The document issued by the State Food and Drug Administration provides guidance for the control of nitrosamine impurities

▍ source: State Food and Drug Administration ▍ sorting out: looking forward Recently, the State Food and Drug Administration issued a public consultation on the technical guidelines for the research of nitrosamine impurities in chemical drugs (Draft for comments) It is pointed out that in order to standardize and guide the research and review of nitroamine impurities in chemical drugs, the State Drug Administration has organized the drafting of technical guidelines for research on nitroamine impurities in chemical drugs (Exposure Draft), which is now open to the public for comments According to the draft, since the detection of N-nitrosodimethylamine (NDMA) in valsartan APIs in July 2018, various nitrosamine impurities, such as NDMA, N-nitrosodimethylamine (NDEA) and so on, have been successively 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) Nitramine 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); according to the list of carcinogens published by the World Health Organization, NDMA and NDEA belong to category 2A carcinogens According to the 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 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 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 continuously improved based on the research results of all parties and the principle of risk and benefit evaluation In its opinion, the State Food and Drug Administration said that 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 nitroamine impurities in registered applications for listing and listed chemicals 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） Risk of introducing nitrosamine impurities into the process It is known that NDMA and NDEA impurities may be generated through 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） Risks 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 risks 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 risk Some drugs will degrade and produce nitrosamines, such as ranitidine, which will produce nitrosamines at high temperature （1） Basic control concept Because the acceptance limit of nitrosamines in human body is small, 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 The risk assessment method can be FMEA (Failure Mode Effects Analysis) or FMECA (failure mode effects and criticality analysis) as 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 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） Limit control It is suggested to refer to the relevant provisions of ICH M7 (R1) guidelines for the control strategy of nitrosamine impurities in 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 API and preparation lower than the acceptable limit 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.