Stability Study

STABILITY
• 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.
i.e. evaluation of drug under storage conditions (with appropriate tolerances) that test its
thermal stability and, if applicable, its sensitivity to moisture.
• To establish a re-test period for the drug substance or a shelf life for the drug product and
recommended storage conditions.
• In simple words Stability can be also defined as
“The capacity of a drug to remain within specifications established to assure its identity,
strength, quality and purity”
WHAT IS STABILITY

ICH : International Council for Harmonization
ICH-Guidelines
ICH
Q
Quality
E
Efficacy
M
Multidisciplinary
S
Safety

ICH- Guidelines
CODE SUBJECT GUIDELINE
Q1 Stability Q1A,Q1B,Q1C,Q1D,Q1E,Q1F
Q2 Analytical validation Q2A,Q2B
Q3 Impurities Q3A,Q3B,Q3C,Q3D
Q4 Pharmacopoeias Q4,Q4A,Q4B
Q5 Quality of Biotechnological Products Q5A, Q5B, Q5C, Q5D, Q5E
Q6 Specifications Q6A, Q6B
Q7 Good Manufacturing Practice Q7A
Q8 Pharmaceutical Development Q8
Q9 Quality risk management Q9
Q10 Pharmaceutical Quality System Q10
Q11 Development and Manufacture of Drug Substances Q11
Q12 Life cycle management Q12
Q13
Continuous manufacturing of drug substance &
Drug product
Q13
StabilityQ1 Q1A,Q1B,Q1C,Q1D,Q1E,Q1F

ICH- Stability (Q1)
Q1 Stability (Q1A,Q1B,Q1C,Q1D,Q1E,Q1F)
Q1A (R2) Stability testing of new drug substance & products (2003)
Q1B Photo stability testing of new drug substance & products (1996)
Q1C Stability testing of new dosage forms (1996)
Q1D
Bracketing & Matrixing designs for stability testing of new drug
substance & products (2002)
Q1E Evaluation of stability data (2003)
Q1F
Stability data package for registration applications in climate
zone III & IV (2006)

WHO Guidelines
WHO : World Health Organization

ICH - Q1 - STABILITY
TESTING
FREQUENCY
Q1A
(October 1993)
Q1A(R)
(November 2000)
Q1A(R2)
(February 2003)
LONG TERM
0, 3, 6, 9, 12,18, 24,
… .months
0, 3, 6, 9, 12,18, 24,
… .months
0, 3, 6, 9, 12,18, 24,
… .months
INTERMEDIATE
0, 3, 6, 9 & 12
months
0, 3, 6, 9 & 12
months
0, 3, 6, 9 & 12
months
ACCELARATED
0, 1, 2, 3 & 6
months
0, 3 & 6
months
0, 3 & 6
months
CHANGE
PROGRESSIVE CHANGES IN ICH GUIDELINE
5 point study to 3 point study

ICH - Q1 – STABILITY
STORAGE
CONDITION
Q1A Q1A(R) Q1A(R2)
LONG TERM
25  20C /
60  5% RH
25  20C /
60  5% RH
25  20C/ 60  5% RH
Or
30  20C/65  5% RH
(Decision is left to the applicant)
INTERMEDIATE
30  20C /
60  5% RH
30  20C /
60  5% RH
30  20C /
65  5% RH
ACCELARATED
40  20C /
75  5% RH
40  20C /
75  5% RH
40  20C /
75  5% RH
CHANGE
CHANGE

TESTING Q1A Q1A(R) Q1A(R2)
Stress Testing
Glossary
Body of the
guideline
Body of the
guideline
Specification
Testing procedure
Acceptance criteria
No cross reference
available
Cross reference
*Q6A & Q6B
Cross
reference
*Q6A & Q6B
No cross reference
available
Cross reference
*Q6A & Q6B
Cross
reference
*Q6A & Q6B
CHANGE
CHANGE

What
to
know
Selection of batches
Container closure system
Specification
Testing frequency
Storage conditions
Stability Commitment
Evaluation
Statements / Labelling
In-use & Hold time studies
Variations
Ongoing studies

STRESS TESTING
 Studies undertaken to assess the effect of severe conditions on the drug product.
 Such studies include photo stability testing and specific testing on certain products,
(e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid
products).
e.g. cyclic studies for semi-solid products or freeze–thaw studies for liquid products.
Freeze – Thaw stability study:
It is a stability testing that allows you to determine if your formulae will remain stable
under various conditions like freezing or Over heating.
 Photo stability Testing (ICH Q1B) should be an integral part of stress testing.

