[Federal Register Volume 59, Number 183 (Thursday, September 22, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-23380]


[[Page Unknown]]

[Federal Register: September 22, 1994]


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Part X





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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International Conference on Harmonisation; Stability Testing of New 
Drug Substances and Products; Guideline; Availability; Notice
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[Docket No. 93D-0139]

 
International Conference on Harmonisation; Stability Testing of 
New Drug Substances and Products; Guideline; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is publishing a final 
guideline entitled ``Stability Testing of New Drug Substances and 
Products.'' Prepared under the auspices of the International Conference 
on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH), the guideline is intended to 
reflect formal scientific principles for stability testing of drugs. 
This guideline should be useful to applicants submitting new drug 
applications (NDA's) for new molecular entities and associated drug 
products.

DATES: Effective September 22, 1994. Submit written comments at any 
time. Sponsors submitting future applications may be asked to explain 
any differences from the approach suggested in the guideline.

ADDRESSES: Submit written comments on the guideline to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guideline 
are available from the CDER Executive Secretariat Staff (HFD-8), Center 
for Drug Evaluation and Research, Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855.
FOR FURTHER INFORMATION CONTACT:

    Regarding the guideline: Charles Kumkumian, Center for Drug 
Evaluation and Research (HFD-102), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-6758.
    Regarding the ICH: Janet Showalter, Office of Health Affairs (HFY-
1), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-443-1382.

SUPPLEMENTARY INFORMATION: In recent years, many important initiatives 
have been undertaken by regulatory authorities and industry 
associations to promote international Harmonisation of regulatory 
requirements. FDA has participated in many meetings designed to enhance 
Harmonisation and is committed to seeking scientifically based 
harmonized regulatory requirements for pharmaceutical development. One 
of the goals of Harmonisation is to identify and then reduce 
differences in technical requirements for drug development.
     ICH was organized to provide an opportunity for tripartite 
Harmonisation 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 
Harmonisation 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 Industry 
Associations, the Japanese Ministry of Health and Welfare, the Japanese 
Pharmaceutical Manufacturers and Researchers of America, FDA, and the 
U.S. Pharmaceutical Manufacturers Association. 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.
     At a meeting held on March 23 and 24, 1992, the ICH Steering 
Committee agreed that the draft tripartite guideline entitled ``Draft 
Tripartite Guideline for the Stability Testing of New Drug Substances 
and Products'' should be made available for comment. Subsequently, the 
draft guideline was made available for comment by the European Union 
and Japan, as well as by FDA (see 58 FR 21086, April 16, 1993), in 
accordance with their consultation procedures. The comments were 
analyzed and the guideline was revised as necessary.
     With this notice, FDA is publishing a final guideline entitled 
``Stability Testing of New Drug Substances and Products.'' This 
guideline has been endorsed by all ICH sponsors. The guideline 
addresses the generation of stability information for submission to FDA 
in NDA's for new molecular entities and associated drug products.
     This guideline may be useful immediately to applicants submitting 
NDA's to FDA. Sponsors submitting future applications may be asked to 
explain any differences from the approach suggested in this guideline.
     Additional ICH stability documents will be appended to this 
harmonized guideline when they have been finalized. FDA intends to 
update its 1987 guideline entitled ``Guideline for Submitting 
Documentation for the Stability of Human Drugs and Biologics'' to 
incorporate the new elements arising from the ICH process and other 
changes in stability testing that have occurred since 1987. For 
example, the updated guideline may include information and guidance on 
stability issues for investigational new drug applications, stability 
parameters for different dosage forms, recommendations for statistical 
analysis, stability testing for generic drugs, stability testing for 
biological and biotechnological products, and stability data 
presentation formats. Certain aspects of the updated guideline will 
also apply to products subject to licensing under the Public Health 
Service Act (biological products) and submitted to the Center for 
Biologics Evaluation and Research.
     Until the 1987 guideline is updated as needed and ICH sections are 
incorporated, FDA intends to provide both the ICH harmonized guideline, 
as contained in this notice, and the 1987 FDA guideline when 
information pertaining to stability testing of human drug and 
biological products is requested. At a future date, FDA may issue a new 
guideline publication that combines the guideline contained in this 
Federal Register notice with a revised 1987 FDA guideline.
     In the past, guidelines have generally been issued under 
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of 
guidelines to state procedures or standards of general applicability 
that are not legal requirements but that are acceptable to FDA. The 
agency is now in the process of revising Sec. 10.90(b). Therefore, this 
guideline is not being issued under the authority of Sec. 10.90(b), and 
it does not create or confer any rights, privileges, or benefits for or 
on any person, nor does it operate to bind FDA in any way.
     As with all of FDA's guidelines, the public is encouraged to 
submit written comments with new data or other new information 
pertinent to this guideline. The comments in the docket will be 
periodically reviewed, and where appropriate, the guideline will be 
amended. The public will be notified of any such amendments through a 
notice in the Federal Register.
     Interested persons may, at any time, submit written comments on 
the guideline to the Dockets Management Branch (address above). Two 
copies of any comments are to be submitted, except that individuals may 
submit one copy. Comments are to be identified with the docket number 
found in brackets in the heading of this document. The guideline and 
received comments may be seen in the office above between 9 a.m. and 4 
p.m., Monday through Friday.The text of the final guideline follows:

