[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]
_______________________________________________________________________
Part X
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Stability Testing of New
Drug Substances and Products; Guideline; Availability; Notice
-----------------------------------------------------------------------
[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