STABILITY STUDIES ICH Guidelines Q1A-Q1F
Outline
Objective of Stability testing
Scope of Stability testing
Rationale of stability studies
Advantages of stability studies
Variables affecting the stability
Adverse effects of instability of drugs
Stability Testing
Terminologies
ICH Q1A (R2)
ICH Q1B
ICH Q1C
ICH Q1D
ICH Q1E
References
Drug
Stability
“A measure of how
pharmaceutical products maintains its quality attribute over a time.”
Objective of
Stability Testing
"…… 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 & light, & enables recommended storage conditions, re-test
periods & shelf lives to be
established”
Scope of Stability
Testing
•
Provide evidence as to how the quality of the drug
product varies with time.
•
Establish shelf life for the drug product.
•
Determine recommended storage conditions.
•
Determine container closure system suitability.
Rationale
of Stability Studies
•
Chemical degradation of the product leads to
lowering of the concentration of the drug in the dosage form.
•
Toxic products may be formed, due to chemical
degradation of the active ingredient.
Advantage
of Stability Studies
•
Assurance to the patient
•
Economic considerations
•
Legal requirement
Variables that might
affect the stability
•
Formulation
•
Packaging
•
Site and method of manufacture
•
API
•
Finished product
•
Batch size
•
Batch to batch variability
•
Process validation
•
Quality risk management
•
Container labelling
•
Changes to product
Adverse
effect of Instability of Drugs
Loss of active drug (e.g. aspirin hydrolysis, oxidation of
adrenaline)
Loss of vehicle (e.g. evaporation of water from o/w creams,
evaporation of alcohol from alcoholic mixtures)
Loss of content uniformity (e.g. creaming of emulsions,
impaction of suspensions)
Loss of elegance (e.g. fading of tablets and colored
solutions)
Reduction in bioavailability (e.g. ageing of tablets
resulting in a change in dissolution profile)
Production of potential toxic materials (e.g. Breakdown products from drug degradation)
Types of
Stability
A Drug must
possess following types of stability
• CHEMICAL:
Each active ingredient retains its chemical integrity and labeled potency
within the specified limit.
• PHYSICAL:
The physical stability properties
includes appearance, palatability, uniformity, dissolution and suspend ability
are retained.
• MICROBIOLOGICAL:
Sterility or resistance to microbial growth is retained according to
specified requirement.
• THERAPEUTIC:
Therapeutic activity remains unchanged.
• TOXICOLOGIC:
No significant increase in toxicity occurs.
Stability studies are
incorporated at all stage of the drugs product life cycle, can be segregated
into 6 different stages:
STAGE 1- Early stage stress and accelerated testing
with drug substances.
STAGE 2- Stability on pre-formulation batches.
STAGE 3- Stress testing on scale-up batches.
STAGE 4- Accelerated and long term testing for
registration purposes.
STAGE 5- On-going stability testing
STAGE 6- Follow-up stabilities
Stability
Testing
Development studies
•
Characterise compatibility with common
excipients.
•
Characterise stability profile of API (E.g.
susceptibility to acid, base, light, oxygen etc)
•
Characterise stability profile of early
formulations (Especially susceptibility to heat, humidity & light)
Confirmatory studies
•
Long term & accelerated studies on the
product as it is to be registered
ICH
Guideline for Stability Testing
The ICH has so far released six guidelines for
|
ICH GUIDELINES |
TITLE |
|
Q 1 A |
Stability testing of new drug substances and products (second revision) |
|
Q1B |
Stability testing : photo stability testing of new drug substance and products. |
|
Q1C |
Stability testing for new dosage forms |
|
Q1D |
Bracketing and matrixing designs for stability testing of drug substances and products |
|
Q1E |
Evaluation of stability data |
|
Q1F |
Stability data package for registration application in climatic zones III and IV |
Terminologies
Adapted from ICH 2006
•
Production batch
•
Pilot scale batch
•
Re-test period(API)
•
Accelerated testing
•
Intermediate testing
•
Stress testing
•
Bracketing
•
Matrixing
Climatic
Zones
•
Partition of the world into four temperature
classes based on kinetic averaging of monthly temperatures,
•
Zones (Futscher & Schumacher 1972):
I Temperate (21oC/45%RH)
II Subtropical (25oC/60%RH
with possibly high RH)
III Hot & dry (30oC/35%RH)
IV Hot & wet (30oC/70%RH)
•
The temperatures above are kinetic averages.
