Rapporteur: Dr. Shigeo Kojima
Date: 16 July 1997
Step 4 Document
2. SCOPE OF THE GUIDELINE
3. GENERAL PRINCIPLES
3.1 CLASSIFICATION OF RESIDUAL SOLVENTS BY RISK ASSESSMENT
3.2 METHODS FOR ESTABLISHING EXPOSURE LIMITS
3.3 OPTIONS FOR DESCRIBING LIMITS OF CLASS 2 SOLVENTS
3.4 ANALYTICAL PROCEDURES
3.5 REPORTING LEVELS OF RESIDUAL SOLVENTS
4. LIMITS OF RESIDUAL SOLVENTS
4.1 SOLVENTS TO BE AVOIDED
4.2 SOLVENTS TO BE LIMITED
4.3 SOLVENTS WITH LOW TOXIC POTENTIAL
4.4 SOLVENTS FOR WHICH NO ADEQUATE TOXICOLOGICAL DATA WAS FOUND
APPENDIX 1. LIST OF SOLVENTS INCLUDED IN THE GUIDELINE
APPENDIX 2. ADDITIONAL BACKGROUND
A2.1 ENVIRONMENTAL REGULATION OF ORGANIC VOLATILE SOLVENTS
A2.2 RESIDUAL SOLVENTS IN PHARMACEUTICALS
APPENDIX 3. METHODS FOR ESTABLISHING EXPOSURE LIMITS
The objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.
Residual solvents in pharmaceuticals are defined here 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 solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of drug substance may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent may sometimes be a critical parameter in the synthetic process. This guideline 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.
Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements. Drug products should contain no higher levels of residual solvents than can be supported by safety data. Some solvents that are known to cause unacceptable toxicities (Class 1, Table 1) should be avoided in the production of drug substances, excipients, or drug products unless their use can be strongly justified in a risk-benefit assessment. Some solvents associated with less severe toxicity (Class 2, Table 2) should be limited in order to protect patients from potential adverse effects. Ideally, less toxic solvents (Class 3, Table 3) should be used where practical. The complete list of solvents included in this guideline is given in Appendix 1.
The lists are not exhaustive and other solvents can be used and later added to the lists. Recommended limits of Class 1 and 2 solvents or classification of solvents may change as new safety data becomes available. Supporting safety data in a marketing application for a new drug product containing a new solvent may be based on concepts in this guideline or the concept of qualification of impurities as expressed in the guideline for drug substance (Q3A, Impurities in New Drug Substances) or drug product (Q3B, Impurities in New Drug Products), or all three guidelines.
Residual solvents in drug substances, excipients, and in drug products are within the scope of this guideline. Therefore, testing should be performed for residual solvents when production or purification processes are known to result in the presence of such solvents. It is only necessary to test for solvents that are used or produced in the manufacture or purification of drug substances, excipients, or drug product. Although manufacturers may choose to test the drug product, a cumulative method may be used to calculate the residual solvent levels in the drug product from the levels in the ingredients used to produce the drug product. If the calculation results in a level equal to or below that recommended in this guideline, no testing of the drug product for residual solvents need be considered. If, however, the calculated level is above the recommended level, the drug product should be tested to ascertain whether the formulation process has reduced the relevant solvent level to within the acceptable amount. Drug product should also be tested if a solvent is used during its manufacture.
This guideline does not apply to potential new drug substances, excipients, or drug products used during the clinical research stages of development, nor does it apply to existing marketed drug products.
The guideline applies to all dosage forms and routes of administration. Higher levels of residual solvents may be acceptable in certain cases such as short term (30 days or less) or topical application. Justification for these levels should be made on a case by case basis.
See Appendix 2 for additional background information related to residual solvents.
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 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
Known human carcinogens, strongly
suspected human carcinogens, and environmental hazards.
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.
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.
The method used to establish permitted
daily exposures for residual solvents is
presented in Appendix 3. Summaries of the toxicity data that were
used to establish limits are published in Pharmeuropa, Vol. 9,
No. 1, Supplement, April 1997.
Two options are available when setting limits for Class 2 solvents.
