The United States Pharmacopeia (USP) defines Residual Solvents as organic volatile chemicals that are used in or produced during the manufacturing of Active Pharmaceutical Ingredients (APIs), inactive ingredients (excipients), and dietary ingredients or in the preparation of drug or dietary supplement products. The use of solvents in the synthesis of APIs, excipients or dietary ingredients is looked upon as a critical element in the process but unfortunately, its total removal from the end product is not easily achieved. Because residual solvents do not provide therapeutic benefit, they should be removed to the extent possible, to meet safety-based limits, ingredient and product specifications, good manufacturing practices, or other quality-based requirements.
The USP has created General Chapter <467> entitled “Residual Solvents” for the purpose of defining acceptable amounts of residual solvents in drug and dietary supplement products for the safety of the patients or product users. Tests for residual solvents are generally not discussed in specific USP Monographs since the selection of solvents varies between manufacturers. For this reason, the limits established in General Chapter <467> are intended for all ingredients and products with few exceptions.
In addition to establishing acceptable limits for each residual solvent, USP <467> also provides suitable testing procedures, although alternative validated methods are permitted. USP General Chapter <1467> entitled “Residual Solvents – Verification of Compendial Procedures and Validation of Alternative Procedures” is an informational chapter which provides insights relating to the proper verification of compendial residual solvents test procedures and validation of alternative test procedures.
USP <467> establishes three (3) classes of residual solvents and provides a risk assessment of each.
| Residual Solvent Class | Risk Assessment | Examples |
|---|---|---|
| Class 1 (Solvents to be avoided) | Known or strongly suspected human carcinogens. Solvents known to have ozone-depleting properties. | Benzene Carbon Tetrachloride 1,2 Dichloroethane |
| Class 2 (Solvents to be limited) | Nongenotoxic animal carcinogens or possible causative agents of other irreversible toxicity. Solvents suspected of other significant but reversible toxicities. | Acetonitrile Chloroform Hexane Methanol |
| Class 3 (Solvents with low toxic potential) | Solvents with low toxic potential to humans; no health-based exposure limit is needed. | Acetic Acid Acetone Ethanol Isopropanol |
*Gas Chromatography – Head Space with Flame Ionization Detection.
*Gas Chromatography – Head Space with Flame Ionization Detection.
*Loss on Drying allowable in certain situations.
*Gas Chromatography – Head Space with Flame Ionization Detection.
Whenever possible, the substance under test must be dissolved so as to release residual solvents for measurement. If the sample is a solid which cannot be dissolved, pulverization is allowable but strict monitoring is required to avoid loss of any volatile solvent(s) which may be present.
In the final days of 2022, Congress passed and the President signed the Modernization of Cosmetics Regulation Act of 2022 commonly known by its acronym “MoCRA”. Its intent is to modernize federal regulatory oversight of cosmetic and personal care products and create a comprehensive and uniform national framework for their regulation.
Under MoCRA, FDA has been granted broad and far-reaching authority to ensure that cosmetic products are not adulterated. The Food, Drug and Cosmetic (FD & C) Act defines “adulterated” as products containing poisons or other filthy, putrid, decomposing or otherwise deleterious substances, or products which have been prepared, packed or held under unsanitary conditions whereby they may have become contaminated or rendered injurious to health. There is little doubt that the presence of toxic solvents such as Benzene, 1,4-Dioxane and/or others at unacceptable levels in a cosmetic product would lead FDA to conclude that the product is adulterated and demand its immediate recall. (MoCRA also provides FDA the authority of issuing mandatory recalls of adulterated cosmetic products.)
Although USP General Chapter <467> “Residual Solvents” specifies its application to therapeutic products such as drugs and dietary supplements, it is prudent for cosmetic manufacturers and cosmetic product owners to conduct risk assessments and residual solvents testing of their products and the raw materials of which they are composed so as to avoid possible FDA enforcement action based upon the authorities now granted to FDA under MoCRA.
CPT operates an expertly staffed, state-of-the-art Analytical Chemistry Lab employing USP-specified instrumentation and procedures required for Residual Solvents testing. This includes multiple Gas Chromatographs equipped for Head-Space analysis. Our in-house experts are ready to speak with you and offer their advice as to the best approach for handling your residual solvents testing needs for drug products, dietary supplements, cosmetic products, and the raw materials of which they are composed. Give us a call, even if you only wish to learn more about Residual Solvents testing for any type of product distributed within the US.
Please Note: CPT℠ only performs testing for companies. We do not perform product testing for the general public.
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