The Drug Administration issued a document to provide guidance for the control of nitrosamine impurities

, the State Drug Administration issued an opinion on the existence of two types of carcinogen nitrosamine impurities in some of the drugs.Recently, the State Drug Administration issued a public consultation on the technical guidelines for the study of nitrosamine impurities in the chemical drug Central Asia (draft for comments) in the detection of nitrosamine impuritiesIt was pointed out that, in order to regulate and guide the research and review of nitroamine impurities in Central Asia, the State Drug Administration has organized the drafting of the Technical Guidelines for the Study of Nitroamine Impurities in Central Asia for Chemical Drugs (Draft for Comments), and is now open to public consultation.According to the Draft, since July 2018, N-nitrodiamine (NDMA) has been detected in other sartan-type API drugs, such as NDMA, N-Nitrodythylamine (NDEA) and so on.Further investigations revealed that nitrosamine impurities were also detected in individual suppliers of non-sartan-type drugs such as renitridine.Nitroamine impurities are "queue of concern" substances referred to in the guidelines for assessing and controlling DNA reactive (mutation-causing) impurities in drugs to limit the risk of potential cancer;According to the CPDB database, some nitrosamine impurities have publicly available carcinogenic data, such as NDMA, NDEA, N-Nitro-N-Methyl-4-Amino butyric acid (NMBA), N-Nitrodydiamine (NDBA), etc.

The State Drug Administration provides guidance and guidance for the control of nitrosamineNDMA is a common nitrosamine found in water and food, including bacon and grilled meats, dairy products and vegetables. All people are exposed to a certain level of NDMA. The FDA and the international scientific community do not believe that low levels of intake can cause harm. The acceptable intake limit for NDMA in the United States is 96 ng.Long-term exposure to high acceptable levels of genotoxic substances such as NDMA may increase the risk of cancer, but people who take drugs containing NDMA equal to or below acceptable levels daily for 70 years do not increase their risk of cancer.At present, drug regulatory agencies in various countries are actively carrying out the corresponding exploration and research on nitrosamine impurities in drugs, and this guiding principle will be based on the results of various research results and risk benefit assessment principles continue to improve.In its opinion, the State Drug Administration said that in order to ensure the safety and quality of drugs can be controlled and to achieve effective risk control, these technical guidelines have been formulated to provide guidance for the research and control of nitroamine impurities in Central Asia, which are registered for listing and listed chemicals.

a variety of reasons for the production of nitrosamine-like impuritiesAs far as we know, nitrosamine impurities have many causes, such as process generation, degradation pathways and pollution introduction. Specifically, nitrosamine impurities may be introduced through the following means:(i) risk of nitrosamine impurities introduced by the processThat is, under certain conditions, amine compounds, especially midamine, react with sodium nitrite (NaNO2) or other nitrite reagents to produce nitrosamine impurities.The introduction of nitrosamine impurities with high risk of introducing nitrosamine impurities using materials that can introduce zhongamine and nitrites (including starting materials, solvents, reagents, catalysts, intermediates, etc.) is used in the same process step, and nitrosamine impurities may occur even if materials that introduce midamine and nitrites are used in different process steps, respectively.In addition to the material itself with a mid-amine structure, the possible sources of mid-amine are: beramine, shamide and seasonal ammonium may introduce mid-amine impurities, aramid solvents (e.g. N, N-dimethylamine, N-methylcarpenone, etc.) may produce zhongamine under appropriate conditions (e.g. acidity, high temperature, etc.).Nitrite reagents may be introduced from: nitrites, substances prepared by nitrites (e.g., sodium laminate, etc.), oxidation of amine compounds, etc.Nitrosamine impurities may also be produced during the production or storage of the preparation when conditions are in place.(ii) Risks introduced by pollutionThe use of materials contaminated with nitrosamine impurities (starting materials, intermediates, solvents, reagents, catalysts, etc.) in the production of API may pose a risk of nitrosamine impurities.The use of recycled materials also risks introducing nitrosamine impurities. Examples of nitrosamine contamination of recycled materials found include phthalates, triclosan chloride (used as a source of tetrine for overlapping nitride), N, N-dmymide (DMF).Different varieties are produced on the same production line, resulting in cross-contamination due to incomplete cleaning.(iii) Degradation creates riskscertain drugs themselves degrade to produce nitrosamine impurities, such as renitridine, which produce nitrosamine impurities at high temperatures.

