21446 Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices

F. Submission and Deadline

Submit the original and two copies of

PHS 5161–1 (OMB Number 0937–0189).

By May 1, 2000, submit the

application to the Grants Management

Specialist identified in the ‘‘Where to

Obtain Additional Information’’ section

of this announcement.

1. Deadline: Applications will be

considered as meeting the deadline if

they are either:

a. Received on or before the stated

deadline date; or

b. Sent on or before the deadline date.

(Applicants must request a legibly dated

U.S. Postal Service postmark or obtain

a legibly dated receipt from a

commercial carrier or the U.S. Postal

Service.

Private metered postmarks shall not

be acceptable proof of timely mailing.)

2. Late Applications: Applications

which do not meet the criteria in 1(a) or

1(b) above are considered late

applications and will be returned to the

applicant.

G. Evaluation Criteria

The application will be evaluated

according to the following criteria by an

independent review group appointed by

CDC.

1. Need statement. The extent to

which the applicant identifies specific

opportunities and existing gaps related

to the purpose of the program. (10

points)

2. Objectives. The degree to which

short- and long-term objectives are

specific, measurable, attainable, time

phased, and realistic. (20 points)

3. Operational Plans. The adequacy of

the applicant’s plan to carry out the

proposed activities, including the extent

to which the applicant plans to work

collaboratively with other organizations

and individuals who may have an

impact on cancer prevention and

control objectives. (25 points)

4. Evaluation Plan. The extent to

which the evaluation plan appears

capable of monitoring progress toward

meeting project objectives. (25 points)

5. Program Management. The extent

to which proposed staff appear to be

qualified and possess capacity to

perform the project. (20 points)

6. Budget. The extent to which each

line-item budget and narrative

justification for Projects 1, 2, 3 and 4 are

reasonable and consistent with the

purpose and objectives of the program.

(Not weighted)

7. Human Subjects. Does the

application adequately address the

requirements of Title 45 CFR Part 46 for

the protection of human subjects? (Not

Weighted)

8. The degree to which the applicant

has met the CDC Policy requirements

regarding the inclusion of women,

ethnic, and racial groups in the

proposed research. This includes:

1. The proposed plan for the inclusion

of both sexes and racial and ethnic

minority populations for appropriate

representation.

2. The proposed justification when

representation is limited or absent.

3. A statement as to whether the

design of the study is adequate to

measure differences when warranted.

4. A statement as to whether the plans

for recruitment and research for study

participants include the process of

establishing partnerships with

community(ies) and recognition of

mutual benefits.

H. Other Requirements

Technical Reporting Requirements

Provide CDC with the original plus

two copies of the following:

1. Annual written progress report

must be submitted 30 days after the end

of each budget period.

2. Financial status report (FSR) must

be submitted 90 days after the end of

each budget period.

3. Final financial and performance

reports, must be submitted 90 days after

the end of the project period.

Send all reports to the Grants

Management Specialist identified in the

‘‘Where to Obtain Additional

Information’’ section of this

announcement.

The following additional

requirements are applicable to this

program. For a complete description of

each, see Attachment I in the

application package.

AR–1 Human Subjects Requirement

AR–2 Requirements for Inclusion of

Women and Racial and Ethnic Minorities

in Research

AR–9 Paperwork Reduction Act

Requirements

AR–10 Smoke-Free Workplace

Requirements

AR–11 Healthy People 2010

AR–12 Lobbying Restrictions

AR–20 Conference Support

I. Authority and Catalog of Federal

Domestic Assistance Number

This program is authorized under

sections 301(a), 317(k)(2) of the Public

Health Service Act [42 U.S.C. 241(a) and

247b(k)(2)], as amended. The Catalog of

Federal Domestic Assistance Number

for this program is 93.283.

J. Where To Obtain Additional

Information

To obtain additional information

contact: Nealean K. Austin, Grants

Management Specialist Grants

Management Branch, Procurement and

Grants Office Announcement 00037

Centers for Disease Control and

Prevention (CDC) Room 3000, 2920

Brandywine Road, Atlanta, GA 30341,

telephone (770)–488–2754, E-mail

address nea1@cdc.gov

See also the CDC home page on the

Internet: http://www.cdc.gov

For program technical assistance,

contact: Corinne Graffunder, Chief,

Section A, Program Services Branch,

Division of Cancer Prevention and

Control, National Center for Chronic

Disease Prevention and Health

Promotion, Centers for Disease Control

and Prevention (CDC), 4770 Buford

Highway, NE., Mailstop K–57, Atlanta,

GA 30341–3724, telephone (770) 488–

4880, fax (770) 488–3230.

Dated: April 17, 2000.

John L. Williams,

Director, Procurement and Grants Office,

Centers for Disease Control and Prevention

(CDC).

[FR Doc. 00–9956 Filed 4–20–00; 8:45 am]

BILLING CODE 4163–18–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 93D–0139]

International Conference on

Harmonisation; Draft Revised

Guidance on Q1A(R) Stability Testing

of New Drug Substances and Products

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

draft revised guidance entitled ‘‘Q1A(R)

Stability Testing of New Drug

Substances and Products.’’ The draft

revised guidance, which updates a

guidance on the same topic published in

the Federal Register of September 22,

1994 (the 1994 guidance), was prepared

under the auspices of the International

Conference on Harmonisation of

Technical Requirements for Registration

of Pharmaceuticals for Human Use

(ICH). The draft revised guidance

clarifies the 1994 guidance, adds

information, and provides consistency

with more recently published ICH

guidances. The draft revised guidance is

intended to reflect formal scientific

principles for stability testing of drugs

and should be useful to applicants

submitting new drug applications for

new molecular entities and associated

drug products.

Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices 21447

1This draft revised guidance represents the

agency’s current thinking on stability testing of new

drug substances and products. 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.

DATES: Submit written comments by

June 5, 2000.

ADDRESSES: Submit written comments

on the draft revised guidance to the

Dockets Management Branch (HFA–

305), Food and Drug Administration,

5630 Fishers Lane, rm. 1061, Rockville,

MD 20852. Copies of the draft revised

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. Single copies of the draft revised

guidance may be obtained by mail from

the Office of Communication, Training,

and Manufacturers Assistance (HFM–

40), Center for Biologics Evaluation and

Research (CBER), or by calling the CBER

Voice Information System at 1–800–

835–4709 or 301–827–1800. Copies may

be obtained from CBER’s FAX

Information System at 1–888–CBER–

FAX or 301–827–3844.

FOR FURTHER INFORMATION CONTACT:

Regarding the guidance: Chi Wan

Chen, Center for Drug Evaluation

and Research (HFD–830), Food and

Drug Administration, 9201

Corporate Blvd., Rockville, MD

20850, 301–827–2001.

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.

In October 1999, the ICH Steering

Committee agreed that a draft revised

guidance entitled ‘‘Q1A(R) Stability

Testing of New Drug Substances and

Products’’ should be made available for

public comment. The draft revised

guidance is a revision of an ICH

guidance on the same topic published in

the Federal Register of September 22,

1994 (59 FR 48754). The draft revised

guidance 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.

In accordance with FDA’s good

guidance practices (62 FR 8961,

February 27, 1997), this document is

now being called a guidance, rather than

a guideline.

The draft revised guidance provides

guidance on the information to be

submitted in the stability data package

for a new drug substance or drug

product. The revisions add information

on stability storage conditions: (1) For

drug substances and products intended

to be stored in a refrigerator or freezer

and (2) for drug products packaged in

semipermeable containers. The

revisions clarify the guidance on: (1)

Testing frequencies for stability studies

at accelerated and intermediate

conditions and (2) stability

commitments.

The draft revised guidance recognizes

certain regional regulatory constraints.

The Preamble and Objective sections of

the 1994 guidance were revised to

recognize that, in some regions,

guidance does not constitute a

regulatory requirement. The Storage

Conditions sections of the 1994

guidance were revised to recognize that,

in some regions, stability amendments

to pending applications are not

permissable.

The draft revised guidance includes

references to three recently published

ICH guidances: (1) ‘‘Q1B Photostability

Testing of New Drug Substances and

Products,’’ (2) ‘‘Q6A Specifications: Test

Procedures and Acceptance Criteria for

New Drug Substances and New Drug

Products: Chemical Substances,’’ and (3)

‘‘Q6B Specifications: Test Procedures

and Acceptance Criteria for

Biotechnological/Biological Products.’’

This draft guidance applies in general

to new dosage forms and

biotechnological/biological products as

does the original Q1A guidance.

Additional guidance specific to the

stability testing of new dosage forms

and biotechnological/biological

products can be found in two previously

published ICH guidances entitled ‘‘Q1C:

Stability Testing of New Dosage Forms’’

and ‘‘Q5C: Quality of Biotechnological

Products: Stability Testing of

Biotechnological/Biological Products,’’

respectively.

This draft revised guidance represents

the agency’s current thinking on

stability testing of new drug substances

and products. 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 submit to the

Dockets Management Branch (address

above) written comments on the draft

revised guidance on or before June 5,

2000. 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 revised 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 at http://

www.fda.gov/cder/guidance/index.htm

or http://www.fda.gov/cber/

publications.htm.

The text of the draft revised guidance

follows:

Q1A(R): Stability Testing of New Drug

Substances and Products 1

Preamble

The following guidance defines the

stability data package for a new drug

substance or drug product that is sufficient

for a registration application within the three

regions of the EC, Japan, and the United

States. It does not seek necessarily to cover

21448 Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices

the testing for registration in or export to

other areas of the world.

The principle that stability information

generated in any one of the three regions of

the EC, Japan, and the United States would

be mutually acceptable in both of the other

two regions has been established, provided

the information is consistent with this

guidance and the labeling is in accord with

national/regional requirements.

The guidance seeks to exemplify the core

stability data package for new drug

substances and products, but leaves

sufficient flexibility to encompass the variety

of different practical situations that may be

encountered due to specific scientific

considerations and characteristics of the

materials being evaluated. Alternative

approaches may be used when there are

scientifically justifiable reasons.

Specific details of the sampling and testing

for particular dosage forms/packaging, etc.,

are not covered in this guidance.

Objective

The purpose of stability testing is to

provide evidence on how the quality of a

drug substance or drug product varies with

time under the influence of a variety of

environmental factors, such as temperature,

humidity, and light, and enables

recommended storage conditions, retest

periods, and shelf lives to be established.

Scope

The guidance addresses the information to

be submitted in registration applications for

new molecular entities and associated drug

products. This guidance does not currently

seek to cover the information to be submitted

for abbreviated or abridged applications,

variations, clinical trial applications, etc.

The choice of test conditions defined in

this guidance is based on an analysis of the

effects of climatic conditions in the three

areas of the EC, Japan, and the United States.

The mean kinetic temperature in any region

of the world can be derived from climatic

data (Grimm, W., Drugs Made in Germany,

28:196–202, 1985 and 29:39–47, 1986).

