2 Sources of impurities in various
drugs
The ICH guidelines clearly stipulate that the source of impurities in
drugs that exceed the identification limit must be clarified. Impurity
source analysis is the basis for drug impurity control. Identifying the
source of impurities can optimize the synthesis process, prescription
process, packaging and storage conditions of the drug. Analyzing the
actual impurity generation pathway to optimize drug production, storage,
and transpoFrtation by inferring the potential impurities that may be
generated, so as to achieve the purpose of impurity control. Fig. 1
shows the main sources of impurities.
2.1 Sources of impurities in
synthetic
drugs
The impurities of synthetic drugs can be divided into process impurities
and degradation products according to their sources. In the production
process of synthetic drugs, some starting materials, intermediates and
by-products can all be regarded as impurities. 13, 14Unreasonable prescription process design, reaction between excipients
and Active Pharmaceutical Ingredients (API) also produce some
impurities. The type and amount of such impurities are often determined
by the optimization level of process parameters. Angelo et al.15 studied the effects of excipients and pH on dimer
impurities of the penicillin. Fig. 2 shows the degradation pathways of
penicillin. After penicillin 1 is degraded to penicillic acid 2, the pH
value of the solution is increased and the degradation of other products
is further accelerated. Experiments show that the addition of sodium
citrate that was used to change the pH of the solution can inhibit the
formation of dimer impurities, but the addition of EDTA have not much
effect on the dimer content. Vossen et al. 16optimized the formulation process of amlodipine liquid formulations that
treatment the hypertension in children and adolescents through stability
tests to avoid the formation of precipitation during storage.
The oxidation, hydrolysis, polymerization, isomerization and other
reactions of API can also introduce new impurities during the storage
and transportation of medicines because of various environmental
changes, such as: temperature, humidity and light, 17and unreasonable packaging selection can also cause the polymer or
element impurities of the packaging to penetrate into the drug.18 Such impurities are called degradation products and
usually determined the degradation pathway through stability tests and
forced degradation tests. 19 The forced degradation
test is that the drug is destroyed by high temperature, high humidity,
strong light irradiation, acid hydrolysis, alkali hydrolysis and
oxidation, 20 which can obtain a large amount of
impurity information in a short time and provide guidance for the
packaging and storage conditions of drugs to avoid and reduce the
generation of drug degradation products.
Some elemental impurities are introduced when the catalysts or reagents
added intentionally during the synthesis of drugs. Of course, it is not
ruled out that the introduction of elemental impurities is related to
contact packaging and metal devices that are not resistant to acid and
alkali. 21 The toxicity of elemental impurities cannot
be ignored. For example, acute and chronic exposure to cadmium can cause
damage to the reproductive system, kidney, liver, bone, lung,
cardiovascular and other tissues in the body, and can suppress immunity
and cause teratogenesis. 22 Although copper is an
essential element for the human body, a high concentration can also
cause changes in the body, such as: lipid metabolism, neuronal activity.23 In addition, the element impurities in the drugs
have no effect on curing diseases, and may also catalyze the degradation
of active pharmaceutical ingredients, so as to cause side effects and
adverse reactions. The ICH Q3D categorizes element impurities into three
categories based on their permitted daily exposure and their likelihood
of occurrence in pharmaceuticals and puts forward control requirements
for them. 3 Similar regulations were also issued by
the current United States Pharmacopoeia (USP) in general chapter
<231>, <232> and
<233> and European Pharmacopoeia (EP).24
2.2 Sources of impurities in natural
drugs
The ICH guidelines limit the types of drugs, and only provide a
illustrative decision tree for the supervision of impurities in
synthetic drugs. Some biopharmaceuticals (vaccines, cell metabolites,
plasma, plasma products, etc.) and natural drugs are not applicable.
Only some pharmacopoeias provide standards for the quality control of
impurities. The natural drugs come from a wide range of sources, and the
quality of natural drugs from different places is also quite different.
It is likely to be mixed with some improper origins and incorrect
medicinal parts to introduce some impurities. Li et al.25 used Fourier transform near-infrared spectroscopy
combined with chemometrics analysis to identify the authenticity of
Rhodiola from four different base sources and provide a valuable
reference for the safety and effectiveness of clinical application of
Rhodiola. In addition, some single-component preparations that extracted
and separated from natural drugs will introduce some impurities that
similar chemical structures and properties due to insufficient
production technology. 26 The natural drugs can absorb
or accumulate heavy metal elements from the natural environment during
the growth process, and pesticide is used. The impurity inspections of
natural drugs preparations also focus on harmful elements,27 pesticide residues 28 and
mycotoxins. 29 Nan et al. 27discussed the content and proportion of heavy metals Pd, Cu, As, Cd, Hg
in different tissues of peony medicinal materials and in different
months, and the results showed that the content of different species of
heavy metal can change during the growing period of plants and the total
content of heavy metals can migrate from different tissues. It is
pointed out that it is more scientific and reasonable to analyses the
species of heavy metals during growing period of plant medicine.
2.3 Sources of impurities in
biopharmaceuticals
Biopharmaceuticals are different from general chemicals. The active
ingredients of biopharmaceuticals are generally proteins, peptides,
nucleic acids, enzymes, hormones, etc. They are more sensitive to
factors such as humidity, temperature, pH, and light. It is prone to
degradation changes such as oxidation, aggregation or fission.30 Biopharmaceuticals will face a complex multi-phase
system that contains microbial cells, metabolites, unused culture
medium, etc in the production process, so the concentration of the
target product is very low and the impurity content is high. It is more
difficult to separate the active ingredients and impurities without
destroying the activity of the target product. 31 If a
drug with higher purity is required, the separation steps required will
increase, and the yield of the drug will decrease accordingly. Some new
extraction and separation methods have been proposed to solve this
challenge. Gaƫlle et al. 32 studied the hydrophilic
nanohydrogel particles that are used for the extraction and purification
of recombinant proteins. Zhang et al. 33 report a
bifurcated continuous field-flow fractionation chip for high-yield and
high-throughput nucleic acid extraction and purification and increase
the nucleic acid extraction rate compared with commercial equipment. The
risk of elemental impurities being introduced in biopharmaceuticals is
very low. 3 Because the production of
biopharmaceuticals does not require metal ions as catalysts or reagents,
the elements impurities that added to the culture medium are also trace
amounts and will not accumulate, and the purification process of
biopharmaceuticals (extraction, separation, etc.) can also remove the
introduced elements impurities.