 15000 300 1 ＜DL 101 0.03
Sb 1200 6000 120 1 ＜DL 105 0.1
Sn 6000 30000 600 1 ＜DL 100 0.03


Permitted concentration:
The permitted concentration when 1 mL of the eye drop solution is used per day. For the tablets, the permitted concentration for the daily intake (0.2 g).
(The caliculation to convert PDE to concentration is used option 3 that is calculation of concentrations for the finished product.)

Concentration after treatment:
The permitted concentration limit in the measurement solution after the sample is pretreated.
Additive concentration: The additive concentration in the solution used in the additive recovery test
Converted detection limit in the eye drop solution (3 σ):
The detection limit in the measurement solution (3 σ) × the dilution rate (5)

Converted detection limit for the tablets (3 σ):
The detection limit in the measurement solution (3 σ) × the dilution rate (50)
<DL: Less than the detection limit (3 σ)


Reference Material: ICH Q3D Guideline for Elemental Impurities (STEP 2b)


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