Drug Substance

General

Information on the stability of the drug

substance is an integral part of the systematic

approach to stability evaluation.

Stress Testing

Stress testing helps determine the intrinsic

stability of the molecule by establishing

degradation pathways in order to identify the

likely degradation products and to validate

the stability indicating power of the

analytical procedures used. Stress testing is

conducted to provide data on forced

decomposition products and decomposition

mechanisms. The severe conditions that may

be encountered during distribution can be

covered by stress testing. These studies

should establish the inherent stability

characteristics of the molecule, such as the

degradation pathways, and lead to

identification of degradation products and

hence support the suitability of the proposed

analytical procedures. The detailed nature of

the studies will depend on the individual

drug substance and type of drug product.

This testing is likely to be carried out on

a single batch of material and to include the

effect of temperatures in 10 degrees Celsius

(°C) increments (e.g., 50 °C, 60 °C) above the

accelerated temperature test condition and

humidity (e.g., 75 percent RH or greater)

where appropriate and oxidation and

photolysis on the drug substance plus its

susceptibility to hydrolysis across a wide

range of pH values when in solution or

suspension.

Photostability testing should be an integral

part of stress testing. (The standard

conditions for photostability testing are

defined in ICH Q1B.)

It is recognized that some degradation

pathways can be complex and that, under

forcing conditions, decomposition products

may be observed that are unlikely to be

formed under accelerated or long-term

testing. This information may be useful in

developing and validating suitable analytical

methods, but it may not always be necessary

to examine specifically for all degradation

products if it has been demonstrated that in

practice these are not formed.

Results from these studies will form an

integral part of the information provided to

regulatory authorities.

Selection of Batches

Data from formal stability studies should

be provided on at least three batches of the

drug substance. The batches manufactured to

a minimum of pilot scale should be by the

same synthetic route and use a method of

manufacture and procedure that simulates

the final process to be used on a

manufacturing scale.

The overall quality of the batches of drug

substance placed on formal stability studies

should be representative of the quality of the

material used in clinical studies and of the

quality of material to be made on a

manufacturing scale.

Supporting stability data may be provided

using stability data generated from batches of

drug substance made on a laboratory scale.

Packaging/Containers

The stability studies should be conducted

on material stored in a container closure

system that is the same as or simulates the

packaging proposed for storage and

distribution.

Test Attributes, Test Procedures, and Test

Acceptance Criteria

Test attributes, test procedures, and

acceptance criteria are defined in ICH Q6A

and Q6B.

The testing should cover attributes of the

drug substance susceptible to change during

storage and likely to influence quality, safety,

and/or efficacy. Stability information should

cover, as appropriate, the physical, chemical,

biological, and microbiological attributes of

the drug substance. Validated stabilityindicating test procedures should be applied.

The need for and extent of replication will

depend on the results from validation

studies.

Acceptance criteria are numerical limits,

ranges, and other criteria for the specific tests

described and should include individual and

total upper limits for impurities and

degradation products. The acceptance criteria

should be derived from batches of the

material used in the preclinical and clinical

studies.

Testing Frequency

Frequency of testing should be sufficient to

establish the stability attributes of the drug

substance. For drug substances with a

proposed retest period of at least 12 months,

the frequency of testing at the long-term

storage condition will normally be every 3

months over the first year, every 6 months

over the second year, and then annually.

For the accelerated storage conditions, a

minimum of three test points, including the

initial and end points (e.g., 0, 3, and 6

months) is recommended. Where an

expectation (based on development

experience) exists that results from

accelerated storage are likely to approach

significant change criteria, increased testing

should be conducted either by testing

additional samples at the final time point or

by inclusion of a fourth time point in the

protocol.

When testing at the intermediate storage

condition is necessary as a result of failure

at the accelerated storage condition, a

minimum of four test points, including the

initial and end points, is recommended (e.g.,

0, 6, 9, and 12 months).

Storage Conditions

In general, a drug substance should be

evaluated for stability as appropriate under

storage conditions that test both thermal

stability and stability at conditions of

elevated humidity. The storage conditions

and length of studies chosen should be

sufficient to cover storage, shipment, and

subsequent use.

The storage condition at which long-term

testing is conducted will be reflected in the

labeling and retest date. The long-term

testing should cover a minimum of 12

months’ duration at the time of submission

and should be continued for a sufficient

period to cover the proposed retest period.

Additional data accumulated during the

assessment period of the registration

application should be submitted to the

authorities if requested. Data from the

accelerated storage condition or from the

intermediate storage condition, as

appropriate, may be used to evaluate the

impact of short-term excursions outside the

label storage conditions (such as might occur

during shipping).

Significant change is defined as failure to

meet the specification.

Long-term, accelerated, and, where

appropriate, intermediate storage conditions

for drug substances are detailed in the

sections below. Alternative storage

conditions are allowable if justified. If not

covered by a subsequent section, a drug

substance should be considered as belonging

to the general case.

General Case for Drug Substances

Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices 21449

Study Storage Condition Minimum Time Period at Submission

Long-term 25 °C ± 2 °C/60% RH ± 5% RH 12 months

Intermediate 30 °C ±2 °C/60% RH ± 5% RH 6 months

Accelerated 40 °C ± 2 °C/75% RH ± 5% RH 6 months

When ‘‘significant change’’ occurs at any time during 6 months’ storage at the accelerated storage condition, additional testing

at the intermediate storage condition should be conducted and evaluated against significant change criteria. The initial application

should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition.

