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GMP News No. 153
13 December 2001
Validationof Analytical Methods:
At seminars on "Validation of analytical methods" the questionemerges again and again as to how "INTERMEDIATE PRECISION" - asit is referred to in ICH Guidelines Q2A and Q2B - is to be verified andexpressed.
ICH lays down that Intermediate Precisionis to cover the various influences within a laboratory, i.e. conductinganalyses on two different (or several) days by different laboratory staffmembers, with different equipment (if available), etc. This is to examinein accordance with ICH Guideline Q2A the effects of random events on theprecision of an analytical method. Intermediate Precision therefore givesa first indication already of the future transferability of an analyticalmethod, but it must not be confused with robustness since in the testingof the robustness of an analysis method deliberate changes are made withan assumed influence on the results.
How can we now determine IntermediatePrecision?
The easiest option is to summarize orcompare without comment the two series of numbers obtained. This proceduremight not always be sufficient when applying for marketing authorization.
Furthermore, the two series of numbers(e.g. 6 [or 10] measurements each with a mean and relative standarddeviation) can be compared with the aid of statistical tests (F- andt-test). However, argumentation problems often ensue when the test arrivesat the result that the two series of measurements differ statisticallysignificantly (particularly frequent and problematical in case of goodperformance, i.e. little scatter)! Inthis case it is recommended that the validation SOP used be furnished withan opening clause in case a difference is statistically significant butanalytically irrelevant.
In practice the procedure has provedsuccessful of calculating the mean and the relative standard deviationfrom all results obtained in test for intermediate precision andprescribing an acceptance criterion for the standard deviation (e.g. 3%relative standard deviation for intermediate precision in case of 2%relative standard deviation for the repetition precision).
Furthermore, FDA also expects anextensive validation protocol now already in which methodology andacceptance criteria for the individual validation parameters are defined.The basis of the acceptance criteria for the validation parameters is, ofcourse, always the specification.
Summary compiled after the CONCEPTseminar "Validation of analytical methods" held on September25/26, 2001 in Ladenburg, Germany.