Q1A R2 - ICH GUIDELINES FOR STABILITY TESTS FOR NEW DRUG

1. Stability Testing of
New Drug Substances &
Products
Q1A(R2)
ICH Guideline

2. 1
OUTLINE • Introduction
• Objective
• Scope
• General Principle
• Guidelines For Drug Substance
• Guidelines For Drug Product
• Reference

3. 2
Introduction
 The International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use (ICH) is
unique in bringing together the regulatory authorities and
pharmaceutical industry to discuss scientific and technical
aspects of pharmaceuticals.
 ICH's mission is to achieve greater harmonisation worldwide
to ensure that safe, effective and high quality medicines are
developed, and registered and maintained in the most
resource efficient manner whilst meeting high standards.

4. 3
Objective
 ICH Q1A (R2) guideline specifies the stability data package
necessary for a new drug substance or product registration
application in EU, Japan & USA.
 It aims to standardize the core stability data while allowing
for scientific flexibility due to specific scientific
considerations.

5. 4
Scope
 ICH Q1A (R2) guideline addresses the information to be
submitted in registration applications for new molecular
entities and associated drug products.
 It does not cover abbreviated applications, variations, or
clinical trial applications, nor detail the testing for specific
dosage forms.
 Additional guidance for new dosage forms and
biotechnological/biological products is available in ICH
guidelines Q1C and Q5C.

6. 5
General Principle
 Understand how drug quality is affected over time by
environmental factors (temp., humidity & light).
 Establish shelf life of the drug product.
 Determine recommended storage conditions.
 Test conditions are based on climatic analysis in the EU,
Japan & USA. Acceptance of stability data among these
regions is a key principle of the guideline.

7. 6
Guidelines For Drug Substances
1- General:
 Stability of the drug substance is an integral part of the
systematic approach to stability evaluation.
2- Stress Testing:
 To determine the intrinsic stability of the molecule to identify
the degradation product, establish the degradation
pathways & validate the stability indicating power of the
analytical method.
 It is carried out on a single batch of the drug substance.

8. 7
Guidelines For Drug Substances
3- Selection of Batches:
 Data should be provided on at least three primary batches.
 The batches should be manufactured to a minimum of pilot
scale batches by the same procedures used for the final
product.
4- Container Closure System:
 Should be conducted on the drug substance packaged in a
container closure system that is same as or simulates the
packaging proposed for storage and distribution.

9. 8
Guidelines For Drug Substances
5- Specification:
 Includes list of tests, reference to analytical procedures &
proposed acceptance criteria.
6- Testing Frequency:
 Establish the stability profile, with specific intervals.
A- Long Term Studies B- Accelerated Storage C- Intermediate Storage
Every 3 months over the
first year, then every 6
months and annually
thereafter (e.g. 0, 3, 6,
12, 18 & 24 months).
Minimum of 3 time
points over a 6 months
study (e.g. 0, 3 & 6
months).
4 time points (e.g. 0, 6,
9, 12 months) over a
12 months study if
significant change at
accelerated condition.

10. 9
Guidelines For Drug Substances
7- Storage Conditions:
A- General case: B- In a
refrigerator:
C- In a freezer: D- Below -
20°C:
Type of
Study
Storage Condition Minimum period
Long term 25°C ± 2°C/60% RH ±
5% RH
or
30°C ± 2°C/65% RH ± 5%
RH
12 months
Accelerated 40°C ± 2°C/75% RH ± 5%
RH
6 months
Intermediate 30°C ± 2°C/65% RH ± 5%
RH
6 months
Type of
Study
Storage Condition Minimum period
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C/60% RH ± 5%
RH
6 months
Type of
Study
Storage Condition Minimum period
Long term -20°C ± 5°C 12 months
 Drug substances intended for
storage below -20°C should be
treated on a case-by-case basis.

11. 10
Guidelines For Drug Substances
8- Stability Commitment:
 When available long term stability data don’t cover the
proposed retest period, a commitment should be made to
continue the stability studies.
 For submission includes long-term stability data on 3
batches cover proposed retest period, a post approval
commitment is unnecessary, or:
If the submission includes
data from stability studies on
at least 3 production
batches, a commitment
should be made to continue
these studies through the
proposed retest period.
If fewer than 3 batches, a
commitment should be made
to continue these studies
through the proposed retest
period and to place
additional batches, to a total
of at least 3.
If the submission does not
include stability data on
production, a commitment
should be made to place the
first 3 batches on long-term
stability studies through the
proposed retest period.