Drug Substances Intended for Storage in a Refrigerator

Study Storage Condition Minimum Time Period at Submission

Long-term 5 °C ± 3 °C 12 months

Accelerated 25 °C ± 2 °C/60% RH ± 5% RH 6 months

Data from refrigerated storage should be assessed according to the evaluation section of this guidance, except where explicitly

noted below.

If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed retest period

should be based on the real-time data available at the long-term storage condition.

If significant change occurs within the first 3 months’ testing at the accelerated storage condition, data should be supplied to

cover use of the drug substance outside of the label storage condition. It is not necessary to continue to test a product to 6 months

when an obvious significant change has occurred within the first 3 months.

Drug Substances Intended for Storage in a Freezer

Study Storage Condition Minimum Time Period at Submission

Long-term ¥20 °C ± 5 °C 12 months

For drug substances intended for storage in

a freezer, the retest period should be based

on the real-time data presented at the longterm storage condition. In the absence of an

accelerated storage condition for drug

substances intended to be stored in a freezer,

testing at an elevated temperature (e.g., 5 °C

± 3 °C or 25 °C ± 2 °C) on a single batch

should be conducted to support use of the

drug substance outside of the proposed label

storage condition.

Drug Substances Intended for Storage Below

¥20 °C

Drug substances intended for storage below

¥20 °C should be treated on a case-by-case

basis.

Stability Commitment

When available long-term stability data on

primary batches do not cover the proposed

retest period granted at the time of approval,

the studies should be continued postapproval

in order to firmly establish the retest period.

Where the submission includes long-term

storage data from three production batches

covering the proposed retest period, no

postapproval commitment is necessary.

Otherwise, the appropriate alternative from

those shown below should be followed:

1. If the submission includes stability data

on at least three production batches, a

commitment should be made to continue

these studies through the proposed retest

period.

2. If the submission includes stability data

on fewer than three production batches, a

commitment should be made to continue

these studies through the proposed retest

period and to place additional production

batches, to a total of at least three, on longterm stability studies through the proposed

retest period.

3. If the submission does not include

stability data on production batches, a

commitment should be made to place the

first three production batches on long-term

stability studies through the proposed retest

period.

The stability protocol used for long-term

studies for the stability commitment should

be the same as that for the primary batches

unless otherwise scientifically justified.

Evaluation

The design of the stability study is to

establish, based on testing a minimum of

three batches of the drug substance and

evaluating the stability information (covering

as appropriate the physical, chemical,

biological, and microbiological attributes), a

retest period applicable to all future batches

of the drug substance manufactured under

similar circumstances. The degree of

variability of individual batches affects the

confidence that a future production batch

will remain within specification throughout

the assigned retest period.

The data may show so little degradation

and so little variability that it is apparent

from looking at the data that the requested

retest period will be granted. Under these

circumstances, it is normally unnecessary to

go through the formal statistical analysis;

providing a full justification for the omission

would be sufficient.

An acceptable approach for quantitative

characteristics that are expected to change

with time is to determine the time at which

the 95 percent one-sided confidence limit for

the mean degradation curve intersects the

acceptable specification limit. If analysis

shows that the batch-to-batch variability is

small, it is advantageous to combine the data

into one overall estimate, and this can be

done by first applying appropriate statistical

tests (e.g., p values for level of significance

of rejection of more than 0.25) to the slopes

of the regression lines and zero time

intercepts for the individual batches. If it is

inappropriate to combine data from several

batches, the overall retest period may depend

on the minimum time a batch may be

expected to remain within acceptable and

justified limits.

The nature of any degradation relationship

will determine the need for transformation of

the data for linear regression analysis.

Usually the relationship can be represented

by a linear, quadratic, or cubic function on

an arithmetic or logarithmic scale. Statistical

methods should be employed to test the

goodness of fit of the data on all batches and

combined batches (where appropriate) to the

assumed degradation line or curve.

Limited extrapolation of the real-time data

from the long-term testing storage condition

beyond the observed range to extend the

retest period at approval time may be

undertaken, particularly where the

accelerated data support this. However, this

assumes that the same degradation

relationship will continue to apply beyond

the observed data. Hence the use of

21450 Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices

extrapolation should be justified in each

application in terms of what is known about

the mechanism of degradation, the goodness

of fit of any mathematical model, batch size,

existence of supportive data, etc.

Any evaluation should cover not only the

assay, but also the levels of degradation

products and other appropriate attributes.

Statements/Labeling

A storage temperature range may be used

in accordance with relevant national/regional

requirements. The range should be based on

the stability evaluation of the drug substance.

Where applicable, specific instructions

should be provided, particularly for drug

substances that cannot tolerate freezing. The

use of terms such as ‘‘ambient conditions’’ or

‘‘room temperature’’ is unacceptable.

A retest period should be derived from the

stability information.

Drug Product

General

The design of the formal stability studies

for the drug product should be based on

knowledge of the behavior and properties of

the drug substance and on experience gained

from clinical formulation studies and from

stability studies on the drug substance. The

likely changes on storage and the rationale

for the selection of attributes to test in the

formal stability studies should be stated.

Photostability Testing

Photostability testing should be conducted

on at least one primary batch of the drug

product if appropriate. (The standard

conditions for photostability testing are

defined in ICH Q1B.)