Photo stability:
To demonstrate light exposure does not result in unacceptable change on a single batch of
material
systematic approach to photo stability testing such as:
i) Tests on the drug substance;
ii) Tests on the exposed drug product outside of the immediate pack; and if necessary ;
iii) Tests on the drug product in the immediate pack; and if necessary ;
iv)Tests on the drug product in the marketing pack.
Light Source:
a) D65/ID65 (A light source emitting significant radiation below 320 nm)
b) A near UV fluorescent light source having a spectral distribution from 320nm to
400nm.
STRESS TESTING
It may be appropriate to test certain products such as infusion liquids, dermal creams, etc.,
to support their photo stability in-use. The extent of this testing should depend on and relate
to the directions for use, and is left to the applicant’s discretion.
The analytical procedures used should be suitably validated.

SELECTION OF BATCHES
Finished product containing new API:
 Stability study on at least three primary batches of each proposed strength of at least two pilot
scale.
Finished product containing existing API:
 Stability study on at least two primary batches of each proposed strength of at least one pilot
scale.
 Where possible batches of drug product should be manufactured by using different batches of the
drug substance.

CONTAINER CLOSURE SYSTEM
 Similar to container closure system proposed for marketing (including, as appropriate, any
secondary packaging and container label).
 Any available studies carried out on the drug product outside its immediate container or in other
packaging materials can form a useful part of the stress testing of the dosage form or can be
considered as supporting information, respectively.

SPECIFICATION
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.
The testing should cover, as appropriate, the physical, chemical, biological, and microbiological
attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests
(e.g., for a dose delivery system).
Analytical procedures should be fully validated and stability indicating. Whether and to what extent
replication should be performed will depend on the results of validation studies.
Shelf life acceptance criteria should be derived from consideration of all available stability information
It may be appropriate to have justifiable differences between the shelf life and release acceptance
criteria based on the stability evaluation and the changes observed on storage
Reference ICH Q6A , Q6B & Q3B.

TESTING FREQUENCY
 Long Term :
 Intermediate :
 Accelerated :
First year : Every 3 months.
Second year : Every 6 months.
Thereafter : Annually.
0, 6, 9, 12 months. (Min 4 time point)
0, 3, 6 months. (Min 3 time point)
Where an expectation exists that results from accelerated studies are likely to approach significant
change criteria, increased testing should be conducted either by adding samples at the final time
point or by including a fourth time point in the study design.
When testing at the intermediate storage condition is called for as a result of significant change at the
accelerated storage condition, a minimum of four time points(0,6,9,12) study is recommended.
Reduced designs, i.e., Matrixing or bracketing, where the testing frequency is reduced or certain factor
combinations are not tested at all, can be applied, if justified.

STORAGE CONDITION
Stability data must demonstrate stability of the medicinal product throughout its intended shelf
life under the climatic conditions prevalent in the target countries.
Merely applying the same requirements appropriate to other markets could potentially lead to
substandard products if stability studies are conducted at the storage conditions for countries in
Climatic Zone I/II when the products are supplied in countries in Climatic Zones III and IV.
In order to reduce the amount of stability testing required, four long term conditions were defined
based on climate conditions as follows.
United States of America 25 °C/60% or 30 °C/65% RH1
United Kingdom 25 °C/60% or 30 °C/65% RH1
India 30 °C/70% RH
Australia 25 °C/60% or 30 °C/65% RH2
Japan 25 °C/60% or 30 °C/65% RH1
China 30 °C/65% RH

STORAGE CONDITION
Storage Time :
Should be sufficient to cover storage, shipment and subsequent use with due regard to the climatic
conditions in which the product is intended to be marketed.
Orientation of product during storage:
The orientation of the product during storage, i.e. upright, on the side or inverted, as well as the
rationale for the orientation, may need to be included in a protocol where contact of the product with
the closure system may be expected to affect the stability of the products contained (e.g. liquids and
semisolids), or where there has been a change in the container-closure system.
Tolerance to storage conditions:
Defined acceptable variation as given further slides.
The equipment used should be capable of controlling the storage conditions within the ranges defined
in these guidelines. The storage conditions should be monitored and recorded.

