A tiered approach to threshold of regulation

Theoretical Purge Factor Determination as a Control Strategy for Potential Mutagenic Impurities in the Synthesis of Drug Substances

“…14,15 The limit was set based on the analysis of 343 carcinogens, 16 expanded to more than 700 carcinogens from a carcinogenic potency database. [17][18][19] A simple linear extrapolation from 50 % tumor incidence (TD50) data for the most sensitive species and most sensitive site to a 1 in 10 6 incidence was used, which makes the principle very conservative. 14 Some high potency genotoxic carcinogens like aflatoxin-like-, N-nitroso-, and azoxy-compounds have to be excluded from the TTC approach.…”

Threshold of Toxicological Concern (TTC)

“…In a tiered approach, methods were established for extending the U.S. FDA concept for food contact articles by using structure-activity relationships, genotoxicity, and short-term toxicity data (Cheeseman et al, 1999). The thresholds of concern suggested are: 1) general threshold of 1.5 µg/person/day, 2) a threshold of 15 µg/person/day for chemicals without structural alerts for carcinogenicity or with negative mutagenicity test, and 3) a threshold of 45 µg/person/day for chemicals without structural alerts for carcinogenicity or with negative mutagenicity test (Ames test) and with an appropriate acute toxicity test with LD 50 >1000 mg/kg bodyweight.…”

“…This EMEA draft has been on an external review and the result from this review is not yet available. Rulis, 1989Munro et al, 1996Rulis, 1989Munro et al, 1996Cheeseman, 1999ECETOC, 2004 2 The GLEVs obtained from the hazard category approach is intended for consumers. For occupational exposure the corresponding threshold is GEV.…”

“…However, for application of a TTC in the assessment of acceptable limits of genotoxic impurities in drug substances a value of 1.5 μg/person/day, corresponding to 10-5 lifetime risk of cancer can be justified as for pharmaceuticals a benefit exists. Some high potency structural groups (Cheeseman et al, 1999 ;Kroes et al, 2004) require compoundspecific toxicity data. The TTC value may vary according to the profile of the genotoxicity results.…”

Liquid Chromatography Mass Spectrometric Method for Quantification of Potential Genotoxic Impurity in Bendamustine Hydrochloride

“…This TTC value was estimated to be 1.5 μg/person/day. [10][11][12][13][14][15] From the evaluation study of genotoxic and carcinogenic impurities in the synthetic scheme of Bendamustine Hydrochloride, one intermediate ( …”