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    Home > Medical News > Latest Medical News > State Food and Drug Administration: technical guidelines for the study of nitrosamine impurities in chemicals

    State Food and Drug Administration: technical guidelines for the study of nitrosamine impurities in chemicals

    • Last Update: 2020-01-13
    • Source: Internet
    • Author: User
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    In order to standardize and guide the research and evaluation of nitrosamine impurities in chemical drugs, the State Drug Administration has organized the drafting of technical guidelines for research on nitroamine impurities in chemical drugs (Draft for comments), which is now open to the public for comments Please feed back relevant opinions to yangq@cde.org.cn by February 9, 2020 The title of the email should indicate "feedback on technical guidelines for research of nitrosamine impurities in chemical drugs" Annex: technical guidelines for research on nitrosamine impurities in chemical drugs (Draft for comments) technical guidelines for research on nitrosamine impurities in chemical drugs (Draft for comments) I overview Since the detection of N-nitrosodimethylamine (NDMA) in valsartan API in July 2018, various nitrosamine impurities, such as NDMA, N-nitrosodimethylamine (NDEA), etc., have been detected in other Sha Tan APIs Further investigation found that nitrosamine impurities were also detected in non - sartan drugs from individual suppliers (such as ranitidine) Nitrosamine impurities belong to the "Concern Group" substances mentioned in ICH M7 (R1) (evaluation and control of DNA reactive (mutagenic) impurities in drugs to limit potential carcinogenic risks) [1]; NDMA and NDEA belong to category 2A carcinogens according to the list of carcinogens published by the World Health Organization [2]; according to CPDB (carcinogenicity potency) Database) database, some nitrosamine impurities have public carcinogenicity data, such as NDMA, NDEA, n-nitroso-n-methyl-4-aminobutyric acid (NMBA), n-nitrosodibutylamine (ndba), etc In order to ensure the safety and quality control of drugs and achieve effective risk control, the technical guidelines are hereby formulated to provide guidance for the research and control of nitrosamine impurities in registered applications for listing and listed chemicals The applicant shall earnestly fulfill the main responsibility of drug quality management, carry out full life-cycle management of drug safety and quality, and try to avoid the introduction of nitrosamine impurities If it can not be completely avoided, the risk of nitrosamine impurities in the drug shall be fully assessed, and the nitrosamine impurities shall be controlled below the safety limit 2、 According to the current knowledge, there are many reasons for the formation of nitrosamine impurities, such as process generation, degradation pathway and pollution introduction Specifically, nitrosamine impurities may be introduced through the following ways: (1) the risk of nitrosamine impurities introduced by the process is currently known, and NDMA and NDEA impurities may be generated through the nitrosation mechanism That is to say, under certain conditions, amines, especially secondary amines, react with sodium nitrite (NaNO2) or other nitrifying agents to produce nitrosamines impurities Materials (including starting materials, solvents, reagents, catalysts, intermediates, etc.) that can introduce secondary amines and nitrites are used in the same process step, with high risk of introducing nitrosamine impurities; even if materials that can introduce secondary amines and nitrites are used in different process steps, nitrosamine impurities may be generated In addition to the secondary amine structure, secondary amines may come from primary amines, tertiary amines and quaternary amines, and secondary amines may be produced by amides (such as N, N-dimethylformamide, N-methylpyrrolidone, etc.) under suitable conditions (such as acidity, high temperature, etc.) Nitrous reagents may be introduced from nitrite, nitrite, nitrite, substances prepared from nitrite (such as sodium azide), oxidation of amines, etc When the conditions are met, nitrosamine impurities may also be produced in the production or storage process of the preparation (2) The risk introduced by pollution the use of materials (starting materials, intermediates, solvents, reagents, catalysts, etc.) contaminated by nitrosamine impurities in the production process of API may bring the risk of nitrosamine impurities There is also a risk of introducing nitrosamine impurities into recycled materials Examples of nitrosamines contamination of recovered materials have been found to include o-xylene, tributyltin chloride (used as a source of tributyltin azide), N, N-dimethylformamide (DMF) In the same production line production of different varieties, due to incomplete cleaning, resulting in cross contamination (3) Degradation risks some drugs will degrade and produce nitrosamine impurities, such as ranitidine at high temperature 3、 Control strategy (1) basic control concept because of the small acceptable limit of nitrosamine impurities in human body, it is difficult to detect and control trace impurities Therefore, the control of nitrosamine impurities should be based on avoidance and supplemented by control Avoidance mainly refers to avoiding the generation of nitrosamine impurities as far as possible in the R & D stage of drugs from the aspects of the selection of API process route, the selection and quality control of materials, and the optimization of process conditions according to the causes of the generation of nitrosamine impurities, and strictly implementing the operation specifications in the production process The drug manufacturer shall fully communicate with the manufacturers of various materials (the API shall include starting materials, solvents, reagents, catalysts, intermediates, etc., and the preparation shall include API, auxiliary materials, packaging materials, etc.) to systematically evaluate the material production and recovery process Risk assessment methods can adopt FMEA (Failure Mode Effects Analysis) or FMECA (Failure Mode, Effects and Criticality Analysis) [5] described in ICH Q9 (quality risk management), or other scientific and reasonable methods If it is found that there is a risk of the formation of nitrosamine impurities, the necessity of using nitrite, related