The composition of pharmaceutical preparations is complex, and elemental impurities may be introduced in various production processes. These elemental impurities may not only affect the efficacy of the drug, but also an important factor affecting the quality and safety of the drug.

According to the Q3D elemental impurity guide issued by the International Conference of Harmonization (ICH), the introduction of elemental impurities in pharmaceutical preparations and the limit requirements are analyzed, and it is found that elemental impurities are relatively regularly distributed in the periodic table. , And the existence of elemental impurities has a greater relationship with their toxicity, which is intended to provide a reference for drug quality monitoring.

The International Conference on Drug Registration Technology Coordination (ICH) Q3D Elemental Impurity Guidelines is a quality guideline for the control of elemental impurities in new drug preparations, which aims to provide a global guideline for the qualitative and quantitative control of elemental impurities in new drug preparations and their excipients. According to the general rules of relevant metal element impurities in the United States Pharmacopoeia 39 and the European Pharmacopoeia 9.0, the differences between these guidance documents and ICH Q3D are summarized.

Results and conclusions: Q3D mainly includes the safety evaluation of potential element impurities, categories, risk assessment and control of element impurities, and conversion between Permitted Daily Exposure (PDE) and concentration limits. The risk assessment of elemental impurities should consider the source of potential elemental impurities and the way the drug is taken, compare the level of specific elemental impurities with PDE, and evaluate the possibility of the element in the drug. For elemental impurities that need to be controlled after risk assessment, the element concentration limits can be set in three ways according to the drug dosage and PDE. This helps pharmaceutical manufacturers decide which elements to perform additional control through risk assessment, thereby effectively protecting drugs quality.

1. The source of elemental impurities in pharmaceutical preparations

The composition of pharmaceutical preparations is complex, including raw materials, excipients, catalysts, etc. There are many types of inorganic elements that make up each component, and some of them directly or indirectly participate in various physiological and biochemical processes of the human body to affect the activity of drugs, such as calcium, magnesium, sodium, and potassium. The other part, such as zinc, iron, etc., is not beneficial to the efficacy of the drug and may even produce toxic reactions that affect the quality of the drug, that is, elemental impurities. The International Conference of Harmonization (ICH) released the Q3D elemental impurity guidelines in December 2014, and the latest revision was made in March 2019. The guidelines include the classification, risks, concentration limits, etc. of elemental impurities A detailed evaluation was carried out to provide guidelines for the qualitative and quantitative control of elemental impurities in new drug formulations and their excipients, and to establish a Permitted Daily Exposure (PDE) for elemental impurities.

This article summarizes the distribution of elemental impurities in the periodic table of chemical elements that are closely related to drug quality and safety, analyzes the introduction pathways and limit requirements of these elemental impurities in pharmaceutical preparations, and lists some elemental impurities in different forms of the same element and the human body. The healthy relationship aims to provide scientific guidance for the monitoring of elemental impurities in pharmaceutical preparations and the quality control of pharmaceuticals.

2. Classification of element impurities in pharmaceutical preparations

The elemental impurities of pharmaceutical preparations include some of the trace elements necessary for the human body that may be introduced in each component and some metal elements that have not been found in the human body, such as cadmium, mercury, lead, palladium, etc. There are only a dozen metal elements related to living organisms, which are relatively low in biological bodies. They belong to "trace elements", such as manganese, cobalt, copper, nickel, chromium, etc. These elements are regularly distributed in the periodic table of chemical elements , Mainly the third and fourth period alkali metals, alkaline earth metals and fourth period transition metals. The essential trace elements of the human body have their specified relative content in the normal body. For example, chromium is related to glucose metabolism and insulin secretion. It contains about 6 mg in the body of an average adult. Cobalt is the central metal ion of vitamin B12 and participates in the production of various enzymes. The catalytic process contains about 1.1 to 1.5 mg in the body of an average adult; and for metal elements that have not yet been discovered in the human body, once they enter the body, they can interact with amino acids or proteases through coordination bonds even in very small amounts. Closely combined, thereby affecting the normal physiological processes of the living body.

