[Federal Register Volume 62, Number 85 (Friday, May 2, 1997)]
[Notices]
[Pages 24302-24309]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-11439]
[[Page 24301]]
_______________________________________________________________________
Part VIII
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Draft Guideline on
Impurities: Residual Solvents; Availability; Notice
Federal Register / Vol. 62, No. 85 / Friday, May 2, 1997 / Notices
[[Page 24302]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97D-0148]
International Conference on Harmonisation; Draft Guideline on
Impurities: Residual Solvents; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is publishing a draft
guideline entitled ``Impurities: Residual Solvents.'' The draft
guideline was prepared under the auspices of the International
Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH). The draft guideline recommends
acceptable amounts of residual solvents in pharmaceuticals for the
safety of the patient, and recommends the use of less toxic solvents in
the manufacture of drug substances and dosage forms.
DATES: Written comments by June 16, 1997.
ADDRESSES: Submit written comments on the draft guideline to the
Dockets Management Branch (HFA-305), Food and Drug Administration,
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the draft
guideline are available from the Drug Information Branch (HFD-210),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, 301-827-4573.
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: John J. Gibbs, Center for Drug Evaluation
and Research (HFD-820), Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301-443-3490.
Regarding the ICH: Janet J. Showalter, Office of Health Affairs
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857, 301-827-0864.
SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
have been undertaken by regulatory authorities and industry
associations to promote international harmonization of regulatory
requirements. FDA has participated in many meetings designed to enhance
harmonization and is committed to seeking scientifically based
harmonized technical procedures for pharmaceutical development. One of
the goals of harmonization is to identify and then reduce differences
in technical requirements for drug development among regulatory
agencies.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from both
regulatory and industry representatives. FDA also seeks input from
consumer representatives and others. ICH is concerned with
harmonization of technical requirements for the registration of
pharmaceutical products among three regions: The European Union, Japan,
and the United States. The six ICH sponsors are the European
Commission, the European Federation of Pharmaceutical Industries
Associations, the Japanese Ministry of Health and Welfare, the Japanese
Pharmaceutical Manufacturers Association, the Centers for Drug
Evaluation and Research and Biologics Evaluation and Research, FDA, and
the Pharmaceutical Research and Manufacturers of America. The ICH
Secretariat, which coordinates the preparation of documentation, is
provided by the International Federation of Pharmaceutical
Manufacturers Associations (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and the IFPMA, as well as observers from the World
Health Organization, the Canadian Health Protection Branch, and the
European Free Trade Area.
At a meeting held on November 7, 1996, the ICH Steering Committee
agreed that a draft guideline entitled ``Impurities: Residual
Solvents'' should be made available for public comment. The draft
guideline is the product of the Quality Expert Working Group of the
ICH. Comments about this draft will be considered by FDA and the
Quality Expert Working Group.
Residual solvents in pharmaceuticals are organic volatile chemicals
that are used or produced in the synthesis of drug substances or
excipients, or in the preparation of drug products. They are not
completely removed by practical manufacturing techniques. The draft
guideline recommends acceptable amounts of residual solvents in
pharmaceuticals for the safety of the patient. The draft guideline
recommends the use of less toxic solvents and describes levels
considered to be toxicologically acceptable for some residual solvents.
The draft guideline applies to residual solvents in drug substances,
excipients, and drug products, and to all dosage forms and routes of
administration. The draft 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.
Appendices 4, 5, and 6 (toxicity data for Class 1, Class 2, and
Class 3 solvents) are not published with the draft guideline, but may
be seen at the Dockets Management Branch (address above) and are
available via the Internet using the World Wide Web (WWW) (http://
www.fda.gov/cder/guidance.htm).
This guideline represents the agency's current thinking on
acceptable amounts of residual solvents in pharmaceuticals. It does not
create or confer any rights for or on any person and does not operate
to bind FDA or the public. An alternative approach may be used if such
approach satisfies the requirements of the applicable statute,
regulations, or both.
Interested persons may, on or before June 16, 1997, submit to the
Dockets Management Branch (address above) written comments on the draft
guideline. Two copies of any comments are to be submitted, except that
individuals may submit one copy. Comments are to be identified with the
docket number found in brackets in the heading of this document. The
draft guideline and received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday. An electronic version
of this guideline is available via Internet using the WWW `(http://
www.fda.gov/cder/guidance.htm).
