Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices 67377

Toxicological profile NTIS order No. CAS No.

1. Di–N–OCTYLPHTHALATE ............................................................... PB98–101033 000117–84–0

2. ETHYLENE GLYCOL/ ...................................................................... PB98–101108 000107–21–1

PROPYLENE GLYCOL ..................................................................... 000057–55–6

3. HEXACHLOROETHANE .................................................................. PB98–101041 000067–72–1

4. HMX .................................................................................................. PB98–101058 002691–41–0

5. HYDRAULIC FLUIDS ....................................................................... PB98–101066 VARIOUS

6. HYDRAZINES ................................................................................... PB98–101025 000302–01–2

1,1-DIMETHYLHYDRAZINE .......................................................... 000057–14–7

1,2-DIMETHYLHYDRAZINE .......................................................... 000540–73–8

DIMETHYLHYDRAZINE ................................................................ 030260–66–3

7. MINERAL-BASED CRANKCASE OIL .............................................. PB98–101066 008002–05–9

8. TITANIUM TETRACHLORIDE .......................................................... PB98–101074 007550–45–0

9. WHITE PHOSPHORUS .................................................................... PB98–101082 007723–14–0

Dated: December 17, 1997.

Georgi Jones,

Director, Office of Policy and External Affairs,

Agency for Toxic Substances and Disease

Registry.

[FR Doc. 97–33508 Filed 12–23–97; 8:45 am]

BILLING CODE 4163–70–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Centers for Disease Control and

Prevention

National Vaccine Advisory Committee

(NVAC), Subcommittee on Future

Vaccines, Subcommittee on

Immunization Coverage, and

Subcommittee on Vaccine Safety:

Meetings

In accordance with section 10(a)(2) of

the Federal Advisory Committee Act

(Pub. L. 92–463), the Centers for Disease

Control and Prevention (CDC)

announces the following Federal

advisory committee meetings.

Name: National Vaccine Advisory

Committee (NVAC).

Times and Dates: 9 a.m.–2 p.m., January

12, 1998. 8:30 a.m.–1:15 p.m., January 13,

1998.

Place: Hubert H. Humphrey Building,

Room 800, 200 Independence Avenue, SW,

Washington, DC 20201.

Status: Open to the public, limited only by

the space available.

Notice: In the interest of security, the

Department has instituted stringent

procedures for entrance to the Hubert H.

Humphrey Building by non-government

employees. Thus, persons without a

government identification card should plan

to arrive at the building each day either

between 8 and 8:30 a.m. or 12:30 and 1 p.m.

so they can be escorted to the meeting.

Entrance to the meeting at other times during

the day cannot be assured.

Purpose: This committee advises and

makes recommendations to the Director of

the National Vaccine Program on matters

related to the Program responsibilities.

Matters To Be Discussed: Agenda items

will include updates on the National Vaccine

Program Office (NVPO) activities; the

National Vaccine Plan and NVAC’s role in

defining priorities for action; unmet needs

funding—past, present and future; adult

immunization: report of the workgroup; use

of non-traditional sites for adult

immunization; influenza: a growing need for

pandemic preparedness; and a discussion on

vaccines for international travel.

In addition, there will be updates on

welfare reform and effects on immunization;

moving towards a Department of Health and

Human Services’ vaccine safety action plan;

work group on philosophical exemptions—

final report; the presidential initiative on

immunization registries; global use of

critically needed vaccines—strategies to

consider. There will be reports from the

Subcommittee on Immunization Coverage,

Subcommittee on Future Vaccines, and

Subcommittee on Vaccine Safety.

Name: Subcommittee on Immunization

Coverage.

Time and Date: 2 p.m.–5 p.m., January 12,

1998.

Place: Hubert H. Humphrey Building,

Room 423A, 200 Independence Avenue, SW,

Washington, DC 20201.

Status: Open to the public, limited only by

the space available.

