STABILITY TESTING OF PHARMACEUTICAL FORMULATION

UNDER ICH GUIDELINES

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INTRODUCTION
Objectives of the Guideline

The following guideline is a revised version of the

ICH Q1A guideline and defines the stability data
package for a new drug substance or drug product
that is sufficient for a registration application within
the three regions of the EC, Japan, and the United
States. It does not seek necessarily to cover the
testing for registration in or export to other areas of
the world.

The guideline seeks to exemplify the core stability

data package for new drug substances and products,
but leaves sufficient flexibility to encompass the
variety of different practical situations that may be
encountered due to specific scientific considerations
and characteristics of the materials being evaluated.
Alternative approaches can be used when there are
scientifically justifiable reasons.

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Scope of the Guideline

The guideline addresses the information to be

submitted in registration applications for new
molecular entities and associated drug products.
This guideline does not currently seek to cover the
information to be submitted for abbreviated or
abridged applications, variations, clinical trial
applications, etc. Specific details of the sampling and
testing for particular dosage forms in their proposed
container closures are not covered in this guideline.
Further guidance on new dosage forms and on
biotechnological/biological products can be found in
ICH guidelines Q1C and Q5C, respectively.

General Principles

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 to establish a

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re-test period for the drug substance or a shelf life

for the drug product and recommended storage
conditions. The choice of test conditions defined in
this guideline is based on an analysis of the effects of
climatic conditions in the three regions of the EC,
Japan and the United States. The mean kinetic
temperature in any part of the world can be derived
from climatic data, and the world can be divided into
four climatic zones, I-IV. This guideline addresses
climatic zones I and II. The principle has been
established that stability information generated in
any one of the three regions of the EC, Japan and the
United States would be mutually acceptable to the
other two regions, provided the information is
consistent with this guideline and the labeling is in
accord with national/regional requirements.

ICH started
The birth of ICH took place at a meeting in
April 1990, hosted by the EFPIA in Brussels.

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Purpose of ICH
The objective of ICH is to increase
international harmonization of technical
requirements to ensure that safe, effective, and
high quality medicines are developed and
registered in the most efficient and cost
effective manner.

Members Of ICH

• The Ministry of Health, • The European

Labour & Welfare (MHLW) Commission (EC) •
• Japan Pharmaceutical European Federation of
Manufacturers Association Pharmaceutical (JPMA) Industries and
Associations (EFPIA)
• The Food & Drug
Administration (FDA) •

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 INDEX
[Link]. Particular Page
No.
1. INTRODUCTION 1-5
2. Stability testing of new drug 6-11
- substances & products
3. Photostability testing of new drug 12-15
- substances & products
4. Stability testing for new dosage forms 16

-
5. Bracketing and Matrixing Design 17-19
Stability Testing of New drug
substances and products
20-22
Evaluation of Stability of Data
6. 23-33
Stability data package for Registration
Applications in Climatic Zones III and IV
7. CONCLUSION 34-35
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Purpose of ICH
The objective of ICH is to increase
international harmonization of technical
requirements to ensure that safe, effective, and
high quality medicines are developed and
registered in the most efficient and cost
effective manner.

Members Of ICH

• The Ministry of Health, • The European

Labour & Welfare (MHLW) Commission (EC) •
• Japan Pharmaceutical European Federation of
Manufacturers Association Pharmaceutical (JPMA) Industries and
Associations (EFPIA)
• The Food & Drug
Administration (FDA) •

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ICH STEERING COMMITTEE ICH SECRETARIAT •

Concerned with
• Determines the policies & preparation for,
procedures for ICH. documentation of,
meetings of the SC.
• Selects topics for
harmonization.

• They meet twice a year.