The text of the draft guideline follows:
Impurities: Residual Solvents
1. Introduction
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 synthesis of
drug substances or excipients, or in the preparation of drug
products. They 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.
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
[[Page 24303]]
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 list. Recommended limits of Class 1 and 2
solvents or classification of solvents may change as new safety data
become available. (The process for updating and maintaining the
guideline is under review by the ICH Steering Committee.) 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 substances (Q3A, Impurities in New Drug
Substances) or drug product (Q3B, Impurities in New Drug Products)
or all three guidelines.
2. Scope of the Guideline
Residual solvents in drug substances, excipients, or 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. 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 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. The drug product should also
be tested if a Class 1 or Class 2 solvent is used during its
manufacture. If no Class 1 or Class 2 solvent is used in the
manufacture or purification of the drug substance, excipient, or
drug product, then a statement by the applicant or vendors to that
effect would be acceptable and no testing would be necessary.
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
for short-term (e.g., 30 days or less) or local application.
Justification for these levels should be made on a case-by-case
basis.
Given the implications of this guideline for the pharmaceutical
industry and suppliers, a period of transition (approximately 2
years) will be provided when the guideline is finalized and
implemented according to regional procedures (Step 5). See Appendix
2 for additional background information related to residual
solvents.
3. General Principles
3.1 Classification of Residual Solvents by Risk Assessment
The term ``tolerable daily intake'' (TDI) is used by the
International Program on Chemical Safety (IPCS) to describe exposure
limits of toxic chemicals, and the term ``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. They were evaluated for their possible
risk to human health and placed into one of three classes as
follows:
(1) Class 1 solvents: Solvents to be avoided--
Known human carcinogens, strongly suspected human carcinogens,
and environmental hazards.
(2) Class 2 solvents: Solvents to be limited--
Nongenotoxic animal carcinogens or possible causative agents of
other irreversible toxicity such as neurotoxicity or teratogenicity;
solvents suspected of other significant but reversible toxicities.
(3) 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 PDE's of 50
milligrams (mg) or more per day.
3.2 Methods for Establishing Exposure Limits
See Appendix 3 for an explanation of the method used to
establish exposure limits.
3.3 Options for Describing Limits of Class 2 Solvents
Two options are available when setting limits for Class 2
solvents.
Option 1: The concentration limits in parts per million (ppm)
stated in Table 2 can be used. They were calculated using equation
(1) below by assuming a product mass of 10 grams (g) administered
daily.
[GRAPHIC] [TIFF OMITTED] TN02MY97.053
Here, the 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 whatever the dose and use. Therefore, this
option may be applied if the daily dose is not known or fixed. Any
excipient or drug substance that meets the limits given in Option 1
therefore may be used in any drug product. However, it is not
considered necessary for each component of the drug product to
comply with the limits given in Option 1.
Option 2: 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 level has been reduced to the practical
minimum, i.e., the limits are realistic in relation to the
manufacturing capability and 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 content of residual acetonitrile is given in the
following table.
------------------------------------------------------------------------
Amount in Acetonitrile
Component formulation 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
[[Page 24304]]
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 content of residual acetonitrile is given in the
following table.
------------------------------------------------------------------------
Amount in Acetonitrile
Component formulation content Daily exposure
------------------------------------------------------------------------
Drug substance 0.3 g 800 ppm 0.24 mg
Excipient 1 0.9 g 2,000 ppm 1.80 mg
Excipient 2 3.8 g 800 ppm 3.04 mg
Drug product 5.0 g 1,016 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 steps to reduce the
amount of acetontirile 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 with residual
solvent at a higher level.
3.4 Analytical Procedures
Residual solvents are typically determined using chromatographic
techniques such as gas chromatography. Any harmonized 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 nonspecific method such as loss on drying may be used.
Validation of methods for residual solvents should conform to
ICH guidelines ``Validation of Analytical Procedures: Definition and
Terminology'' and ``Validation of Analytical Procedures:
Methodology.''
4. Limits of Residual Solvents
4.1 Solvents to Be Avoided
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. Toxicity data for Class 1 solvents are summarized in
Appendix 4. The solvent 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)
----------------------------------------------------------------------------------------------------------------
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 1,500 Environmental hazard
----------------------------------------------------------------------------------------------------------------
4.2 Solvents to Be Limited
Solvents in Table 2 should be limited in pharmaceutical products.