Purpose: This subcommittee will identify

and propose solutions that provide a

multifaceted and holistic approach to

reducing barriers that result in low

immunization coverage for children.

Matters To Be Discussed: This

subcommittee will hold a discussion on the

review of recommendations from the

document, ‘‘Strategies to Sustain

Immunization Coverage,’’ and the

finalization of those recommendations.

Name: Subcommittee on Future Vaccines.

Time and Date: 2 p.m.–5 p.m., January 12,

1998.

Place: Hubert H. Humphrey Building,

Room 405A, 200 Independence Avenue, SW,

Washington, DC 20201.

Status: Open to the public, limited only by

the space available.

Purpose: The Subcommittee on Future

Vaccines will develop policy options and

guide national activities which will lead to

accelerated development, licensure, and best

use of new vaccines in the simplest possible

immunization schedules.

Matters To Be Discussed: This

subcommittee will hold discussions

regarding the continued evaluation of

methods to remove barriers to development,

licensure and use of safe and effective new

vaccines; combination vaccines, strategic

options; and defining future vaccines policy

issues for travelers’ vaccines.

Name: Subcommittee on Vaccine Safety.

Time and Date: 2 p.m.–5 p.m., January 12,

1998.

Place: Hubert H. Humphrey Building,

Room 800, 200 Independence Avenue, SW,

Washington, DC 20201.

Status: Open to the public, limited only by

the space available.

Purpose: This subcommittee will review

issues relevant to vaccine safety and adverse

reactions to vaccines.

Matters To Be Discussed: This

subcommittee will hold discussions

regarding its goals; a report from the Task

Force on Safer Childhood Vaccines; a project

report on benefit-risk communication

curriculum development; and agenda items

for the next meeting.

Agenda items are subject to change as

priorities dictate.

Contact Person for More Information:

Felecia D. Pearson, Committee Management

Specialist, NVPO, CDC, 1600 Clifton Road,

NE, M/S D50, Atlanta, Georgia 30333,

telephone 404/639–4450.

Dated: December 19, 1997.

Carolyn J. Russell,

Director, Management Analysis and Services

Office, Centers for Disease Control and

Prevention (CDC).

[FR Doc. 97–33666 Filed 12–23–97; 8:45 am]

BILLING CODE 4163–18–P

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.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

guidance entitled ‘‘Q3C Impurities:
67378 Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices

1This 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.

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

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
Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices 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-bycase 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.

( ) ( ) 1 1000 Concentration ppm PDE

dose = ×

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.

Component Amount in formulation Acetonitrile 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.
67380 Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices

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.

Component Amount in formulation Acetonitrile content Daily exposure

Drug substance 0.3 g 800 ppm 0.24 mg

Excipient 1 0.9 g 2,000 ppm 1.80 mg

Excipient 2 3.8 g 800 ppm 3.04 mg

Drug product 5.0 g 1,016 ppm 5.08 mg

In this example, the product meets neither

the Option 1 nor the Option 2 limit according

to this summation. The manufacturer could

test the drug product to determine if the

formulation process reduced the level of

acetonitrile. If the level of acetonitrile was

not reduced during formulation to the

allowed limit, then the manufacturer of the

drug product should take other steps to

reduce the amount of acetonitrile in the drug

product. If all of these steps fail to reduce the

level of residual solvent, in exceptional cases

the manufacturer could provide a summary

of efforts made to reduce the solvent level to

meet the guidance value, and provide a riskbenefit 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)

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 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

Solvent PDE (mg/day) Concentration

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
Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices 67381

TABLE 2.—CLASS 2 SOLVENTS IN PHARMACEUTICAL PRODUCTS—Continued

Solvent PDE (mg/day) Concentration

limit (ppm)

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

Xylene1 21.7 2,170

1 Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.

