Authored by Dean Marbury, Technical Director, Microbac Laboratories, Southern Testing and Research Division

The term “Residual Solvents” refers to compounds used in the manufacturing of pharmaceutical materials that may not be completely removed after processing.  They have been of concern to the FDA and other regulators for several decades.  The USP has traditionally provided for the testing and setting of specification limits for residual solvents through general chapter <467> “OVI” (Organic Volatile Impurities).   In July 2008, a new and very different version of <467> became effective, and the FDA provided guidance that NDA and ANDAs would need to comply with <467>.  This includes currently marketed NDA/ANDA articles, thus establishing <467> as the governing regulation for residual solvents for all finished products in the market, regardless of whether a monograph for the product exists.  Topical or short-term drug products may not be covered by USP <467> and the FDA determines what levels of residual solvents may be allowable in such formulations on a case-by-case basis.

Over 60 solvents are included in <467>.  Limits are given only for finished products.  However, testing for residual solvents in raw materials may be highly recommended as this solvent may be carried through the process and remain in the finished product.  Early in the process, control is usually more cost-effective compared to remediation or even rejection of final product.  This decision can be made based on the knowledge of the manufacturing process chemistry.  FDA does not require testing for solvents that are known not to be present in finished products or that can be demonstrated to be below established limits.  Responsibility for meeting the specification for residual solvents lies with the company marketing the product, regardless of up-stream supply chain factors.

In the revised <467>, residual solvents of concern are listed in three classes based largely on toxicological factors and possible patient exposure.  Considerations used by the USP in assigning solvents to a given classification were based, in part, on toxicological parameters.  Solvents are labeled as Class 1, Class 2, and Class 3 based on their suspected toxicity.  See Tables below.

If residual solvents are potentially present in a material, the extent of analytical testing is determined by the compound’s classification.  If a manufacturer uses a Class I solvent in the production of a finished product or if a raw material used in the finished product was manufactured with a Class I solvent, testing by USP <467> must be performed for that solvent.  For Class 2(a) and 2(b) solvents, testing may be obviated if the manufacturer can demonstrate that such solvents cannot be present above specification limits based on exposure calculations and/or loss-on-drying (LOD) data.  However, Class II (c) solvents do not have validated methods, and alternative methods must be validated by the testing laboratory for each matrix to be tested.  Class 3 solvents must be determined if suspected to be present. These compounds have a relatively high limit (no greater than 5000 ppm).  As with Class 2(c) solvents, the USP does not provide validated methods, and it is incumbent on the manufacturer to use methods validated for these solvents in their specific matrix.  A further challenge is that USP lists other residual solvents (See Table 4) that do not have adequate toxicological data, some of which are analytically challenging. Ethylene oxide is not placed in a specific classification, but its testing is required only when specified in individual monographs.

The USP does not consider the residual solvents included in <467> as an exhaustive list, and indicates that it is the responsibility of the manufacturer to notify the USP of the identity of new, non-listed solvents upon approval of the solvent’s use by a “competent regulatory authority”.  Ancillary information is also required by the USP regarding the approved residual solvent limit for the article and for the analytical methodology used to establish that limit.  This information will then be addressed in the article’s individual monograph.

Note that a further analytical complexity is added if solvents are present from two or more USP classifications.  Testing only for the more stringently controlled solvent alone may not be sufficient to meet USP requirements, and multiple analytical approaches may need to be developed and validated.

Both water-soluble and non-water soluble solvents are included in <467>.  Also, some solvents are recognized as hard to analyze by conventional headspace sample introduction, including organic acids and bases.  Other problematic solvents include DMF, DMI, and DMSO.

These issues complicate the decision-making, as supply chain vendors of raw materials may not test for RS, according to <467>.  Also, internal manufacturing or synthesis of materials, such as API, may involve use of Class I materials, or materials that may contain Class 1 and 2 solvents from upstream processing or manufacturing.  For these reasons, careful assessment of all aspects of the manufacturing and development of product constituents is required to produce a sampling/analysis plan that is cost-effective and meets FDA requirements for finished products.