STORAGE CONDITION
Short-term due to door openings - Acceptable.
More than 24 hrs – Should be documented & assessment required.
The effect of excursions due to equipment failure should be assessed, and reported if judged to
affect stability results.
EXCURSIONS:

STABILITY
(i) General case
Study Storage condition
Minimum time period covered
by data at submission
Long term
25°C ± 2°C/60% RH ± 5% RH
(or) (Decision is left to the applicant)
30°C ± 2°C/65% RH ± 5% RH
12 months
Intermediate 30°C ± 2°C/65% RH ± 5% RH 6 months
Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months
If 30°C  2°C/65% RH  5% RH is the long-term condition, there is no intermediate
condition.
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
STORAGE CONDITION

STABILITY
SIGNIFICANT CHANGE
In general, “significant change” for a drug product is defined as:
1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for
potency when using biological or immunological procedures;
2. Any degradation product’s exceeding its acceptance criterion;
3. 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:
4. Failure to meet the acceptance criterion for pH; or
5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.
Containers packed in impermeable and semi permeable
STORAGE CONDITION

STABILITY
(ii) Drug Products intended for storage in a refrigerator
Long term 5°C ± 3°C 12 months
Accelerated
25°C ± 2°C/60% RH ± 5% RH
30°C ± 2°C/65% RH ± 5% RH
30°C ± 2°C/75% RH ± 5% RH
6 months
If “significant change” occurs between 3 & 6 months of accelerated study, data on long term
study should be submitted. If “significant change” occurs within 3 months of accelerated
study, it is unnecessary to continue further testing.
Whether accelerated stability studies are performed at 25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH ±
5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is based on a risk-based evaluation. Testing at a more severe
accelerated condition can be an alternative to the storage condition at 25 °C/60% RH or 30 °C/65% RH.
STORAGE CONDITION

(iii) Drug substances intended for storage in a freezer
Long term - 20°C ± 5°C 12 months
In the absence of an accelerated storage condition for drug 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) 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.
Drug substances intended for storage below -20°C should be treated on a case-by-case
basis.
STORAGE CONDITION

Evaluation of the stability information, as appropriate, results from the physical, chemical,
biological, and microbiological tests.
Data should be presented in an appropriate format (e.g., tabular, graphical, narrative) and an
evaluation of such data should be included in the application.
Extrapolation:
is the practice of using a known data set to infer 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.
Evaluation of stability data

PRODUCTS INTENDED FOR ROOM TEMPERATURE STORAGE
Accelerated
condition
Long term /ACC Data
Long term Data
willing to
statistical
analysis
Retest period / Shelf life (Y)
(X= available long term data)
No significant
change
Little or no variability
over time
-NA- Y = 2x (Should NMT X+12)
Showing variability over
time
Yes Y = 2x (Should NMT X+12)
No Y = 1.5x (Should NMT X+6)
Accelerated
condition
Intermediate Data
Long term Data
willing to
statistical
analysis
Retest period / Shelf life
Significant change
Significant change -NA- Y = x
No Significant change
Yes Y = 1.5x (Should NMT X+6)
No Y = x + 3

EVOLUTION OF STABILITY DATA TO ESTABLISH RETEST FOR DRUG
SUBSTANCE INTENDED FOR ROOM TEMPERATURE STORAGE
If no significant change at accelerated stability data for 6 months.
Long-term and accelerated data showing little or no change over time and little or no variability
X Y
Accelerated
(6months)
Long Term
(9 months OK)
y = 2x (Should not more than X+12)
re-test date is 18 Months
Accelerated
(6months)
Long Term
(12 months OK)
Accelerated
(6months)
Long Term
(18 months OK)
Accelerated
(6months
Long Term
(24 months OK)
Accelerated
(6months)
Long Term
(36 months OK)
y = x
(No extrapolation beyond 36 months)

EVOLUTION OF STABILITY DATA TO ESTABLISH
RETEST FOR DRUG SUBSTANCE
X Y
Accelerated
(6months)
Intermediate
9 months OK
y = 1.5x (should not more than x+6)
re-test date is 13.5 months
Accelerated
(6months)
Intermediate
12 months OK
y = 1.5x (should not more than x+6)
re-test date is 18 months
Where significant change occurs at the intermediate condition, the
proposed retest period or shelf life should not exceed the period
covered by long-term data. In addition, a retest period or shelf life
shorter than the period covered by long-term data could be called for.
If significant change at accelerated stability data for 6 months.

