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Case study I 4-hydrazinobenzoic acid in a life saving oncology product NOVARTIS Synthesis involves 4-hydrazinobenozoic acid (4-HBA) ‣ Hydrazine is IARC Group 2B, 1,2-dimethylhydrazine is in Group 2A ‣ 4-HBA is a weak Salmonella mutagen ‣ 4-HBA does not induce chromosome aberrations in vitro ‣ Limited published data indicate tumorigenic effects in rats (one dose level only tested in drinking water, low survival) but: Agaricus bisporus, the major cultivated mushroom of the Western Hemisphere (=champignon), contains 4-HBA at a level of 10 µg/g (10ppm) wet mushroom weight ‣ One champignon meal (200 g) contains 2000 µg 4-HBA ‣ Does exposure to 4-HBA really constitute a genotoxic/tumorigenic risk? ‣ Which level would be acceptable in a pharmaceutical (life saving) preparation with life-long high daily dose • Would 5 or 10 ppm be too much, can we compare the risk in XYZ123 with eating champignons? 5ppm 4-HBA in XYZ123 (the current limit) translates into an exposure of 10µg/day ‣ This level is considered appropriate based on the life-threatening indication and the relatively weak genotoxic/carcinogenic potential of this hydrazine L. Müller, Swissmedic, 21-Oct-2003
Case study II epoxide degradation product in mometasone (published case) NOVARTIS Mometasone (corticosteroid): ‣ Daily dose ~1600 µg Epoxide degradation product in aequeous systems The epoxide is a toxicological concern Limit setting approach according to TTC: ‣ 1.5 µg < 1000 ppm! Alternative: toxicological testing ‣ Limited to 1000ppm ‣ Below threshold of toxicological concern (not published with that reasoning) ‣ Apparently no specific toxicity studies ‣ Proactive limitation in the absence of detailed tox data? L. Müller, Swissmedic, 21-Oct-2003
Page 1 and 2: NOVARTIS Impurities - Issues in reg
Page 3 and 4: General approach for identification
Page 5 and 6: Potential presence of reactive impu
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: Are there alternative concepts for
Page 27 and 28: Decision tree for assessment of acc
Page 29 and 30: Next Activities on genotoxic impuri

Investigational

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