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Analytical Results Variability and Rational Development of Acceptance Criteria for Active Drug Ingredients and Finished Drugs / 1st Communication: Active drug ingredients The relationship between acceptance criteria and analytical variability is discussed for assays of pure substances, content of active ingredient in finished drug products and for impurities in order to establsih general rules for setting limits. Variabilities caused by production processes and analytical procedures have to be considered, whereas drug safety is the general prerequisite.
New concepts have been discussed at a workshop of the division Drug Control/ Pharmaceutical Analysis of the German Pharmaceutical Society DPhG, Deutsche Pharmazeutische Gesellschaft e.V., Frankfurt/Main) on 31 January 2002. For drug substances, it has been suggested to perform three analyses and to define acceptable standard deviations for classes of methods. Target standard deviations (TSD) for classes of methods were determined in collaborative studies. New specification limits can be calculated from the maximum sum of allowed impurities and the expected analytical variability.
In Europe, for drug products the acceptance limits are usually set to 95-105 % of the nominal content. This is reasonable for the most but unsatisfactory in some cases. Increased analytical variability from e.g. matrix effects or low drug concentrations often cannot be compensated for without exceptional efforts. Here individual acceptance limits are required. The Horwitz equation is a promising concept to estimate expected ranges of analytical variability, especially for low-concentrated analytes. From this equation, a maximum acceptable variab-ility for a certain analyte concentration can be derived. This value can be used to justify the experimentally obtained variability which is subsequently the basis of individual specification limits. Moreover, a pragmatic proposal to set acceptance criteria for impurity testing is presented. The proposals disclosed in the following article are the basis for a consensus paper of the German Pharmaceutical Society about acceptance criteria.