[Federal Register Volume 62, Number 247 (Wednesday, December 24, 1997)]
[Notices]
[Pages 67377-67388]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-33639]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 97D-0148]


International Conference on Harmonisation; Guidance on 
Impurities: Residual Solvents

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a 
guidance entitled ``Q3C Impurities:

[[Page 67378]]

 Residual Solvents.'' The guidance was prepared under the auspices of 
the International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use (ICH). The guidance 
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: Effective December 24, 1997. Submit written comments at any 
time.

ADDRESSES: Submit written comments on the guidance to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guidance 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 guidance: John J. Gibbs, Center for Drug Evaluation 
and Research (HFD-820), Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857, 301-827-6430.
    Regarding 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 (CDER) and Biologics Evaluation and Research 
(CBER), 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.
    In the Federal Register of May 2, 1997 (62 FR 24302), FDA published 
a draft tripartite guideline entitled ``Impurities: Residual Solvents'' 
(Q3C). The notice gave interested persons an opportunity to submit 
comments by June 16, 1997.
    After consideration of the comments received and revisions to the 
guidance, a final draft of the guidance was submitted to the ICH 
Steering Committee and endorsed by the three participating regulatory 
agencies on July 17, 1997.
    In accordance with FDA's Good Guidance Practices (62 FR 8961, 
February 27, 1997), this document has been designated a guidance, 
rather than a guideline.
    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 guidance 
recommends acceptable amounts of residual solvents in pharmaceuticals 
for the safety of the patient. The guidance recommends the use of less 
toxic solvents and describes levels considered to be toxicologically 
acceptable for some residual solvents. The guidance applies to residual 
solvents in drug substances, excipients, and drug products, and to all 
dosage forms and routes of administration. The guidance 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.
    This guidance 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.
    As with all of FDA's guidances, the public is encouraged to submit 
written comments with new data or other new information pertinent to 
this guidance. The comments in the docket will be periodically 
reviewed, and, where appropriate, the guidance will be amended. The 
public will be notified of any such amendments through a notice in the 
Federal Register.
    Interested persons may, at any time, submit written comments on the 
guidance to the Dockets Management Branch (address above). 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 guidance 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 guidance is 
available on the Internet (http://www.fda.gov/cder/guidance.htm).
    The text of the guidance follows:

Q3C Impurities: Residual Solvents \1\
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    \1\ This guidance 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.
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1. Introduction

    The objective of this guidance is to recommend acceptable 
amounts for residual solvents in pharmaceuticals for the safety of 
the patient. The guidance 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 guidance 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

[[Page 67379]]

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 guidance 
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 guidance or the concept of qualification of 
impurities as expressed in the guidance for drug substance (Q3A, 
Impurities in New Drug Substances) or drug product (Q3B, Impurities 
in New Drug Products), or all three guidances.

2. Scope of the Guidance

    Residual solvents in drug substances, excipients, and drug 
products are within the scope of this guidance. 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 considered necessary to test for solvents that 
are used or produced in the manufacture or purification of drug 
substances, excipients, or drug products. 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 guidance, 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 guidance 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 guidance 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 of this document 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 guidance 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 guidance 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--
    Nongenotoxic 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 PDE's of 50 
milligrams (mg) or more per day.

3.2 Methods for Establishing Exposure Limits

    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.

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] TN24DE97.015

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), as shown in Option 1 in 
the previous paragraph, 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, and 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 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         
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 guidance.

[[Page 67380]]

    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 are 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 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 guidance value, and provide a 
risk-benefit analysis to support allowing the product to be utilized 
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 guidances ``Q2A Text on Validation of Analytical Procedures'' 
and ``Q2B Validation of Analytical Procedures: Methodology.''

3.5 Reporting Levels of Residual Solvents

    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 guidance. 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:
<bullet>  Only Class 3 solvents are likely to be present. Loss on 
drying is less than 0.5 percent.
<bullet>  Only Class 2 solvents X, Y, * * * are likely to be 
present. All are below the Option 1 limit. (Here the supplier would 
name the Class 2 solvents represented by X, Y, * * * .)
<bullet>  Only Class 2 solvents X, Y, * * * and Class 3 solvents are 
likely to be present. Residual Class 2 solvents are below the Option 
1 limit and residual Class 3 solvents are below 0.5 percent.
    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 percent, respectively, they should be 
identified and quantified.

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. The solvent 1,1,1-Trichloroethane is included in Table 1 
because it is an environmental hazard. The stated limit of 1,500 ppm 
is based on a review of the safety data.

          Table 1.--Class 1 Solvents in Pharmaceutical Products         
                    (Solvents That Should Be Avoided)                   
------------------------------------------------------------------------
                              Concentration                             
         Solvent               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 
because of their inherent toxicity. 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.

