ICH GUIDELINES FOR

STABILITY STUDIES

6/14/2016
 CONTENTS:-

Q1A(R2)-Stability Testing of New Drug Substances &

Products
Q1B- Photo stability Testing of New Drug Substances &
Products
Q1C-Stability Testing for New Dosage Forms
Q1D-Bracketing and Matrixing Designs for Stability Testing
of New Drug Substances and Products
Q1E-Evaluation for stability data
Q1F-Stability Data Package for Registration Applications in
Climatic Zones III and IV
Conclusions
References 2
ICH guideline Q1-A(stability
studies)
Objectives of the Guideline :-

The guideline defines the stability data package for a new drug substance
or drug product that is sufficient for a registration application within the
three regions of the EC, Japan, and the United States.

Scope:-
Addresses the information to be submitted in registration
applications for new molecular entities and associated drug product

General Principles :-

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.
To establish a retest period for the drug substance or a shelf life for the
drug product and recommending storage conditions.
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 THE ZONE CONCEPT
Zone I Zone II Zone III Zone IV
Temperate Mediterranean Hot/ dry Very Hot/moist

Kinetic average Kinetic average Kinetic average Kinetic average

temp. 21°c temp. 25°c temp. 30°c temp. 30°c
Yearly average Yearly average Yearly average Yearly average
relative relative relative relative
humidity 45% humidity 60% humidity 35% humidity 75%
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 STRESS
TESTING
⚫ To validate the stability indicating power of the analytical procedures.
⚫ To identify stability-affecting factors such as ambient temperature, humidity
and light and to select packing materials which protects the formulation
against such effects
⚫ To identify potential degradants of the API and assess if they can be formed
during manufacture or storage of the formulation
⚫ To select manufacturing process for particular drug substance

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 SELECTION OF BATCHES
Applicability Minimum number Size and type
of batches
New drug 3 Pilot Scale
substance
New Drug product 3 Two pilot scale,
one small scale

Container and closures

⚫ Testing should be done using container And closures proposed for storage and
distribution. Container orientation for solution, dispersion system and semi
solid product is important. Up right position used to study the effect of
temperature and relative humidity and on the side position can be used to
study the interaction between product-container- closures.

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SPECIFICATION
• list of tests,
• reference to analytical procedure,
• proposed acceptance criteria
Test Attributes
• attributes that are susceptible to changed storage,
• influence quality, safety and/or efficacy
• Should cover physical, chemical, biological and microbiological attributes.

Testing frequency
For long term stability:-
Normally be every three month over the first year, every six month over the
second year, and annually there after through the proposed shelf life.
For accelerated stability study:-
 A minimum three time point including initial and final time point (e.g. 0,3,and 6
month) from a six month study is recommended.
For intermediate stability study :-
A minimum of four point including initial and final point from a 12 month study.
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 Storage condition
Long term testing should cover a minimum of 12 months duration on at least three
primary batches at time of submission and should be continued sufficient to cover
the proposed re-test period
Drug product- general case
study Storage condition Duration
Long term 25°C ± 2°C/60% ± 5% RH or 12 months
30°C ± 2°C/65% ± 5% RH
Intermediate 30°C ± 2°C/65% ± 5% RH 6 months

Accelerated 40°C ± 2°C/75% ± 5% RH 6 months

Note:-
 It is up to the applicant, to decide whether long term stability is performed at
25°C ± 2°C/60% ± 5% RH or 30°C ± 2°C/65% ± 5% RH.
 If 30°C ± 2°C/65% ± 5% is the long-term condition, there is no intermediate
condition.
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 Drug substances intended for storage in a refrigerator

Study Storage condition Minimum time

period at submission
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C/60% ± 5% RH 6 months

If significant change between 3 and 6 months at accelerated testing

propose re-test data based on real time data.

If significant change within 3 months discussion should address

excursions outside label storage. Single batch shorter than
3 months with more frequent testing.
Drug substance intended for storage in a freezer
Study Storage condition Minimum time
period at submission

Long term -20 °C ± 5°C 12 months

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 Stability Commitment
• long term stability data do not cover proposed re-test period granted at time
of approval, commitment should be made to continue post approval to
establish re-test period
• Not required for Submission which includes data from 3 production
batches, commitment to continue through proposed re-test period.
• Fewer than three production batches commitment continue with these
studies through proposed re-test period and place additional production
batches to a total of three on long term stability through proposed re-test
period
• No Production batches commitment to place first three production batches
on long term stability studies through proposed re-test period.

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EVALUATION
⚫ Evaluation should include results from the physical, chemical,biological
and microbiological tests.
e.g. physical parameter to evaluated for tablet.
1) Appearance
2) Friability
3) Hardness
4) Colour,Odour
5) Dissolution
6) Moisture absorption

STATEMENT AND LABELING

⚫ Storage Statement:-

Storage statement established for labeling should be in accordance with

national/regional requirements.
⚫ Re-test date:-
1.Statement based on stability evaluation
2.The re-test date should be displayed on the container label.