The Southern Testing and Research Division of Microbac Laboratories, Inc. has been providing analytical services for USP <467> testing since its introduction into the USP.  Microbac’s Southern Testing Division has over 15 years of development, validation, and release testing experience for residual/trace level solvents and impurities in pharmaceutical and manufacturing intermediates, raw materials, and finished products.  In addition to on-demand development and testing services provided on request, it has a committed, in-house, pro-active development program for validating a variety of solvents over a wide range of matrices.

This effort minimizes the time and costs to our customers for their specific residual solvent testing requirements.  In addition, Southern Testing has developed numerous screening procedures, including gas chromatography with mass spectrometric detection (GC/MS) to aid in determining the identity and concentration of residual solvents in matrices for which the manufacturer may not have the expertise or resources.  Microbac’s extensive instrumental capacity includes GC/MS and GC/FID, both with headspace and direct-injection, HPLC, HPLC/MS/MS and Ion Chromatography (IC).  Southern Testing also has numerous chemists and metrologists with extensive experience and expertise in residual solvent analytical methodology.

Furthermore, STRL has an active program in developing and validating unique methods for the “difficult” compounds that are readily applicable to client-specific matrices.  Because of this, qualification of methods for specific new matrices is frequently rapid and cost-effective, and meets USP general chapter <1226> requirements for matrix-specific method qualification.

Table 1. Class 1 Residual Solvents
(solvents that should be avoided)

Solvent/Concentration Limit (ppm)/Concern
Benzene/2/Carcinogen
Carbon tetrachloride/4/Toxic and environmental hazard
1,2-Dichloroethane/5/Toxic
1,1-Dichloroethene/8/Toxic
1,1,1-Trichloroethane/1500/Environmental hazard

Table 2. Class 2 Residual Solvents

Solvent/Subclass/PDE (mg/day)/Concentration Limit (ppm)
Acetonitrile/a/4.1/410
Chlorobenzene/a/3.6/360
Chloroform/b/0.6/60
Cyclohexane/a/38.8/3880
1,2-Dichloroethene (cis- and trans-)/a/18.7/1870
1,2-Dimethoxyethane/b/1.0/100
N,N-Dimethylacetamide/c/10.9/1090
N,N-Dimethylformamide/c/8.8/880
1,4-Dioxane/a/3.8/380
2-Ethoxyethanol/c/1.6/160
Ethylene glycol/c/6.2/620
Formamide/c/2.2/220
Hexane/b/2.9/290
Methanol/a/30.0/3000
2-Methoxyethanol/c/0.5/50
Methylbutylketone/b/0.5/50
Methylcyclohexane/a/11.8/1180
Methylene chloride/a/6.0/600
N-Methylpyrrolidone/c/5.3/530
Nitromethane/b/0.5/50
Pyridine/b/2.0/200
Sulfolane/c/1.6/160
Tetrahydrofuran/a/7.2/720
Tetraline/b/1.0/100
Toluene/a/8.9/890
Trichloroethylene/b/0.8/80
Xylene*/a/21.7/2170

* Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene

Table 3. Class 3 Residual Solvents

Solvent/Solvent
Acetic acid/Heptane
Acetone/Isobutyl acetate
Anisole/Isopropyl acetate
1-Butanol/Methyl acetate
2-Butanol/3-Methyl-1-butanol
Butyl acetate/Methylethylketone
tert-Butylmethyl ether/Methylisobutylketone
Cumene/2-Methyl-l-propanol
Dimethyl sulfoxide/Pentane
Ethanol/1-Pentanol
Ethyl acetate/1-Propanol
Ethyl ether/2-Propanol
Ethyl formate/Propyl acetate
Formic acid

Note:  Class 3 Residual Solvents Specification: Not More Than 5000 ppm

Table 4. Class 4 Residual Solvents
(for which no adequate toxicological data was found)

Solvent/Solvent
1,1-Diethoxypropane/Methyl isopropyl ketone
1,1-Dimethoxymethane/Methyltetrahydrofuran
2,2-Dimethoxypropane/Solvent hexane
Isooctane/Trichloroacetic acid
Isopropyl ether/Trifluoroacetic acid

For more information, please contact: microbac_info@microbac.com.