Residual Solvent Analysis in Pharmaceuticals

Residual Solvent Analysis
in Pharmaceuticals
Anil M. Dwivedi
WEST PHARMACEUTICAL
R
Residual solvents in pharmaceuticals are
organic, volatile chemicals that are either
used or produced during the manufacturing
of drug substances, excipients, or drug
products and may be hazardous to human
health. However, their acceptance limits and
classification vary among the three major
pharmacopeia. The author discusses the
regulatory status of the various
classifications of residual solvents with
regard to USP, PhEur, and JP.
Anil M. Dwivedi, PhD, is director of
contract laboratory services at West
Pharmaceutical Services, Inc., 101 Gordon
Dr., Lionville, PA 19341, tel. 610.594.2900,
www.westpharma.com or www.
westdrugdelivery.com.
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Pharmaceutical Technology
NOVEMBER 2002
esidual solvents in pharmaceuticals (commonly known
as organic volatile impurities or OVIs) are organic
volatile chemicals that are either used or produced during the manufacture of active pharmaceutical ingredients, excipients, and drug products. These products also may
become contaminated by such solvents from packaging, storage in warehouses, or from shipping and transportation. Because residual solvents have no therapeutic benefits but may be
hazardous to human health and to the environment, one must
ensure that they are either not present in the products or are
present only below acceptable levels. However, each pharmacopeia handles residual solvents differently, and their lists of
toxic solvents and the corresponding acceptable limits vary,
thereby making the development of one data set for drug approval in the European countries, in Japan, and in the United
States difficult. In this article, the author discusses the present
status of the harmonization efforts by the International Conference on Harmonization (ICH) and provides information
about analytical methods.
Introduction
Some organic solvents are used often during the synthesis of
active drug substances and excipients or in the preparation of
drug products to enhance the yield, increase solubility, or for
crystallization (1–3). Although these solvents are critical to the
synthetic process, they have no therapeutic value and, in some
cases, may be toxic. Thus, these solvents must be selected carefully because their complete removal using manufacturing
processes is difficult. It is a drug manufacturer’s responsibility
to ensure that any residual solvents (i.e., OVIs) present in the
final product are not harmful to humans. Medicinal products
should not contain higher levels of residual solvents than can
be supported by safety data. Solvents known to cause unacceptable toxicity should be avoided unless their use can be justified on the basis of a risk–benefit assessment.
For some time, each regulatory agency has been using various guidelines for residual solvents in medicinal products. Consequently, the pharmacopeia of the United States (USP), Europe (PhEur), and Japan (JP) listed residual solvents with
different acceptance limits. Efforts were made to harmonize the
guideline so that the data, once generated, could be used for the
drug approval process in the European Union, in the United
States, and in Japan. On 17 July 1997, the ICH Harmonized Tripartite Guideline reached step four of the ICH process and was
recommended for adoption by the ICH steering committee (4).
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This guideline does not apply to potential new drug substances, excipients,
Concentration Limit
or drug products used during the cliniSolvent
(ppm)
Concern
cal research stages of development. It also
Benzene
2
Carcinogen
does not apply to existing drug products
Carbon tetrachloride
4
Toxic and environmental hazard
on the market. The guideline does, how1,2-Dichloroethane
5
Toxic
ever, apply to all dosage forms and routes
1,1-Dichloroethene
8
Toxic
of administration. Higher levels of resid1,1,1-Trichloroethane
1500
Environmental hazard
ual solvents may be acceptable in certain
cases such as a short-term (30 days) or
topical application, with proper justification made on a caseTable II: Class 2 solvents.
by-case basis.
Table I: Class 1 solvents (should be avoided).
Solvent
Concentration Limit (ppm)
Acetonitrile
410
Chlorobenzene
360
Chloroform
60
Cyclohexane
3880
Dichloromethane (methylene chloride)
600
1,4-Dioxane
380
1,1,2-Trichloroethylene
80
1,2-Dimethoxyethane
100
2-Ethoxyethanol
160
2-Methoxyethanol
50
Methylbutyl ketone
50
Nitromethane
50
Sulfolane
160
Tetralin
100
Pyridine
200
Toluene
890
Formamide
220
1,2-Dichloroethene
1870
N,N-Dimethylacetamide
1090
N,N-Dimethylformamide
880
Ethyleneglycol
620
Hexane
290
Methanol
3000
Methylcyclohexane
1180
N-Methylpyrrolidone
4840
Xylene
2170
The scope
Residual solvents in drug substances, excipients, and drug products fall into the scope of the ICH guideline as follows: If a production or purification process is known to result in the presence of such solvents, the product should be tested. Testing
should be performed only for those solvents that are used or
produced during manufacture or purification. A cumulative
method may be used to calculate the residual solvent levels in
the drug product on the basis of the levels in the ingredients
used to produce the drug product. If the cumulative levels are
below or equal to the recommended levels in the guideline, the
drug product need not be tested for residual solvents. However,
if the cumulative levels are above the recommended level, the
drug product must be tested for residual solvents to ensure that
the manufacturing and purification processes have reduced the
levels to be within the acceptable range.
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Pharmaceutical Technology
NOVEMBER 2002
Solvent classification
Residual solvents are classified into three classes on the basis of
the toxicity level and the degree to which they can be considered an environmental hazard. The list provided in the guideline is not exhaustive, and one should evaluate the synthesis and
manufacturing processes for all possible residual solvents.
Class 1. Class 1 solvents are known carcinogens and are
strongly suspected of being harmful to humans and of being
environmental hazards. They should be avoided, if possible.
However, if using them to produce a medicinal product with a
significant therapeutic value is unavoidable, then their levels
should be controlled as shown in Table I, unless otherwise justified. 1,1,1-Trichloroethane is included in this table because it
is an environmental hazard.
