Permitted daily exposures solvents

Solvents with low toxic potential No health-based exposure limit is needed solvents with permitted daily exposure of 50 mg or more per day... 

The long-term stability of an oral liquid formulation can also be affected by a number of unexpected reasons. Contamination by solvents used during the tank cleaning or even in the manufacture of excipients or API can be a source of instability of an oral solution. Uncontrolled levels of Class I, II, or III solvents could lead to the rejection of a batch or an excipient vendor. Class III solvents have a permitted daily exposure of 50 mg or less per day. (See the International Conferences on Harmonization, Impurities Guidelines for Residual Solvents. Q3C, Federal Register 1997 62(247) 67377 and also http //www.fda.gov/cvm/Guidance/guidelOO.PDF). 

List taken from International Conference on Harmonization (ICH), harmonized tripartite (Europe, Japan, United States) guideline entitled Impurities Guideline for Residual Solvents. The above solvents are categorized as Class 3 solvents, with low toxic potential to man. Class 3 solvents have permitted daily exposures (PDEs) of 50 mg or more per day. 

Class II solvents with possible toxic activity or that present reversible toxicity. This class includes 25 solvents, such as acetonitrile, methanol, cyclohexane, and methylene chloride. For each solvent there is a permitted daily exposure dose (PDF) and an acceptable level of concentration in the final product (Table 8.2). 

The level of Class 1 residual solvents should be strictly controlled below the concentration limits for every individual solvent (for example the limit for benzene is 2 ppm). Class 2 solvents are controlled according to the permitted daily exposures (PDFs) and maximum daily dose (Option 1 and Option 2). ICH Q3C provides PDFs for all Class 2 solvents. For Class 3 Solvents, ICH Q3C suggests that a PDF of 50mg/day or less would be acceptable without justification. For solvents for which no adequate toxicological data are found, manufacturers should supply justification for residual levels of these solvents in pharmaceutical products. 

ICH Q3C guides in determining, on a safety basis, acceptable residual solvent levels for intake by use of the term permitted daily exposure (PDE). This Guidance classifies residual solvents used in the synthesis and processing into four categories. The Guidance recommends that Class I solvents be avoided. These include benzene, carbon tetrachloride, 1,2-dichloromethane, 1,1-dichloroethane, and 1,1,1-trichloroethane. Table 2 is an example from the list of Class II solvents that should be limited because of their inherent toxicity either by calculation of concentration (PPM) or by PDE. 

The guideline contains extensive lists of solvents of all three classes, with limits for each. Known toxicology data are given for each solvent, with definitions for parameters and methods of establishing exposure limits such as permitted daily exposure (PDE), no-observed-effect level (NOEL), lowest-observed-effect level (LOEL), tolerable daily intake (TDI), and acceptable daily intake (ADI). 

ICH Q3C(R5) provides guidance on the permitted daily exposure (PDE) of common solvents, which translates to a residual solvent specification in the API, based upon the daily dose. Solvents are grouped into classes that broadly mirror the ranking of solvents in solvent selection guidance, as summarised in Table 8.3. ... 

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