Selection of Batches

Data from formal stability studies are to be

provided on at least three batches of the drug

product. Two of the three batches should be

at least pilot scale. The third batch may be

smaller (e.g., 25,000 to 50,000 tablets or

capsules for solid oral dosage forms). The

manufacturing process used for primary

batches should simulate that to be applied to

production batches and should provide

product of the same quality and meet the

same quality specification as that intended

for marketing. Where possible, batches of the

drug product should be manufactured using

different batches of drug substance.

Laboratory scale batches are not acceptable

for formal stability studies. Data on

associated formulations or packaging may be

submitted as supporting stability data.

Packaging/Containers

The stability testing should be conducted

on the dosage form stored in the packaging

proposed for marketing. Additional testing of

unprotected drug product can form a useful

part of stress testing and packaging

evaluation, as can studies carried out on

other related packaging materials in

supporting the definitive package(s).

Test Attributes, Test Procedures, and

Acceptance Criteria

Test attributes, test procedures, and

acceptance criteria, including the concept of

release and shelf life specifications, are

defined in ICH Q6A and Q6B.

The testing should cover those attributes

susceptible to change during storage and

likely to influence quality, safety, and/or

efficacy. Analytical test procedures should be

fully validated, and the assays should be

stability-indicating. The need for and extent

of replication will depend on the results of

validation studies.

The range of testing should cover, as

appropriate, chemical and/or biological

stability, loss of preservative, physical

properties, characteristics, functionality, and

microbiological attributes.

Acceptance criteria should relate to the

release limits (where applicable) to be

derived from consideration of all the

available stability information. The shelf life

specification could allow acceptable and

justifiable differences from the release

specification based on the stability

evaluation and the changes observed on

storage. It should include specific upper

limits for degradation products, the

justification for which should be influenced

by the levels observed in material used in

preclinical studies and clinical trials. The

justification for the limits proposed for

certain other tests, such as particle size and/

or dissolution rate, should reference the

results observed for batch(es) used in

bioavailability and/or clinical studies. Any

differences between the release and shelf life

specifications for antimicrobial preservatives

should be supported by preservative efficacy

testing.

Testing Frequency

Frequency of testing should be sufficient to

establish the stability attributes of the drug

product. For products with a proposed shelf

life of at least 12 months, the frequency of

testing at the long-term storage condition will

normally be every 3 months over the first

year, every 6 months over the second year,

and then annually.

For the accelerated storage conditions, a

minimum of three test points, including the

initial and end points (e.g., 0, 3, and 6

months), is recommended. Where an

expectation (based on development

experience) exists that results from

accelerated storage are likely to approach

significant change criteria, increased testing

should be conducted either by testing

additional samples at the final time point or

by inclusion of a fourth time point in the

protocol.

When testing at the intermediate storage

condition is necessary as a result of failure

at the accelerated storage condition, a

minimum of four test points, including the

initial and end points is recommended (e.g.,

0, 6, 9, and 12 months).

Matrixing or bracketing can be applied, if

justified. (See Glossary.)

Storage Conditions

In general, a drug product should be

evaluated under storage conditions that test

the thermal stability and, if appropriate, its

sensitivity to moisture or, for liquid products

in semipermeable containers, potential for

solvent loss. The storage conditions and

length of studies chosen should be sufficient

to cover storage, shipment, and subsequent

use.

Stability of the drug product after

reconstituting or diluting according to

labeling should be addressed to provide

appropriate and supportive information.

The storage condition at which long-term

testing is conducted will be reflected in the

labeling and expiration date. The long-term

testing should cover a minimum of 12

months’ duration at the time of submission

and should be continued for a sufficient

period to cover the proposed shelf life.

Additional data accumulated during the

assessment period of the registration

application should be submitted to the

authorities if requested. Data from the

accelerated storage condition or from the

intermediate storage condition as appropriate

may be used to evaluate the impact of shortterm excursions outside the label storage

conditions (such as might occur during

shipping).

In general, significant change is defined as:

1. A 5 percent potency change from the

initial assay value;

2. Any specified degradant exceeding its

acceptance criteria;

3. Failure to meet acceptance criteria for

appearance and physical properties (e.g.,

color, phase separation, resuspendibility,

delivery per actuation, caking, hardness); and

as appropriate to the product type;

4. The pH exceeding its acceptance criteria;

and

5. Dissolution exceeding the acceptance

criteria for 12 dosage units.

Long-term, accelerated, and, where

appropriate, intermediate storage conditions

for drug products are detailed in the sections

below; alternative storage conditions are

allowable if justified. If not covered by a

subsequent section, a drug product should be

considered as belonging to the general case.

General Case

Study Storage Condition Minimum Time Period at Submission

Long-term 25 °C ± 2 °C/60% RH ± 5% RH 12 months

Intermediate 30 °C ± 2 °C/60% RH ± 5% RH 6 months

Accelerated 40 °C ± 2 °C/75% RH ± 5% RH 6 months

Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices 21451

When ‘‘significant change’’ occurs at any

time during 6 months’ storage at the

accelerated storage condition, additional

testing at the intermediate storage condition

should be conducted and evaluated against

significant change criteria. The initial

application should include a minimum of 6

months’ data from a 12-month study at the

intermediate storage condition.

Drug Products Stored in Impermeable

Containers

The sensitivity to moisture or the potential

for solvent loss is not a concern for drug

products packaged in impermeable

containers that provide a permanent barrier

to passage of moisture or solvent, e.g.,

semisolids in sealed aluminum tubes,

solutions in sealed glass ampules. Thus,

stability studies for products stored in

impermeable containers may be conducted

under any relative humidity.