PRODUCTS INENDED FOR BELOW ROOM TEMPERATURE STORAGE (Refrigerator)
Accelerated
condition
Long term /ACC Data
Long term Data
willing to
statistical
analysis
Retest period / Shelf life (Y)
(X= available long term data)
No significant
change
Little or no variability
over time
-NA- Y = 1.5x (Should NMT X+6)
Showing variability over
time
Yes Y = 1.5X (Should NMT X+12)
No Y = X+3
Accelerated
condition
Retest period / Shelf life
Significant change Y = x

Testing conditions where stability has
been shown
Required labeling statement
Additional labeling
statement, where relevant
25  20C / 60  5% RH (long term)
40  20C / 75  5% RH (accelerated)
or
30  20C / 65  5% RH (long term)
40  20C / 75  5% RH (accelerated)
None
Do not refrigerate or freeze.
25  20C / 60  5% RH (long term)
30  20C / 65  5% RH (intermediate)
or
30  20C / 65  5% RH (long term)
Do not store above 30 0C
or
Store below 30 0C.
Do not refrigerate or freeze
25  20C / 60  5% RH (long term)
Do not store above 25 0C
or Store below 25 0C.
Do not refrigerate or freeze.
5  30C (long term)
Store in a refrigerator or
Store & transport refrigerated
Do not freeze
Below zero
Store in a freezer or Store &
transport frozen None
STATEMENT & LABELLING

S.No Storage problem
Additional labeling statements*
depending on the packaging
1. Sensitivity to moisture. Keep the container tightly closed
2.
Sensitivity to moisture. Store in the original package.
3. Sensitivity to light Store in the original package.
4.
Sensitivity to light
Keep the container in the outer
carton.
Note:
1. An explanation for the labeling statement should be given in
the package leaflet (e.g. “in order to protect from light”) and
on the outer packaging, where space permits.
2. The actual name of the container should be used, eg. Bottle.
STATEMENT & LABELLING

INUSE STABILITY
The purpose of in-use stability testing is to provide information for the labelling on the
preparation, storage conditions and utilization period of multidose products after opening,
reconstitution or dilution of a solution.
Ex:
Antibiotic injection supplied as a powder for reconstitution
A moisture-sensitive or hygroscopic solid oral FPP in a large format multidose container (e.g. high
density polyethylene (HDPE) bottle of 500 tablets)
A 30-day in-use period is normally considered acceptable without further supporting data
The physical, chemical and microbial properties of the FPP that are susceptible to change during
storage should be determined over the period of the proposed in-use shelf life
This testing should be performed on primary batches of the reconstituted or diluted FPP or the
solid oral FPP (as above), throughout the proposed in-use period as part of the stability studies at
the initial and final time points and, if long-term data covering the shelf life are not available at
the time of submission, at 12 months or the last time point at which data will be available.

HOLDTIME STABILITY
Hold-time studies of bulk products, e.g. coated tablets prior to final packaging.
For example,
when the bulk product may be stored for a period exceeding 30 days before being packaged and/or
shipped from a manufacturing site to a packaging site, the stability of the bulk product in the
intended bulk container should be evaluated and studied.
Similar considerations should apply to intermediates that are stored and used for periods
exceeding 30 days.
Further guidance can be found in the WHO General guidance on hold-time studies.

ONGOING STABILITY STUDIES
The purpose of the ongoing stability programme is to monitor the product over its shelf life and to determine that
the product remains, and can be expected to remain, within specifications under the storage conditions on the
label.
The ongoing stability programme should be described in a written protocol and results formalized as a report.
The protocol for an ongoing stability programme should extend to the end of the shelf-life period and should
include, but not be limited to, the following parameters:
–– number of batch(es) per strength and different batch sizes, if applicable. The batch size should be recorded,
if batch sizes differ;
–– relevant physical, chemical, microbiological and biological test parameters with acceptance criteria or
reference to the attached specifications;
–– reference to test methods;
–– description of the container-closure system(s);
–– testing frequency (generally at 6 months and annual time points is sufficient for ongoing studies);
–– description of the conditions of storage (standardized conditions for long-term testing as described in these
guidelines, and consistent with the product labelling, should be used); and
–– other applicable parameters specific to the FPP.

ONGOING STABILITY STUDIES
Unless otherwise justified, at least one batch per year of product manufactured in every strength and every
primary packaging type, if relevant, should be included in the stability programme (unless none is produced during
that year).
In certain situations additional batches should be included in the ongoing stability programme. For example, an
ongoing stability study should be conducted after any significant change or significant deviation to the process
or container closure system. Any reworking, reprocessing or recovery operation should also be considered for
inclusion.
OOS results or significant atypical trends should be investigated. Any confirmed significant change or OOS
result should be reported immediately to the relevant competent authorities.
A summary of all the data generated, including any interim conclusions on the programme, should be written and
maintained. This summary should be subjected to periodic review.

KIRANREDDY MUNNANGI
https://www.analyticalstudents.blogspot.com

Stability Study

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