Therapeutic Dose: Residual Solvents and a Trace of Cooperation

The new guidelines are evidence of multinational law enforcement at its best.

By Emil Ciurczak, Contributing Editor

The latest FDA Guidance on residual solvents [1] is interesting on several levels. On the plus side, this cooperation between the FDA, USP, and ICH [2] is an excellent example of multi-national law enforcement and one set of rules for everybody. In the age of outsourcing and companies that are engaged in producing and selling in many countries (and continents), the country-to-country regulations that tended to restrict free trade are slowly disappearing.

In fact, with respect to inter-agency cooperation, the FDA Guidance even states, “This guidance is intended to assist manufacturers in responding to the issuance of the United States Pharmacopeia (USP) requirement for the control of residual solvents [3,4] in drug products marketed in the United States.” Two major product categories are:

  1. Compendial drug products that are not marketed under an approved NDA or ANDA can comply with USP General Chapter <467> “Residual Solvents” and the Federal Food, Drug, and Cosmetic Act (a.k.a., “the Act”).
  2. Holders of NDAs or ANDAs for compendial drug products should report changes in chemistry, manufacturing, and controls specifications to FDA to comply with General Chapter <467> and 21 CFR 314.70.

The residual solvents are given in three categories by the ICH Q3C Guidance: Class 1, Solvents to be avoided, Class 2, Solvents to be limited, and Class 3, Solvents with low toxic potential. These categories are based on health experimental hazards.

Classification of Residual Solvents by Risk Assessment (as per ICH Q3C)

The term "tolerable daily intake" (TDI) is used by the International Program on Chemical Safety (IPCS) to describe exposure limits of toxic chemicals and "acceptable daily intake" (ADI) is used by the World Health Organization (WHO) and other national and international health authorities and institutes. The new term "permitted daily exposure" (PDE) is defined in the present guideline as a pharmaceutically acceptable intake of residual solvents to avoid confusion of differing values for ADI's of the same substance.

Residual solvents assessed in this guideline are listed in Appendix 1 (Q3C) by common names and structures. They 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. These are known human carcinogens, strongly suspected human carcinogens, and environmental hazards. As examples we have Benzene (2ppm Carcinogen), Carbon tetrachloride (4ppm Toxic and environmental hazard), 1,2-Dichloroethane (5ppm Toxic), 1,1-Dichloroethene (8ppm Toxic), 1,1,1-Trichloroethane (1500ppm Environmental hazard).

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; for instance, acetonitrile and methanol.

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 PDEs of 50 mg or more per day. Some common solvents include Acetic acid, Heptane, Acetone Isobutyl acetate, Anisole, Isopropyl acetate, 1-Butanol Methyl acetate.

These are the positive points of the cooperation among agencies. The best way to address the downside is to refer to Yogi Berra. Once, when receiving an award (MVP?), he was quoted as saying, “I want to thank everyone who made this award necessary.” To paraphrase Yogi, the industry would like to thank all the countries who made this Guidance necessary.

As has been seen in recent instances (i.e., DEG in toothpaste, melamine in gluten, OSC in heparin), API’s and excipients now need better and more specific analytical methods to determine purity. Since more products are also being made in these countries that supplied tainted raw materials, newer and more sensitive methods, along with stricter limits are needed. The Guidance from FDA is another step in the safety of the supply chain and should be lauded.

1. Guidance for Industry: Residual Solvents in Drug Products Marketed in the United States, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). November 2009.
2. ICH Topic Q3C (R3): Impurities: Residual Solvents; NOTE FOR GUIDANCE ON IMPURITIES: RESIDUAL SOLVENTS; (CPMP/ICH/283/95). March 1998.
3. USP General Chapter <467>: “Residual Solvents” and the Federal Food, Drug, and Cosmetic Act (the Act).
4. USP General Chapter <467> and 21 CFR 314.70.

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