Recently, the FDA announced three consecutive recall notices of ranitidine, and the problem of nitrosamine impurities has been pushed to the air outlet. On January 10, the State Food and Drug Administration issued the "Technical Guiding Principles for the Study of Nitrosamine Impurities in Chemical Drugs (Draft for Solicitation of Comments)".
Regarding nitrosamine impurities, the State Food and Drug Administration finally released relevant technical guidelines for comments. Soliciting opinions has two calculation methods for the limits of nitrosamine impurities, and gives examples:
Example 1: Limit of nitrosamine impurities with TD50 value recommended by the authority
In general, for mutagenic impurities with positive carcinogenicity data, it is recommended to calculate the daily acceptable intake (AI) based on the TD50 value of the carcinogenic substance in the CPDB (CarcinogenicityPotencyDatabase) database. The TD50 values of NDMA in mice and rats were 0.189 mg / kg / day and 0.0959 mg / kg / day, respectively. According to the more conservative rat TD50 value of 0.0959mg / kg / day and human body weight of 50kg, the maximum daily intake of human NDMA is calculated as: 0.0959mg / kg / day × 50kg / 50000 = 0.0000959mg / day ≈ 96ng / Day, at this time the corresponding tumor risk is one in 100,000. If calculated according to the maximum daily dose of 320mg of valsartan, the NDMA limit is set to:
96ng / 320mg = 0.00003% = 0.30ppm.
Example 2: Limit of nitrosamine impurities with TD50 value not found in the authority database [7b]
There is no TD50 data for DIPNA and EIPNA in the CPDB database. According to the method suggested in Chapter 7.5 of ICHM7 (R1), specific cases can be combined to use the carcinogenicity data of other compounds whose structure is closely related to the current compound as the carcinogenicity of the current compound. Sexual data. In order to confirm the closely related structures, based on the results of SAR analysis and the characteristics that these compounds can form alkyl diazonium ions, it is believed that the carcinogenicity data of NDEA can be used to calculate the AI values of DIPNA and EIPNA. According to the results of Sulc et al. (2010), alkyl N-nitrosamines can be converted into the corresponding alkyl diazo ions that can cause covalent modification of DNA in vivo through α-hydroxylation process, and simultaneously release the carbonyl group Compounds.
According to the daily dose of valsartan and the cycle of medication, referring to the calculation method of Example 1, it can be concluded that the maximum daily intake of people with DIPNA and EIPNA is 26.5ng / day, and the corresponding tumor risk is 1 in 100,000 at this time. One.