Toxicological overview of impurities in pharmaceutical products☆

Genotoxic Impurities in Pharmaceuticals

“…For genotoxic compounds without sufficient evidence for a thresholdrelated mechanism, the guideline proposes a policy of controlling levels to "as low as reasonably practicable" (ALARP) principle, where avoiding is not possible. On the other hand, this guideline provides no advice on acceptable TTCs for drugs during development, especially for trials of short duration (Jacobson-Kram and McGovern, 2007). The pharmaceutical research and manufacturing association (PhRMA) has established a procedure for the testing, classification, qualification, toxicological risk assessment, and control of impurities processing genotoxic potential in pharmaceutical products.…”

“…Table 1 illustrates a series of thresholds described in ICH Q3A(R) that trigger reporting, identification, and qualification requirements. Subsequently, Table 2 depicts the thresholds for reporting, identification, and qualification of impurities in new drug products (ICH, 2006;Jacobson-Kram and McGovern, 2007). In addition, two options for standard test battery for genotoxicity are available in the ICH S2 (R1) guideline (ICH, 2008) ii.…”

Drug Substance and Drug Product Impurities, Now what?

“…3 For impurities that need to be qualified, the guidance notes that additional toxicology studies can be avoided by lowering the level of the impurity present in the drug substance to levels below the qualification threshold or by providing safety data from the published scientific literature. If neither option is feasible, empirical toxicology testing will have to be performed to qualify the impurity.…”

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

“…For this reason regulatory agencies established standards which assure that unavoidable impurities are limited to have no or acceptable levels of risk. 3 Identification and control of potential mutagenic/genotoxic impurities in drug substances or drug products is still a challenging task for pharmaceutical companies. Hence, an overview of regulatory guide-lines will be presented in this review article, together with identification and control strategies, especially the theoretical purge factor determination approach and its practical application.…”