International Conference on Harmonisation; Draft Guideline on Impurities: Residual Solvents; Availability

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