PDE's 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. Available toxicity data are
summarized in Appendix 5.
Table 2.--Class 2 Solvents in Pharmaceutical Products
------------------------------------------------------------------------
Concentration
Solvent PDE (mg/day) Limit (ppm)
------------------------------------------------------------------------
Acetonitrile 4.1 410
Chlorobenzene 3.6 360
Chloroform 0.6 60
Cyclohexane 38.8 3,880
1,2-Dichloroethene 18.7 1,870
Dichloromethane 6.0 600
1,2-Dimethoxyethane 1.0 100
N,N-Dimethylacetamide 10.9 1,090
[[Page 24305]]
N,N-Dimethylformamide 8.8 880
1,4-Dioxane 3.8 380
2-Ethoxyethanol 1.6 160
Ethyleneglycol 3.1 310
Formamide 2.2 220
Hexane 2.9 290
Methanol 30.0 3,000
2-Methoxyethanol 0.5 50
Methylbutyl ketone 0.5 50
Methylcyclohexane 11.8 1,180
N-Methylpyrrolidone 48.4 4,840
Nitromethane 0.5 50
Pyridine 2.0 200
Sulfolane 1.6 160
Tetralin 1.0 100
Toluene 8.9 890
1,1,2-Trichloroethene 0.8 80
Xylene\1\ 21.7 2,170
------------------------------------------------------------------------
\1\ usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl
benzene.
4.3 Solvents with Low Toxic Potential
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 percent 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. Available toxicity data
for Class 3 solvents are summarized in Appendix 6.
Table 3.--Class 3 Solvents Which Should Be Limited by GMP or Other
Quality-Based Requirements
------------------------------------------------------------------------
Acetic Acid Heptane
Acetone Isobutyl acetate
Anisole Isopropyl acetate
1-Butanol Methyl acetate
2-Butanol 3-Methyl-1-butanol
Butyl Acetate Methylethyl ketone
tert-Butylmethyl ether Methylisobutyl ketone
Cumene 2-Methyl-1-propanol
Dimethylsulfoxide Pentane
Ethanol 1-Propanol
Ethyl acetate 1-Pentanol
Ethyl ether 2-Propanol
Ethyl formate Propyl acetate
Formic acid Tetrahydrofuran
------------------------------------------------------------------------
4.4 Additional Solvents
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 were
found. Manufacturers should supply justification for residual levels
of these solvents in pharmaceutical products.
Table 4.--Solvents for Which No Adequate Toxicological Data Were Found
------------------------------------------------------------------------
1,1-Diethoxypropane Methylisopropyl ketone
1,1-Dimethoxymethane Methyltetrahydrofuran
2,2-Dimethoxypropane Petroleum ether
Isooctane Trichloroacetic acid
Isopropyl ether Trifluoroacetic acid
------------------------------------------------------------------------
Glossary
Genotoxic carcinogens: Carcinogens that produce cancer by
affecting genes or chromosomes.
LOAEL: Abbreviation for lowest-observed-adverse effect level.
LOEL: Abbreviation for lowest-observed effect level.
Lowest-observed-adverse effect level: The lowest dose of a
substance in a study or group of studies that produces biologically
significant increases in frequency or severity
[[Page 24306]]
of harmful effects in the exposed humans or animals.
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.
NEL: Abbreviation for no effect level.
Neurotoxicity: The ability of a substance to cause adverse
effects on the nervous system.
NOAEL: Abbreviation for no-observed-adverse effect level.
No effect level: The dose of substance at which there are no
biologically significant increases in frequency or severity of any
effects in the exposed humans or animals.
NOEL: Abbreviation for no-observed effect level.
No-observed-adverse effect level: The dose of substance at which
there are no biologically significant increases in frequency or
severity of harmful effects in the exposed humans or animals.
No-observed-effect level: The dose of substance at which there
are no biologically significant increases in frequency or severity
of any observed 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.
Teratogenicity: The occurrence of structural malformations in a
developing fetus when a substance is administered during pregnancy.
Appendix 1. List of Solvents Included in the Guideline
(Note: The chemical structures have been deleted.)