Option 1: The concentration limits in ppm stated in Table 2 can be used. They were calculated using equation (1) below by assuming a product mass of 10 g administered daily.
Here, PDE is given in terms of mg/day and dose is given in g/day.
These limits are considered acceptable for all substances, excipients, or products. Therefore this option may be applied if the daily dose is not known or fixed. If all excipients and drug substances in a formulation meet the limits given in Option 1, then these components may be used in any proportion. No further calculation is necessary provided the daily dose does not exceed 10 g. Products that are administered in doses greater than 10 g per day should be considered under Option 2.
Option 2: It is not considered necessary for each component of the drug product to comply with the limits given in Option 1. The PDE in terms of mg/day as stated in Table 2 can be used with the known maximum daily dose and equation (1) above to determine the concentration of residual solvent allowed in drug product. Such limits are considered acceptable provided that it has been demonstrated that the residual solvent has been reduced to the practical minimum. The limits should be realistic in relation to analytical precision, manufacturing capability, reasonable variation in the manufacturing process, and the limits should reflect contemporary manufacturing standards.
Option 2 may be applied by adding the amounts of a residual solvent present in each of the components of the drug product. The sum of the amounts of solvent per day should be less than that given by the PDE.
Consider an example of the use of
Option 1 and Option 2 applied to acetonitrile in a drug product.
The permitted daily exposure to acetonitrile is 4.1 mg per day;
thus, the Option 1 limit is 410 ppm. The maximum administered
daily mass of a drug product is 5.0 g, and the drug product contains
two excipients. The composition of the drug product and the calculated
maximum content of residual acetonitrile are given in the following
|Component||Amount in formulation||Acetonitrile content||Daily exposure|
|Drug substance||0.3 g||800 ppm||0.24 mg|
|Excipient 1||0.9 g||400 ppm||0.36 mg|
|Excipient 2||3.8 g||800 ppm||3.04 mg|
|Drug Product||5.0 g||728 ppm||3.64 mg|
Excipient 1 meets the Option 1 limit, but the drug substance, excipient 2, and drug product do not meet the Option 1 limit. Nevertheless, the product meets the Option 2 limit of 4.1 mg per day and thus conforms to the recommendations in this guideline.
Consider another example using acetonitrile
as residual solvent. The maximum administered daily mass of a
drug product is 5.0 g, and the drug product contains two excipients.
The composition of the drug product and the calculated maximum
content of residual acetonitrile is given in the following table.
|Component||Amount in formulation||Acetonitrile content||Daily exposure|
|Drug substance||0.3 g||800 ppm||0.24 mg|
|Excipient 1||0.9 g||2000 ppm||1.80 mg|
|Excipient 2||3.8 g||800 ppm||3.04 mg|
|Drug Product||5.0 g||1016 ppm||5.08 mg|
In this example, the product meets
neither the Option 1 nor the Option 2 limit according to this
summation. The manufacturer could test the drug product to determine
if the formulation process reduced the level of acetonitrile.
If the level of acetonitrile was not reduced during formulation
to the allowed limit, then the manufacturer of the drug product
should take other steps to reduce the amount of acetonitrile in
the drug product. If all of these steps fail to reduce the level
of residual solvent, in exceptional cases the manufacturer could
provide a summary of efforts made to reduce the solvent level
to meet the guideline value, and provide a risk-benefit analysis
to support allowing the product to be utilised with residual solvent
at a higher level.
Residual solvents are typically determined using chromatographic techniques such as gas chromatography. Any harmonised procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure for a particular application. If only Class 3 solvents are present, a non-specific method such as loss on drying may be used.
Validation of methods for residual
solvents should conform to ICH guidelines "Text on Validation
of Analytical Procedures" and "Extension of the ICH
Text on Validation of Analytical Procedures."
Manufacturers of pharmaceutical products need certain information about the content of residual solvents in excipients or drug substances in order to meet the criteria of this guideline. The following statements are given as acceptable examples of the information that could be provided from a supplier of excipients or drug substances to a pharmaceutical manufacturer. The supplier might choose one of the following as appropriate:
If Class 1 solvents are likely to be present, they should be identified and quantified.
"Likely to be present" refers to the solvent used in the final manufacturing step and to solvents that are used in earlier manufacturing steps and not removed consistently by a validated process.