Drug Products Packaged in Semipermeable

Containers

Aqueous-based products packaged in

semipermeable containers should be

evaluated for potential water loss in addition

to physical, chemical, biological, and

microbiological stability. This evaluation can

be carried out under conditions of low

relative humidity as discussed below. Other

comparable approaches may be developed

and reported for nonaqueous, solvent-based

products.

Ultimately, the shelf life for aqueous-based

drug products stored in semipermeable

containers should justify storage in low

relative humidity environments. To

accommodate this, it should be demonstrated

that the drug product will remain within its

approved acceptance criteria throughout the

proposed shelf life if stored at a temperature

of 25 °C and at the reference relative

humidity of 40 percent RH.

Study Storage Condition Minimum Time Period at Submission

Long-term 25 °C ± 2 °C/40% RH ± 5% RH 12 months

Intermediate 30 °C ± 2 °C/60% RH ± 5% RH 6 months

Accelerated 40 °C ± 2 °C/not more than (NMT) 25% RH 6 months (water loss after 3 months)

An acceptable alternative approach to

storage at the reference reduced humidity (for

both long-term and accelerated storage) is to

perform the stability studies under higher

relative humidity and to derive the water loss

at reduced relative humidity through

calculation. This may be done by

experimentally determining the permeation

coefficient for the container and closure

system or the ratio of water loss between the

two humidity conditions at the same

temperature as shown in the example below.

The permeation coefficient for any packaging

system may be experimentally determined to

cover a worst case alternative relative to the

proposed drug product.

A significant change in water loss for a

product packaged in a semipermeable

container has occurred when there has been

a water loss of greater than 5 percent after 3

months’ storage equivalent to 40 °C/NMT 25

percent RH. However, for small single-dose

products, a water loss of greater than 5

percent after 3 months’ storage equivalent to

40 °C/NMT 25 percent RH may be acceptable

if justified.

A significant change in water loss alone

will not necessitate testing at the

intermediate storage condition.

Example Approach for Determining

Percentage Water Loss

An appropriate approach for calculating an

equivalent percentage water loss for a

product stored at a reference relative

humidity from data generated from an

alternative relative humidity at the same

temperature is described below. A linear rate

of moisture loss over the storage period

should be demonstrated.

A mean percentage weight loss at the

reference relative humidity should be

calculated from that measured at the

alternative relative humidity at a given

temperature after a specified storage period.

For example, the equivalent weight loss

after 3 months’ storage at NMT 25 percent RH

(at 40 °C) is the product of the percentage

weight loss at 75 percent RH (at 40 °C) after

3 months, multiplied by 3.0 from the table

below.

Other valid calculated relative humidity

ratios than those in the table below may also

be used.

Alternative Humidity Nominated Humidity Ratio

60% RH 25% RH 2.4

60% RH 40% RH 1.5

75% RH 25% RH 3.0

Drug Products Intended for Storage in a Refrigerator

Study Storage Condition Minimum Time Period at Submission

Long-term 5 °C ± 3 °C 12 months

Accelerated 25 °C ± 2 °C/60% RH ± 5% RH 6 months

Data from refrigerated storage should be assessed according to the evaluation section of this guidance except where explicitly

noted below.

If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed shelf life should

be based on the real-time data available from the long-term storage condition.

If significant change occurs within the first 3 months’ testing at the accelerated storage condition, data should be supplied to

cover use of the drug product outside of the label storage condition. It is not necessary to continue to test a product to 6 months

when an obvious significant change has occurred within the first 3 months.

21452 Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices

Drug Products Intended for Storage in a Freezer

Study Storage Condition Minimum Time Period at Submission

Long-term ¥20 °C ± 5 °C 12 months

For drug products intended for storage in

a freezer, the shelf life should be based on

the real-time data presented at the long-term

storage condition. In the absence of an

accelerated storage condition for drug

products intended to be stored in a freezer,

data from elevated temperature (e.g., 5 °C ±

3 °C or 25 °C ± 2 °C) on a single batch should

be obtained to support use of the drug

product outside of the proposed label storage

condition.

Drug Products Intended for Storage Below

¥20 °C

Drug products intended for storage below

¥20 °C should be treated on a case-by-case

basis.

Stability Commitment

When available long-term stability data on

primary batches do not cover the proposed

shelf life granted at the time of approval, the

studies should be continued postapproval in

order to firmly establish the shelf life.

Where the submission includes long-term

storage data from three production batches

covering the proposed shelf life, no

postapproval commitment is necessary.

Otherwise, the appropriate alternative from

those shown below should be followed.

1. If the submission includes stability data

on at least three production batches, a

commitment should be made to continue

these studies through the proposed shelf life.

2. If the submission includes stability data

on fewer than three production batches, a

commitment should be made to continue

these studies through the proposed shelf life

and to place additional production batches,

to a total of at least three, on long-term and

accelerated stability studies through the

proposed shelf life.

3. If the submission does not include

stability data on production batches, a

commitment should be made to place the

first three production batches on long-term

and accelerated stability studies through the

proposed shelf life.

The stability protocol used for studies on

commitment batches should be the same as

that for the primary batches unless otherwise

scientifically justified.

Where a significant change has occurred at

the accelerated storage condition for the

primary batches, testing on the commitment

batches should be conducted at the

intermediate storage condition instead of the

accelerated storage condition. As an

alternative, testing may be conducted at the

accelerated storage condition for the

commitment batches. However, if significant

change occurs at the accelerated storage

condition on the commitment batches,

testing at the intermediate storage condition

should also be conducted.

