This document summarizes ICH guidelines for stability testing of drug substances and products. It discusses the key topics covered by ICH Q1 including stability protocols, studies at different storage conditions, evaluation of stability data, and design approaches like bracketing and matrixing. The guidelines provide recommendations for parameters to test at different timepoints under long term, intermediate, and accelerated conditions. Statistical analysis of batch variability is important to establish a retest or expiry date. Photostability testing and requirements for new dosage forms are also outlined. Overall the ICH Q1 guidelines aim to standardize stability testing practices to ensure quality, safety and efficacy of drugs over their shelf life.

1. List of current ICH quality guiDeline stability
Presented by:
B.Kavita
M.PHARMACY 1st yr
Department of pharmaceutical analysis
Nirmala college of pharmacy

2. Contents :
Introduction
ICH topics
Stability protocol & report
• Stability testing of new drug substances & products
• Photo stability testing of new drug substances & products
• Stability testing of dosage forms
• Bracketing & matrixing design for stability testing of new drug
substance & products
• Evaluation of stability data
References

3. Stability:
 Stability of pharmaceutical product may be defined
as the capability of a particular formulation in a
specific container/closure system to remain with its
physical, chemical, microbiological, therapeutic and
toxicological specification.
Stability studies types :
Long term stability study
Intermediate stability study
Accelerated stability study

4. Organizations Regulating Stability Guidelines

5. The International Conference Of Harmonization
of technical requirements for registration of
pharmaceuticals for human use.
It is unique in bringing together the regulatory
authorities of Europe ,Japan ,US & experts from
pharmaceutical industries to discuss the scientific
and technical aspects of the product registration

6. ICH
TOPICS
QUALITY
(Q)
SAFETY
(S)
EFFICACY
(E)
MULTIDISIPLINARY
(M)
Related to
mfg. QA
Non clinical
pharmacology
& toxicology
studies
Clinical safety,
dose response
studies, good
clinical practices ,
clinical evaluation
Medical terminology,
electronic standards
for transmission of
regulatory
information etc.

7. ICH –Quality
Quality topic of ICH consist of 6 sub topics as
follows:
Q1: Stability testing
Q2: Analytical method validation
Q3: Impurity testing
Q4: Pharmacopoeial harmonization
Q5: Quality of bio technological products
Q6: Specifications for the new drug substances & products

8. Stability testing guidelines:
They include six sub topics, they are
• Stability testing of new drug
substances & products
ICHQ1A(R2)
• Photo stability testing of new drug
substances & productsICHQ1B
• Stability testing of dosage formsICHQ1C
• Bracketing & matrixing design for
stability testing of new drug substance
& products
ICHQ1D
• Evaluation of stability dataICHQ1E

9. Stability Studies are preformed on ...
Drug Substances (DS)/API:
The unformulated drug substance that may
subsequently be formulated with excipients to
produce the dosage form.
Drug Products (DP)/finished product:
The dosage form in the final
immediate packaging intended for
Marketing.---(API & Excipients)
Where and Why?

10. Stability Protocol & Report

11. Q1A(R2)
guidelines
Stress testing
Selection of
batches
Container
closure system
specification
Testing
frequency
Storage
conditions
Stability
commitment
Evaluation
Q1A (R2) guide lines
Stress testing
Carried out on a single batch and it include the
effect of temperatures, humidity where appropriate
oxidation & photolysis on DS
Scope: help to identify degradation products ,
degradation pathway & intrinsic stability of the
molecule
Atleast 3 primary batches of the drug substance
should be representative to quality of material
used for production scale.
Statement&labelling

12. Q1A(R2)
guidelines
Stress testing
Selection of
batches
Container
closure system
specification
Testing
frequency
Storage
conditions
Stability
commitment
Evaluation
Container closure system
Stability study conducted on the drug
substance
Packed in a container closure system
i.e., same or stimulate packaging
proposed for Storage & distribution.
Specification
These guide lines states the list of test,
references to analytical procedure
acceptance criteria.
Statement&labelling

13. Q1A(R2)
guidelines
Stress testing
Selection of
batches
Container
closure system
specification
Testing
frequency
Storage
conditions
Stability
commitment
Evaluation
Testing frequency
Type of study Testing frequency
Long term studies For drug sub. With a
proposed re test period of
at least 12 months.
1st year……….3months
2nd……………..6month
There after……annually
Through the proposed re-
test period
Accelerated studies Min. 3 time points(0,3,6
months),from a 6-month
study
Intermediate studies Min. 4 time points
(0,6,9,12 months),for a
12month study.
Statement&labelling

14. Q1A(R2)
guidelines
Stress testing
Selection of
batches
Container
closure system
specification
Testing
frequency
Storage
conditions
Stability
commitment
Evaluation
Study Storage condition
Minimum time period
covered by data at
submission
Long term 25°C ± 2°C / 60% ± 5% R.H or
30°C ± 2°C / 65% ± 5% R.H.
12 months
Intermediate 30°C ± 2°C / 65% ± 5% R.H. 6 months
Accelerated 40°C ± 2°C / 75% ± 5% R.H. 6 months
Storage conditions
Statement&labelling
Drug products - General case