          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       

[[Page 67381]]

                                                                        
Dichloromethane                                 6.0           600       
1,2-Dimethoxyethane                             1.0           100       
N,N-Dimethylacetamide                          10.9         1,090       
N,N-Dimethylformamide                           8.8           880       
1,4-Dioxane                                     3.8           380       
2-Ethoxyethanol                                 1.6           160       
Ethyleneglycol                                  6.2           620       
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 
5,000 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 (GMP).

   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                
Dimethyl sulfoxide                   Pentane                            
Ethanol                              1-Pentanol                         
Ethyl acetate                        1-Propanol                         
Ethyl ether                          2-Propanol                         
Ethyl formate                        Propyl acetate                     
Formic acid                          Tetrahydrofuran                    
------------------------------------------------------------------------

4.4 Solvents for Which No Adequate Toxicological Data Were Found

    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               
------------------------------------------------------------------------


[[Page 67382]]

Glossary

    Genotoxic carcinogens: Carcinogens that 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.
    Teratogenicity: The occurrence of structural malformations in a 
developing fetus when a substance is administered during pregnancy.

BILLING CODE 4160-01-F

[[Page 67383]]

Appendix 1. List of Solvents Included in the Guidance
[GRAPHIC] [TIFF OMITTED] TN24DE97.007


[[Page 67384]]

[GRAPHIC] [TIFF OMITTED] TN24DE97.008



[[Page 67385]]

[GRAPHIC] [TIFF OMITTED] TN24DE97.009



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[GRAPHIC] [TIFF OMITTED] TN24DE97.010



BILLING CODE 4160-01-F

[[Page 67387]]

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 
Environmental Health Criteria (EHC) monographs and the Integrated 
Risk Information System (IRIS). The objectives of such groups as the 
IPCS, the U.S. Environmental Protection Agency (EPA), and 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 guidance 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 Cooperation and Development, EPA, and the FDA 
Red Book.

Appendix 3. Methods for Establishing Exposure Limits

    The Gaylor-Kodell method 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 guidance 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 (EHC 170, WHO, 1994). 
These methods are similar to those 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 
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 NOEL or the LOEL in the most relevant 
animal study as follows:
[GRAPHIC] [TIFF OMITTED] TN24DE97.011

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 EHC (EHC 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:
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:
[GRAPHIC] [TIFF OMITTED] TN24DE97.012

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 guidance.
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 
nonrodents.
    F3 = 5 for a 3-month study in rodents, or a 2-year study in 
nonrodents.
    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., 
nongenotoxic 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 toxicity.
    The weight adjustment assumes an arbitrary adult human body 
weight for either sex of 50 kilograms (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<SUP>-1</SUP> day<SUP>-1</SUP>. 
The PDE for acetonitrile in this study is calculated as follows:
[GRAPHIC] [TIFF OMITTED] TN24DE97.013

    In this example,
F1 = 12 to account for the extrapolation from mice to humans.
F2 = 10 to account for differences between individual humans.

[[Page 67388]]

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                     425 g   Mouse             43 liter (L)/day 
 weight                               respirat                          
                                      ory                               
                                      volume                            
                                                                        
Pregnant                     330 g   Rabbit                 1,440 L/day 
 rat body                             respirat                          
 weight                               ory                               
                                      volume                            
                                                                        
Mouse                         28 g   Guinea                   430 L/day 
 body                                 pig                               
 weight                               respirat                          
                                      ory                               
                                      volume                            
                                                                        
Pregnant                      30 g   Human                 28,800 L/day 
 mouse                                respirat                          
 body                                 ory                               
 weight                               volume                            
                                                                        
Guinea                       500 g   Dog                    9,000 L/day 
 pig body                             respirat                          
 weight                               ory                               
                                      volume                            
                                                                        
Rhesus                      2.5 kg   Monkey                 1,150 L/day 
 monkey                               respirat                          
 body                                 ory                               
 weight                               volume                            
                                                                        
Rabbit                        4 kg   Mouse        5 milliliter (mL)/day 
 body                                 water                             
 weight                               consumpt                          
 (pregnan                             ion                               
 t or                                                                   
 not)                                                                   
                                                                        
Beagle                     11.5 kg   Rat water                30 mL/day 
 dog body                             consumpt                          
 weight                               ion                               
                                                                        
Rat                      290 L/day   Rat food                  30 g/day 
 respirat                             consumpt                          
 ory                                  ion                               
 volume                                                                 
                                                                        
                                                                        

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 (m<SUP>3</SUP>). Consider as an 
example the rat reproductive toxicity study by inhalation of carbon 
tetrachloride (molecular weight 153.84) summarized in Pharmeuropa, 
Vol. 9, No. 1, Supplement, April 1997, page S9.
[GRAPHIC] [TIFF OMITTED] TN24DE97.014

The relationship 1000 L = 1 m<SUP>3</SUP> is used to convert to mg/
m<SUP>3</SUP>.

    Dated: December 16, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-33639 Filed 12-23-97; 8:45 am]
BILLING CODE 4160-01-F