This presentation outlines the ICH Guideline for Stability Testing of New Drug Substances and Products, Q1A(R2). It serves as a comprehensive framework for ensuring the stability of new pharmaceuticals, with a focus on the requirements for registration applications within the EC, Japan, and the United States. The guideline emphasizes a balance between a standardized approach and the flexibility to adapt to specific scientific considerations and characteristics of the materials under evaluation.

1. ICH Guideline:
Stability Testing of
New Drug Substances
and Products
Q1A(R2)
This presentation outlines the ICH Guideline for Stability Testing of New Drug
Substances and Products, Q1A(R2). It serves as a comprehensive framework for
ensuring the stability of new pharmaceuticals, with a focus on the requirements
for registration applications within the EC, Japan, and the United States. The
guideline emphasizes a balance between a standardized approach and the
flexibility to adapt to specific scientific considerations and characteristics of the
materials under evaluation.
by Trishala Bhatt

2. 1.1. Introduction and Objectives
The revised ICH Q1A guideline specifies the stability data package
necessary for a new drug substance or product registration application
in the EC, Japan, and the US.
It aims to standardize the core stability data while allowing for
scientific flexibility due to specific scientific considerations.
Alternative approaches are available for scientifically justifiable
reasons.

3. 1.2. Scope of the Guideline
Registration
Applications
The guideline addresses
the information to be
submitted in registration
applications for new
molecular entities and
associated drug products.
Exclusions
This guideline does not
cover abbreviated
applications, variations, or
clinical trial applications,
and it does not detail the
testing for specific dosage
forms.
Further Guidance
Additional guidance for new dosage forms and
biotechnological/biological products is available in ICH
guidelines Q1C and Q5C.

4. 1.3. General Principles
Stability testing is essential to understand how drug quality is affected
over time by environmental factors.
It helps establish the re-test period or shelf life and the recommended
storage conditions.
The test conditions are based on climatic analysis in the EC, Japan, and
the United States, focusing on climatic zones I and II. The mutual
acceptance of stability data among these regions is a key principle of
the guideline.

5. 2. Guidelines for Drug Substance
1 Importance of Stability
Understanding the stability of drug substances is
fundamental to the development and evaluation of
pharmaceuticals.
2 Stress Testing
Stress testing aims to identify degradation products,
establish degradation pathways, and validate analytical
procedures.
3 Stress Testing Methods
Methods include testing the effects of temperature (in 10°C
increments (e.g., 50°C, 60°C, etc.) above that for
accelerated testing), humidity, oxidation, photolysis,
photostability, and hydrolysis across various pH levels.

6. Selection of Batches and
Container Closure System
Batch Selection
At least three primary batches,
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.
Packaging for Stability
Stability studies must be conducted on the
drug substance packaged in a container
closure system that simulates the storage
and distribution packaging.

7. Specification and Testing Frequency
Specification
Specification involves a list of tests,
analytical procedures, and acceptance
criteria, which are further discussed in
ICH Q6A and Q6B.
Testing Attributes
Tests should cover physical, chemical,
biological, and microbiological attributes
that could change during storage, and
influence quality, safety, and/or efficacy.
Replication should be performed will
depend on the results.
Frequency of Testing
Testing frequency should establish the stability profile, with specific intervals for long
term and accelerated conditions.
Long Term Studies Every 3 months over the first year, then every 6 months
and annually thereafter(e.g., 0, 3, 6, 12, 18, 24 months).
Accelerated Storage Minimum of three time points over a 6-month study (e.g.,
0, 3, and 6 months).
Intermediate Storage Four time points (e.g., 0, 6, 9, 12 months) over a 12-month
study if significant change at accelerated condition.

8. Storage Conditions
Study Storage Condition Minimum Time Period
Long Term 25°C ± 2°C/60% RH ± 5% RH
or 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
*It is up to the applicant to decide whether long term stability studies are performed at 25 ±
2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.
**If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.
Long-term studies at 25°C ± 2°C/60% RH ± 5% RH should include additional testing at the
intermediate storage condition if significant change occurs during 6 months' testing at the
accelerated storage condition, unless justified otherwise.