reagents and solvents that may form nitrosamine impurities in the process shall be analyzed first, and the production process that may generate nitrosamine impurities shall be avoided as far as possible [6] The control assisted strategy refers to that when assessing the risk of nitrosamine impurity residues in drugs and related processes cannot be avoided, this step should be adjusted to the early stage of the process as far as possible, and the subsequent multi-step operation should be used to reduce the risk of nitrosamine impurity residues At the same time, it is necessary to analyze the structure of nitrosamines that may be generated according to the process route, optimize the process, and formulate detailed process control strategies to ensure the effective removal of such impurities in the production process When nitrosamine impurities are produced by degradation, the conditions of degradation should be analyzed, and the risk of degradation impurities should be reduced by optimizing the production process, prescription, storage conditions, etc Appropriate analytical methods should be established for the varieties with the residual risk of nitrosamine impurities to ensure that the nitrosamine impurities in the finished products are lower than the limit requirements (2) It is suggested to refer to the relevant provisions of ICH M7 (R1) guidelines for the control strategy of nitrosamine impurities in limited control drugs, so as to ensure that the final control strategy and impurity limit have sufficient and reasonable scientific basis The carcinogenic risk of nitrosamines is high, and the TTC of 1.5 μ g / day proposed by ICH M7 (R1) is not enough to control the risk The applicant shall determine the types of nitrosamine impurities to be controlled according to the material properties, process, production process, degradation, analysis and test results of the R & D varieties and the requirements of the regulatory authority The international agency for research on cancer (IARC) lists nitrosamine impurities as class 2A carcinogens (possibly carcinogenic to humans, but with limited evidence and sufficient evidence for carcinogenicity of experimental animals) ICH M7 (R1) is a class I mutagenic impurity Therefore, the control of nitrosamine impurities in drugs should be in accordance with ICH Based on the requirements of M7 (R1), a control strategy is developed to make the level of such impurities in APIs and preparations lower than the acceptable limit TD50 of nitrosamine impurities with TD50 value (50% tumor incidence) can be found in authoritative organization database, which generally comes from authoritative organization database such as CPDB The risk of carcinogenesis of nitrosamine impurities is high First, find out the TD50 value of the most sensitive species and the most sensitive tumor site (or choose the TD50 value of animal species with more conservative or higher safety factor) Set the corresponding risk of tumor occurrence as 1 / 100000, and calculate the body weight as 50kg, then the daily acceptable intake of nitrosamine impurities (acce Ptable intake, AI) is: TD50 (mg / kg / day) × 50kg / 50000 Combined with the maximum daily dosage specified in the legal instructions of each drug, the control limit of nitrosamine impurities in the drug can be calculated The formula is: limit = AI / daily dosage Refer to example 1 attached to this article for details 2 If the TD50 value of nitrosamine impurity is not found in the authoritative organization database and the TD50 value is not found in the authoritative organization database, the following methods can be used to obtain the control limit of the nitrosamine impurity, and the minimum value is recommended: A refer to the international authoritative organization, such as who and international program on chemical Safety, IPCS) and other published data or established risk assessment methods B Similar to the existing TD50 value of nitrosamines, the TD50 value can be used to calculate the impurity limit As in example 2 (3) The establishment of detection methods for the analysis and test of nitrosamine impurities in drugs can refer to the methods published by the authority or developed by ourselves It is necessary to note that the sensitivity of the analysis method should match the demonstrated impurity limit, and a complete methodological verification should be carried out with impurity reference substance to ensure the accurate and effective detection of nitrosamine impurities If the enterprise adopts the self-developed method, it is necessary to prove that the method is equivalent to or better than the method officially published by the same variety (4) Life cycle risk control For the products declared for marketing, the applicant shall carry out risk assessment of nitrosamine impurities in the R & D process, fully study the varieties with potential risks of nitrosamine impurities, submit the research data and test results of nitrosamine impurities in the corresponding chapters of the application materials, and pay attention to the representative batches and batches of samples used for research Academic basis For marketed drugs, the drug approval number holder / manufacturer shall also take the initiative to assess the risk of nitrosamine impurities If there is a potential risk of nitrosamine impurities, please refer to the requirements of these guidelines and other relevant guidelines for research, and take corresponding measures according to the research results to prevent or minimize the exposure of nitrosamine impurities in patients Dew 4、 Other NDMA is a common nitrosamine substance found in water and food, including bacon and barbecue, dairy products and vegetables All will be exposed to a certain level of NDMA FDA and international scientific groups do not believe that low levels of intake can cause harm The acceptable intake limit of NDMA in the United States is 96ng Long term exposure to higher than acceptable levels of genotoxic substances, such as NDMA, may increase the risk of cancer, but people who take drugs containing NDMA at or below acceptable levels daily for 70 years will not increase the risk of cancer 【8】 At present, the drug regulatory agencies of various countries are actively carrying out corresponding exploration and Research on the nitrosamine impurities in drugs This guiding principle will be based on the research results of all parties
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