课件：FDA对药物杂质的控制要求——美国仿制药申报最新要求和案例分析.pptVIP

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课件：FDA对药物杂质的控制要求——美国仿制药申报最新要求和案例分析.ppt

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Limits of Residual Solvents: Class 1 Class 1 Residual solvents (Table 1): Should not be used in the manufacturing of drug substances, excipients or drug products because of unacceptable toxicities or deleterious environmental effects of the residual solvents. However, if there use is unavoidable, their levels should be restricted as shown in Table 1. Table 1. Class 1 Residual Solvents Solvent Concentration Limit (ppm) Concern Benzene 2 Carcinogen Carbon tetrachloride 4 Toxic and environmental Hazard 1,2-Dichlorothane 5 Toxic 1,1-Dichlorothane 5 Toxic 1,1,1-Trichlorothane 1500 Environmental Hazard Limits of Residual Solvents: Class 2 Class 2: 26 solvents Class 2 Residual Solvents: should be limited in drug substances, excipients or drug products because of their inherent toxicities. Their levels should be restricted as shown in Table 2. Concentration limits vary between 50 (Methylbutylketone) and 3880 (cyclohexane). When Class 2 residual solvents are used (or produced) in the manufacturing or purification process, they should be identified and quantified. Table 2. Class 2 Residual Solvents Solvent PDE (mg/day) Concentration Limit (ppm) Acetonitrile 4.1 410 Chlorobenzene 3.6 360 Chloroform 0.6 60 Cyclohexane 38.8 3880 1,2-Dichloroethane 18.7 1870 1,2-Dimethylacetamide 10.9 1090 N,N-Dimethylformamide 8.8 880 1,4-Dioxane 3.8 380 2-Ethoxyethanol 1.6 160 Table 2. Class 2 Residual Solvents Continued… Solvent PDE (mg/day) Concentration Limit (ppm) Ethylene glycol 6.2 620 Formamide 2.2 220 Hexane 2.9 290 Methanol 30.0 3000 2-Methoxyethanol 0.5 50 Methylbutylketone 0.5 50 Methycyclohexane 11.8 1180 Methylene chloride 6.0 600 N-methylpyrrolidone 5.3 530 Table 2. Class 2 Residual Solvents Continued… Solvent PDE (mg/day) Concentration Limit (ppm) 1,2-Dimethoxyethane 1.0 100 Nitromethane 0.5 50 Pyridine 2.0 200 Sulfolane 1.6 160 Tetrahydrofuran 7.2 720 Tetralin 1.0 100 Toluene 8.9 890 Trichloroethylene 0.8 80 Xylenes 21.7 2170 Limits of Residual Solvents: Class 3 Class 3: 28