If solvents of Class 2 or Class 3 are present at greater than their Option 1 limits or 0.5%, respectively, they should be identified and quantified.
Solvents in Class 1 should not be
employed in the manufacture of drug substances, excipients, and
drug products because of their unacceptable toxicity or their
deleterious environmental effect. However, if their use is unavoidable
in order to produce a drug product with a significant therapeutic
advance, then their levels should be restricted as shown in Table
1, unless otherwise justified. 1,1,1-Trichloroethane is included
in Table 1 because it is an environmental hazard. The stated
limit of 1500 ppm is based on a review of the safety data.
TABLE 1. Class 1 solvents in pharmaceutical products (solvents that should be avoided).
Solvents in Table 2 should be limited
in pharmaceutical products because of their inherent toxicity.
PDEs are given to the nearest 0.1 mg/day, and concentrations are
given to the nearest 10 ppm. The stated values do not reflect
the necessary analytical precision of determination. Precision
should be determined as part of the validation of the method.
TABLE 2. Class 2 solvents in pharmaceutical products.
60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene
Solvents in Class 3 (shown in Table
3) may be regarded as less toxic and of lower risk to human health.
Class 3 includes no solvent known as a human health hazard at
levels normally accepted in pharmaceuticals. However, there are
no long-term toxicity or carcinogenicity studies for many of the
solvents in Class 3. Available data indicate that they are less
toxic in acute or short-term studies and negative in genotoxicity
studies. It is considered that amounts of these residual solvents
of 50 mg per day or less (corresponding to 5000 ppm or 0.5% under
Option 1) would be acceptable without justification. Higher amounts
may also be acceptable provided they are realistic in relation
to manufacturing capability and good manufacturing practice.
Table 3. Class 3 solvents which should be limited by GMP or other quality-based requirements.
|Butyl acetate||Methylethyl ketone|
|tert-Butylmethyl ether||Methylisobutyl ketone|
|Ethyl formate||Propyl acetate|
The following solvents (Table 4)
may also be of interest to manufacturers of excipients, drug substances,
or drug products. However, no adequate toxicological data on which
to base a PDE was found. Manufacturers should supply justification
for residual levels of these solvents in pharmaceutical products.
Table 4. Solvents for which no adequate
toxicological data was found.
|Isopropyl ether||Trifluoroacetic acid|
genotoxic carcinogens: Carcinogens which produce cancer by affecting genes or chromosomes.
LOEL: Abbreviation for lowest-observed effect level.
lowest-observed effect level: The lowest dose of substance in a study or group of studies that produces biologically significant increases in frequency or severity of any effects in the exposed humans or animals.
modifying factor: A factor determined by professional judgment of a toxicologist and applied to bioassay data to relate that data safely to humans.
neurotoxicity: The ability of a substance to cause adverse effects on the nervous system.
NOEL: Abbreviation for no-observed-effect level.
no-observed-effect level: The highest dose of substance at which there are no biologically significant increases in frequency or severity of any effects in the exposed humans or animals.
PDE: Abbreviation for permitted daily exposure.
permitted daily exposure: The maximum acceptable intake per day of residual solvent in pharmaceutical products.
reversible toxicity: The occurrence of harmful effects that are caused by a substance and which disappear after exposure to the substance ends.
strongly suspected human carcinogen: A substance for which there is no epidemiological evidence of carcinogenesis but there are positive genotoxicity data and clear evidence of carcinogenesis in rodents.
The occurrence of structural malformations in a developing fetus
when a substance is administered during pregnancy.
