[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
----------------------------------------------------------------------------------------------------------------
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

 
----------------------------------------------------------------------------------------------------------------
                Study                           Storage Condition             Minimum Time Period at Submission
----------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------


[[Page 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  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