Stability Testing of New Drug Products and Substances

 ICH Harmonized Tripartite Guideline Endorsed by the ICH Steering 
Committee at Step 4 of the ICH Process, 27 October 1993

Preamble

    The following guideline sets out information on stability 
testing for a Registration Application within the three areas of the 
EC, Japan, and the USA. It does not seek necessarily to cover the 
testing that may be required for registration in or export to other 
areas of the world.
     The guideline seeks to exemplify the core stability data 
package appropriate for new drug substances and products. It is not 
always necessary to follow this when there are scientifically 
justifiable reasons for using alternative approaches.
     The guideline provides a general indication of the information 
on product stability to be generated, but leaves sufficient 
flexibility to encompass the variety of different practical 
situations required for specific scientific situations and 
characteristics of the materials being evaluated.
     The principle that information on stability generated in any 
one of the three areas of the EC, Japan, and the USA would be 
mutually acceptable in both of the other two areas has been 
established, provided it conforms to the elements of this guideline 
and the labelling is in accord with national/regional requirements.
     Details of the specific requirements for sampling, test 
requirements for particular dosage forms/packaging, etc., are not 
covered in this guideline.

 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 guideline primarily addresses the generation of stability 
information for submission in Registration Applications for new 
molecular entities and associated drug products.
    This guideline does not currently seek to cover the generation 
of stability information for abbreviated or abridged applications, 
variations, clinical trial applications, etc.
    The choice of test conditions defined in this guideline is based 
on an analysis of the effects of climatic conditions in the three 
areas of the EC, Japan, and the USA. 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 to 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.

Formal Studies

    Primary stability studies are intended to show that the drug 
substance will remain within specification during the retest period 
if stored under recommended storage conditions.

Selection of Batches

    Stability information from accelerated and long-term testing is 
to be provided on at least three batches. The long-term testing 
should cover a minimum of 12 months duration on at least three 
batches at the time of submission.
    The batches manufactured to a minimum of pilot plant 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 
stability should be representative of both the quality of the 
material used in preclinical and clinical studies and the quality of 
material to be made on a manufacturing scale.
    Supporting information may be provided using stability data on 
batches of drug substance made on a laboratory scale.
     The first three production batches of drug substance 
manufactured postapproval, if not submitted in the original 
Registration Application, should be placed on long-term stability 
studies using the same stability protocol as in the approved drug 
application.

Test Procedures and Test Criteria

    The testing should cover those features susceptible to change 
during storage and likely to influence quality, safety, and/or 
efficacy. Stability information should cover as necessary the 
physical, chemical, and microbiological test characteristics. 
Validated stability-indicating testing methods should be applied. 
The need for extent of replication will depend on the results of 
validation studies.

Specification

    Limits of acceptability should be derived from the profile of 
the material as used in the preclinical and clinical batches. It 
will need to include individual and total upper limits for 
impurities and degradation products, the justification for which 
should be influenced by the levels observed in material used in 
preclinical studies and clinical trials.

Storage Conditions

    The length of the studies and the storage conditions should be 
sufficient to cover storage, shipment, and subsequent use. 
Application of the same storage conditions as applied to the drug 
product will facilitate comparative review and assessment. Other 
storage conditions are allowable if justified. In particular, 
temperature sensitive drug substances should be stored under an 
alternative, lower temperature condition which will then become the 
designated long-term testing storage temperature. The 6 months 
accelerated testing should then be carried out at a temperature at 
least 15  deg.C above this designated long-term storage temperature 
(together with the appropriate relative humidity (RH) conditions for 
that temperature). The designated long-term testing conditions will 
be reflected in the labelling and retest date. 