The Zone
Concept
|
Region |
Zone I & II Countries |
Zone III & IV
Countries |
|
Europe |
All Countries |
---- |
|
America |
Argentia,
Canada,Bolivia etc. |
Barbodas, Brazil,
Venezuela, Panama etc (IV) |
|
Asia |
Japan, Afganistan,
Israel etc |
Bangladesh, Hong
Kong, India etc |
|
Africa |
Egypt, South Africa,
Zimbabwe etc |
Mali, Uganda, Nigeria
etc |
|
Australian/Oceanic |
Australia, New
Zealand |
Papua-New Guinea,
Fiji etc |
Stability Testing of New Drugs Substances and Product Q1A (R2)
Current step 4 version dated 6 February 2003
Stability
Testing of API
•
General
•
Stress Testing
•
Selection of Batches
•
Container Closure System
•
Specification
•
Testing Frequency
•
Storage Conditions
•
Stability Commitment
•
Evaluation
•
Statements/Labelling
General
Information on the stability of the drug substance is an
integral part of the systematic approach to stability evaluation.
Stress Testing
Main tool that predict the stability problems.
Foundation for developing and validating analytical
methods. For an API the following
approaches may be used:
When available, it is acceptable to provide relevant data
published in the scientific literature to support the identified degradation
pathways and products.
When no data is available, stress testing should be
performed.
The nature of the stress testing will depend on the
individual active substance and the type of pharmaceutical product involved.
The Role of Stress
Testing
Stress testing of the active substance can help in
Identification of degradants
Identification of degradation pathways
Determination of which type(s) of stress affect the
molecule:
◦
Photo-stability
◦
High Temperature
◦
Low Temperature
◦
Oxidation
◦
pH extremes
◦
Water
Oxidation:
Typically done by placing the drug substance in aqueous
solution of hydrogen peroxide.
Goal is significant degradation (typically 10-30% of API)
◦
Can identify degradants
◦
Determine whether protective packaging is
required
◦
Determine if an antioxidant should be considered
for the drug product formulation.
pH:
Typically done by adding drug substance to buffered aqueous
solutions at pH values from 1-10
◦
Decide if the molecule will survive passage
through the stomach
– Is
enteric coating necessary?
– Should
the drug be given by injection?
Typical Stress
Conditions
|
Stress factor |
Conditions |
|
Heat |
10°C increments |
|
Humidity |
75%RH or greater |
|
Acid |
0.1N Hcl |
|
Base |
0.1N NaOH |
|
Oxidative |
3%H2O2 |
|
Photolytic |
Xenon, Metal hailde lamp
or Near UV, White florescent
lamp |
Selection of Batches
Data from formal stability studies should be provided on at
least three primary batches of the active substance.
The batches should be manufactured to a minimum of pilot scale
by the same synthetic route as, and using a method of manufacture and procedure
that simulates the final process to be used for, production batches.
Container Closure
System
The stability studies should be conducted on the active
substance packaged in a container closure system that is the same as or
simulates the packaging proposed for storage and distribution.
Specification
•
Stability studies should include testing of
those attributes of the drug substance that are susceptible to change during
storage and are likely to influence quality, safety, and/or efficacy.
•
The testing should cover, as appropriate, the
physical, chemical, biological, and microbiological attributes. e.g.
appearance, assay, degradation.
