Nmpa issued technical guidelines for the study of nitrosamine impurities in chemicals for comments

Source: State Food and Drug Administration Recently, FDA announced three recall announcements of ranitidine in a row, and the problem of nitrosamine impurity was pushed to the air outlet On January 10, the State Food and Drug Administration issued the technical guidelines for the study of nitrosamine impurities in chemical drugs (Draft for comments) For nitrosamine impurities, the State Food and drug administration finally issued relevant technical guidelines for comments For the limit of nitrosamine impurities, there are two calculation methods, and an example is given: In general, for mutagenic impurities with positive carcinogenic data, it is recommended to calculate the daily acceptable intake (AI) according to the TD50 value of carcinogenic substances in the CPDB (carcinogenicity potency database) database The TD50 values of NDMA in mice and rats were 0.189mg/kg/day and 0.0959mg/kg/day, respectively According to the more conservative TD50 value of rats 0.0959mg/kg/day and human body weight 50kg, the maximum daily intake of NDMA for human is: 0.0959mg/kg/day × 50kg / 50000 = 0.00009599mg/day ≈ 96ng / day, at this time, the corresponding risk of tumor occurrence is 1 / 100000 If the maximum daily dose of valsartan is 320mg, the NDMA limit is set as follows: 96ng/320mg=0.00003%=0.30ppm。 TD50 data of dipna and eipna are not available in CPDB database According to the method recommended in Chapter 7.5 of ichm7 (R1), carcinogenicity data of other compounds closely related to current compounds can be used as carcinogenicity data of current compounds in combination with specific cases In order to confirm the closely related structures, based on the results of SAR analysis and the characteristics of the formation of alkyl diazonium ions, it is considered that the carcinogenicity data of NDEA can be used to calculate the AI values of dipna and eipna According to sulc et al (2010), alkyln-nitrosamines can be converted into corresponding DNA Covalently Modified alkyldiazonium ions through α - hydroxylation process in vivo, and release carbonyl compounds at the same time According to the daily dosage and medication cycle of valsartan, referring to the calculation method of example 1, it can be concluded that the maximum daily intake of dipna and eipna is 26.5ng/day, at this time, the corresponding tumor risk is one in 100000 General Department of State Food and Drug Administration solicits opinions on technical guidelines for research of nitrosamine impurities in chemical drugs (Draft for comments) Issued on January 10, 2020 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 the study of nitrosamine impurities in chemical drugs (Draft for comments) General Department of State Food and Drug Administration January 6, 2020 Enclosure (Draft for comments) 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 guideline [1] of ichm7 (R1) (evaluation and control of DNA reactive (mutagenic) impurities in drugs to limit potential carcinogenic risks); NDMA and NDEA belong to category 2A carcinogens according to the list of carcinogens published by the World Health Organization [2]; according to the database of CPDB (carcinogenicity potency database), Some nitrosamine impurities have published 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 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 [4]: （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 effectiveness analysis) or FMECA (failure mode, effectiveness 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） Limit control It is suggested to refer to the relevant provisions of guideline ICH M7 (R1) 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 ichm7 (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 nitrosamines as class 2A carcinogens (possibly carcinogenic to humans, but with limited evidence and sufficient evidence for carcinogenicity to experimental animals) The provisions of ichm7 (R1) are class I mutagenic impurities Therefore, the control of nitrosamines in drugs should be formulated on the basis of meeting the requirements of ichm7 (R1) Develop strategies to keep levels of these impurities below acceptable limits in APIs and preparations 1 It can find out the nitrosamine impurities with TD50 value (50% tumor incidence) in the authoritative database TD50 of substance generally comes from the database of CPDB and other authorities 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 Ptableintake, 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 calculation formula is: Limit = AI / daily dose Refer to example 1 attached to this article for details 2 No nitrosamine impurities with TD50 value were found in the database of the authority If the TD50 value cannot be found in the authoritative organization database, the following methods can be used to obtain the control limit of the nitrosamine impurities, and the minimum value is recommended: A You can refer to the data published or risk assessment methods established by international authorities, such as who, international program on Chemical Safety (IPCS) B Similar to the existing TD50 value of nitrosamines, the TD50 value can be used to calculate the impurity limit