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 Photo stability testing: Q1-B
A systematic approach to photo stability testing is recommended covering, as
appropriate, studies such as :
i) Tests on the active substance;
ii) Tests on the exposed product outside of the immediate pack, and if necessary ;
iii) Tests on the product in the immediate pack; and if necessary ;
iv) Tests on the product in the marketing pack.

Light sources:
1. D65/ID65 emission

2.standard such as an artificial daylight fluorescent lamp combining visible and

ultraviolet (UV) outputs, xenon, or metal halide lamp.

3. D65 is the internationally recognized standard for outdoor daylight as defined

in ISO 10977 (1993). ID65 is the equivalent indoor indirect daylight standard.
For a light source emitting significant radiation below 320 nm, an appropriate
filter(s) may be fitted to eliminate such radiation.
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 NEW DOSAGE FORMS-Q1 C
definition:
A new dosage form is defined as a medicinal product which is a different
pharmaceutical product type, but containing the same active substance as
included in an existing product approved by the pertinent regulatory
authority.
.Include:
products of a different route of administration (e.g., oral to parenteral), new
specific functionality/delivery systems (e.g., immediate release tablet to
modified release tablet) and different dosage forms of the same route of
administration (e.g., capsule to tablet, solution to suspension).
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 with proper justification.
e.g., 6 months accelerated and 6 months long term data from ongoing
studies may be acceptable in certain justified cases.
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 STABILITY TEST PARAMETERS FOR VARIOUS
TYPES OF PRODUCTS
Tablets -Appearance, colour, odour, assay, disintegration/dissolution, moisture
and friability or hardness testing.
Hard gelatin capsules - Appearance, colour , odour of contents, assay,
disintegration/dissolution, moisture and microbial limits.
Soft gelatin capsules - Appearance, colour , odour of contents, assay,
disintegration/dissolution, moisture, microbial limits, pH , leakage and pellicle
formation.
Emulsions -Appearance including phase separation, colour , odour , assay, pH,
viscosity, preservative content, weight loss and microbial limits.
 Suppositories - Appearance, colour , assay, particle size, softening range,
appearance, dissolution and microbial limits.
Small volume parenteral Drug injection- Appearance, colour , assay, ph,
preservative, content, particulate matter, sterility and pyrogenicity.
Large volume parenteral - Appearance, colour , assay, ph, preservative content,
particulate matter, sterility and pyrogenicity.
Transdermals - Appearance, assay, leakage, microbial limit/sterility, peel and
adhesive forces, drug release rate. 13
Bracketing and Matrixing Designs For Stability Testing Of
New Drug Substances And Products-Q1D.
Study
design

Full study Reduced study

design design

Not sample of all designed factors for

Samples of all every combination are tested at all
designed factors for time points
every combination
are tested at all time
points
Bracketing Matrixing

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 BRACKETING :-
 Bracketing is the design of a stability schedule such that only sample on the
extremes of certain design factor (e.g., strength, container size and/or fill)
are tested at all time points as in a full design.
 The design assumes that the stability of any intermediates level is
represented by the stability of the extremes tested.
Example of a bracketing design:-

Strength 50 mg 75 mg 100 mg
Batch 1 2 3 1 2 3 1 2 3
Container size 15 ml T T T T T T
100 ml
500 ml T T T T T T

Key:-T = sample tested

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MATRIXING:
-
 Matrixing is the design of a stability schedule such that a selected subset of
the total number of possible samples for all factor combination would be
tested at a specified time point.
 At a subsequent time point, another subset of sample for all factor
combinations would be tested.
 The design assumes that the stability of each subset of samples tested
represents the stability of all samples at a given time.

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 EVALUATION FOR STABILITY
DATA-Q1E
 The parent guidelines states that regression analysis is an appropriate
approach to analyzing quantitative stability data for retest period or shelf
life estimation and recommends that a statistical test for batch for pool
ability be performed using a level of significance of 0.25.
 This guidelines is intended to provide recommendation on how to use
stability data generated in accordance with the principle detailed in the ICH
guideline – Q1A(R) stability testing of new drug substances and product.
 Extrapolation:-

 Extrapolation is the practice of using a known data set to inter information

about future data.
 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.

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STABILITY DATA PACKAGE FOR REGISTRATIO
APPLICATIONS IN
CLIMATIC ZONES III AND IV- Q1F

 A product shelf life should be established according to climatic conditions

in which the product is to be marketed.
 Storage condition recommended by manufactures on the basis of stability
studies are meant to guarantee the maintenance of quality, safety and
efficacy throughout the shelf-life of product.
 Temperature and humidity determine the storage conditions and so they
greatly affect the stability of drug product.
 Climatic conditions in countries where the product is to be marketed should
be carefully.

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 Stability studies should be planned on the basis of pharmaceutical R&D
and regulatory requirements.

 Forced degradation studies reveal the intrinsic chemical properties of the

API, while formal stability studies establish the retest date.

 The shelf life (expiry date) of FPPs is derived from formal stability studies.

 Variability and time trends of stability data must be evaluated by the

manufacturer in order to propose a retest date or expiry date.

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