Testing Frequency
For long term studies:
Year 1: every 3 months
Year 2: every 6 months Subsequent years: annually
At accelerated storage conditions: (6 month study)
Minimum three points including t0 and tfinal,
e.g. 0 3 6
(initial) (final)
At intermediate storage conditions: (12 month study)
Four points including t0 and tfinal,
e.g. 0 3 6
12
(initial) (final)
Storage Condition
A drug substance should be evaluated
•
To test its thermal stability
•
Its sensitivity to moisture(if applicable)
•
The long-term testing (minimum of 12 months) on
at least 3 primary batches at the time
of submission and
•
Should be continued for a period of time
sufficient to cover the proposed re-test period.
General Case
|
Study |
Storage condition |
Minimum time period
covered by data at submission |
|
Long Term* (Ambient) |
25º C ± 2º C 60%RH ± 5% |
12 months |
|
Intermediate**
(controlled) |
30º C ± 2º C 65%RH ± 5% |
6 months |
|
Accelerated |
40º C ± 2º C 75%RH ± 5% |
6 months |
If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5%
RH and “significant change” occurs at
any time during six months’ testing at
the accelerated storage condition, additional testing at the intermediate storage condition should be
conducted and evaluated against
significant change criteria.
Significant change – failure to meet its specification
Drug Substances
Intended for Storage in a Refrigerator
|
Study |
Storage condition |
Minimum time period
covered by data at submission |
|
Long Term |
5º C ± 3º C |
12 months |
|
Accelerated |
25º C ± 2º C 60%RH ± 5% |
6 months |
If significant change occurs between 3 and 6 months testing
at the accelerated storage condition, the proposed re-test period should be based
on the real time data available at the long term storage condition.
Drug Substances
Intended for Storage in a Freezer
|
Study |
Storage condition |
Minimum time
period covered by data at submission |
|
Long Term |
-20º C ± 5º
C |
12 months |
In the absence of an accelerated storage condition for
active substances intended to be stored in a freezer, testing on a single batch
at an elevated temperature (e.g. 5°C ± 3°C or 25°C ± 2°C or 30°C ± 2°C) for an
appropriate time period should be conducted to address the effect of short term
excursions outside the proposed label storage condition.
e.g., during shipping or handling
Stability Commitment
•
When available long-term stability data does not
cover the proposed re-test period, a commitment should be made to continue
stability studies in order to firmly establish the re-test period.
•
Where the data submitted is from fewer than 3
production batches, a commitment should be made to continue the long-term
studies with additional production batches, to a total of at least 3.
•
If the submission does not include stability
data on production batches, a commitment should be made to place the first 3
production batches on long-term studies through the proposed re- test period.
Evaluation
Minimum of 3 batches of drug substance is tested.
The degree of variability of individual batches affects the
confidence that a future production batch will remain within specification
throughout the assigned re-test period.
The analyst must found the batch to batch variability &
if it is small than only it is accepted & it can be done by different
statistical test’s (P value for level of significance for rejection).
Where the data show so little degradation and so little
variability then it is normally unnecessary to go through the statistical
analysis; providing a justification for the omission should be sufficient.
Statements/Labelling
A storage statement should be established for the labelling
based on the stability evaluation of the active substance.
Where applicable, specific instructions should be provided,
particularly for active substances that cannot tolerate freezing. Terms such as
“ambient conditions” or “room temperature” must be avoided.
Stability
Testing of Drug Products
•
General
•
Selection of Batches
•
Container Closure System
•
Specification
•
Testing Frequency
•
Storage Conditions
•
Stability Commitment
•
Evaluation
•
Statements/Labelling
General
The design of the formal stability studies for the
pharmaceutical product should be based on knowledge of the behavior and
properties of the active substance, from stability studies on the active
substance, and on experience gained from clinical formulation studies.
Selection of Batches
Data from stability studies should be provided on at least
three primary batches of the pharmaceutical product.
The primary batches should be of the same formulation and
packaged in the same container closure system as proposed for marketing.
Two of the three batches should be at least pilot scale
batches and the third one can be smaller, if justified.
