International Conference on Harmonisation; Guidance on Impurities: Residual Solvents

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

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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:

Only Class 3 solvents are likely to be present. Loss on

drying is less than 0.5 percent.

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, * * * .)

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

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\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

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[[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

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Appendix 1. List of Solvents Included in the Guidance

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BILLING CODE 4160-01-F

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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-1 day-1.

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 (m3). 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 m3 is used to convert to mg/

m3.

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