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STABILITY
Stability of a Pharmaceutical preparation can be
defined as “the capability of a particular formulation in
a specific container/closure system to remain within
its physical, chemical, microbiological, therapeutic &
toxicological specification throughout its shelf life”.
Purpose of stability testing
➢ To ensure the efficacy, safety and quality of active
drug substance and dosage forms.
➢ To establish shelf life or expiration period and to
support label claims
Stability testing of new drug substances
& products Q1
Principle -
➢ To provide evidence how quality of drug substance or
product varies
➢ To establish a retest period for drug substance or shelf
life for drug product

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DRUG SUBSTANCE
Stress testing -
• To identify degradation product

• To evaluate its susceptibility to hydrolysis

➢ Carried out on a single drug substance

➢ Photostability is an integral part of this testing

Selection of batches -
➢ Studies carried on atleast 3 primary batches
➢ The primary batch should be of pilot scale
➢ Should be packed in same container closure system
as proposed for storage and distribution

Testing Frequency-
To establish the stability profile of drug substance

For long-term storage For intermediate storage

12 month study 12 month study

– Testing frequency 0 3 6 9 1 - Testing frequency 0 6 12
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For accelerated storage If significant change occur

6 month study – Increase the testing by adding
– Testing frequency 0 3 6 sample at final time point
(initial) (final – Include 4th time point in study
design
STORAGE CONDITION-

➢ Drug system is evaluated to test

• Its thermal stability
• Sensitivity to moisture

• Table 1:: General case

Study Storage condition Minimum time
period for
data
submission
LONG TERM 12 MONTH
25ºC±2ºC/60%RH±5%RH
Or
30ºC±2ºC/65%RH±5%RH
INTERMEDIATE 30°C±2°C/65%RH±5%RH 6 MONTH

ACCELERATED 40°C±2°C/75%RH±5%RH 6 MONTH

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Long term studies

0 6 12 Significant change 0 3 6 12
Additional testing at intermediate condition

Table 2: Drug substance intended for storage in a

refrigerator
Study Storage condition
Minimum
time
period for
data
submission
LONG TERM 5°C±3°C 12 MONTH

ACCELERATED 25°C±2°C/60%RH±5%RH 6 MONTH

0 3 6

Significant change
Retest Period – 12 month

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DRUG PRODUCT
➢ Stability studies based on
• Behavior & properties of drug substance
• The stability study of drug substance

Selection of batches
Testing frequency
Storage condition
• General case
• Drug product stored under refrigerator
• Drug products packaged in impermeable
containers
▪ act as a barrier to moisture or solvents
▪ conducted at controlled humidity condition

• Drug products packaged in semi-permeable

containers
▪ aqueous products should be evaluated for
water loss
▪ conducted at low relative humidity

Statements & labeling

• The statement should be based on the stability evaluation
of drug substance.

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• Specific instruction should be provided for drug substance

that cannot tolerate freezing.
• Terms such as “ambient condition” or “room temperature”
should be avoided.
• Retest period derived from stability information.
• Retest date should be displaced on container label

Limited extrapolation of the real time data from the

long term storage condition beyond the observed
range to extend the shelf life can be undertaken at
approval time, if justified. This justification should be
based on what is known about the mechanisms of
degradation, the results of testing under accelerated
conditions, the goodness of fit of any mathematical
model, batch size, existence of supporting stability
data, etc. However, this extrapolation assumes that
the same degradation relationship will continue to
apply beyond the observed data. Any evaluation
should consider not only the assay but also the
degradation products and other appropriate
attributes. Where appropriate, attention should be
paid to reviewing the adequacy of the mass balance
and different stability and degradation performance.

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Photostability testing of new drug

substances & products
Photostability testing studies include:

• 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
Option 2: Cool white fluorescent & near UV lamp
Procedure –

➢ Sample exposed to light source/actinometric

system
Eg: Quinine chemical actinometry 2%w/v
[Link] of quinine monohydrochloride
dihydrate

• Option 1: In 20ml colourless ampoule

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• Option 2: In 1cm quartz cell

Change in absorbance calculated by
A = AT-A0
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 © EMEA 2006 16 go through the formal
statistical analysis; providing a justification for the
omission should be sufficient

An approach for analyzing data of a quantitative attribute

that is expected to change with time is to determine the
time at which the 95 one-sided confidence limit for the
mean curve intersects the acceptance criterion. If
analysis shows that the batch-to-batch variability is small,
it is advantageous to combine the data into one overall
estimate. This can be done by first applying appropriate
statistical tests (e.g., p values for level of significance of
rejection of more than 0.25) to the slopes of the
regression lines and zero time intercepts for the
individual batches. If it is inappropriate to combine data
from several batches, the overall shelf life should be
based on the minimum time a batch can be expected to
remain within acceptance criteria.