Evaluation

A systematic approach should be adopted

in the presentation and evaluation of the

stability information, which should cover, as

appropriate, physical, chemical, biological,

and microbiological quality attributes,

including particular properties of the dosage

form (for example, dissolution rate for solid

oral dosage forms).

Where the data show so little degradation

and so little variability that it is apparent

from looking at the data that the requested

shelf life will be granted, it is normally

unnecessary to go through the formal

statistical analysis; providing a justification

for the omission should be sufficient.

The design of the stability study is to

establish, based on testing a minimum of

three batches of the drug product, a shelf life

and label storage instructions applicable to

all future batches of the drug product

manufactured and packed under similar

circumstances. The degree of variability of

individual batches affects the confidence that

a future production batch will remain within

specification throughout its shelf life.

An acceptable approach for quantitative

characteristics that are expected to change

with time is to determine the time at which

the 95 percent one-sided confidence limit for

the mean degradation curve intersects the

acceptance criterion. If analysis shows that

the batch-to-batch variability is small, it is

advantageous to combine the data into one

overall estimate, and this can be done by first

applying appropriate statistical tests (e.g., p

values for level of significance of rejection of

more than 0.25) to the slopes of the

regression lines and zero time intercepts for

the individual batches. If it is inappropriate

to combine data from several batches, the

overall shelf life may depend on the

minimum time a batch may be expected to

remain within acceptable and justified limits.

The nature of the degradation relationship

will determine the need for transformation of

the data for linear regression analysis.

Usually the relationship can be represented

by a linear, quadratic, or cubic function on

an arithmetic or logarithmic scale. Statistical

methods should be employed to test the

goodness of fit on all batches and combined

batches (where appropriate) to the assumed

degradation line or curve.

Limited extrapolation of the real-time data

presented from the long-term storage

condition beyond the observed range to

extend the shelf life at approval time,

particularly where the accelerated data

support this, may be undertaken. However,

this assumes that the same degradation

relationship will continue to apply beyond

the observed data, and hence the use of

extrapolation should be justified in each

application in terms of what is known about

the mechanisms of degradation, the goodness

of fit of any mathematical model, batch size,

existence of supportive data, etc.

Any evaluation should consider not only

the assay, but the levels of degradation

products and appropriate attributes. Where

appropriate, attention should be paid to

reviewing the adequacy of the mass balance

and different stability and degradation

performance.

The stability of the drug product after

reconstituting or diluting according to

labeling should be addressed to provide

appropriate and supportive information.

Statements/Labeling

A storage temperature range may be used

in accordance with relevant national/regional

requirements. The range should be based on

the stability evaluation of the drug product.

Where applicable, specific instruction should

be provided, particularly for drug products

that cannot tolerate freezing.

The use of terms such as ‘‘ambient

conditions’’ or ‘‘room temperature’’ is

unacceptable.

There should be a direct linkage between

the label statement and the demonstrated

stability characteristics of the drug product.

Annex 1

Glossary and Information

The following terms have been in general

use, and the following definitions are

provided to facilitate interpretation of the

guidance.

Accelerated testing: Studies designed to

increase the rate of chemical degradation or

physical change of a drug substance or drug

product by using exaggerated storage

conditions as part of the formal stability

studies. These data, in addition to long-term

stability studies, may also be used to assess

longer-term chemical effects at

nonaccelerated conditions and to evaluate

the impact of short-term excursions outside

the label storage conditions such as might

occur during shipping. Results from

accelerated testing studies are not always

predictive of physical changes.

Bracketing: The design of a stability

schedule so that at any time point only the

samples on the extremes, for example, of

container size and/or dosage strengths, are

tested. The design assumes that the stability

of the intermediate condition samples are

represented by those at the extremes.

Where a range of dosage strengths is to be

tested, bracketing designs may be particularly

applicable if the strengths are very closely

related in composition (e.g., for a tablet range

made with different compression weights of

a similar basic granulation, or a capsule range

made by filling different plug fill weights of

the same basic composition into different

size capsule shells). Where a range of sizes

of immediate containers is to be evaluated,

Federal Register / Vol. 65, No. 78 / Friday, April 21, 2000 / Notices 21453

bracketing designs may be applicable if the

composition of the container and the type of

closure are the same throughout the range.

Climatic zones: The concept of dividing

the world into four zones based on defining

the prevalent annual climatic conditions.

Commitment batches: Production batches

of a drug substance or drug product for

which the stability studies will be initiated

or completed postapproval through a

commitment made in the registration

application.

Dosage form: A pharmaceutical product

type (for example, tablet, capsule, solution,

cream) that contains a drug substance

generally, but not necessarily, in association

with excipients.

Drug product: The dosage form in the final

immediate packaging intended for marketing.

Drug substance: The unformulated drug

substance that may subsequently be

formulated with excipients to produce the

drug product.

Excipient: Anything other than the drug

substance in the dosage form.

Expiration date: The date placed on the

container/labels of a drug product

designating the time during which a batch of

the product is expected to remain within the

approved shelf life specification if stored

under defined conditions, and after which it

must not be used.

Formal stability studies: Long-term and

accelerated (and intermediate) studies

undertaken on primary and/or commitment

batches according to a prescribed stability

protocol to establish or confirm the retest

period of a drug substance or the shelf life

of a drug product.

Impermeable containers: Containers that

provide a permanent barrier to the passage of

gases or solvents.

