Cceptance Criteria in Thbstances

General Information
General Information
New Expression of Acceptance Criteria
in the Test for Related Substances
For information of the stakeholders
In European Pharmacopoeia monographs, the acceptance criteria for related substances have so far usually been
expressed in terms of comparison of peak areas (“… not more than the area of the principal peak in the chromatogram
obtained with reference solution …”), which, strictly speaking, leads to a pass/fail decision but not to a true quantitative
test result.
As the requirements for related substances in Ph. Eur. monographs have been adapted to the principles of ICH Guideline
Q3A(R2) and VICH Guideline 10, many users have requested to apply a similar format for the expression of the acceptance
criteria in Ph. Eur. monographs. An enquiry was published in Pharmeuropa 22.2.
Based on the feedback of the enquiry, it has been decided:
• to apply the new expression of acceptance criteria by numerical values for new monographs and major revision
projects, wherever possible;
• to maintain existing monographs in comparative style until they undergo a major revision.
The way of expressing the criteria will not have any impact on the validity of the test as such. Respective statements to this
end will be added to the General Notices and chapter 5.10. Control of impurities.
Stakeholders and groups of experts will be asked to apply the following style model when drafting or submitting text
proposals.
Related substances. Liquid chromatography (2.2.29). Carry Time (min) Mobile phase A Mobile phase B
out the test protected from light. (per cent V/V) (per cent V/V)
Solvent mixture: water R, methanol R (10:90 V/V). 0–3 60 40
Test solution. Dissolve 50.0 mg of the substance to be 3 – 16 60  49 40  51
examined in the solvent mixture and dilute to 50.0 mL with
the solvent mixture. Flow rate: 1.2 mL/min.
Reference solution (a). Dilute 1.0 mL of the test solution to Detection: spectrophotometer at 238 nm.
100.0 mL with the solvent mixture. Dilute 1.0 mL of this Injection: 10 μL.
solution to 10.0 mL with the solvent mixture.
Identification of impurities: use the chromatogram
Reference solution (b). Dissolve 10 mg of modelon for peak supplied with modelon for peak identification CRS and
identification CRS (containing impurities C, D and F) in the chromatogram obtained with reference solution (b)
the solvent mixture and dilute to 10.0 mL with the solvent
to identify the peaks due to impurities C, D and F; use the
mixture.
chromatogram obtained with reference solution (c) to
Reference solution (c). Dissolve 5.0 mg of modelon identify the peak due to impurity B.
impurity B CRS in the solvent mixture and dilute to 50.0 mL
Relative retention with reference to modelon
with the solvent mixture. Dilute 1.0 mL of the solution to
(retention time = about 6 min): impurity C = about 0.4;
100.0 mL with the solvent mixture.
impurity G = about 0.8; impurity D = about 0.9;
Column: impurity F = about 1.2; impurity B = about 1.9.
— size: l = 0.10 m, Ø = 4.0 mm; System suitability: reference solution (b):
— stationary phase: octadecylsilyl silica gel for
— resolution: minimum 2.5 between the peaks due to
chromatography R (5 μm).
impurity D and modelon; minimum 1.5 between the
Mobile phase: peaks due to modelon and impurity F.
— mobile phase A: mix 10 volumes of acetonitrile R and 90 Calculation of percentage contents:
volumes of a 0.68 g/L solution of potassium dihydrogen
phosphate R previously adjusted to pH 5.0 with 0.5 M — for impurity B, use the concentration of impurity B in
potassium hydroxide R; reference solution (c);
— mobile phase B: mix equal volumes of acetonitrile R and — for impurity C, multiply the peak area by the correction
a 0.68 g/L solution of potassium dihydrogen phosphate factor 1.5;
R previously adjusted to pH 5.0 with 0.5 M potassium — for impurities other than B, use the concentration of
hydroxide R; modelon in reference solution (a).
© PHARMEUROPA Vol. 23 No. 2, April 2011 259

General Information
Limits: Other detectable impurities (the following substances would,

— impurity B: maximum 0.3 per cent; if present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general
— impurity C: maximum 0.2 per cent;
acceptance criterion for other/unspecified impurities and/or
— impurity D: maximum 0.15 per cent; by the general monograph Substances for pharmaceutical
— unspecified impurities: for each impurity, maximum use (2034). It is therefore not necessary to identify these
0.10 per cent; impurities for demonstration of compliance. See also 5.10.
— total: maximum 0.6 per cent; Control of impurities in substances for pharmaceutical use):
— reporting threshold: 0.05 per cent. E, F, G, H, I.
IMPURITIES
Specified impurities: B, C, D.
260 © PHARMEUROPA Vol. 23, No. 2, April 2011

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© PHARMEUROPA Vol. 23 No. 2, April 2011 259

Limits: Other detectable impurities (the following substances would,

260 © PHARMEUROPA Vol. 23, No. 2, April 2011

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