Stability studies should be performed on each individual
strength and container size of the drug product unless bracketing or matrixing
is applied.
Container Closure System
Stability testing should be conducted on the dosage form
packaged in the container closure system proposed for marketing (including, as
appropriate, any secondary packaging and container label).
Specifications
The testing should cover, as appropriate, the physical,
chemical, biological, and microbiological attributes, preservative content
(e.g. antioxidant, antimicrobial preservative).
Analytical procedures should be fully validated, and
stability indicating.
Testing Frequency
For long term studies:
Year 1: every 3 months
Year 2: every 6 months Subsequent years: annually
At accelerated storage conditions: (6 month study)
Minimum three points including t0 and tfinal,
e.g. 0 3
6
(initial) (final)
At intermediate storage conditions: (12 month study)
Four points including t0 and tfinal,
e.g. 0 3
6 12
(initial) (final)
Storage Conditions
A drug substance should be evaluated
To test its thermal stability
Its sensitivity to moisture or potential for solvent loss
(if applicable)
The storage conditions and the lengths of studies chosen
should be sufficient to cover storage, shipment, and subsequent use with due
regard to the climatic zone(s) in which the product is intended to be marketed.
Photostability testing should be conducted on at least one
primary batch of the pharmaceutical product if appropriate.
General Case
|
Study |
Storage condition |
Minimum time period
covered by data at submission |
|
Long Term* |
25º C ± 2º C 60%RH ± 5% |
12 months |
|
Intermediate** |
30º C ± 2º C 65%RH ± 5% |
6 months |
|
Accelerated |
40º C ± 2º C 75%RH ± 5% |
6 months |
If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5%
RH and “significant change” occurs at
any time during 6 months’ testing at the
accelerated storage condition, additional testing at the
intermediate storage condition should be
conducted and evaluated against
significant change criteria
In general, “significant change” for a drug product is
defined as:
•
A 5% change in assay from its initial value;
•
Any degradation product’s exceeding its
acceptance criterion;
•
Failure to meet the acceptance criteria for
appearance, physical attributes, and
functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery
per actuation); however, some changes in
physical attributes (e.g., softening of
suppositories, melting of creams) may be expected under accelerated conditions; and, as appropriate
for the dosage form:
•
Failure to meet the acceptance criterion for pH;
or
•
Failure to meet the acceptance criteria for
dissolution for 12 dosage units.
Drug products packaged in impermeable containers:
Sensitivity to moisture or potential for solvent loss is not
a concern for drug products packaged in impermeable containers.
Thus, stability studies can be conducted under any
controlled or ambient humidity condition.
Drug products packaged in semi-permeable containers:
Aqueous-based products packaged in semi- permeable
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.
|
Study |
Storage condition |
Minimum time
period covered by data at
submission |
|
Long Term* |
25º C ± 2º C 40%RH ± 5% |
12 months |
|
Intermediate** |
30º C ± 2º C 65%RH ± 5% |
6 months |
|
Accelerated |
40º C ± 2º C NMT25%RH |
6 months |
A 5% loss in water from its initial value is considered a
significant change for a product packaged in a semi-permeable container after
an equivalent of 3 months’ storage at 40°C/NMT 25% RH.
Drug Products
Intended for Storage in a Refrigerator
|
Study |
Storage condition |
Minimum time
period covered by data at submission |
|
Long Term |
5º C ± 3º C |
12 months |
|
Accelerated |
25º C ± 2º C 60%RH ± 5% |
6 months |
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.
Drug Products Intended
for Storage in a Freezer
|
Study |
Storage condition |
Minimum time
period covered by data at submission |
|
Long Term |
-20º C ± 5º
C |
12 months |
For drug products intended for storage in a freezer, the
shelf life should be based on the real time data obtained at the long term storage
condition.
Stability Commitment
If the submission includes data from stability studies on at
least 3 production batches, a commitment should be made to continue the long
term studies through the proposed shelf life and the accelerated studies for 6
months.