9. Special Storage Conditions
Study Storage Condition Minimum Time Period
Refrigerated Drugs
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C/60% RH ± 5% RH 6 months
Freezer Storage
Long term - 20°C ± 5°C 12 month

10. Special Storage Conditions
Refrigerated Drugs
If a significant change occurs within
3 to 6 months of testing at
accelerated storage, the proposed re-
test period should be based on real-
time data.
If significant change occurs within the
first 3 months, further testing on a
single batch for a period shorter than
3 months with more frequent testing is
recommended.
Freezer Storage
For drugs intended for freezer storage,
the re-test period is based on real-time
data at -20°C ± 5°C.
If no accelerated storage condition is
available, testing at elevated
temperatures(e.g., 5°C ± 3°C or 25°C
± 2°C) should be conducted to
address short-term excursions outside
the label storage condition.
Below Freezing
Drugs stored below -20°C are evaluated on a case-by-case basis for stability.

11. Stability Commitment
1 Post-Approval Studies
A commitment to continue stability
studies post-approval is required to
establish the re-test period.
2 Production Batches
If fewer than three production
batches are tested, a commitment to
test additional batches through the
re-test period is needed.
3 Protocol Consistency
The stability protocol for post-approval studies should match that of the primary
batches unless justified otherwise.

12. Evaluation of Stability Data
3
Batches
Stability is based on testing a
minimum of three batches of
the drug substance.
95%
Confidence
The time at which the 95%
confidence limit intersects
the acceptance criterion is
determined.
12
Months
Long term testing should
cover a minimum of 12
months' duration at
submission time.

13. Statements and Labeling
Storage Statement
This section should be based on the
stability evaluation and must comply
with national/regional requirements.
Re-test Period
A re-test period is derived from
stability information, The re-test date,
if applicable, should be clearly
displayed on the container label,
ensuring that the drug substance
remains within specification
throughout its intended shelf life.

14. 3. Guidelines for Drug Product
General Principles
1 Study Design
Stability studies for drug products are based on the
understanding of the drug substance's behavior, properties,
and data from prior studies and clinical trials.
2 Storage Changes
It is essential to predict the likely changes that may occur
during storage and select the appropriate attributes to be
tested in formal stability studies.
3 Rationale
The rationale behind the selection of attributes for testing
should be clearly stated, providing a scientific basis for the
stability study design.

15. Photostability Testing
Photostability testing is a crucial aspect of stability studies, ensuring that the drug product does
not degrade when exposed to light.
This testing should be performed on at least one primary batch of the drug product, following
the standard conditions outlined in ICH Q1B.
The results help in understanding the product's stability under light exposure and in determining
appropriate packaging to protect against such degradation.

16. Selection of Batches for Stability Studies
Primary Batches
Data from stability
studies should be
provided on at least
three primary batches,
reflecting the same
formulation and
packaging as the
marketed product.
Manufacturing Process
The manufacturing process for these
batches should simulate production
batches, ensuring the product quality
and specifications are consistent.
Two of three batches should be pilot
scale, with the third smaller if
justified. Where possible,
manufacture drug products using
different batches of the substance.
Additional Data
Supporting data from
different batches of
the drug substance
can be provided to
further substantiate
stability.

17. Container Closure System
Stability testing must also consider the container closure system, as it plays a significant role in
maintaining the drug product's integrity.
Testing should be conducted on the dosage form packaged in the container closure system
proposed for marketing, including secondary packaging and labels if applicable.
Studies on the drug product outside its immediate container or in other packaging materials can
offer valuable stress testing data or serve as supporting information.

18. Specification in Stability Studies
Consist
Specifications include a
list of tests, analytical
procedures, and
acceptance criteria for
both release and shelf life.
addressed in ICH Q6A
and Q6B and for
degradation products in
Q3B.
Attributes
Testing should cover
attributes likely to change
during storage and affect
the drug product's quality,
safety, and efficacy. the
physical, chemical,
biological, and
microbiological attributes,
preservative content and
functionality tests (e.g.,
for a dose delivery
system).
Validation
Analytical procedures
must be fully validated
and stability-indicating,
with replication
depending on validation
results.

19. General Case Stability Testing
Study Storage condition Minimum time period covered
by data at submission
Long term* 25°C ± 2°C/60% RH ± 5% RH or
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
*It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/60%
RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.
**If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.
•Long-term studies at 25°C ± 2°C/60% RH ± 5% RH should include additional testing at the
intermediate storage condition if a "significant change" occurs during 6 months' testing.
•This change should include a minimum of 6 months' data from a 12-month study at the intermediate
storage condition.
•Significant changes for a drug product include a 5% change in assay, failure to meet potency,
degradation product, appearance, physical attributes, functionality, pH, and dissolution criteria for 12
dosage units.

