What are residual solvents in a drug?
Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents are not completely removed by the manufacturing techniques. The content of solvents in such products should be evaluated and justified. Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical parameter in the synthetic process. Since there is no therapeutic benefit from solvents, all residual solvents should be removed to meet ICH guidance limits. The term residual implies that these are what remains after efforts to remove them. They are also called Organic volatile Impurities [OVI].
Deleterious effects of residual solvents in drug product
1.Residual solvents are potentially undesirable substances, they either modify the properties of certain compounds or are hazardous to the health of individual.
2. They can create odor problem and color changes in the finished products.
Guidance for residual solvents
ICH guideline Q3C [R6] on impurities: Guideline for residual solvents.
USP <467>.
Objectives
1.The objective of this guidance is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient.
2.The guideline recommends use of less toxic solvents.
Classes of residual solvents.
Residual solvents were evaluated for their possible risk to human health and placed into one of three classes as follows.
Class 1 solvents: Solvents to be avoided
Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.
Class 2 solvents: Solvents to be limited
Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.
Class 3 solvents: Solvents with low toxic potential
Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDE’s [Permitted daily exposure]of 50 mg or more per day.
Class 1 solvents: Solvents to be avoided
1.Solvents in Class 1 should not be employed in the manufacture of drug substances, excipients, and drug products because of their unacceptable toxicity or their deleterious environmental effect.
2.However, if their use is unavoidable in order to produce a drug product with a significant therapeutic advance, then their levels should be restricted as shown in Table-I.
Class 2 solvents: Solvents to be limited
1.Solvents in Table II should be limited in pharmaceutical products because of their inherent toxicity.
2.The stated values do not reflect the necessary analytical precision of determination. Precision should be determined as part of the validation of the method.
Class 3 solvents: Solvents with low toxic potential
1.Solvents shown in Table III may be regarded as less toxic and of lower risk to human health.
2.Class 3 includes no solvent known as a human health hazard at levels normally accepted in pharmaceuticals. However, there are no long-term toxicity or carcinogenicity studies for many of the solvents in Class 3.
3.Available data indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies. It is considered that amounts of these residual solvents of 50 mg per day or less [Corresponding to 5000 ppm or 0.5%] would be acceptable without justification. Higher amounts may also be acceptable provided they are realistic in relation to manufacturing capability and good manufacturing practice.
Solvents for which No adequate toxicological data was found
1.The following solvents listed in Table IV may also be of interest to manufacturers of excipients, drug substances, or drug products.
2.However, no adequate toxicological data on which to base a PDE was found.
3.Manufacturers should supply justification for residual levels of these solvents in pharmaceutical products.
Analytical Procedures
1.Residual solvents are typically determined using chromatographic techniques such as gas chromatography.
2.Any harmonized procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible.
3.Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure for a particular application.
4.If only Class 3 solvents are present, a nonspecific method such as loss on drying may be used.
5.Validation of methods for residual solvents should conform to ICH guidelines text on “Validation of Analytical Procedures and Extension of the ICH Text on Validation of Analytical Procedures”.
6.No testing is required if no solvents are not used in the manufacturing process, however evaluation of the starting materials and finished product is necessary.
Conclusion
Residual solvents from the processes in the manufacturing of pharmaceuticals are hazardous and cause serious problems and must be removed. Pharmaceutical manufacturers should develop a process which can remove the solvents to a very minimum level by efficient filtration, drying methods. Also, the use of fresh solvents aid in the process ensures the purity of the drug product and has an impact in the shelf life of the drug product. Validated process validation will provide assurance that the residual solvents that are tested are uniform in the drug product and every portion of the drug that reaches the patient is uniform.
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