If the submission includes data from stability studies on
fewer than three production batches, a commitment should be made to continue
the long term studies through the proposed shelf life and the accelerated
studies for 6 months, and to place additional production batches, to a total of
at least three, on long term stability studies through the proposed shelf life
and on accelerated studies for 6 months.
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 shelf
life and on accelerated studies for 6 months.
Evolution
A systematic approach should be adopted in the presentation and
evaluation of the stability information.
Minimum of 3 batches of drug product was tested
The analyst must found the batch to batch variability &
if it is small than only it is accepted & it can be done by different
statistical test's (P value for level of significance for rejection).
Where the data show so little degradation and so little
variability then it is normally unnecessary to go through the formal
statistical analysis; providing a justification for the omission should be
sufficient.
Ongoing Stability
Studies
Purpose: to monitor and determine that API/FPP remains
within specifications under the storage conditions, within the re-test
period/shelf life in all future batches.
The programme should be described in a written protocol.
The programme should include at least one production batch
per year, tested at least annually.
An ongoing study should be conducted after any significant
change to the synthetic route/manufacturing process or container which may
impact stability.
Stability Indicating
Quality Parameter
Stability studies should include testing of those attributes
of the Drug product that are susceptible to change during storage and are
likely to influence quality, safety and/or efficacy.
For instance, in case of tablets:
- appearance
- hardness
- friability
- moisture
content
- dissolution
time
- degradants
- assay
- microbial
purity
Dosage form
Consideration
|
Dosage form |
Evaluation |
|
Tablets |
Appearance, colour, odour, assay, degradation products,
dissolution, moisture and friability. |
|
Hard gelatin capsules |
Appearance, colour, odour, assay, degradation products,
dissolution, moisture and microbial
limits |
|
Soft gelatin capsules |
Appearance, colour, odour, assay, degradation products,
dissolution, moisture and microbial limits, pH, leakage. |
|
Emulsions |
Appearance, colour, odour, assay, degradation
products, microbial limits, pH, viscosity, preservative content and
distribution of dispersed phase globules. |
|
Oral solutions |
Appearance, colour, odour, assay, degrad ation products, PH,microbial limits, preservative content. |
|
Oral suspensions |
Appearance, colour, odour, assay, degrad ation products, PH, microbial limits, preservative content, redispersibility, rheological properties, mean size and distribution of particle. |
|
Oral powders |
Appearance, colour, moisture, and reconstitution time. |
|
Inhalations and nasal sprays |
Appearance, colour, odour, assay, degrad ation products, dose content uniformity, microscopic evalution, water content, leak rate, microbial limits. |
|
Topical, opthalamic, ointments, creams, lotions, pastes,
gels, solutions. |
Appearance, clarity, colour, homgeneity, odour, pH, resuspendibility, viscosity,
particle size distribution, assay,
degradation products, preservatives,
microbial limits, weight loss |
|
Small volume parenterals |
Appearance, colour, clarity, assay, presarvative content,
degradation products, particulate
matter, sterility, |
|
Large volume parenterals |
Appearance, colour, clarity, assay, presarvative
content, degradation products, particulate matter, sterility, pH, pyrogenicity,
volume. |
Accelerated Stability
This stability study run under more stressful conditions
than expected for long term storage to account for any changes outside the
label storage conditions
The goal is to get a quick understanding of what may be
expected from a long term study.
Stability
Testing: Photostability Testing of New Drugs Substances and Products Q1B
Current Step 4
Version dated 6 November 1996
Photostability
Testing
Photo-stability testing studies include:
(Single batch) (no photo-stability studies after
administration)
•
Test on drug substance.
•
Test on exposed drug product outside the
immediate pack.
•
Test on drug product in the immediate pack.
•
Test on drug product in the marketing pack.
Light source
Option 1: Artificial daylight lamp combining both
visible & UV output similar to D65 & ID65.
