Federal Register, Volume 65 Issue 78 (Friday, April 21, 2000)

[Federal Register Volume 65, Number 78 (Friday, April 21, 2000)]
[Notices]
[Pages 21446-21453]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-9942]

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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.

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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.

[[Page 21447]]

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

[[Page 21448]]

the testing for registration in or export to other areas of the
world.
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\1\ 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.
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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 ( deg.C) increments (e.g., 50 deg.C, 60 deg.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
stability-indicating 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

[[Page 21449]]

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Study Storage Condition Minimum Time Period at Submission
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Long-term 25 deg.C 2 deg.C/60% 12 months
RH 5% RH
Intermediate 30 deg.C 2 deg.C/60% 6 months
RH 5% RH
Accelerated 40 deg.C 2 deg.C/75% 6 months
RH 5% RH
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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

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Study Storage Condition Minimum Time Period at Submission
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Long-term 5 deg.C 3 deg.C 12 months
Accelerated 25 deg.C 2 deg.C/60% 6 months
RH 5% RH
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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

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Study Storage Condition Minimum Time Period at Submission
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Long-term -20 deg.C 5 deg.C 12 months
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For drug substances intended for storage in a freezer, the
retest period 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 substances intended to be stored in a
freezer, testing at an elevated temperature (e.g., 5 deg.C
3 deg.C or 25 deg.C 2 deg.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 deg.C

Drug substances intended for storage below -20 deg.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 long-term
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

[[Page 21450]]

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 short-term
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

[[Page 21451]]

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 deg.C and at the reference relative humidity of
40 percent RH.

----------------------------------------------------------------------------------------------------------------
Study Storage Condition Minimum Time Period at Submission
----------------------------------------------------------------------------------------------------------------
Long-term 25 deg.C 2 deg.C/40% 12 months
RH 5% RH
Intermediate 30 deg.C 2 deg.C/60% 6 months
RH 5% RH
Accelerated 40 deg.C 2 deg.C/not 6 months (water loss after 3 months)
more than (NMT) 25% RH
----------------------------------------------------------------------------------------------------------------

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 deg.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 deg.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 deg.C) is the product of the percentage
weight loss at 75 percent RH (at 40 deg.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 deg.C 3 deg.C 12 months
Accelerated 25 deg.C 2 deg.C/60% 6 months
RH 5% RH
----------------------------------------------------------------------------------------------------------------

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.

[[Page 21452]]

Drug Products Intended for Storage in a Freezer

----------------------------------------------------------------------------------------------------------------
Study Storage Condition Minimum Time Period at Submission
----------------------------------------------------------------------------------------------------------------
Long-term -20 deg.C 5 deg.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 deg.C 3 deg.C or
25 deg.C 2 deg.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 deg.C

Drug products intended for storage below -20 deg.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,

[[Page 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, low-density 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