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DRUG SUBSTANCE

• Evaluate the photosensitivity •Information

• Its used alone or in solution • Placed in
chemically inert
• & transparent containers.
• Variety of exposure condition
Presentation of the samples
➢ Physical characteristic of the sample should be
taken care

➢ Interaction between the sample and material

eliminate

➢ Small amount of solid sample placed in glass or

plastic dish
➢ If its liquid sample its exposed in chemically inert
and transparent container

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Analysis of samples –
➢ Should be performed with the control
➢ Sample examine for change
• in physical property
• in assay and degradants

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Stability testing for new dosage forms

A new dosage form is defined as a drug product
which is a different pharmaceutical product type,
but contain the same active substance as
included in the existing drug product.

Eg: Different administration route (oral to

parenteral)
➢ Specific delivery systems (immediate release
tablet to modified release tablet)

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BRACKETING & MATRIXING

DESIGN FOR STABILITY TESTING
OF NEW DRUG SUBSTANCE &
PRODUCT

• A full study design is one in which samples of

every combination of all design factors are
tested at all time points.
• A reduced design one in which sample for
every factor combination are not tested at all
time points.

BRACKETING -
Bracketing is the design of a stability schedule
such that samples on the extremes of certain
design factors are tested at all time points.

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•
Capsules of different strengths ➢ Bracketing cannot be
made with different fill plug sizes applied when different
from same powder blend, excipients are used
• Tablets of different strengths among strengths.
manufactured by compressing ➢ Bracketing can be
applied varying amounts of same to study of container
granulation, and closure system.
• Oral solution of different strengths ➢ Characteristics of the
with formulations that differ only in container closure
system minor excipients (eg: colourant, include:
flavourings).

• container wall thickness,

• surface area to volume ratio, • water vapour
permeation headspace to volume ratio rate.
•

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•
MATRIXING
Matrixing is the design of a stability schedule
such that the selected subset of the total
number of possible samples for all factor
combination would be tested at a time point.

3rd Month 6th Month

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EVALUATION OF STABILITY
DATA
➢ Q1E provides recommendations on :
• How to use stability data generated according
to Q1A(R2).
• When and how a retest period or a shelf life
can be extended beyond the period covered
by long-term data.
➢ Data evaluation for retest period or shelf life
estimation for drug substance or product
intended for room temperature storage.

NO YES
significant change

Accelerated condition
If No
The retest period or shelf life depend upon the
long-term data and accelerated data.

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NO change with time

YES
& variability
Long-Term and accelerated data
If no : The product remains within the proposed
retest period.
if yes: Statistical analysis used in establishing a
retest period

NO Data amenable to
YES
statistical analysis
If no: Should not be more than 6 months beyond
the period covered by long term data i.e. 12+6
if yes: Should not be more than 12 month
beyond
the period covered by long-term data. i.e.
12+12

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If YES
The retest period or shelf life depend on
intermediate condition and long-term
condition

NO YES
significant change

Intermediate condition
if yes: Should not exceed the period covered by
longterm data.
If no : Statistical analysis used in establishing a retest
period

NO Data amenable to YES

statistical analysis
If no: Can be up to 3month beyond the
period covered by long
term data.i.e.12+3
if yes: Should not be more than 6 month beyond the
period covered by long-term data. i.e.
12 + 6

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STABILITY DATA PACKAGE FOR

REGISTRATION APPLICATIONS
IN CLIMATIC ZONE III AND IV
Q1F
Stability storage conditions for Zone- III & IV countries
Types of study

Long term
Product Accelerated

Solid oral dosage forms , solids for 40 C /̊75% RH 30 C and ̊ 35/70%RH

reconstitution , dry and lyophilized powders (Zone- III & IV)
in glass vials

Liquid in glass bottles, vials, sealed, glass 40 C/ambient ̊ 30 C/ ambient ̊

ampoules, which provide an impermeable humidity humidity
barrier to water loss

Drug products in the semi permeable 40 C/̊15%RH 30 C/̊40%RH

containers

Drug products to be indented to be stored 30 C and ̊ 5±3 ̊ C with

at 35/75%RH (Zone- monitoring but not
refrigerator temperature III & IV) or 30 C ̊ control of humidity
Ambient humidity
for liquid products

