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What about highly toxic impurities? NOVARTIS “Identification of impurities present at an apparent level of not more than (≤) the identification threshold is generally not considered necessary. However, analytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacological effects at a level not more than (≤) the identification threshold. All impurities should be qualified as described later in this guideline.” “For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled.” ‣ Issue: How to control, if you do not know the structure? L. Müller, Swissmedic, 21-Oct-2003
Potential presence of reactive impurities in drug substances NOVARTIS Process-related ‣ Starting materials e.g. alkylating agents and similar reactive species ‣ Intermediates / by-products e.g. strong acid/alcohol interactions ‣ Catalysts, ligands Long-term storage ‣ Degradation products (by oxidation?) Complete elimination of such impurities is often not feasible L. Müller, Swissmedic, 21-Oct-2003
Page 1 and 2: NOVARTIS Impurities - Issues in reg
Page 3: General approach for identification
Page 7 and 8: Genotoxic impurities - how to detec
Page 9 and 10: LOEL in genotoxicity assays by stru
Page 11 and 12: Our Novartis policy regarding (geno
Page 13 and 14: Verification/falsification of struc
Page 15 and 16: Setting limits based on toxicity da
Page 17 and 18: The dilemma of lacking data is a ma
Page 19 and 20: Translate Threshold of Toxicologica
Page 21 and 22: Advantages of Using the TTC Concept
Page 23 and 24: Are there alternative concepts for
Page 25 and 26: Case study II epoxide degradation p
Page 27 and 28: Decision tree for assessment of acc
Page 29 and 30: Next Activities on genotoxic impuri

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