From an analytical-chemistry perspective, to meet current requirements regarding genotoxic impurities, how does it change
the level, extent, or type of analytical testing that needs to be performed for an analysis of a particular active ingredient
or finished drug product? Is typical impurity testing sufficient, or what additional testing or approaches may be required?
Consider the GTI control requirements, taking into account the TTC limit (1.5 µg/person/day) and the corresponding levels
of the GTI in the drug substance, it can be calculated that for a daily dose of 1 g/person the limit for the GTI is 1.5 ppm
and for a daily dose of 100 mg/person the corresponding limit is 15 ppm. This translates into target limits for GTI detection
and quantification at levels of about 1 ppm, that is almost 500 times lower than those for classical impurity analysis (1
ppm versus 0.05%). Typical impurity testing is not suitable for GTI determination since their quantitation limit is generally
500 ppm (0.05%). Assessing multiple impurities in the low ppm range can be a significant analytical problem and challenge.
Liquid chromatography (LC) with ultraviolet (UV) detection and gas chromatography (GC) with flame ionization detection are
often adequate for the impurities at 100 ppm level. In the range of 1–10 ppm or lower, hyphenated mass spectrometry (MS) techniques
such as LC–MS and GC–MS are by far the most appropriate techniques. These techniques, due to sensitivity and selectivity,
have been widely used in GTI analysis.
In addition to sensitivity and specificity, other challenges in GTI analysis may include:
- Sample matrix interferences: techniques such as pre/post-treatment derivatization may be used to overcome these challenges.
- Analytes which are chemically reactive or unstable: special handling techniques may be required to overcome low recover or
- Analytes which are not suitable for common analytical detectors.
One of the FDA draft guidance recommendations on GTIs involves changing the synthetic or purification route to reduce or
remove the impurity (1). Has this—or will this—become a challenge for drug manufacturers, particularly, if the synthesis of
API involves intermediates or raw materials not internally produced and if these are be considered a source of the resulting
impurity? If so, how is that addressed?
Changing synthetic routes or using purification could effectively avoid generating GTIs during the synthesis. However, route
selection takes into account both yields and manufacturability considerations. Because of their intrinsic high reactivity,
reactants and intermediates used in manufacturing processes may be genotoxic substances and it may not be suitable to avoid
When changing synthetic routes is not feasible, pGTIs and GTIs are identified by a careful analysis of both the degradation
products and the manufacturing process, taking into account reagents, intermediates and by-products. When the presence of
a GTI is established, an explanation why no alternative to the use/formation of this impurity is possible (including alternate
synthetic routes) should be provided as part of the pharmaceutical assessment. The technical effort aimed at reducing the
GTI level according to ALARP, or as low as reasonably practical, should be documented. This latter part of the pharmaceutical
assessment could give rise to some practical applicability issues.
For the intermediates or raw materials not internally produced, most companies are conducting rigorous testing to control
impurities, or even establish specifications.