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Residual Solvents: Compliance Information and Resources

Last Updated: October 6, 2008

USP encourages all global manufacturers to conform to the standards delineated in the USP–NF General Notices and General Chapter <467> Residual Solvents (official July 1, 2008) to ensure that drug substances, excipients, and products are subject to relevant control of residual solvents, and that the tests for residual solvents, the acceptance criteria, and, when needed, the reference materials for the tests (official USP Reference Standards) are the same from one manufacturer to another.

This Hot Topics page provides a portal for all relevant information and resources available to help you conform to the USP standard for residual solvents.

What are Residual Solvents?

According to USP 32-NF 27:

For pharmacopeial purposes, 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 residual solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of a drug substance or an excipient may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical element in the synthetic process. This general chapter does not address solvents deliberately used as excipients nor does it address solvates. However, the content of solvents in such products should be evaluated and justified.

Documentary Standards

USP–NF

Please remember that per the General Notices, all drug substances, excipients, and products are subject to relevant control of Residual Solvents.

Important documents to access in your USP–NF regarding residual solvents:

Pharmacopeial Forum

Review the Pharmacopeial Forum (PF) for any proposed updates or changes to the USP–NF. Currently, there is a proposed change published in PF 34(5) regarding General Chapter <467>.

Contact Information

For publications ordering information, please visit the USP Catalog or contact USP Customer Service at +1-301-881-0666, 1-800-227-8772 (U.S. and Canada), or 00-800-4875-5555 (Europe)

For technical questions, please contact Dr. Horacio Pappa at .

Pharmacopeial Education (PE)

Practical Applications of Chapter <467> Residual Solvents (Lecture Only)
This one-day lecture moves beyond an overview of the new requirements to focus on implementation issues in the lab. Analytical procedures contained in Chapter <467> and alternative testing protocols will be covered, as well as common points of confusion and concerns encountered by the industry.

More Info

Contact Information
Call 301-230-6304 or email the PE department at .

Stay informed of all upcoming courses through the Pharmacopeial Education Bulletin

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Reference Standards

USP has developed 36 new residual solvents Reference Standards designed to support the procedures in General Chapter <467> Residual Solvents. These standards were manufactured in a GMP facility and contain the class 1 or class 2 solvent mixed in pure DMSO.

Four of these standards are mixture standards designed to screen your product for the allowable level of class 1 and class 2 solvents. With each residual solvents mixture you will receive a typical chromatogram on the USP certificate for Procedure A and/or Procedure B where appropriate. These certificates containing the chromatogram can be downloaded by clicking the order button for each residual solvents mixture.

Residual Solvents Mixture - Class 1 (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 1 - Benzene (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 1 - Carbon Tetrachloride (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 1 - 1,2-Dichloroethane (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 1 - 1,1-Dichloroethene (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 1 - 1,1,1-Trichloroethane (1.2 mL/ampule; 3 ampules) Order
Residual Solvents Class 2 - Mixture A (1.2 mL/ampule; 3 ampules) Order
Residual Solvents Class 2 - Mixture B (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Mixture C (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Acetonitrile (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Chlorobenzene (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Chloroform (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Cyclohexane (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - 1,2-Dichloroethene (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Methylene Chloride (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - 1,2-Dimethoxyethane (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - N,N-Dimethylacetamide (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - N,N-Dimethylformamide (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - 1,4-Dioxane (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - 2-Ethoxyethanol (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Ethylene Glycol (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Formamide (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Hexane (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Methanol (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - 2-Methoxyethanol (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Methylbutylketone (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Methylcyclohexane (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - N-Methylpyrrolidone (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Nitromethane (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Pyridine (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Sulfolane (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Tetrahydrofuran (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Tetralin (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Toluene (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Trichloroethylene (1.2 mL/ampule; 3 ampules) Order
Residual Solvent Class 2 - Xylenes (1.2 mL/ampule; 3 ampules) Order

Class 3 solvent Reference Standards are being provided as pure solvents listed in the USP catalog. See General Chapter <467> Table 3 on page 166 for a detailed list of class 3 solvents.

Contact Information
For additional Reference Standard ordering information, please visit the USP Catalog or contact Customer Service at +1-301-881-0666, 1-800-227-8772 (U.S. and Canada), or 00-800-4875-5555 (Europe)

For technical questions, please contact USP at .

Web-based Information

Links to FDA Statements Regarding Residual Solvents

Frequently Asked Questions

Residual Solvents FAQs

Other USP Links

January 2007 USP/PDA Residual Solvents Educational Conference Summary and Presentations

Pharmaceutical Ingredient Verification Program
Consider USP's Pharmaceutical Ingredient Verification Program as a demonstration of the quality of your Pharmaceutical Ingredients and assurance in meeting the requirements of General Chapter <467>.