Solvent Other Names Structure
|Acetic acid||Ethanoic acid||CH3COOH||Class 3|
|Butyl acetate||Acetic acid butyl ester||CH3COO(CH2)3CH3||Class 3|
|tert-Butylmethyl ether||2-Methoxy-2-methyl- propane||(CH3)3COCH3||Class 3|
|Carbon tetrachloride||Tetrachloromethane||CCl4||Class 1|
|Dichloromethane||Methylene chloride||CH2Cl2||Class 2|
|1,2-Dimethoxyethane||Ethyleneglycol dimethyl ether
|Ethanol||Ethyl alcohol||CH3CH2OH||Class 3|
|Ethyl acetate||Acetic acid ethyl ester||CH3COOCH2CH3||Class 3|
|Ethyl ether||Diethyl ether
|Ethyl formate||Formic acid ethyl ester||HCOOCH2CH3||Class 3|
|Formic acid||HCOOH||Class 3|
|Isobutyl acetate||Acetic acid isobutyl ester||CH3COOCH2CH(CH3)2||Class 3|
|Isopropyl acetate||Acetic acid isopropyl ester||CH3COOCH(CH3)2||Class 3|
|Methanol||Methyl alcohol||CH3OH||Class 2|
|2-Methoxyethanol||Methyl Cellosolve||CH3OCH2CH2OH||Class 2|
|Methyl acetate||Acetic acid methyl ester||CH3COOCH3||Class 3|
|Propyl acetate||Acetic acid propyl ester||CH3COOCH2CH2CH3||Class 3|
60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene
Several of the residual solvents
frequently used in the production of pharmaceuticals are listed
as toxic chemicals in Environmental Health Criteria (EHC) monographs
and the Integrated Risk Information System (IRIS). The objectives
of such groups as the International Programme on Chemical Safety
(IPCS), the United States Environmental Protection Agency (USEPA),
and the United States Food and Drug Administration (USFDA) include
the determination of acceptable exposure levels. The goal is protection
of human health and maintenance of environmental integrity against
the possible deleterious effects of chemicals resulting from long-term
environmental exposure. The methods involved in the estimation
of maximum safe exposure limits are usually based on long-term
studies. When long-term study data are unavailable, shorter term
study data can be used with modification of the approach such
as use of larger safety factors. The approach described therein
relates primarily to long-term or life-time exposure of the
general population in the ambient environment, i.e. ambient
air, food, drinking water and other media.
Exposure limits in this guideline are established by referring to methodologies and toxicity data described in EHC and IRIS monographs. However, some specific assumptions about residual solvents to be used in the synthesis and formulation of pharmaceutical products should be taken into account in establishing exposure limits. They are:
1) Patients (not the general population) use pharmaceuticals to treat their diseases or for prophylaxis to prevent infection or disease.
2) The assumption of life-time patient exposure is not necessary for most pharmaceutical products but may be appropriate as a working hypothesis to reduce risk to human health.
3) Residual solvents are unavoidable components in pharmaceutical production and will often be a part of drug products.
4) Residual solvents should not exceed recommended levels except in exceptional circumstances.
5) Data from toxicological studies
that are used to determine acceptable levels for residual solvents
should have been generated using appropriate protocols such as
those described for example by OECD, EPA, and the FDA Red Book.
The Gaylor-Kodell method of risk
assessment (Gaylor, D. W. and Kodell, R. L.: Linear Interpolation
algorithm for low dose assessment of toxic substance. J Environ.
Pathology, 4, 305, 1980) is appropriate for Class 1 carcinogenic
solvents. Only in cases where reliable carcinogenicity data are
available should extrapolation by the use of mathematical models
be applied to setting exposure limits. Exposure limits for Class
1 solvents could be determined with the use of a large safety
factor (i.e., 10,000 to 100,000) with respect to the no-observed-effect
level (NOEL). Detection and quantitation of these solvents should
be by state-of-the-art analytical techniques.
Acceptable exposure levels in this
guideline for Class 2 solvents were established by calculation
of PDE values according to the procedures for setting exposure
limits in pharmaceuticals (Pharmacopeial Forum, Nov-Dec 1989),
and the method adopted by IPCS for Assessing Human Health Risk
of Chemicals (Environmental Health Criteria 170, WHO, 1994).
These methods are similar to those used by the USEPA (IRIS) and
the USFDA (Red Book) and others. The method is outlined here
to give a better understanding of the origin of the PDE values.
It is not necessary to perform these calculations in order to
use the PDE values tabulated in Section 4 of this document.