Option 2: Cool white fluorescent & near UV lamp
(320-400nm)
output similar to that specified in ISO 10977
max. energy emission
between 350-370 nm
Procedure
E.g.: Quinine chemical actinometry: 2%w/v aq.solution of quinine monohydrochloride dihydrate
Stability
Testing for New Dosage Forms Annex to the ICH Harmonised Tripartite Guideline
on Stability Testing for New Drugs and Products Q1C
Current Step 4
version dated 6 November 1996
New Dosage Form
This document is an annex to the ICH parent stability
guideline and addresses the recommendations on what should be submitted regarding
stability of new dosage forms by the owner of the original application, after
the original submission for new drug substances and products
A new dosage form is defined as a drug product which is a different
pharmaceutical product type, but contains the same active substance as included
in the existing drug product approved by the pertinent regulatory authority.
Stability protocols for new dosage forms should follow the
guidance in the parent stability guideline in principle. However, a reduced stability
database at submission time may be acceptable in certain justified cases.
Bracketing
and Matrixing Design for Stability Testing of New Drug Substances and Products
Q1D
Current Step 4
version dated 7 February 2002
Bracketing
It is the design of a stability schedule such that only
samples on the extremes of certain design factors, e.g., strength, package
size, are tested at all-time points as in a full design.
The design assumes that the stability of any intermediate
levels is represented by the stability of the extremes tested. Where a range of
strengths is to be tested, bracketing is applicable if the strengths are
identical or very closely related in composition.
e.g.: for a tablet range made with different compression
weights of a similar basic granulation.
Bracketing can be applied to different container sizes or
different fills in the same container closure system.
Bracketing Design
+ indicates- Sample tested
|
Pack type |
Label strength and batch numbers (X,Y,Z) |
||||||||
|
10 mg |
20mg |
30mg |
|||||||
|
X |
Y |
Z |
X |
Y |
Z |
X |
Y |
Z |
|
|
Alu/Alu blister cards of 10 tablets |
+ |
+ |
+ |
- |
- |
- |
+ |
+ |
+ |
|
HDPE pack of 30
tablets |
+ |
+ |
+ |
- |
- |
- |
+ |
+ |
+ |
|
HDPE pack of 100 tablets |
- |
- |
- |
- |
- |
- |
- |
- |
- |
|
HDPE pack of 1000
tablets |
+ |
+ |
+ |
- |
- |
- |
+ |
+ |
+ |
Matrixing
It is the design of a stability schedule such that a
selected subset of the total number of possible samples for all factor
combinations is tested at a specified time point.
At a subsequent time point, another subset of samples for
all factor combinations is tested.
The design assumes that the stability of each subset of
samples tested represents the stability of all samples at a given time point.
}
One half reduction
}
One third reduction
Matrixing Design
Example of Matrixing Design on Time Points for a Product
with Two Strengths
|
one-half reduction |
|||||||||
|
Time points
(months) |
0 |
3 |
6 |
9 |
12 |
18 |
24 |
36 |
|
|
S1 |
Batch 1 |
+ |
+ |
- |
- |
+ |
- |
+ |
+ |
|
Batch 2 |
+ |
- |
+ |
+ |
+ |
- |
+ |
+ |
|
|
Batch 3 |
+ |
- |
+ |
- |
+ |
+ |
- |
+ |
|
|
S2 |
Batch 1 |
+ |
- |
+ |
+ |
+ |
+ |
- |
+ |
|
Batch 2 |
+ |
+ |
- |
- |
+ |
+ |
- |
+ |
|
|
Batch 3 |
+ |
+ |
- |
+ |
+ |
- |
+ |
+ |
|
Evaluation
for Stability Data Q1E
Current Step 4
version dated 6 February 2003
Evaluation for
Stability Data
Data Presentation-
• Data
for all attributes should be presented in an appropriate format (e.g., tabular,
graphical, narrative) and an evaluation of such data should be included in the
application.
