What is geno toxic impurity ?
According to current regulatory practice it is assum ed that (in vivo) genotoxic com pounds have the potential to dam age DNA at any level of exposure and that such dam age may lead/contribute to tumour development.
Thus for genotoxic carcinogens it is prudent to assum e that there is no discernible threshold and that any level of exposure carries a risk.
However, the existence of mechanisms leading to biologically meaningful threshold effects is increasingly acknowl edged also for genotoxic events.
This holds true in particular for com pounds interacting with non-DNA targets and also for potential mutagens, which are rapidly detoxified before com ing into contact with critical targets.
The regulatory approach to such chemicals can be based on the identification of a critical No-Observed-Effect Level
(NOEL) and use of uncertainty factors.
Even for compounds which are able to react with the DNA molecule, extrapolation in a linear manner from effects in high-dose studies to very low level (human) exposure may not be justified due to several protective mechanisms operating effectively at low doses.
However, at present it is extremely difficult to experimentally prove the existence of threshold for the genotoxicity of a given mutagen.
Thus, in the absence of appropriate evidence supporting the existence of a threshold for a genotoxic com pound making it difficult to define a safe dose it is necessary to adopt a concept of a level of exposure that carries an acceptable risk.
The toxicological assessm ent of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue and not addressed in sufficient detail in the existing ICH Q3X guidances.
The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessm ent of acceptable limits.
In the absence of data usually needed for the application of one of the established risk assessm ent methods, i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed.
A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associ ated 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. Higher limits may be justified under certain conditions such as short-term exposure periods. The concentration limits in ppm of genotoxic impurity in drug substance derived from TTC can be calculated based on the expected daily dose to the patient using equation.
Concentration Limit (ppm) =
TTC [micro g / day] -> Threshold of Toxicological ConcernAccording to current regulatory practice it is assum ed that (in vivo) genotoxic com pounds have the potential to dam age DNA at any level of exposure and that such dam age may lead/contribute to tumour development.
Thus for genotoxic carcinogens it is prudent to assum e that there is no discernible threshold and that any level of exposure carries a risk.
However, the existence of mechanisms leading to biologically meaningful threshold effects is increasingly acknowl edged also for genotoxic events.
This holds true in particular for com pounds interacting with non-DNA targets and also for potential mutagens, which are rapidly detoxified before com ing into contact with critical targets.
The regulatory approach to such chemicals can be based on the identification of a critical No-Observed-Effect Level
(NOEL) and use of uncertainty factors.
Even for compounds which are able to react with the DNA molecule, extrapolation in a linear manner from effects in high-dose studies to very low level (human) exposure may not be justified due to several protective mechanisms operating effectively at low doses.
However, at present it is extremely difficult to experimentally prove the existence of threshold for the genotoxicity of a given mutagen.
Thus, in the absence of appropriate evidence supporting the existence of a threshold for a genotoxic com pound making it difficult to define a safe dose it is necessary to adopt a concept of a level of exposure that carries an acceptable risk.
The toxicological assessm ent of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue and not addressed in sufficient detail in the existing ICH Q3X guidances.
The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessm ent of acceptable limits.
In the absence of data usually needed for the application of one of the established risk assessm ent methods, i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed.
A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associ ated 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. Higher limits may be justified under certain conditions such as short-term exposure periods. The concentration limits in ppm of genotoxic impurity in drug substance derived from TTC can be calculated based on the expected daily dose to the patient using equation.
Concentration Limit (ppm) =
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Dose [micro g / day]
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