PDE is derived from the no-observed-effect
level (NOEL), or the lowest-observed effect level (LOEL) in the
most relevant animal study as follows:
The PDE is derived preferably from a NOEL. If no NOEL is obtained, the LOEL may be used. Modifying factors proposed here, for relating the data to humans, are the same kind of "uncertainty factors" used in Environmental Health Criteria (Environmental Health Criteria 170, World Health Organization, Geneva, 1994), and "modifying factors" or "safety factors" in Pharmacopeial Forum. The assumption of 100% systemic exposure is used in all calculations regardless of route of administration.
The modifying factors are as follows:
F1 = A factor to account for extrapolation between species
F1 = 5 for extrapolation from rats to humans
F1 = 12 for extrapolation from mice to humans
F1 = 2 for extrapolation from dogs to humans
F1 = 2.5 for extrapolation from rabbits to humans
F1 = 3 for extrapolation from monkeys to humans
F1 = 10 for extrapolation from other animals to humans
F1 takes into account the comparative surface area:body weight ratios for the species concerned and for man. Surface area (S) is calculated as:
S = kM0.67 (2)
in which M = body mass, and the constant
k has been taken to be 10. The body weights used in the equation
are those shown below in Table A3.1.
F2 = A factor of 10 to account for variability between individuals
A factor of 10 is generally given
for all organic solvents, and 10 is used consistently in this
F3 = A variable factor to account for toxicity studies of short-term exposure
F3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7 years for cats, dogs and monkeys).
F3 = 1 for reproductive studies in which the whole period of organogenesis is covered.
F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents.
F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents.
F3 = 10 for studies of a shorter duration.
In all cases, the higher factor has
been used for study durations between the time points, e.g. a
factor of 2 for a 9-month rodent study.
F4 = A factor that may be applied in cases of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity. In studies of reproductive toxicity, the following factors are used:
F4 = 1 for fetal toxicity associated with maternal toxicity
F4 = 5 for fetal toxicity without maternal toxicity
F4 = 5 for a teratogenic effect with maternal toxicity
F4 = 10 for a teratogenic effect
without maternal toxicity
F5 = A variable factor that may be applied if the no-effect level was not established
When only an LOEL is available, a
factor of up to 10 could be used depending on the severity of
The weight adjustment assumes an arbitrary adult human body weight for either sex of 50 kg. This relatively low weight provides an additional safety factor against the standard weights of 60 kg or 70 kg that are often used in this type of calculation. It is recognized that some adult patients weigh less than 50 kg; these patients are considered to be accommodated by the built-in safety factors used to determine a PDE. If the solvent was present in a formulation specifically intended for pediatric use, an adjustment for a lower body weight would be appropriate.
As an example of the application of this equation, consider a toxicity study of acetonitrile in mice that is summarized in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997, page S24. The NOEL is calculated to be 50.7 mg kg-1 day-1. The PDE for acetonitrile in this study is calculated as follows:
In this example,
F1 = 12 to account for the extrapolation from mice to humans
F2 = 10 to account for differences between individual humans
F3 = 5 because the duration of the study was only 13 weeks
F4 = 1 because no severe toxicity was encountered
F5 = 1 because the no effect level was determined
Table A3.1. Values used in the
calculations in this document.
|rat body weight||425 g||mouse respiratory volume||43 L/day|
|pregnant rat body weight||330 g||rabbit respiratory volume||1440 L/day|
|mouse body weight||28 g||guinea pig respiratory volume||430 L/day|
|pregnant mouse body weight||30 g||human respiratory volume||28,800 L/day|
|guinea pig body weight||500 g||dog respiratory volume||9,000 L/day|
|Rhesus monkey body weight||2.5 kg||monkey respiratory volume||1,150 L/day|
|rabbit body weight
(pregnant or not)
|4 kg||mouse water consumption||5 mL/day|
|beagle dog body weight||11.5 kg||rat water consumption||30 mL/day|
|rat respiratory volume||290 L/day||rat food consumption||30 g/day|
The equation for an ideal gas, PV
= nRT, is used to convert concentrations of gases used in inhalation
studies from units of ppm to units of mg/L or mg/m3.
Consider as an example the rat reproductive toxicity study by
inhalation of carbon tetrachloride (molecular weight 153.84) is
summarized in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997,
The relationship 1000 L = 1 m3
is used to convert to mg/