4.3 Solvents with Low Toxic Potential

Solvents in Class 3 (shown in Table

3) may be regarded as less toxic and of

lower risk to human health. Class 3

includes no solvent known as a human

health hazard at levels normally

accepted in pharmaceuticals. However,

there are no long-term toxicity or

carcinogenicity studies for many of the

solvents in Class 3. Available data

indicate that they are less toxic in acute

or short-term studies and negative in

genotoxicity studies. It is considered

that amounts of these residual solvents

of 50 mg per day or less (corresponding

to 5,000 ppm or 0.5 percent under

Option 1) would be acceptable without

justification. Higher amounts may also

be acceptable provided they are realistic

in relation to manufacturing capability

and good manufacturing practice (GMP).

TABLE 3.—CLASS 3 SOLVENTS WHICH SHOULD BE LIMITED BY GMP OR OTHER QUALITY-BASED REQUIREMENTS

Acetic acid Heptane

Acetone Isobutyl acetate

Anisole Isopropyl acetate

1-Butanol Methyl acetate

2-Butanol 3-Methyl-1-butanol

Butyl acetate Methylethyl ketone

tert-Butylmethyl ether Methylisobutyl ketone

Cumene 2-Methyl–1-propanol

Dimethyl sulfoxide Pentane

Ethanol 1-Pentanol

Ethyl acetate 1-Propanol

Ethyl ether 2-Propanol

Ethyl formate Propyl acetate

Formic acid Tetrahydrofuran

4.4 Solvents for Which No Adequate

Toxicological Data Were Found

The following solvents (Table 4) may also

be of interest to manufacturers of excipients,

drug substances, or drug products. However,

no adequate toxicological data on which to

base a PDE were found. Manufacturers

should supply justification for residual levels

of these solvents in pharmaceutical products.

TABLE 4.—SOLVENTS FOR WHICH NO ADEQUATE TOXICOLOGICAL DATA WERE FOUND

1,1-Diethoxypropane Methylisopropyl ketone

1,1-Dimethoxymethane Methyltetrahydrofuran

2,2-Dimethoxypropane Petroleum ether

Isooctane Trichloroacetic acid

Isopropyl ether Trifluoroacetic acid
67382 Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices

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
Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices 67383

Appendix 1. List of Solvents Included in the Guidance
67384 Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices
Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices 67385
67386 Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices

BILLING CODE 4160–01–F
Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices 67387

Appendix 2. Additional Background

A2.1 Environmental Regulation of Organic

Volatile Solvents

Several of the residual solvents frequently

used in the production of pharmaceuticals

are listed as toxic chemicals in

Environmental Health Criteria (EHC)

monographs and the Integrated Risk

Information System (IRIS). The objectives of

such groups as the IPCS, the U.S.

Environmental Protection Agency (EPA), and

FDA include the determination of acceptable

exposure levels. The goal is protection of

human health and maintenance of

environmental integrity against the possible

deleterious effects of chemicals resulting

from long-term environmental exposure. The

methods involved in the estimation of

maximum safe exposure limits are usually

based on long-term studies. When long-term

study data are unavailable, shorter term

study data can be used with modification of

the approach such as use of larger safety

factors. The approach described therein

relates primarily to long-term or lifetime

exposure of the general population in the

ambient environment, i.e., ambient air, food,

drinking water, and other media.

A2.2 Residual Solvents in Pharmaceuticals

Exposure limits in this guidance are

established by referring to methodologies and

toxicity data described in EHC and IRIS

monographs. However, some specific

assumptions about residual solvents to be

used in the synthesis and formulation of

pharmaceutical products should be taken

into account in establishing exposure limits.

They are as follows:

(1) Patients (not the general population)

use pharmaceuticals to treat their diseases or

for prophylaxis to prevent infection or

disease.

(2) The assumption of lifetime patient

exposure is not necessary for most

pharmaceutical products but may be

appropriate as a working hypothesis to

reduce risk to human health.

(3) Residual solvents are unavoidable

components in pharmaceutical production

and will often be a part of drug products.

