1 Introduction
As the public pays more and more attention to the safety of drugs, the
study of impurities has become the key to drug quality control.
International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH), U.S. Food and Drug
Administration (FDA) and other institutions have issued various
guidelines for impurities. Among them, the ICH was the first to
formulate guidelines on impurities. In 1995 and 1996, guidelines for
“Impurities in New Drug Substances” and “Impurities in New Drug
Products” were promulgated and revised in subsequent years by the ICH.
In the ICH Q3A(R2) guideline, impurities are divided into organic
impurities, elemental impurities and residual solvents according to
their physical and chemical properties, and the limits of organic
impurities are specified based on the permitted daily exposure. If the
impurity content is greater than the reporting limit, the impurity needs
be reported in the test report. If the impurity content is greater than
the identification limit, the chemical structure of the impurity must be
confirmed. If the impurity content exceeds the quality control limit,
it’s necessary to clarify the safety of the impurity, or reduce the
impurity content below the quality control limit through process
optimization and other ways. 1 Q3C 2and Q3D 3 also give detailed guidelines for residual
solvents and elemental impurities, and they provide guidance on the
content and limits of impurity studies for drug declaration. The U.S.
FDA also promulgated “Guidance for Industry Drug Product Chemistry,
Manufacturing, and Controls Information” in 1998, 4and provided clear technical requirements for the study of impurities.
Impurities are any substances that affect the purity of drugs.
Impurities that are related to the quality of drugs not only affect the
purity of medicines and reduce the efficacy, but also affect the safety
of human medication. For example, β-lactam antibiotics have the
characteristics of strong bactericidal activity and wide indications,
but the polymer impurities of β-lactam antibiotics can quickly cause
hypersensitivity reactions, especially lactam antibiotics for injection.5 Chiral impurities that cause adverse reactions are
also frequently reported. Li et al. 6 study the
toxicity of the chiral compound muscone that is an active ingredient in
natural musk. The chiral compound muscone can be divided into s-muscone
and r-muscone. The research results show both of them are acutely toxic
to zebrafish embryos, but s-muscone has higher toxicity at the same
concentration. It’s necessary to synthesize the chiral isomer of muscone
to ensure the safety of medication. Yi et al. 7reported the genotoxicity of impurities in the rabeprazole that was used
to treat gastrointestinal diseases. The silico analysis that used the
Derek and Sarah software showed that the impurity 2-[[4-(3-methoxy
propane)-3-methyl -2-pyridyl] methiony l]-1H-benzimidazole has a
warning structure, and it is proposed that this impurity should be
controlled within the limit of 0.01%. It can be seen that genotoxic
impurities are extremely important to the safety of drugs, and some
regulations on genotoxic impurities have also been promulgated. The M7
guidelines for genotoxic impurities promulgated by ICH in 2013,8 “guidline on the limits of genotoxic impurities”
promulgated by the European Medicines Agency (EMA) in 20079 and the FDA promulgated “Guidance for Industry,
Genotoxic and Carcinogenic Impurities in Drug Substances and Products:
Recommend Approaches”in 2008 to put forward clear requirements for
genotoxic impurities. 10
Nowadays, the research concept of impurity has shifted from the concept
of purity and limit to the direction of impurity profile. The concept of
impurity profile is to understand the source, content, structure,
physical and chemical properties, biological activity of each impurity
in the drug, and to give a reasonable quality control limit after
integrating all information. Impurity source analysis is the basis of
drug impurity control. 11, 12 To clarify the source of
impurities has important guiding significance for optimizing the
synthesis process, prescription process, packaging and storage
conditions of drugs. Analysis method is a instrument to obtain impurity
information. Choosing a suitable analysis method can ensure the
effective detection of impurities. Diversified analysis methods also
make it possible to effectively control different types of impurities.
The following introduces the sources of impurities in various drugs, and
focuses on the analysis techniques used in the impurity research
process.