Impurities may be introduced during the synthesis, production of pharmaceutical preparations, storage and transportation of APIs. One class of impurities can cause DNA damage in the body at low levels of concentration, resulting in mutagenic and carcinogenic effects, known as genotoxic impurities. Genotoxic impurities pose a huge threat to the safety of drugs. FDA, EMEA, ICH, USP, NMPA and other authoritative agencies have issued relevant guidelines, requiring strict analysis and control of genotoxic impurities generated in the production process of APIs and preparations.
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Control of genotoxic impurities throughout the whole life cycle of drug development, which is a complex and precise project. Our company has extensive experience in the field of drug genotoxic impurity analysis, and has the ability to provide genotoxic impurities research services for global generic drug companies.
Classification of genotoxic impurities
ICH M7 guidelines classify genotoxic impurities into five categories. ICH uses the TTC (Threshold of Toxicological Concern) value, a risk management tool, to set quality standards.
Evaluation of genotoxic impurities
The mutagenicity of the impurities usually is determined by the results of a bacterial mutation test (Ames), and carcinogenicity is determined by the results of an animal carcinogenicity test and human carcinogenicity evidence. Our company evaluates genotoxic impurities in the following ways.
We search databases for compounds containing data from existing carcinogenicity and mutagenicity studies.
In the absence of supporting safety data, regulations and guidelines have adopted an "alert structure" as a marker to distinguish common from genotoxic impurities. For impurities containing alert structures, potential genotoxic impurities can be evaluated with (Q)SAR software.
Development of analysis methods
If there are genotoxic impurities in your synthetic pathway, or there is no suitable method to remove the genotoxic impurities, we can help you to establish a suitable method to analyze and control the genotoxic impurities. Compared with other impurity analysis methods, the difficulty of genotoxic impurity analysis lies in the high requirement of specificity and the many interferences such as excipients. Moreover, the limit of genotoxic impurities is low, so analytical instruments must have a high level of sensitivity and stability.
- Determine the separation method
According to API and impurity properties, the appropriate separation means are selected.
- For compounds that are non-volatile and stable in the solution/mobile phase, liquid chromatography is applied for method development.
- Multidimensional liquid chromatography is suitable for substances that are stable in solution and not volatile. It is mainly suitable for the qualitative and quantitative application of some compounds without changing existing methods (mobile phase containing non-volatile buffer salts).
- Gas chromatography is suitable for volatile and stable compounds.
- Supercritical fluid technology is suitable for the analysis of unstable, chiral impurities that are difficult to separate.
After selecting the appropriate separation method, the detector with the appropriate sensitivity is selected according to the purpose of analysis and the limit requirements of impurities.
- Single quadruple mass spectrometry
- Triple quadruple mass spectrometry
- Quadruple time-of-flight mass spectrometry
Our company has a full set of advanced analytical and testing instruments to meet the detection needs of genotoxic impurities, and provide control strategies for generic drug enterprises. Enhance your quality control process with our expertise in the analysis and evaluation of impurities in pharmaceutical products.