Solvent Other Names Class
Acetic acid Ethanoic acid Class 3
Acetone 2-Propanone Class 3
Propan-2-one
Acetonitrile Class 2
Anisole Methoxybenzene Class 3
Benzene Benzol Class 1
1-Butanol n-Butyl alcohol Class 3
Butan-l-ol
2-Butanol sec-Butyl alcohol Class 3
Butan-2-ol
Butyl acetate Acetic acid butyl ester Class 3
tert-Butylmethyl ether 2-Methoxy-2-methyl-propane Class 3
Carbon tetrachloride Tetrachloromethane Class 1
Chlorobenzene Class 2
Chloroform Trichloromethane Class 2
Cumene Isopropylbenzene Class 3
(1-Methyl)ethylbenzene
Cyclohexane Hexamethylene Class 2
1,2-Dichloroethane sym-Dichloroethane Class 1
Ethylene dichloride
Ethylene chloride
1,1-Dichloroethene 1,1-Dichloroethylene Class 1
Vinylidene chloride
1,2-Dichloroethene 1,2-Dichloroethylene Class 2
Acetylene dichloride
Dichloromethane Methylene chloride Class 2
1,2-Dimethoxyethaneether Ethyleneglycol dimethyl Class 2
Monoglyme
Dimethyl Cellosolve
N,N-Dimethylacetamide DMA Class 2
N,N-Dimethylformamide DMF Class 2
Dimethyl sulfoxide Methylsulfinylmethane Class 3
Methyl sulfoxide
DMSO
1,4-Dioxane p-Dioxane Class 2
[1,4]Dioxane
Ethanol Ethyl alcohol Class 3
2-Ethoxyethanol Cellosolve Class 2
Ethyl acetate Acetic acid ethyl ester Class 3
Ethyleneglycol 1,2-Dihydroxyethane Class 2
1,2-Ethanediol
Ethyl ether Diethyl ether Class 3
Ethoxyethane
1,1'-Oxybisethane
Ethyl formate Formic acid ethyl ester Class 3
Formamide Methanamide Class 2
Formic acid Class 3
Heptane n-Heptane Class 3
Hexane n-Hexane Class 2
Isobutyl acetate Acetic acid isobutyl ester Class 3
Isopropyl acetate Acetic acid isopropyl ester Class 3
Methanol Methyl alcohol Class 2
[[Page 24307]]
2-Methoxyethanol Methyl Cellosolve Class 2
Methyl acetate Acetic acid methyl ester Class 3
3-Methyl-l-butanol Isoamyl alcohol Class 3
Isopentyl alcohol
3-Methylbutan-l-ol
Methylbutyl ketone 2-Hexanone Class 2
Hexan-2-one
Methylcyclohexane Cyclohexylmethane Class 2
Methylethyl ketone 2-Butanone Class 3
MEK
Butan-2-one
Methylisobutyl ketone 4-Methylpentan-2-one Class 3
4-Methyl-2-pentanone
MIBK
2-Methyl-l-propanol Isobutyl alcohol Class 3
2-Methylpropan-l-ol
N-Methylpyrrolidone 1-Methylpyrrolidin-2-one Class 2
1-Methyl-2-pyrrolidinone
Nitromethane Class 2
Pentane n-Pentane Class 3
1-Pentanol Amyl alcohol Class 3
Pentan-l-ol
Pentyl alcohol
1-Propanol Propan-1-ol Class 3
Propyl alcohol
2-Propanol Propan-2-ol Class 3
Isopropyl alcohol
Propyl acetate Acetic acid propyl ester Class 3
Pyridine Class 2
Sulfolane Tetrahydrothiophene 1,1-dioxide Class 2
Tetrahydrofuran Tetramethylene oxide Class 3
Oxacyclopentane
Tetralin 1,2,3,4-Tetrahydro-naphthalene Class 2
Toluene Methylbenzene Class 2
1,1,1-Trichloroethane Methylchloroform Class 1
1,1,2-Trichloroethene Trichloroethene Class 2
Xylene\1\ Dimethybenzene Class 2
Xylol
\1\ Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene
Appendix 2. Additional Background
A2.1 Environmental Regulation of Organic Volatile Solvents
Several of the residual solvents frequently used in the
production of pharmaceuticals are listed as toxic chemicals in the
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 U.S.
Environmental Protection Agency (EPA), and the U.S. FDA 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 lifetime exposure of the general
population in the ambient environment, i.e., ambient air, food,
drinking water, and other media.
A2.2 Residual Solvents in Pharmaceuticals
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 as follows:
(1) Patients (not the general population) use pharmaceuticals to
treat their diseases or for prophylaxis to prevent infection or
disease.