According to the toxicity of the elements to the human body and the possibility of occurrence in pharmaceutical preparations, ICH Q3D classifies element impurities into three categories. The first category is more toxic to humans and must be tested and restricted in all routes of administration; the second category, including category 2A and category 2B, category 2A has a higher probability of appearing in pharmaceutical preparations, and is used in all administration routes. Testing is required in all drug routes. Category 2B has a low probability of appearing in pharmaceutical preparations, so testing is not required. If it is intentionally added in the production process of APIs, excipients, etc., testing is required; Category III, oral administration is more toxic to humans Low, only need to be tested in injection administration and inhalation administration route. Because pharmaceutical preparations introduce excessive or toxic element impurities in the raw materials, production and other processes, which will have a significant impact on life, in order to ensure the quality and safety of drugs, the control threshold of elemental impurities in pharmaceutical preparations must be controlled to the PDE of the element. 30%.

3. The distribution and introduction of various element impurities in the periodic table of chemical elements

The periodic table of chemical elements currently includes 118 chemical elements, arranged in a table according to the atomic number from small to large. There are 7 horizontal rows and 7 periods, and 18 columns are divided into 18 groups. Each element has its own unique structure. The composition and physical and chemical properties of the elements in the same group are similar, including alkali metal elements, alkaline earth metal elements, transition elements, main group metal elements, metalloid elements, non-metal elements, halogens and rare gases.

Elemental impurities are mainly distributed in the fourth, fifth, and sixth period transition elements, main group metal elements, metalloid elements and non-metal elements in the periodic table of chemical elements, and a small part of alkali metal elements and alkaline earth metal elements.

1), transition elements

The transition element has a large atomic radius, has a variable oxidation state and good coordination performance, and can be combined with enzymes or proteins in the human body in various coordination forms to affect physiological processes. ICH Q3D defines 16 transition elements as elemental impurities. The elemental impurities in the third transition system are not easily metabolized due to their larger atomic radius and reduced ionicity. They are easy to accumulate in the body and are more toxic. For example, cadmium and mercury are harmful to the human body. Highly toxic, it can cause damage to the kidneys and reproductive system. It is the first elemental impurity; and the vanadium, chromium, cobalt, nickel, copper, and molybdenum in the first transition system are essential trace elements for the human body, but due to their different existence The shape or content has different effects on the human body, and it is also classified as elemental impurities.

2) Main group metal elements

ICH Q3D classifies 1 alkali metal (lithium), 1 alkaline earth metal (barium) and 3 other main group metal elements (tin, thallium, lead) as elemental impurities, of which tin is also an essential trace element for the human body. Lead is an element that is extremely toxic to the human body and can damage many systems such as nerves, digestion and cardiovascular systems. It is the first element impurity.

3), metal-like elements

Arsenic (As): Located at the 33rd position in the periodic table of chemical elements, it is a group A element and arsenic is an essential trace element for the human body. However, because arsenic accumulates in the body, excessive arsenic can cause cardiovascular disease or cancer, etc. Arsenic is designated as the first element impurity, which may be passed through auxiliary materials (such as dipotassium hydrogen phosphate, mannitol, polyethylene glycol), production equipment (such as polypropylene bottles, silica gel filling tubes, glassware), and airtight containers (such as Xilin). The introduction of pharmaceutical preparations such as bottles, rubber stoppers, etc. ICH Q3D pointed out that the allowable daily exposure (PDE) of arsenic in different administration routes are: 15 μg/day for oral administration, 15 μg/day for injection administration, and 15 μg/day for inhalation administration. It is 2 μg/day.

Antimony (Sb): Located at the 51st position in the periodic table of chemical elements, it is a group A element whose oral toxicity is low, and it is a third element impurity. Its possible introduction into pharmaceutical preparations is similar to that of arsenic. ICH Q3D points out that antimony is given in different doses. The allowable daily exposure (PDE) in the drug route is: 1200 μg/day for oral administration, 90 μg/day for injection administration, and 20 μg/day for inhalation administration.

4), non-metallic elements

Selenium (Se): Located at the 34th position in the periodic table of chemical elements, a group A element is one of the essential nutrients for the human body, but if it exceeds the nutritional level, it will cause poisoning. It is less likely to appear in drugs. It is a 2B elemental impurity. It may be introduced into pharmaceutical preparations in the production process of APIs and excipients. ICH Q3D points out that the allowable daily exposure (PDE) of selenium in different routes of administration are: Oral administration is 2 μg/day, injection administration is 80 μg/day, and inhalation administration is 130 μg/day.