Long-term testing: Stability studies under

the recommended storage condition, for the

retest period or shelf life proposed (or

approved) for labeling.

Mass balance: The process of adding

together the assay value and levels of

degradation products to see how closely

these add up to 100 percent of the initial

value, with due consideration of the margin

of analytical error.

Matrixing: The statistical design of a

stability schedule so that only a fraction of

the total number of samples is tested at any

specified sampling point. At a subsequent

sampling point, different sets of samples of

the total number would be tested. The design

assumes that the stability of the samples

tested represents the stability of all samples.

The differences in the samples for the same

drug product should be identified as, for

example, covering different batches, different

strengths, different sizes of the same

container and closure, and, possibly, in some

cases, different container/closure systems.

Matrixing can cover reduced testing when

more than one variable is being evaluated.

Thus the design of the matrix will be dictated

by the factors being covered and evaluated.

This potential complexity precludes

inclusion of specific details and examples,

and it may be desirable to discuss design in

advance with the regulatory authority, where

this is possible. In every case, it is essential

that all batches are tested initially and at the

end of the long-term testing.

Mean kinetic temperature: A single derived

temperature that, if maintained over a

defined period, affords the same thermal

challenge to a drug substance or drug product

as would have been experienced over a range

of both higher and lower temperatures for an

equivalent defined period. The mean kinetic

temperature is higher than the arithmetic

mean temperature and takes into account the

Arrhenius equation.

When establishing the mean kinetic

temperature for a defined period, the formula

of J. D. Haynes (J. Pharm. Sci. 60:927–929,

1971) can be used.

New molecular entity: A substance that has

not previously been registered as a new drug

substance with the national or regional

authority concerned.

Pilot scale: The manufacture of either drug

substance or drug product by a procedure

fully representative of and simulating that to

be applied on a full manufacturing scale.

For solid oral dosage forms, this is

generally taken to be at a minimum scale of

one-tenth that of full production or 100,000

tablets or capsules, whichever is the larger.

Primary batch: A batch of drug substance

or drug product used in a formal stability

study from which stability data are submitted

in a registration application for the purpose

of establishing a retest period or shelf life,

respectively. A primary batch should be at

least a pilot scale batch (except in the case

of drug product where one of the three

batches can be smaller); but it may also be

a production batch.

Production batch: A batch of a drug

substance or drug product manufactured at

production scale by using production

equipment in a production facility as

specified in the application.

Retest date: The date after which samples

of the drug substance should be examined to

ensure that the material is still suitable for

use.

Retest period: The period of time during

which the drug substance can be considered

to remain within the specification and

therefore acceptable for use in the

manufacture of a given drug product,

provided that it has been stored under the

defined conditions. After this period, a batch

destined for use in the manufacture of a drug

product should be retested for compliance

with specifications and then used

immediately.

Semipermeable containers: Containers that

allow the passage of solvent, usually water,

while preventing solute loss. The mechanism

for solvent transport occurs by absorption

into one container surface, diffusion through

the bulk of the container material, and

desorption from the other surface. Transport

is driven by a partial-pressure gradient.

Examples of semipermeable containers

include plastic bags and semirigid, lowdensity polyethylene (LDPE) pouches for

large volume parenterals, and LDPE ampules,

bottles, and vials.

Shelf life: The time interval that a drug

product is expected to remain within the

approved shelf life specification provided

that it is stored under the conditions defined

on the label in the proposed containers and

closure.

Specification: See ICH Q6A and Q6B.

Specification—release: The combination of

physical, chemical, biological, and

microbiological tests and acceptance criteria

that determine the suitability of a drug

product at the time of its release.

Specification—shelf life: The combination

of physical, chemical, biological, and

microbiological tests and acceptance criteria

that determine the suitability of a drug

substance throughout its retest period or that

a drug product should meet throughout its

shelf life.

Storage conditions tolerances: The

acceptable variation in temperature and

relative humidity of storage facilities.

The equipment should be capable of

controlling the storage condition within the

ranges defined within the body of this

document. The actual temperature and

humidity should be monitored during

stability storage. Short-term spikes due to

opening of doors of the storage facility are

accepted as unavoidable. The effect of

excursions due to equipment failure should

be addressed by the applicant and reported

if judged to impact stability results.

Excursions that exceed the defined tolerances

for more than 24 hours should be described

in the study report and their impact assessed.

Stress testing (Drug substance): Studies

undertaken to elucidate intrinsic stability

attributes. Such testing is part of the

development strategy and is normally carried

out under more severe conditions than those

used for accelerated tests.

Stress testing (Drug product):

Photostability testing should be an integral

part of stress testing (see ICH Q1B).

Special test conditions for specific

products (e.g., metered-dose inhalations,

creams, emulsions) may need additional

stress studies.

Supporting stability data: Data other than

from formal stability studies, such as stability

data on early synthetic route batches of drug

substance, small scale batches of materials,

investigational formulations not proposed for

marketing, related formulations, product

presented in containers and/or closures other

than those proposed for marketing,

information regarding test results on

containers, and other scientific rationale that

support the analytical procedures, the

proposed retest period or shelf life and

storage conditions.

Footnote

This guidance has been developed within

the Quality Expert Working Group of the ICH

Process. Additional topics continue to be

discussed within the Expert Working Group

and will be the subject of future guidance

documents.

Dated: April 14, 2000.

Margaret M. Dotzel,

Acting Associate Commissioner for Policy.

[FR Doc. 00–9942 Filed 4–20–00; 8:45 am]

BILLING CODE 4160–01–F