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Division 4.1.1 Methods for the analysis of the active substance as manufactured

United Kingdom

Original text. Later amendments are not shown.

Methods shall be provided, with a full description, for the determination of:

  1. (a)

    pure active substance in the active substance as manufactured and specified in the dossier submitted in support of approval under Regulation (EC) No 1107/2009;

  2. (b)

    significant and relevant impurities and additives (such as stabilisers) in the active substance as manufactured.

The applicability of existing CIPAC methods shall be assessed and reported. In case of use of a CIPAC method, further validation data shall not be required, but example chromatograms shall be submitted, where available.

The specificity of the methods shall be determined and reported. In addition, the extent of interference by other substances present in the active substance as manufactured (such as impurities or additives), shall be determined.

The linearity of methods shall be determined and reported. The calibration range shall extend (by at least 20 %) beyond the highest and lowest nominal content of the analyte in relevant analytical solutions. Either duplicate determinations at three or more concentrations or single determinations at five or more concentrations shall be made. The equation of the calibration line and the correlation coefficient shall be reported and a typical calibration plot shall be submitted. In cases where a non-linear response is used, this shall be justified by the applicant.

The precision (repeatability) of the methods shall be determined and reported. A minimum of five replicate sample determinations shall be made and the mean, the relative standard deviation and the number of determinations shall be reported.

For the determination of the active substance content, an assessment of accuracy of the method shall be made by an assessment of the interference and precision.

As regards additives and significant and relevant impurities:

  • the accuracy of the methods shall be determined on at least two representative samples at levels appropriate to the batch data and material specification. The mean and the relative standard deviation of the recoveries shall be reported,

  • the experimental determination of the limit of quantification (LOQ) shall not be required. However, it shall be demonstrated that the methods are sufficiently precise to analyse significant impurities at levels appropriate to the material specification and relevant impurities at a concentration equivalent to at least 20 % less than the specification limit.