(2) The assumption of lifetime 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
the Organization for Economic Cooperation and Development, EPA, and
the FDA Red Book.
Appendix 3. Methods for Establishing Exposure Limits
The Gaylor-Kodell model of risk assessment (Gaylor, D. W., and
R. L. Kodell, ``Linear Interpolation Algorithm for Low Dose
Assessment of Toxic Substance,'' Journal of Environmental Pathology
and Toxicology, 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 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
[[Page 24308]]
used by the U.S. EPA (IRIS) and the U.S. FDA (Red Book) and others.
The method is outlined here to give a better understanding of the
origin of the PDE values. It is necessary to perform these
calculations in order to use the PDE values tabulated in section 4
of this document.
PDE is derived from the NOEL or the LOEL in the most relevant
animal study as follows:
[GRAPHIC] [TIFF OMITTED] TN02MY97.054
The PDE is preferably derived 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, WHO, Geneva, 1994) and ``modifying factors'' or ``safety
factors'' in Pharmacopeial Forum. The assumption of 100 percent
systemic exposure is used in all calculations regardless of route of
administration.
The modifying factors are as follows:
Interspecies differences:
Differences from animals to human.
Max. 12; e.g., factors of 1 for human, 2 for dogs, and 12 for
mice.
Intra-individual differences:
Individual difference in humans.
Factor of 10 is generally given for all organic solvents and 10
is used consistently in this guideline.
Quality and type of available data:
Duration of study; lack of determination of NOEL.
Max. 10; e.g., a factor of 1 is used for a study that lasts at
least one-half lifetime (1 year for rodents, 7 years for dogs). A
factor of 2 used for a 6-month study in rodents, 5 for a 13-week
study, and 10 for a study of 4 weeks or less. When LOEL is used, a
factor up to 10 could be used depending on the severity of the
toxicity.
Additional modifying factors:
In cases where the NOAEL is derived for critical effects such as
nongenotoxic carcinogenicity, neurotoxicity, or teratogenicity.
Max. 10; e.g., factor of 10 when teratogenicity is not
accompanied by significant maternal toxicity. A factor of 3 or 5
might be used for less severe toxicity.
The weight adjustment compensates for the difference in body
weight between the experimental animal and humans. This guideline
assumes a body weight of 50 kilograms (kg) for humans. 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. Adjustments may be made for
pharmaceuticals intended for the pediatric population.
The expressions for PDE in this document are given in the
following format:
[GRAPHIC] [TIFF OMITTED] TN02MY97.055
where:
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 rabbit to humans.
F1 = 10 for extrapolation from other animals to humans.
F2 = A factor of 10 to account for variability between individuals.
F3 = A variable factor to account for toxicity studies of short-term
exposure.
F4 = A factor that may be applied in cases of severe toxicity. 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 NEL was not
established.
As an example of the application of this equation, consider the
toxicity study of acetonitrile in mice that is reported in Appendix
5. The NOEL is calculated to be 50.7 mg
kg-1day-1. The PDE for acetonitrile in this
study is calculated as follows:
[GRAPHIC] [TIFF OMITTED] TN02MY97.056
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 NEL was determined.
Calculations in the appendices follow this format.
The following values are used in the calculations in this
document:
[[Page 24309]]
Rat body weight 425 g
Pregnant rat body weight 330 g
Mouse body weight 28 g
Pregnant mouse body weight 30 g
Guinea pig body weight 500 g
Rhesus monkey body weight 2.5 kg
Rabbit body weight (pregnant or not) 4 kg
Beagle dog body weight 11.5 kg
Rat respiratory volume 290 liter (L)/day
Mouse respiratory volume 43 L/day
Rabbit respiratory volume 1,440 L/day
Guinea pig respiratory volume 430 L/day
Human respiratory volume 28,800 L/day
Dog respiratory volume 9,000 L/day
Monkey respiratory volume 1,150 L/day
Mouse water consumption 5 milliliter (mL)/day
Rat water consumption 30 mL/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/cubic meter (m3). Consider as an
example the inhalation study of carbon tetrachloride (molecular
weight 153.84) reported in Appendix 4.
[GRAPHIC] [TIFF OMITTED] TN02MY97.057
The relationship 1000 L = 1 m3 is used to convert to mg/
m3.
Dated: April 25, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-11439 Filed 5-1-97; 8:45 am]
BILLING CODE 4160-01-F