12. 11
Guidelines For Drug Substances
9- Evaluation:
 Evaluation should cover the assay & levels of degradation
products.
10- Statements/Labeling:
 Established for the labeling in accordance with regional
requirements.
 The statement should be based on the stability evaluation.
 Specific instructions should be provided, particularly for

13. 12
Guidelines For Drug Product
1- General:
 Study design based on knowledge of the behavior,
properties & results from stability studies on the drug
substance, and experience gained from clinical formulation
studies.
2- Photostability Testing:
 Photostability testing should be conducted on at least one
primary batch of the drug product if appropriate.
 The standard conditions for photostability test described in

14. 13
Guidelines For Drug Product
3- Selection of Batches:
 Data from stability studies should be provided on at least 3
primary batches of the drug product.
 2 of the 3 batches should be at least pilot scale batches
and the third one can be smaller, if justified.
 Where possible, batches should be manufactured by using
different batches of the drug substance.

15. 14
Guidelines For Drug Product
4- 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).
 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,

16. 15
Guidelines For Drug Product
5- Specification:
 Specification consist of tests, analytical procedures, and
acceptance criteria for assessing the quality, safety, and
efficacy of drug products.
 Stability studies test attributes of the drug product
susceptible to change during storage, covering physical,
chemical, biological & microbiological aspects, also
preservative content & functionality tests.
 Analytical procedures must be fully validated and stability-

17. 16
 Criteria for determining shelf life should be derived from
comprehensive stability information.
 Primary stability batches should be tested for preservative
effectiveness at proposed shelf life.
6- Testing Frequency:
A- Long Term Studies B- Accelerated Storage C- Intermediate Storage
Every 3 months over the
first year, then every 6
months and annually
thereafter (e.g. 0, 3, 6,
12, 18 & 24 months).
Minimum of 3 time
points over a 6 months
study (e.g. 0, 3 & 6
months).
4 time points (e.g. 0, 6,
9, 12 months) over a
12 months study if
significant change at
accelerated condition.
Guidelines For Drug Product

18. 17
7- Storage Conditions:
A- General case: B- In a
refrigerator:
C- In a freezer: D- Below -
20°C:
Type of
Study
Storage Condition Minimum period
Long term 25°C ± 2°C/60% RH ±
5% RH
or
30°C ± 2°C/65% RH ± 5%
RH
12 months
Accelerated 40°C ± 2°C/75% RH ± 5%
RH
6 months
Intermediate 30°C ± 2°C/65% RH ± 5%
RH
6 months
Type of
Study
Storage Condition Minimum period
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C/60% RH ± 5%
RH
6 months
Type of
Study
Storage Condition Minimum period
Long term -20°C ± 5°C 12 months
 Drug substances intended for
storage below -20°C should be
treated on a case-by-case basis.
Guidelines For Drug Product

19. 18
E- In impermeable containers: F- in
semipermeable containers:
8- Stability Commitment:
 When available long term stability data don’t cover the
proposed retest period, a commitment should be made to
Type of
Study
Storage Condition Minimum period
Long term 25°C ± 2°C/40% RH ± 5%
RH
or
30°C ± 2°C/35% RH ± 5%
RH
12 months
Accelerated 30°C ± 2°C/65% RH ± 5%
RH
6 months
Intermediate 40°C ± 2°C/ NMT 25% RH 6 months
 Stability studies for products
stored in impermeable
containers can be conducted
under any controlled or ambient
humidity condition as sensitivity
to moisture or potential for
solvent loss is not a concern
Guidelines For Drug Product

20. 19
 For submission includes long-term stability data on 3
batches cover proposed retest period, a post approval
commitment is unnecessary, or:
9- Evaluation:
If the submission includes
data from stability studies on
at least 3 production
batches, a commitment
should be made to continue
these studies through the
proposed retest period.
If fewer than 3 batches, a
commitment should be made
to continue these studies
through the proposed retest
period and to place
additional batches, to a total
of at least 3.
If the submission does not
include stability data on
production, a commitment
should be made to place the
first 3 batches on long-term
stability studies through the
proposed retest period.
Guidelines For Drug Product

21. 20
10- Statements/Labeling:
 Established for the labeling in accordance with regional
requirements.
 The statement should be based on the stability evaluation.
 Specific instructions should be provided, particularly for
drug substances that cannot tolerate freezing.
 Terms such as (ambient conditions or room temperature)
avoided.
Guidelines For Drug Product

22. 21
Reference
 International conference on harmonisation of technical
requirements for registration of pharmaceuticals for human
use (ICH) , “Stability testing of New drug substances and
products Q1A(R2)”.

23. BY
THANK YOU
Hossam
Khayyal
PSAU NO.