Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations

Threshold of toxicological concern (TTC) for developmental and reproductive toxicity of anticancer compounds

“…The TTC values that are currently published were derived from databases of large numbers of chemicals representing broad classes of chemicals, such as food additives, industrial chemicals, cosmetics and pharmaceuticals (Dolan et al, 2005;Kroes et al, 2004;Munro et al, 1996a,b). There have been variations in exposure threshold values and uncertainty factors.…”

“…The TTC has long been utilized in industries such as food (Kroes et al, 2004;Munro et al, 1996a,b) or cosmetics (Kroes et al, 2007) and has also been used for residual active pharmaceutical ingredients in manufacturing facilities. Dolan et al (2005) applied the TTC concept to pharmaceutical manufacturing, looking at all endpoints including carcinogenicity, immunotoxicity, neurotoxicity and developmental toxicity for Merck active pharmaceutical ingredients following tiered category thresholds as defined as: Category 1: likely to be carcinogenic (1 lg/day); Category 2: likely to be potent or highly toxic (10 lg/day); and Category 3: not likely to be potent, highly toxic or carcinogenic (100 lg/day). Table 1 provides a summary of the human exposure threshold values for general toxicity and the uncertainty factors used.…”

“…Table 1 provides a summary of the human exposure threshold values for general toxicity and the uncertainty factors used. The TTC methodology as described by Dolan et al, 2005 has been referenced in guidance documents for health-based limits (EMA, 2014a;ISPE, 2010).…”

Thresholds of Toxicological Concern – Setting a threshold for testing below which there is little concern

“…Low levels of these are often present in the final product as impurities with possibly unwanted toxicities including genotoxicity and carcinogenicity. Dolan et al, (2005) suggested acceptable daily intake values (ADIs) for compounds with limited or no toxicity information to support pharmaceutical manufacturing operations by TTC: 1 μg/day for compounds that are likely to be carcinogenic, 10 μg/day for compounds that are likely to be potent or highly toxic, and 100 μg/day for compounds that are not likely to be potent, highly toxic or carcinogenic. Most recently, TTC were adapted also for impurities, residual materials, and contaminants in vaccines (White et al, 2016).…”

Classification of dermal sensitizers in pharmaceutical manufacturing

“…In recent assessments on the application of the threshold of toxicological concern (TTC) concept to pharmaceutical manufacturing operations, thresholds for genotoxic pharmaceutical impurities were reviewed (Hennes, 2012). TTC values for carcinogenic and non-carcinogenic effects of compounds with limited toxicological data were proposed (Dolan et al, 2005). In contrast, there is no generally applicable method to calculate threshold levels for sensitizers at the workplace (DFG 2014).…”