Class 2. Class 2 solvents are nongenotoxic animal carcinogens.
Solvents of this class should be limited in pharmaceutical products because of their inherent toxicity. Table II lists some of
these solvents and their tolerable concentration limit. The limits were calculated on the basis of the permitted daily exposure,
which assumed a daily dose of 10 g of drug product per day.
Class 3. Class 3 solvents have low toxic potential to humans.
However, no long-term toxicity or carcinogenicity data are available for many of them. They have been found less toxic in acute
or short-term studies and negative in genotoxicity studies. A
concentration 0.5% is acceptable without justification. A
higher amount may also be acceptable with proper justification. Table III lists some of the solvents from Class 3.
Others. In addition to these three classes of solvents, some
solvents may be of interest to manufacturers of active substances,
excipients, and drug products. However, no adequate toxicological data based on permitted daily dose are available. Manufacturers must provide justification if they use these solvents in
their products (see Table IV).
The current status of USP, PhEur, and JP
USP. Although the ICH guideline regarding residual solvents in
pharmaceuticals became official in July 1997, USP has not fully
adopted it (5). The current status of each pharmacopeia is different. In the case of USP, residual solvents are tested under
General Chapter 467 “Organic Volatile Impurities.” According to USP, testing should be conducted only if a manufacturer
has indicated the possible presence of a solvent in a product.
Testing may be avoided when a manufacturer has assurance,
based on the knowledge of the manufacturing process and conwww.phar mtech.com
Analytical testing
Table III: Class 3 solvents.
Acetic acid
1-Butanol
tert-Butylmethyl ether
Tetrahydrofuran
Isopropyl acetate
Cumene
Ethyl formate
Methyl acetate
2-Methyl-1-propanol
Propyl acetate
Acetone
2-Butanol
Pentane
Heptane
Methylethyl ketone
Ethyl acetate
Formic acid
3-Methyl-1-butanol
1-Pentanol
Table IV: Solvents without adequate toxicological data.
1,1-Diethoxypropane
1,1-Dimethoxymethane
2,2-Dimethoxypropane
Isooctane
Isopropyl ether
Methylisopropylketone
Methyltetrahydrofuran
Petroleum ether
Trichloroacetic acid
Trifluoroacetic acis
Table V: OVIs.
OVI
Benzene
Chloroform
1,4-Dioxane
Methylene chloride
Trichloroethylene
Concentration Limit (ppm)
2
60
380
600
80
trolled handling, shipping, and storage of the product, that no
potential exists for specific solvents to be present and that the
product, if tested, will comply with the accepted limit. Items
shipped in airtight containers (such as those used for food additives) can be considered not to have acquired any solvents
during transportation.
USP 467 recommends testing for the solvents listed in Table
V. In addition, a test for ethylene oxide is conducted if specified
in the individual monograph. Unless otherwise specified in the
individual monograph, the acceptable limit for ethylene oxide
is 10 ppm. USP does not address all other solvents mentioned
in the ICH guideline.
PhEur. PhEur has fully adopted the ICH guideline regarding
residual solvents (6). Section 2.4.24 of the fourth edition of
PhEur describes how to identify and quantify Class 1 and Class
2 residual solvents. The test methods can be used to identify the
majority of Class 1 and Class 2 solvents when they are unknown
and as limit tests for Class 1 and Class 2 solvents. The methods
also can be used for the quantification of Class 2 solvents when
the limits are 1000 ppm (0.1%) or for the quantification of
Class 3 solvents when required.
JP. The current JP (volume XIV) has adopted the ICH guideline (7). This pharmacopeia defines residual solvents as those
residual organic solvents in pharmaceuticals that should be
tested using gas chromatography to comply with the limits specified in the ICH Harmonized Tripartite Guideline.
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Pharmaceutical Technology
NOVEMBER 2002
Gas chromatography (GC) typically is
used to determine residual solvents, with
the exception of Class 3 solvents, which
can be determined by nonspecific analytical techniques such as loss on drying.
Laboratories such as those at the author’s
company can qualify GC instruments
equipped with headspace analysis that
meet the requirements of USP, PhEur,
and JP. Drug substances, excipients, and
drug products monographed in the pharmacopeia are tested using the test methods specified in the monograph without any additional validation. It is, however, very important that all method system
suitability criteria are met before data are generated. For nonmonographed articles, the laboratory should validate the methods in conformance with ICH and USP methods validation
guidelines before they are used to control the residual solvents
in medicinal products. The use of validated methods is highly
recommended to analyze stability samples and generate data
in compliance with current good manufacturing practices. The
peaks in the gas chromatogram are identified by comparing
their retention times with the residual solvent standards run
under the same chromatographic conditions and along with
the test samples. If there is a co-eluting peak, the test is repeated
using a second column containing a different stationary phase.
If unknown peaks do not match those of the standards, gas
chromatography–mass spectrometry is used to identify the
peaks.
Anisole
Butyl acetate
1-Propanol
Ethanol
Dimethyl sulfoxide
Ethyl ether
Isobutyl acetate
Methylisobutyl ketone
2-Propanol
References
1. J.T. Rubino and S.H. Yalkowsky, Pharm. Res. 4, 220 (1987).
2. L. Borka and J.K. Habelian, Acta Pharm. Jugosl., 40, 71 (1990).
3. S.R. Byrn, Solid-State Chemistry of Drugs (Academic Press, New York,
NY, 1982), pp. 79–148.
4. ICH Harmonized Tripartite Guideline for Residual Solvents, step 4,
17 July 1997.
5. USP 25–NF 20 (2002).
6. Section 5.4, European Pharmacopoeia, 4th edition (2002).
7. Section 5.1, “Residual Solvents Test,” Japanese Pharmacopoeia, edition
XIV (2002). PT
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