• The values of quantitative attributes at
all-time points should be reported as measured (e.g., assay as percent of label
claim).
• If a statistical analysis is performed, the
procedure used and the assumptions underlying the model should be stated and
justified.
• A tabulated summary of the outcome of
statistical analysis and/or graphical presentation of the long-term data should
be included.
Extrapolation
• Extrapolation
is the practice of using a known data set to infer information about future
data (e.g. by using regression line analysis)
• Extrapolation
to extend the retest period or shelf life beyond the period covered by
long-term data can be proposed in the application, particularly if no
significant change is observed at the accelerated condition.
Data
Evaluation for Retest Period or Shelf Life Estimation for Drug Substances or
Products Intended for Room Temperature Storage
No significant change at accelerated condition
Where no significant change occurs at the accelerated
condition, the retest period or shelf life would depend on the nature of the
long-term and accelerated data.
Long-term and accelerated data showing little or no
change over time and little or no variability
Where the long-term data and accelerated data for an
attribute show little or no change over time and little or no variability, it
might be apparent that the drug substance or product will remain well within
the acceptance criteria for that attribute during the proposed retest period or
shelf life.
The proposed retest period or shelf life can be up to twice,
but should not be more than 12 months beyond, the period covered by long-term
data.
Long-term
or accelerated data showing change over time and/or variability
Data not amenable to statistical analysis
Where long-term data are not amenable to statistical
analysis, but relevant supporting data are provided, the proposed retest period
or shelf life can be up to one and-a-half times, but should not be more than 6
months beyond, the period covered by long-term data.
Data amenable to statistical analysis
If long-term data are amenable to statistical analysis but
no analysis is performed, the extent of extrapolation should be the same as
when data are not amenable to statistical analysis
However, if a statistical analysis is performed, it can be
appropriate to propose a retest period
or shelf life of up to twice, but not more
than 12 months beyond, the period covered by long-term data,
Significant change at
accelerated conditions
Where significant change occurs at the accelerated
condition, the retest period or shelf life would depend on the outcome of
stability testing at the intermediate condition as well as at the long-term
condition.
No significant change
at intermediate condition
Where no significant change occurs at the intermediate
condition, the retest period or shelf life would depend on the nature of the
long-term and intermediate data.
Data not amenable to
statistical analysis
When the long-term data for an attribute are not amenable to
statistical analysis, the proposed retest period or shelf life can be up to 3
months beyond the period covered by long-term data.
Data
Amenable to Statistical Analysis
If long-term data are amenable to statistical analysis but
no analysis is performed, the extent of extrapolation should be the same as
when data are not amenable to statistical analysis
However, if a statistical analysis is performed, it can be appropriate to propose a retest period or shelf life of up
to one & half times, but not more
than 6 months beyond, the period covered by long-term data,
SIGNIFICANT CHANGE AT INTERMEDIATE CONDITIONS
Where significant change observed at intermediate
conditions, the proposed retest period or shelf life should not be more than
period covered by long term study.
In addition a retest period or shelf life shorter than data
covered by long term study may be called for.
References
THE FOLLOWING ICH GUIDELINES MAY BE CONSULTED IN THE CONTEXT
OF STABILITY TESTING:
1) ICH
Q1A (R2): Stability testing of new drug substances and products (http://www.ich.org/LOB/media/ MEDIA419.pdf).
2) ICH
Q1B: Photostability testing of new drug substances and products (http://www.ich.org/LOB/media/ MEDIA412.pdf).
3) ICH
Q1C: Stability testing of new dosage forms http://www.ich.org/LOB/media/MEDIA413.pdf).
4) ICH
Q1D: Bracketing and matrixing designs for stability testing of new drug
substances and products (http://www.ich.org/LOB/media/MEDIA414.pdf).
5) ICH
Q1E: Evaluation for stability data (http://www.ich.org/LOB/media/MEDIA415.pdf).
6) V.SAI
KISHORE’s Drug regulatory affairs (pg no 227-288)
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