[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