Drug products intended to be stored at 5±3 C/ ambient ̊ 15±5 ̊ C

freezer temperature humidity

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Long term stability of rh-Cu/Zn-superoxide dismutase

(SOD)-liposomes prepared by the cross-flow
injection technique following International
Conference on Harmonisation
(ICH)-guidelines
▪ Liposomal stability and protein stability were
tested under appropriate conditions.
▪ The size alterations of the vesicles, protein release
and protein activity were also evaluated.
▪ Significant alterations of the liposomes nor any
protein degradation was detected. Eur J Pharm
Biopharm, May 2002

Design and evaluation of self-emulsifying drug delivery

systems (SEDDS) of nimodipine.

▪ The ability of self-emulsifying drug delivery

systems (SEDDS) to improve solubility, dissolution
rate and bioavailability of a poorly water-soluble
calcium channel blocker, nimodipine (NM) was
evaluated.
▪ In vitro dissolution studies indicated that NM
loaded SEDDS could release complete amount of
NM irrespective of the pH of the dissolution media.
▪ NM loaded SEDDS were subjected to various
conditions of storage as per ICH guideline for 3
months.
AAPS PharmSciTech. Feb 2008.
Modified polysaccharides as fast disintegrating
excipients for orodispersible tablets of roxithromycin
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• Modified polysaccharides co grinded treated

agar (C-TAG) and co grinded treated guar gum
(C-TGG) were prepared by subjecting pure
polysaccharides namely agar and guar gum
respectively to sequential processes of wetting,
drying and co grinding with mannitol (1:1).

• Evaluated for particle size distribution, derived

properties, swelling index & biodegradability
.
• In vitro release both at salivary pH and
physiological pH was found to be more than 90%
within 30 min.

• Stability studies carried out as per ICH Q1A

guidelines suggested the formulations to be
stable for a period of 6 months. AAPS
PharmSciTech. Jan 2008

Effect of unconventional curing conditions and storage

on pellets coated with Aquacoat ECD
• Purpose of this study was to develop storage
stable pellets coated with the aqueous
ethylcellulose dispersion Aquacoat ECD.
• Unconventionally harsh curing conditions (60
degrees C/75% RH or 80 degrees C) improved
the storage stability of Aquacoat-coated pellets at
accelerated conditions.

Drug Development and Industrial Pharmacy May 2009

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Background
The ICH guidelines standardize the approach to stability
testing to ensure consistent quality across different
regions. The key guidelines include:

• ICH Q1A(R2): General stability testing for new

drug substances and products.
• ICH Q1B: Photostability testing of drug substances
and products. lOMoAR cPSD|50578160
• ICH Q1C: Stability testing for new
dosage forms.
• ICH Q1D: Bracketing and matrixing designs
for testing.
• ICH Q1E: Evaluation and interpretation of
stability data.
• ICH Q1F: Stability data requirements for
regions with climatic zones III and IV.

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Methodology
Types of Stability Testing

[Link] Stability Testing:

• Designed to speed up the aging process of

• the product.
• Conditions: 40°C ± 2°C and 75% RH ± 5% for 6
months.
• Purpose: Predict long-term stability and determine
potential degradation mechanisms. lOMoAR
cPSD|50578160

[Link]-Term Stability Testing:

• Reflects real-time storage conditions.

• Conditions: 25°C ± 2°C and 60% RH ± 5% for up to 24
months.
• Purpose: Verify product quality under normal storage
conditions.

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[Link] Stability Testing (if required):

▪ Conducted if significant changes are observed under

accelerated conditions.

▪ Conditions: 30°C ± 2°C and 65% RH ± 5%.

[Link] Testing:
• Evaluates the effect of light exposure on product
stability.

Parameters Monitored

• Physical Stability: Appearance, color, and dissolution

properties.
• Chemical Stability: Assay, impurities, and degradation
products. lOMoAR cPSD|50578160
• Microbiological Stability: Sterility or microbial limit
testing.
• Packaging Integrity: Container-closure system
integrity.

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Experimental Design

• Bracketing and Matrixing: Reduce the number of

samples tested by selecting extremes or subsets of
storage conditions (per ICH Q1D).