20. Drug Products in Impermeable
Containers
Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged
in impermeable containers that provide a permanent barrier to passage of moisture or solvent.
Thus, stability studies for products stored in impermeable containers can be conducted under
controlled or ambient humidity condition.

21. Drug Products in Semi-Permeable Containers
Study Storage condition Minimum time period covered
by data at submission
Long term* 25°C ± 2°C/40% RH ± 5% RH or
30°C ± 2°C/35% RH ± 5% RH
12 months
Intermediate** 30°C ± 2°C/65% RH ± 5% RH 6 months
Accelerated 40°C ± 2°C/not more than
(NMT) 25% RH
6 months
*It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/40% RH ± 5%
RH or 30°C ± 2°C/35% RH ± 5% RH.
**If 30°C ± 2°C/35% RH ± 5% RH is the long-term condition, there is no intermediate condition.
•Aqueous-based products packaged in semi-permeable containers should be evaluated for potential water loss,
physical, chemical, biological, and microbiological stability under low relative humidity conditions.
•The study should cover a minimum time period of 12 months at 25°C ± 2°C/40% RH ± 5% RH, 6 months at
30°C ± 2°C/65% RH ± 5% RH, and 6 months at 40°C ± 2°C/not more than (NMT) 25% RH.
•Additional testing at the intermediate storage condition is necessary to evaluate the temperature effect at 30°C
if significant changes occur during the 6 months' testing at the accelerated storage condition.
•A 5% loss in water from its initial value is considered a significant change for a product packaged in a semi-
permeable container after 3 months' storage at 40°C/NMT 25% RH.

22. Drug Products Intended for Refrigerator Storage
Study Storage condition Minimum time period covered
by data at submission
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C/60% RH ± 5% RH 6 months
If the drug product is packaged in a semi-permeable container, drug product's water loss should be
assessed using the evaluation section of this guideline, except where explicitly noted.
If significant changes occur between 3 and 6 months, the shelf life should be based on real-time data
from long-term storage.
If significant changes occur within the first 3 months, further testing should be conducted, and it is
unnecessary to continue testing for 6 months.

23. Drug Products Intended for Freezer Storage
Study Storage condition Minimum time period
covered by data at submission
Long term -20°C ± 5°C 12 months
For freezer-stored drug products, shelf life should be determined using real-time data from
long-term storage conditions. If no accelerated storage is available, testing at elevated
temperatures (e.g., 5°C ± 3°C or 25°C ± 2°C) should be conducted to address short-term
excursions.

24. Drug Products Intended for Storage
Below -20°C
Drug products intended for storage below -20°C should be treated on a case-by-case basis.

25. Stability Commitment for Drug
Products
1 Where the submission includes
long term stability data from
three production batches
covering the proposed shelf life
A post approval commitment is
considered unnecessary.
2 When available long term
stability data on primary
batches do not cover the
proposed shelf life granted at
the time of approval
A commitment should be made to
continue long term studies through
the proposed shelf life and the
accelerated studies for 6 months.
3 When fewer than three
Production batches submitted
A commitment should be made to
add 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.
4 When no data is provided on
production batches
A commitment should be made to
the first three production batches
should be placed on long-term
stability studies and on accelerated
studies for 6 months.

26. Evaluation of Stability Information
A systematic approach
The stability study should
use a systematic approach
to present and evaluate
stability information,
including results from
physical, chemical,
biological, and
microbiological tests.
Purpose
The purpose is to establish
a shelf life and label
storage instructions for
future batches of the drug
product under similar
circumstances.
Validation
The degree of variability
in individual batches
affects the confidence that
a future production batch
will remain within
specification throughout
its shelf life. If data shows
minimal degradation and
variability, formal
statistical analysis is
unnecessary.

27. Statements/Labeling for Drug
Products
A storage statement should be established for the labeling in
accordance with relevant national/regional requirements
The statement should be based on the stability evaluation of the drug product.
also provide specific instructions, avoiding ambiguous terms.
There should be a direct link between the label storage statement
and the demonstrated stability of the drug product
An expiration date should be displayed on the container label.

28. Reference
INTERNATIONAL CONFERENCE ON HARMONISATION OF
TECHNICAL REQUIREMENTS FOR REGISTRATION OF
PHARMACEUTICALS FOR HUMAN USE, ICH HARMONISED
TRIPARTITE GUIDELINE, STABILITY TESTING OF NEW DRUG
SUBSTANCES AND PRODUCTS Q1A(R2), Current Step 4 version dated 6
February 2003