What is the basis for residual solvent limits establishment in ICH Q3?
The basis depends up on the class of solvents used and amount of such solvents present in API’s that may be toxic to humans after using such products. Always the limits must be below the prescribed limits.
Residual solvents are classified into three classes on the basis of the toxicity level and the degree to which they can be considered an environmental hazard. The list provided in the guideline is not exhaustive, and one should evaluate the synthesis and manufacturing processes for all possible residual solvents.
Class 1. Class 1 solvents are known carcinogens and are strongly suspected of being harmful to humans and of being environmental hazards. They should be avoided, if possible. However, if using them to produce a medicinal product with a significant therapeutic value is unavoidable, then their levels should be controlled as shown in Table I, unless otherwise justified. 1,1,1-Trichloroethane is included in this table because it is an environmental hazard.
Class 2. Class 2 solvents are nongenotoxic animal carcinogens. Solvents of this class should be limited in pharmaceutical products because of their inherent toxicity. Table II lists some of these solvents and their tolerable concentration limit. The limits were calculated on the basis of the permitted daily exposure, which assumed a daily dose of 10 g of drug product per day.
Class 3. Class 3 solvents have low toxic potential to humans. However, no long-term toxicity or carcinogenicity data are available for many of them. They have been found less toxic in acute or short-term studies and negative in genotoxicity studies. A concentration 0.5% is acceptable without justification. A higher amount may also be acceptable with proper justification. Table III lists some of the solvents from Class 3.
Others. In addition to these three classes of solvents, some solvents may be of interest to manufacturers of active substances, excipients, and drug products. However, no adequate toxicological data based on permitted daily dose are available.Manufacturers must provide justification if they use these solvents in their products
Residual solvents calculation PDF
Residual solvents.pdf (185.4 KB)
Thanks for detailed clarification.
I wanted to upload the list of those classes of Solvents.There is a problem and it failed to upload. I shall upload that by today evening.You will know names of solvents from that list.