15. 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% ± 5% R.H. 6 months
Drug substances-intended for storage in refrigerator
Study Storage condition Minimum time period
covered by data at
submission
Long term -20°C ± 5°C 12 months
Drug substances/Product- intended for storage in Freezer

16. Q1A(R2)
guidelines
Stress testing
Section of
batches
Container
closure system
specification
Testing
frequency
Storage
conditions
Stability
commitment
Evaluation
Statement&labelling

17. Q1A(R2)
guidelines
Evaluation
Evaluation
The purpose of stability is to establish re-test period(DS)
& shelf life (DP) for future batches based on evaluation of
results obtained from
chemical,physical,biological,microbiological tests.
A systemic approach should be adopted in the
presentation & evaluation of the stability information
which covers the physical ,chemical & biological
parameter
A minimum of 3 batches of drug product was tested.
The analyst must found the batch to batch
variability & if it is small then only it is
accepted & can be done by different statistical tests

18. Significant change of drug substance or product
A 5% change in assay from its initial value
Any degradation product exceeding its acceptance
criteria
Failure to meet acceptance criteria for appearance
,physical attributes (colour,phase separation
,hardness), pH
Failure to meet acceptance criteria for dissolution
for 12 dosage forms

19. Q1A(R2)
guidelines
Stress testing
Section of
batches
Container
closure system
specification
Testing
frequency
Storage
conditions
Stability
commitment
Evaluation
Statement&labelling
Statement & labeling
A storage statement should be
established for labeling in relevant
national or regional requirements
Should be established based on the
stability evaluation of drug substance
Terms such as “Ambient conditions "or
“Room temperature” should be avoided
Retest date for DS & expiry date for DP
should be displayed on the container label
if appropriate

20. Photo stability testing
Light can effect drugs ,causing chemical changes so
evolution of drugs after exposing to light must be carried
on single batch of material selected
Gives idea about how to store drug
Testing carried out on:
Tests on active substance
 Exposed drug product out side of the immediate
pack
Drug product in the immediate pack
 Drug product in the marketing pack
Light sources
Artificial daylight fluorescence lamp combining visible
& UV out put , xenon or metal halide lamp
D65 is for out door day light
ID65 is for indoor indirect day light

21. Procedure
Sample should be exposed to light providing an over all
illumination of not less than 1.2 million lux hours & an
integrated near UV energy of not less than 200 watt hours
/sq.meter
Protected samples (e.g.., wrapped in aluminium foil)are
used as dark controls to evaluate the contribution of
thermally induced change to the total observed change.

23. Stability test for New dosage forms
new dosage forms ……
• Same active substance
• Different administration route
• New specific functionality or delivery systems
• Different dosage forms of same administration route
Stability test parameters for various types of dosage forms
Dosage form Parameter
Appearance, colour ,odour,
assay,disintigration /dissolution,
moisture & friability
Appearance, colour ,odour,
assay,disintigration /dissolution,
moisture &microbial limits
Soft gelatin
capsules
Appearance, colour
,odour,assay,disintigration
/dissolution,moisture ,microbial limits
,pH,leakage & pellicle formation
Tablets
Hard gelatin
capsules

24. Emulsions Appearance including phase seperation
,colour
,odour,assay,pH,viscosity,preservative
content ,weight loss & microbial limits
Suppositories Appearance,colour ,assay ,particle size
,softening range ,dissolution& microbial
limits
Small
volume
Small volume
parentrals
Appearance ,colour,assay,pH, preservative
content ,particulate matter , sterlity &
pyrogenicity
Large volume
Parentrals
Appearance ,colour,assay,pH, preservative
content ,particulate matter , sterlity &
pyrogenicity
Transdermals
Appearance, assay , leakage,sterility, peel &
adhesive forces , drug release rate

25. Bracketing & matrixing design for stability testing of new drug
substance & products
Study design
Full study
design
Reduced study
design
Samples of all
designed factors for
every combination
are tested at all time
points
Not Samples of all designed
factors for every combination
are tested at all time points
Bracketing Matrixing

26. Bracketing
Bracketing is the design of a Stability schedule such
that only samples on the extremes of certain design
factors (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
intermediate levels is represented by the stability of the
extremes tested.
Example of a Bracketing Design

27. Matrixing
 Matrixing is the design of a stability schedule such
that a selected subset of the total number of possible
samples for all factor combinations would be tested at a
specified time point.
At a subsequent time point, another subset of samples
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 point.

29. The parent guideline 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
poolability be performed using a level of significance of 0.25.
This guideline is intended to provide recommendations on how to use
stability data generated in accordance with the principles detailed in the
ICH guideline ―Q1A(R) Stability Testing of New Drug Substances and
Products
Extrapolation
 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 The Stability Data

30.  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.
Conclusion

31. References