4. Elemental impurity analysis and control discussion

The quality of medicine is not only related to the total amount of elemental impurities, but also related to the existence of elemental impurities. When the same element is in different valence states or different molecular composition forms, its effectiveness or toxicity is different. This is mainly due to the chemical element cycle. The electronic layer arrangement of each element in the table is different, which affects the stability. E.g:

Vanadium is an essential trace element for the human body. The toxicity of metallic vanadium is extremely low, but inorganic vanadium compounds are highly toxic, and the toxicity of pentavalent vanadium compounds is far greater than that of trivalent vanadium compounds;

Lead is a highly toxic heavy metal element. The relationship between its toxicity and its chemical form is as follows: Toxicity Alkyl lead compound> Inorganic lead compound> Metal lead. Alkyl lead compound poisoning is generally acute poisoning, which seriously affects the nervous system. And may cause death;

The relationship between the toxicity of mercury and its chemical form is as follows: Toxicity organic mercury compounds>inorganic mercury compounds>elemental mercury. Organic mercury compounds can cause permanent damage to the human nervous system and blood system, but organic mercury compounds are rarely found in medicines. It appears that inorganic mercury compounds affect human physiological processes mainly through the coordination of divalent mercury ions and sulfur-containing amino acids to cause protein denaturation. Therefore, the detection of elemental impurities is generally based on Hg 2+. Therefore, studying the existence of elemental impurities is also important for drug quality monitoring.

At present, the most commonly used method for determining elemental impurities is to use inductively coupled plasma-mass spectrometry (ICP-MS) or inductively coupled plasma atomic emission spectrometry (ICP-AES) to detect a variety of elemental impurities, using atomic absorption spectrometry (AAS) ) To detect single element impurities.

my country approved to join the ICH in June 2017. The National Drug Administration has been in line with international standards and issued the "Technical Requirements for the Consistency Evaluation of Listed Chemical Generic Drugs (Injections) (Draft for Comment)", which clearly stated the requirements in accordance with ICH Q3D It provides for the control and evaluation of elemental impurities that may be introduced into APIs, production equipment, etc. The National Pharmacopoeia Commission’s "Chinese Pharmacopoeia 2020 Edition Four General Principles Draft for Solicitation of Elemental Impurities and Determination Guidelines" in the chapters on the limits of elemental impurities and the determination guidelines pointed out that the limits of elemental impurities in chemical drugs should be controlled in accordance with ICH Q3D and clearly stipulated The scope of application provides confirmation methods and control methods for element impurity limits.

5. Risk assessment of element impurities

USP has created a risk assessment form that considers 24 elements. These elements are 15 elements listed in USP<232>, plus 9 other elements, and are divided into the following categories according to toxicity and the possibility of appearing in drugs: 1, 2A, 2B, and 3. Table 1 is based on different intake routes-oral, injection or inhalation, the types of elements that need to be considered in the risk assessment. In the evaluation, if an element is intentionally added during the production process, the manufacturer must detect it. If the element is not added intentionally, no risk assessment is required. Due to possible environmental impacts, arsenic, cadmium, lead and mercury must be tested.

The evaluation of the elemental impurities that need to be tested is an important step to control costs. When conducting elemental impurity testing, each element must be examined separately according to its specific analytical risks and challenges. If an element is not deliberately added to the product, you can judge whether it needs to be tested according to the type of drug and its way of ingestion. Copper is one such element. If it is not used in the production process, only the inhalation and injection medications need to be tested.

Each element has its own set of potential problems. For example, when testing for mercury, gold must be added. If gold is also required to be tested at the same time, the same sample preparation method cannot be used. For another example, it is beneficial to use hydrochloric acid as a matrix for certain elements, but adding hydrochloric acid may interfere with elements such as arsenic.

Sample preparation is the key to verifying these methods. Therefore, for method verification of 24 analytes, multiple sample preparation methods may be required. It is important that in order to avoid unnecessary complications to the analysis, it is necessary to consider from the beginning whether it is necessary to test all 24 elements.

6. Conclusion

Using ICH Q3D as the regulatory guidelines and standards, strictly monitor and control the total amount of elemental impurities in pharmaceutical preparations, formulate a reasonable evaluation plan based on the impact of different forms of elemental impurities on drug quality, and analyze the possible introduction of elemental impurities to develop control Strategies, such as adjusting relevant production processes, selecting appropriate container equipment, etc., to ensure that elemental impurity level control meets the limit requirements, and provide a strong guarantee for drug quality supervision.