------------------------------------------------------------------------
                                                  Minimum time period at
                               Conditions               submission      
------------------------------------------------------------------------
Long term testing        25  deg.C     12 months.           
                          2  deg.C/60% RH  5%.                                    
Accelerated testing       40  deg.C    6 months.            
                          2  deg.C/75% RH  5%.                                    
------------------------------------------------------------------------

     Where ``significant change'' occurs during 6 months storage 
under conditions of accelerated testing at 40  deg.C  2 
deg.C/75 percent RH  5 percent, additional testing at an 
intermediate condition (such as 30  deg.C  2  deg.C/60 
percent RH  5 percent) should be conducted for drug 
substances to be used in the manufacture of dosage forms tested long 
term at 25  deg.C/60 percent RH and this information included in the 
Registration Application. The initial Registration Application 
should include a minimum of 6 months data from a 12 months study.
     ``Significant change'' at 40  deg.C/75 percent RH or 30  deg.C/
60 percent RH is defined as failure to meet the specification.
     The long-term testing will be continued for a sufficient period 
of time beyond 12 months to cover all appropriate retest periods, 
and the further accumulated data can be submitted to the Authorities 
during the assessment period of the Registration Application.
     The data (from accelerated testing or from testing at an 
intermediate condition) may be used to evaluate the impact of short-
term excursions outside the label storage conditions such as might 
occur during shipping.

Testing Frequency

     Frequency of testing should be sufficient to establish the 
stability characteristics of the drug substance. Testing under the 
defined long-term conditions will normally be every 3 months over 
the first year, every 6 months over the second year, and then 
annually.

Packaging/Containers

    The containers to be used in the long-term, real time stability 
evaluation should be the same as or simulate the actual packaging 
used for storage and distribution.

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 necessary the 
physical, chemical, and microbiological test characteristics), a 
retest period applicable to all future batches of the bulk 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 until the 
retest date.
     An acceptable approach for quantitative characteristics that 
are expected to decrease with time is to determine the time at which 
the 95 percent one-sided confidence limit for the mean degradation 
curve intersects the acceptable lower 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 (for 
example, 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.
    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 the circumstances, it 
is normally unnecessary to go through the formal statistical 
analysis but merely to provide a full justification for the 
omission.
    Limited extrapolation of the real time data beyond the observed 
range to extend expiration dating 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 
must 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 the levels of 
degradation products and other appropriate attributes.

Statements/Labelling

     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 requirements should be stated, 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 stability programme for the finished product 
should be based on the knowledge of the behavior and properties of 
the drug substance and the experience gained from clinical 
formulation studies and from the stability studies on the drug 
substance. The likely changes on storage and the rationale for the 
selection of product variables to include in the testing programme 
should be stated.

Selection of Batches

    Stability information from accelerated and long-term testing is 
to be provided on three batches of the same formulation and dosage 
form in the containers and closure proposed for marketing. 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 long-term testing should cover at least 12 
months duration at the time of submission. The manufacturing process 
to be used should meaningfully simulate that which would be applied 
to large scale batches for marketing. The process should provide 
product of the same quality intended for marketing, and meeting the 
same quality specification as to be applied for release of material. 
Where possible, batches of the finished product should be 
manufactured using identifiably different batches of drug substance.
    Data on laboratory scale batches are not acceptable as primary 
stability information. Data on associated formulations or packaging 
may be submitted as supportive information. The first three 
production batches manufactured postapproval, if not submitted in 
the original Registration Application, should be placed on 
accelerated and long-term stability studies using the same stability 
protocols as in the approved drug application.

Test Procedures and Test Criteria

    The testing should cover those features 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 the extent 
of replication will depend on the results of validation studies.
    The range of testing should cover not only chemical and 
biological stability but also loss of preservative, physical 
properties and characteristics, organoleptic properties, and, where 
required, microbiological attributes. Preservative efficacy testing 
and assays on stored samples should be carried out to determine the 
content and efficacy of antimicrobial preservatives.

Specifications

    Limits of acceptance 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 derivations from the release 
specification based on the stability evaluation and the changes 
observed on storage. It will need to 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 will require reference to 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.

