What is meant by genotoxicity?
Similar term(s): genotoxicity. Definition: Toxic (damaging) to DNA. Substances that are genotoxic may bind directly to DNA or act indirectly leading to DNA damage by affecting enzymes involved in DNA replication, thereby causing mutations which may or may not lead to cancer or birth defects (inheritable damage).
What is genetic impurity?
Regulatory landscape Per the International Council for Harmonization (ICH) S2 (R1) Guideline, genotoxic impurities can be broadly defined as impurities that have been demonstrated to cause deleterious changes in the genetic material regardless of the mechanism.
What is Spike and purge study?
A common method is “impurity fate mapping,” or “spike and purge testing,” to monitor the purging capability of a synthetic process. This testing involves spiking the impurity—for example, to a level of several thousand parts per million—where it occurs and then tracking it through the synthesis.
How is TTC limit calculated?
A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1 in 100,000 over a lifetime) for most pharmaceuticals. From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose.
What causes genotoxicity?
Causes for this structure are mitotic loss of acentric chromosomal fragments (clastogenicity), mechanical problems from chromosomal breakage and exchange, mitotic loss of chromosomes (aneugenicity), and apoptosis.
Is genotoxicity the same as mutagenicity?
The genetic change is referred to as a mutation and the agent causing the change as a mutagen. Genotoxicity is similar to mutagenicity except that genotoxic effects are not necessarily always associated with mutations. All mutagens are genotoxic, however, not all genotoxic substances are mutagenic.
What is fate and purge?
It is important to understand the formation, fate (whether the impurity reacts and changes its chemical structure), and purge (whether the impurity is removed via crystallisation, extraction, etc.) as well as their relationship to the resulting impurities that end up in the drug substance as CQAs.
What are fate and purge studies?
Fate and purge studies challenge the process by deliberately spiking known concentrations of impurities to determine how well they are purged from the process.
What is the difference between genotoxicity and carcinogenicity?
The term “genotoxic carcinogen” indicates a chemical capable of producing cancer by directly altering the genetic material of target cells, while “non-genotoxic carcinogen” represents a chemical capable of producing cancer by some secondary mechanism not related to direct gene damage.
What are two examples of carcinogens?
Carcinogens are substances or exposures that can cause cancer. Examples include home and workplace chemicals, environmental or medical radiation, smoke, and even some viruses and medications.