(4) Residual solvents should not exceed

recommended levels except in exceptional

circumstances.

(5) Data from toxicological studies that are

used to determine acceptable levels for

residual solvents should have been generated

using appropriate protocols such as those

described, for example, by the Organization

for Cooperation and Development, EPA, and

the FDA Red Book.

Appendix 3. Methods for Establishing

Exposure Limits

The Gaylor-Kodell method of risk

assessment (Gaylor, D. W., and R. L. Kodell,

‘‘Linear Interpolation Algorithm for Low

Dose Assessment of Toxic Substance,’’

Journal of Environmental Pathology and

Toxicology, 4:305, 1980) is appropriate for

Class 1 carcinogenic solvents. Only in cases

where reliable carcinogenicity data are

available should extrapolation by the use of

mathematical models be applied to setting

exposure limits. Exposure limits for Class 1

solvents could be determined with the use of

a large safety factor (i.e., 10,000 to 100,000)

with respect to the NOEL. Detection and

quantitation of these solvents should be by

state-of-the-art analytical techniques.

Acceptable exposure levels in this

guidance for Class 2 solvents were

established by calculation of PDE values

according to the procedures for setting

exposure limits in pharmaceuticals

(Pharmacopeial Forum, Nov-Dec 1989), and

the method adopted by IPCS for Assessing

Human Health Risk of Chemicals (EHC 170,

WHO, 1994). These methods are similar to

those used by the U.S. EPA (IRIS) and the

U.S. FDA (Red Book) and others. The method

is outlined here to give a better

understanding of the origin of the PDE

values. It is not necessary to perform these

calculations in order to use the PDE values

tabulated in Section 4 of this document.

PDE is derived from the NOEL or the LOEL

in the most relevant animal study as follows:

PDE

NOEL = ×

× × × ×

Weight Adjustment

F1 F2 F3 F4 F5

( ) 1

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:

S kM = 0 67 2 . ( )

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 halflifetime (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:

PDE mg kg day kg = mg day ×

× × × × =

− − 50 7 50 −

12 10 5 1 1

4 22

1 1

1 . .

In this example, F1 = 12 to account for the extrapolation from

mice to humans.

F2 = 10 to account for differences between

individual humans.
67388 Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices

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 weight 425 g Mouse respiratory volume 43 liter (L)/day

Pregnant rat body weight 330 g Rabbit respiratory volume 1,440 L/day

Mouse body weight 28 g Guinea pig respiratory volume 430 L/day

Pregnant mouse body weight 30 g Human respiratory volume 28,800 L/day

Guinea pig body weight 500 g Dog respiratory volume 9,000 L/day

Rhesus monkey body weight 2.5 kg Monkey respiratory volume 1,150 L/day

Rabbit body weight (pregnant or not) 4 kg Mouse water consumption 5 milliliter (mL)/day

Beagle dog body weight 11.5 kg Rat water consumption 30 mL/day

Rat respiratory volume 290 L/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 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.

n

V

P

RT

atm mg mol

L atm K mol K

mg

L = = mg L

× ×

× = =

− −

− −

300 10 153840

0 082 298

46 15

24.45

1 89

6 1

1 1 .

. . /

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

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Health Care Financing Administration

[Form #HCFA–R–224]

Emergency Clearance: Public

Information Collection Requirements

Submitted to the Office of Management

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In compliance with the requirement

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Paperwork Reduction Act of 1995, the

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HCFA is requesting OMB review and

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Supporting Statute Section 1853(a)(3) of

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as eligible organizations with risksharing contracts under section 1876, to

submit encounter data. Data regarding

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starting January 1, 1998. Other data (as

the Secretary deems necessary) may be

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The BBA also requires the Secretary

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Hospital data from the period, July 1,

1997—June 30, 1998, will serve as the

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Encounter data collected from

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HCFA–1450 (UB–92), Uniform

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