Storage Test Conditions

    The length of the studies and the storage conditions should be 
sufficient to cover storage, shipment, and subsequent use (e.g., 
reconstitution or dilution as recommended in the labelling).
    See the Table below for accelerated and long-term storage 
conditions and minimum times. An assurance that long-term testing 
will continue to cover the expected shelf life should be provided.
    Other storage conditions are allowable if justified. Heat 
sensitive drug products should be stored under an alternative lower 
temperature condition which will eventually become the designated 
long-term storage temperature. Special consideration may need to be 
given to products which change physically or even chemically at 
lower storage conditions, e.g., suspensions or emulsions which may 
sediment or cream, oils, and semi-solid preparations which may show 
an increased viscosity. Where a lower temperature condition is used, 
the 6 months accelerated testing should be carried out at a 
temperature at least 15  deg.C above its designated long-term 
storage temperature (together with appropriate relative humidity 
conditions for that temperature). For example, for a product to be 
stored long-term under refrigerated conditions, accelerated testing 
should be conducted at 25  deg.C  2  deg.C/60 percent RH 
 5 percent RH. The designated long-term testing 
conditions will be reflected in the labelling and expiration date.
    Storage under conditions of high relative humidities applies 
particularly to solid dosage forms. For products such as solutions, 
suspensions, etc., contained in packs designed to provide a 
permanent barrier to water loss, specific storage under conditions 
of high relative humidity is not necessary but the same range of 
temperatures should be applied. Low relative humidity (e.g., 10-20 
percent RH) can adversely affect products packed in semi-permeable 
containers (e.g., solutions in plastic bags, nose drops in small 
plastic containers, etc.) and consideration should be given to 
appropriate testing under such conditions.

------------------------------------------------------------------------
                                                  Minimum time period at
                               Conditions               submission      
------------------------------------------------------------------------
Long term testing        25  deg.C    12 months.            
                          2  deg.C/60% RH  5%.                                    
Accelerated testing      40  deg.C    6 months.             
                          2  deg.C/75% RH  5%.                                    
------------------------------------------------------------------------

     Where ``significant change'' occurs due to accelerated testing, 
additional testing at an intermediate condition, e.g., 30  deg.C 
 2  deg.C/60 percent  5 percent RH should be 
conducted. ``Significant change'' at the accelerated condition is 
defined as:
     1. A 5 percent potency loss from the initial assay value of a 
batch;
     2. Any specified degradant exceeding its specification limit;
     3. The product exceeding its pH limits;
     4. Dissolution exceeding the specification limits for 12 
capsules or tablets;
     5. Failure to meet specifications for appearance and physical 
properties, e.g., color, phase separation, resuspendibility, 
delivery per actuation, caking, hardness, etc.
     Should significant change occur at 40  deg.C/75 percent RH then 
the initial Registration Application should include a minimum of 6 
months data from an ongoing 1 year study at 30  deg.C/60 percent RH; 
the same significant change criteria shall then apply.
     The long-term testing will be continued for a sufficient time 
beyond 12 months to cover shelf life at appropriate test periods. 
The further accumulated data should be submitted to the authorities 
during the assessment period of the Registration Application.
    The first three production batches manufactured postapproval, if 
not submitted in the original Registration Application, should be 
placed on accelerated and long-term stability studies using the same 
stability protocol as in the approved drug application.

Testing Frequency

    Frequency of testing should be sufficient to establish the 
stability characteristics of the drug product. Testing will normally 
be every 3 months over the first year, every 6 months over the 
second year, and then annually. The use of matrixing or bracketing 
can be applied, if justified (see Glossary below).

Packaging Materials

    The testing should be carried out in the final packaging 
proposed for marketing. Additional testing of unprotected drug 
product can form a useful part of the stress testing and pack 
evaluation, as can studies carried out in other related packaging 
materials in supporting the definitive pack(s).

Evaluation

    A systematic approach should be adopted in the presentation and 
evaluation of the stability information which should cover, as 
necessary, physical, chemical, biological, and microbiological 
quality characteristics, including particular properties of the 
dosage form (for example, dissolution rate for oral solid dose 
forms).
    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 dosage form 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 until the expiration date.
    An acceptable approach for quantitative characteristics that are 
expected to decrease with time is to determine the time at which the 
95 percent one-sided confidence limit for the mean degradation curve 
intersects the acceptable lower 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 (for 
example, 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.
    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 but only to provide a 
justification for the omission.
    Limited extrapolation of the real time data beyond the observed 
range to extend expiration dating 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 
must 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, different stability, and degradation performance.
    The stability of the drug products after reconstituting or 
diluting according to labelling should be addressed to provide 
appropriate and supportive information.

Statements/Labelling

    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 requirements should be stated 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 
guideline.

Accelerated Testing

    Studies designed to increase the rate of chemical degradation or 
physical change of an active drug substance or drug product by using 
exaggerated storage conditions as part of the formal, definitive, 
storage programme.
    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 results are not always 
predictive of physical changes.

Active Substance; Active Ingredient; Drug Substance; Medicinal 
Substance

    The unformulated drug substance which may be subsequently 
formulated with excipients to produce the drug product.

