EUROPEAN PHARMACOPOEIA 9.5 2.4.20.

Determination of elemental impurities

07/2018:20420 peroxide, at various concentrations, can be used to dissolve

the samples. The viscosity of sulfuric acid is greater than that
of the other acids and is to be taken into account as it can
affect the overall fluidity of the solution.
The choice of solvents also includes, but is not limited to,
2.4.20. DETERMINATION OF the use of dilute bases, straight or diluted organic solvents,
combinations of acids or bases, and combinations of organic
ELEMENTAL IMPURITIES solvents.
INTRODUCTION Acids, bases, and hydrogen peroxide of high purity must be
This chapter describes the general approach for the used, especially when ICP-MS is employed. For aqueous
determination of elemental impurities in medicinal products solutions, use deionised distilled water R. Diluents must
or substances for pharmaceutical use. As the chemical be checked for interference if they are used in an analysis.
composition of the considered samples and the specification Because it is not always possible to obtain organic solvents
limits for the element(s) of interest vary considerably, it is that are free from elemental impurities, organic solvents of
not possible to describe all suitable sample preparation and the highest purity possible with regard to these contaminants
measurement methods. Therefore, any method that fulfils the must be used. Specifically for ICP techniques, where samples
requirements described in this chapter may be used. are introduced into the plasma via solution nebulisation,
it is important to consider the potential matrix effects and
The results of the analysis are acceptable only if the system interferences that might arise from the solvent. The use of an
suitability has been demonstrated by a suitable test. Before appropriate internal standard and/or matching the standard
the initial use of a method, the analyst must ensure that the matrix with samples should be applied for ICP-AES and
method is appropriate for the samples and instruments used. ICP-MS analyses in cases where accuracy and precision are
This is accomplished by applying a validation procedure to not sufficient. In any case, the selection of an appropriate
methods not described in the individual monograph or by internal standard should take into account the element(s) of
a system suitability test for methods which are described in interest, ionisation energy, wavelengths or masses, and the
the monograph. Decision trees for the choice of the sample nature of the sample matrix.
preparation and the measurement procedures are presented in
Figures 2.4.20.-1 and 2.4.20.-2. Where a sample is found not to be soluble in any acceptable
solvent, a variety of digestion or incineration techniques can
PROCEDURES be employed. These include hot-plate digestion, incineration
As a reference procedure is not provided for each element, and microwave-assisted digestions, using an open- or
matrix and concentration, the choice of procedure according closed-vessel.
to Figures 2.4.20.-1 and 2.4.20.-2, including sample The decision regarding the type of digestion technique to be
preparation, detection technique and instrument parameters, used depends on the nature of the sample being digested, as
is the responsibility of the user. well as on the element(s) of interest and the concentration
Use the flow chart in Figure 2.4.20.-1 to define the sample range of the elements to be quantified. Open-vessel digestion
preparation method and the flow chart in Figure 2.4.20.-2 to is not recommended for the analysis of volatile elements.
define the measurement method. The sample preparation The suitability of a digestion technique, whether open-
method should yield a sufficient quantity of sample to allow or closed-vessel, should be supported by spike recovery
quantification of each element at the specified limit stated in experiments in order to verify that, within an acceptable
the individual monograph or the general chapter. tolerance, volatile elements have not been lost during sample
preparation. The digestion cycle is suitable if a clear solution
All suitable sample preparation methods and measurement is obtained.
techniques (e.g. 2.2.22. Atomic emission spectrometry (AES),
2.2.23. Atomic absorption spectrometry (AAS), 2.2.37. X-ray It is important to consider the selection of the type, the
fluorescence spectrometry (XRFS), 2.2.57. Inductively material of construction, the pretreatment, and the cleaning
coupled plasma-atomic emission spectrometry (ICP-AES), of analytical labware used in elemental analyses. The material
2.2.58. Inductively coupled plasma-mass spectrometry must be inert and, depending on the specific application,
(ICP-MS), 2.4.2. Arsenic, 2.4.8. Heavy metals, 2.4.9. Iron, resistant to caustics, acids, and/or organic solvents. For some
2.4.10. Lead in sugars, 2.4.15. Nickel in polyols, 2.4.31. Nickel in analyses, care must be exercised to prevent the adsorption of
hydrogenated vegetable oils) can be used for the determination elemental impurities onto the surface of a vessel, particularly
of elemental impurities, if the method has been verified before in ultra-trace analyses. Contamination of sample solutions by
the initial use by a system suitability test or a validation elemental impurities and ions present in the container can
procedure according to this chapter. also lead to inaccurate results.
If no sample preparation and/or measurement method is The use of volumetric glassware that does not comply
described in the individual monograph, a suitable sample with Class A requirements of the appropriate International
preparation and/or measurement method must be developed Standard of the International Organization for Standardization
and validated (see Figures 2.4.20.-1 and 2.4.20.-2). (ISO) is acceptable if the validation or the system suitability
test of the method using such glassware have experimentally
SAMPLE PREPARATION demonstrated that the method is suitable for the intended
Sample preparation is critical to the success of elemental purpose.
analysis. Many techniques not using direct measurement are CAUTION : when using high-pressure digestion vessels and
heavily dependent on sample transport. microwave laboratory equipment, the safety precautions and
If an atomisation system is used, the most conventional means operating instructions given by the manufacturer must be
by which samples are introduced into the atomisation system followed.
is by solution nebulisation. In this case, solid samples must
be dissolved in order to be introduced into the atomisation MEASUREMENT
system. Samples may be dissolved in any appropriate solvent. Method. The choice of the techniques depends mainly on
The use of aqueous or dilute nitric acid solutions is strongly the sample matrix and the characteristics and specification
recommended, due to minimal interference with these limits of the element(s) of interest. Analyse according to the
solvents compared to other solvents. Hydrochloric acid, instructions of the manufacturer of the equipment regarding
hydrofluoric acid, perchloric acid, sulfuric acid and hydrogen program and wavelength.