Data Analysis
• Stability data is analyzed statistically to identify
trends.
• Determine the product's shelf life and re-test period
using the Arrhenius equation for accelerated data or
real-time data

Results and Discussion

[Link] Analysis: Evaluate the stability data for any

significant changes in product quality.
[Link]-Life Determination: Establish a scientifically
justified expiration date.
[Link] of Environmental Factors: Assess how
storage conditions influence product degradation.

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GLOSSARY
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 a drug
substance or drug product by using exaggerated storage
conditions as part of the formal stability studies. Data
from these studies, in addition to long term stability
studies, can be used to assess longer term chemical
effects at non-accelerated conditions and to evaluate the
effect of short term excursions outside the label storage
conditions such as might occur during shipping. Results
from accelerated testing studies are not always
predictive of physical changes.

Bracketing
The design of a stability schedule 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
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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).
Bracketing can be applied to different container sizes or
different fills in the same container closure system.
Climatic zones
The four zones in the world that are distinguished by
their characteristic prevalent annual climatic conditions.
This is based on the concept described by W. Grimm
(Drugs Made in Germany, 28:196-202, 1985 and 29:39-
47, 1986).
Commitment batches Production batches of a drug
substance or drug product for which the stability studies
are initiated or completed post approval through a
commitment made in the registration application.
Container closure system
The sum of packaging components that together contain
and protect the dosage form. This includes primary
packaging components and secondary packaging
components, if the latter are intended to provide
additional protection to the drug product. A packaging
system is equivalent to a container closure system.

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Dosage form
A pharmaceutical product type (e.g., tablet, capsule,
solution, cream) that contains a drug substance
generally, but not necessarily, in association with
excipients.
Drug product
The dosage form in the final immediate packaging
intended for marketing.
Drug substance
The unformulated drug substance that may subsequently
be formulated with excipients to produce the dosage
form.
Excipient
Anything other than the drug substance in the dosage
form.
Expiration date
The date placed on the container label of a drug product
designating the time prior to which a batch of the
product is expected to remain within the approved shelf
life specification if stored under defined conditions, and
after which it must not be used.
Formal stability studies
Long term and accelerated (and intermediate) studies
undertaken on primary and/or commitment batches
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according to a prescribed stability protocol to establish

or confirm the re-test period of a drug substance or the
shelf life of a drug product.
Impermeable containers
Containers that provide a permanent barrier to the
passage of gases or solvents, e.g., sealed aluminum tubes
for semi-solids, sealed glass ampoules for solutions.
Intermediate testing
Studies conducted at 30°C/65% RH and designed to
moderately increase the rate of chemical degradation or
physical changes for a drug substance or drug product
intended to be stored long term at 25°C.
Long term testing
Stability studies under the recommended storage
condition for the re-test period or shelf life proposed (or
approved) for labeling.
Mass balance
The process of adding together the assay value and levels
of degradation products to see how closely these add up
to 100% of the initial value, with due consideration of the
margin of analytical error.

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CONCLUSION
Stability testing under ICH guidelines ensures that
pharmaceutical products maintain their intended
safety, efficacy, and quality throughout their shelf
life. By adhering to these guidelines,
pharmaceutical companies can standardize their
testing methods, comply with regulatory
requirements, and provide high-quality products to
patients worldwide
Data, other than those from formal stability studies,
that support the analytical procedures, the
proposed re-test period or shelf life, and the label
storage statements. Such data include (1) stability
data on early synthetic route batches of drug
substance, small scale batches of materials,
investigational formulations not proposed for
marketing, related formulations, and product
presented in containers and closures other than
those proposed for marketing; (2) information
regarding test results on containers; and (3) other
scientific rationales.

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REFERENCES

ICH Q1B: “Photostability Testing of New Drug

Substances and Products”
ICH Q1C: “Stability Testing of New Dosage Forms”
ICH Q3A: “Impurities in New Drug Substances” ICH
Q3B: “Impurities in New Drug Products” ICH Q5C:
“Stability Testing of Biotechnological/Biological
Products”
ICH Q6A: “Specifications: Test Procedures and
Acceptance Criteria for New Drug Substances and
New Drug Products: Chemical Substances”
ICH Q6B: “Specifications: Test Procedures and
Acceptance Criteria for New Drug Substances and
New Drug Products: Biotechnological/Biological
Products”

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