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.