General Notices (1) apply to all monographs and other texts 5539
2.4.20. Determination of elemental impurities EUROPEAN PHARMACOPOEIA 9.5

Figure 2.4.20.-1. – Elemental impurities decision tree : sample preparation

System suitability. A system suitability test must be carried Calculation. The blank value of reagents must be taken into
out on the day of the analysis to ensure that the sample account for the calculation of the content. Upon completion
preparation and measurement system are appropriate. of the analysis, the concentration of a given element in
Acceptance criterion for preparation of sample solution : a clear the sample is calculated by the software of the instrument
solution is obtained. from the concentration of the element in the test solution.
If no calculation software is available or no indication for
Acceptance criterion for measurement system : the measured calculation is given in the general chapter corresponding to
concentration of a standard solution of the element at a
concentration within the range of the used calibration curve
does not differ from the actual concentration by more than
20 per cent.

5540 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 9.5 2.4.20. Determination of elemental impurities

Figure 2.4.20.-2. – Elemental impurities decision tree : measurement

the method used, the concentration of a given element in matrix and instrument used. This is accomplished by
the sample can be calculated from the concentration of the following the validation procedure before the initial use and
element in the solution using the following expression : the system suitability test on the day of the analysis.
For elemental impurities, validation of a limit test must
include specificity and limit of detection.
The following section defines the characteristics for the
C = concentration of element in the analysed sample, acceptability of a quantitative procedure. It must be
in micrograms per gram ; demonstrated experimentally that such a procedure complies
with the validation requirements, with an appropriate system
A = instrument reading of the concentration of the suitability test using material spiked with a suitable reference
element in the sample solution, in micrograms per material. The test materials must be spiked before any sample
millilitre ; preparation steps. For example, if a test material is to be
m = mass of the sample in the initial sample solution, digested, the material must be spiked at the beginning of the
in grams ; digestion procedure.
V1 = volume of the initial sample preparation, in SPECIFICITY
millilitres ; Specificity is the ability to ensure that the analytical procedure
V2 = total volume of any dilution performed, in (sample preparation and measurement) allows a reliable
millilitres ; determination of the element(s) of interest in the presence of
V3 = volume of initial sample preparation used in any components (e.g. carrier gas, impurities, matrix) that may be
dilution performed, in millilitres. expected to be present.
Acceptance criteria : the procedure must be able to assess
unequivocally each elemental impurity to be determined with
VALIDATION REQUIREMENTS this procedure in the presence of components that may be
expected to be present, including other elemental impurities,
Some validation requirements provided below may differ from matrix components and other sources of interference ;
those provided in general chapters of the Ph. Eur. (e.g. 2.2.22 specificity is demonstrated by complying with the accuracy
(AES), 2.2.23 (AAS), 2.2.57 (ICP-AES), 2.2.58 (ICP-MS)). requirement for the element(s) to be determined.
Before the initial use of the selected procedure, the analyst RANGE
must ensure that the sample preparation and measurement Acceptance criterion : range is demonstrated by complying
method are appropriate for the element(s) of interest, sample with the recovery requirement.

General Notices (1) apply to all monographs and other texts 5541
2.4.20. Determination of elemental impurities EUROPEAN PHARMACOPOEIA 9.5

ACCURACY INTERMEDIATE PRECISION

Verify the accuracy using a certified reference material The effect of random events (intra-laboratory variations) on
(elemental impurity solutions CRS may be used) or by the analytical precision of the method must be established.
performing a test for recovery. Acceptable experiments for establishing intermediate
precision include performing the repeatability analysis on
The recovery may be determined on a sample of the substance different days, or with different instrumentation, or by
to be examined, spiked with a known quantity of a reference different analysts. Only 1 of the 3 experiments is required to
standard of the element of interest (3 concentration levels in demonstrate intermediate precision.
the range of 50-150 per cent of the intended specification limit, Acceptance criterion : the relative standard deviation is not
even if the original concentration of the reference standard is more than 25 per cent.
at the specified value), in triplicate.
LIMIT OF QUANTIFICATION
Acceptance criterion : spike recovery is within 70 per cent and Use the results from the accuracy study. Determine the lowest
150 per cent for the mean of 3 replicates at each concentration. concentration meeting the acceptance criterion.
Acceptance criterion : the limit of quantification is below the
REPEATABILITY specification limit.
Test samples: either 6 independent samples of the substance LIMIT OF DETECTION (ONLY APPLICABLE TO LIMIT
to be examined spiked with a suitable reference standard at TESTS)
the specified concentration level, or 3 concentration levels Determine the lowest concentration giving a signal clearly
prepared in triplicate. distinct from that obtained with a blank solution.
Acceptance criterion : the relative standard deviation is in both Acceptance criterion : the limit of detection is not more than
cases not more than 20 per cent. 0.5 times the concentration of the specification limit.

5542 See the information section on general monographs (cover pages)