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 is 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, 
bracketing designs may be applicable if the material of 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.

Dosage Form; Preparation

    A pharmaceutical product type, for example, tablet, capsule, 
solution, cream, etc., that contains a drug ingredient generally, 
but not necessarily, in association with excipients.

 Drug Product; Finished Product

    The dosage form in the final immediate packaging intended for 
marketing.

Excipient

    Anything other than the drug substance in the dosage form.

Expiry/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 (Systematic) Studies

    Formal studies are those undertaken to a preapproval stability 
protocol which embraces the principles of these guidelines.

 Long-Term (Real Time) Testing

    Stability evaluation of the physical, chemical, biological, and 
microbiological characteristics of a drug product and a drug 
substance, covering the expected duration of the shelf life and 
retest period, which are claimed in the submission and will appear 
on the labelling.

Mass Balance; Material 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 precision.
    This concept is a useful scientific guide for evaluating data 
but it is not achievable in all circumstances. The focus may instead 
be on assuring the specificity of the assay, the completeness of the 
investigation of routes of degradation, and the use, if necessary, 
of identified degradants as indicators of the extent of degradation 
via particular mechanisms.

Matrixing

    The statistical design of a stability schedule so that only a 
fraction of the total number of samples are 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 needing to be 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

    When establishing the mean value of temperature, the formula of 
J. D. Haynes (J. Pharm. Sci., 60:927-929, 1971) can be used to 
calculate the mean kinetic temperature. It is higher than the 
arithmetic mean temperature and takes into account the Arrhenius 
equation from which Haynes derived his formula.

New Molecular Entity; New Active Substance

    A substance which has not previously been registered as a new 
drug substance with the national or regional authority concerned.

 Pilot Plant 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 oral solid 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 Stability Data

    Data on the drug substance stored in the proposed packaging 
under storage conditions that support the proposed retest date.
    Data on the drug product stored in the proposed container/
closure for marketing under storage conditions that support the 
proposed shelf life.

Retest Date

    The date when samples of the drug substance should be re-
examined to ensure that 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, the batch should be retested for compliance with 
specification and then used immediately.

Shelf life; Expiration Dating Period

    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--Release

    The combination of physical, chemical, biological, and 
microbiological test requirements that determine that a drug product 
is suitable for release at the time of its manufacture.

Specification--Check/Shelf life

    The combination of physical, chemical, biological and 
microbiological test requirements that a drug substance must meet up 
to its retest date or a drug product must meet throughout its shelf 
life.

Storage Conditions Tolerances

    The acceptable variation in temperature and relative humidity of 
storage facilities.
    The equipment must be capable of controlling temperature to a 
range of  2  deg.C and Relative Humidity to  
5% RH. The actual temperatures and humidities 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 these ranges (i.e.,  2  deg.C 
and/or  5% RH) for more than 24 hours should be 
described in the study report and their impact assessed.

Stress Testing (Drug Substance)

    These studies are undertaken to elucidate intrinsic stability 
characteristics. 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 is conducted to provide data on forced 
decomposition products and decomposition mechanisms for the drug 
substance. The severe conditions that may be encountered during 
distribution can be covered by stress testing of definitive batches 
of drug substance.
    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  deg.C 
increments above the accelerated temperature test condition (e.g., 
50  deg.C, 60  deg.C, etc.), humidity where appropriate (e.g., 75 
percent or greater), oxidation and photolysis on the drug substance 
plus its susceptibility to hydrolysis across a wide range of pH 
values when in solution or suspension.
    Results from these studies will form an integral part of the 
information provided to regulatory authorities.
    Light testing should be an integral part of stress testing. (The 
standard conditions for light testing are still under discussion and 
will be considered in a further ICH document.)
    It is recognized that some degradation pathways can be complex 
and that under forcing conditions decomposition products may be 
observed which 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.

Stress Testing (Drug Product)

    Light testing should be an integral part of stress testing (see 
separate Annex).
    Special test conditions for specific products (e.g., metered 
dose inhalations and creams and emulsions) may require additional 
stress studies.

Supporting Stability Data

    Data other than primary stability data, 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 guideline has been developed within the Expert Working 
Group (Quality) of the International Conference on Harmonisation.
    Discussions are still being pursued within the Expert Working 
Group to define and standardize the conditions for light stability 
testing of active substances and dosage forms and the requirements 
for biological/biotechnological drug substances and products. Once 
agreed, these conditions will be the subject of a separate document.

    Dated: September 15, 1994.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 94-23380 Filed 9-21-94; 8:45 am]
BILLING CODE 4160-01-F