Limits for impurities
Guidelines from the International Conference on Harmonization (ICH) and EMA provide the limits for impurities in drug substances and drug products (1–3). These limits do not apply to GTIs because of their adverse affects, hence it is necessary to determine limits based on the daily dose of the drug substance. This task drains process-development resources. To overcome this problem, scientists have to identify GTIs early in process development, develop analytical methods (i.e., for quantifying the genotoxic impurity), and demonstrate the necessary synthetic process controls.
The Pharmaceutical Research and Manufacturers Association's approach. The Pharmaceutical Research and Manufacturers Association (PhRMA) published a procedure for the testing, classification, qualification, and toxicological risk assessment of GTIs (8). It listed functional groups known to be involved in reactions with DNA that could be used as structural alerts. These functional groups were categorized into aromatic groups (e.g., N-hydroxyaryls, N-acylated aminoaryls, aza-aryl N-oxides, aminoaryls, and alkylated aminoaryls), alkyl and aryl groups (e.g., aldehydes, N-methylols, N-nitrosamines, nitro compounds, carbamates, epoxides, aziridines, propiolactones, propiosultones, N or S mustards, hydrazines, and azo compounds), and hetero aromatic groups (e.g., Michael-reactive acceptors, alkylesters of phosphonates or sulfonates, haloalkenes, and primary halides).
PhRMA also categorized impurities into five classes. Class 1 impurities are genotoxic (i.e., mutagenic) and carcinogenic. These impurities represent the most serious risk, and the default preference is to eliminate them by modifying the process. If this is not possible, the TTC limit can be employed as a last resort. Class 2 impurities are genotoxic, but their carcinogenic potential is not known. These impurities are to be controlled using TTC principles. Class 3 impurities contain problematic structures unrelated to the structure of the API and of unknown genotoxic potential. This group includes impurities with functional moieties that can be linked to genotoxicity based on structure. Class 4 impurities contain problematic structures related to the API. These impurities contain a potentially worrisome functional moiety shared with the parent structure. Class 5 impurities have no problematic structures, and evidence indicates the absence of genotoxicity. These compounds are to be treated as normal impurities and controlled according to the ICH guidelines. If Class 3 or 4 compounds are genotoxic or not tested, they are moved into class 2. If these are nongenotoxic, they are considered as Class 5.