how to control nitrosamine impurities(1) Basic control conceptBecause nitrosamine impurities are less acceptable in the human body, the detection and control of trace impurities is difficult. Therefore, the control of nitrosamine impurities should be avoided mainly, control as a supplement strategy.Avoidance mainly means that in the research and development stage of drugs should be based on the causes of nitrosamine impurities from the choice of RAW drug route, material selection and quality control, process conditions optimization and so on to avoid the production of nitrosamine impurities, and strictly implement the operating norms in the production process.Pharmaceutical production enterprises should fully communicate with the manufacturers of various materials (raw materials should include starting materials, solvents, reagents, catalysts, intermediates, etc., preparations should include raw materials, accessories, packages, etc.) to carry out a systematic assessment of the material production and recovery process. Risk assessment methods may be conducted using the FMEA (Failure Mode Effects Analysis) or FMECA (Failure Mode, Effects and Criticality Analysis) described in ICH Q9 (Quality Risk Management), or other scientifically reasonable methods.If the risk of producing nitrosamine impurities is found, the necessity of using nitrite-like impurities and related reagents and solvents that may form nitrosamine impurities should be analyzed first, and the production process that may produce nitrosamine-like impurities should be avoided.The strategy of controlling as a supplement means that when the drug is assessed to have a risk of nitrosamine impurities residue and the relevant process cannot be avoided, the step should be adjusted to the early stage of the process as far as possible, and the risk of nitrosamine impurities residues should be reduced by subsequent multi-step operation. At the same time, according to the route analysis of the possible production of nitrosamine structure, and optimize the process, develop a detailed process control strategy to ensure the effective removal of such impurities in the production process. 　　In the case of nitrosamine impurities produced by degradation, the conditions produced by degradation should be analyzed to reduce the risk of degradation of impurities by optimizing production processes, prescriptions, storage conditions, etc. 　　Appropriate analytical methods should be established for varieties that are clearly at risk of nitrosamine impurities residues to ensure that the finished Central Asian nitrosamine impurities are below the limit requirements. 　　(2) Limit control drug Central Asian nitrosamine impurities control strategy recommendations refer to the relevant provisions of the ICH M7 (R1) guidelines, should ensure that the final proposed control strategy and impurity limits have a sufficiently reasonable scientific basis. The risk of cancer is high for nitrosamine impurities, and the toxicology attention threshold (TTC) of 1.5 μg/day as set out in ICH M7 (R1) alone is not sufficient to adequately control the risk. 　　The applicant shall determine the type of nitrosamine impurities to be controlled according to the material properties, route, production process, degradation, analysis of test results and requirements of the regulatory authority. 　　The International Agency for Research on Cancer lists nitrosamine impurities as Class 2A carcinogens (which may cause cancer in humans, but has limited evidence and sufficient evidence of carcinogenicity in experimental animals), ICH M7 (R1) ) the provisions belong to class I. mutagenic impurities, therefore, the control of drug Central Asia nitrosamine impurities should be in line with ICH M7 (R1) requirements to develop a control strategy, so that the level of such impurities in the API and preparations below acceptable limits.

to fulfill the full life cycle of risk 　　Applicants should effectively fulfill the main responsibility of drug quality management, the safety and quality of drugs for the entire life cycle management, as far as possible to avoid the introduction of nitrosamine-type impurities, if it is not completely avoided, should fully assess the risk of nitrosamine-type impurities in the drug Central Asia, and nitrosamine impurities to control below the safety limit. 　　For declared listed products, the applicant in research and development, should carry out a risk assessment of nitrosamine impurities, the clear potential risk of nitrosamine impurities varieties should be fully studied, in the corresponding section of the declaration data to submit nitrosamine impurities research data and test results, at the same time should pay attention to the samples used for research batch, batch must be representative and scientific basis.
For listed drugs, drug approval number holders/manufacturers should also take the initiative to assess the risk of nitrosamine impurities, if there is a potential risk of nitrosamine impurities, can refer to the requirements of these guidelines and other relevant guidelines, according to the results of the study to take appropriate measures to prevent or minimize exposure to nitrosamine impurities in patients. (State Drug Administration)
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