1. Stability testing procedures for
pharmaceuticals
according to ICH guidelines
UNDER THE GUIDENCE OF
PROF.B JEEVANA JYOTHI

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
• Evalution of stability data
• Stability data package for the registration
applications of the

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, therape
utic and toxicological specification.
Stability studies types
Long term stability study
Intermediate stability study
Accelerated stability study

4. Factors Affecting Drug Stability
D.E
ratio
D.E &
D.D
interactio
n

5. Need for stability testing
Provide evidence as - how the quality
of drug product varies with time.
Establish shelf life for the drug
product
Determine recommended storage
conditions
Determine container closure system
suitability
Safety point of view of patient
Essential quality attribute

6. Organizations Regulating Stability Guidelines

7. 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

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

9. ICH –Quality
Quality topic of ICH consist of 6 sub
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 &

10. Stability testing guidelines:
They include six sub topics,they are
• 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
• Evalution of stability
data
• Stability data package for the
registration applications of the
climate zones III & IV

11. Where and Why?
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 poduct:
The dosage form in the final
immediate packaging intended for
Marketing.---(API & Excipients)

12. Zone concept
Temperate
zone
KMT- 21⁰c
RH-45%
Mediterian
zone
KMT-25⁰c
RH-60%
Tropical zone
KMT-30⁰c
RH-35%
Desert zone
KMT-30⁰c
RH-70%

14. Stability Protocol & Report

15. Q1A(R2)
guidelines
Q1A (R2) guide lines
Stress testing
Stress testing
Selection of
batches
Container
closure system
specification
Testing
frequency
Storage
conditions
Stability
commitment
Carried out on a single batch and it
include the
effect of tempratures, humidity where
appropriate
oxidation & photolysis on DS
Scope: help to identify degradation
products ,
degradation pathway & intrinsic
stability of the
molecule
Evalution
Statement&labelling
Atleast 3 primary batches of the

16. Q1A(R2)
guidelines
Container closure system
Stress testing
Selection of
batches
Container
closure system
specification
Testing
frequency
Storage
conditions
Stability
commitment
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,
Statement&labelling
references to analytical procedure
Evalution

17. Q1A(R2)
guidelines
Stress testing
Testing frequency
Type of study
Testing frequency
Long term studies
For drug sub. With
a proposed re test
period of atleast 12
months.
1st
year……….3month
s
2nd……………..6mo
nth
There
after……annualy
Through the
proposed re-test
period
Selection of
batches
Container
closure system
specification
Testing
frequency
Storage
conditions
Stability
commitment
Evaluation
Statement & labelling
Accelerated
Min. 3 time

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

19. Drug substances-intended for storage in refridgerator
Study
Storage condition
Minimum time period
covered by data at
submission
Long term
5 C
12 months
Accelerated
25 C
3 C
2 C / 60%
5% R.H.
6 months
Drug substances/Product- intended for storage in Freezer
Study
Storage condition
Minimum time period
covered by data at
submission
Long term
-20 C
12 months
5C

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

21. Q1A(R2)
guidelines
Evalution
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,microbio
logical 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.

22. 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

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

24. Photostability 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 flourosence lamp
combining visible & UV out put , xenon or

25. 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 (eg., wrapped in
aluminium foil)are used as dark controls to
evaluate the contribution of thermally
induced change to the total observed
change.

27. 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 parameteres for various types of dosage forms
Dosage form
Parameter
Appearance,colour
Tablet
,odour,assay,disintigration
s
/dissolution,moisture &
Hard gelatin
friability
capsules Appearance,colour
,odour,assay,disintigration
/dissolution,moisture
&microbial limits
Soft
Appearance,colour
,odour,assay,disintigration

28. Emulsions
Suppositories
Small
volume
Small
Appearance including phase
seperation ,colour
,odour,assay,pH,viscosity,preserv
ative content ,weight loss &
microbial limits
Appearance,colour ,assay
,particle size ,softening range
,dissolution& microbial limits
Appearance ,colour,assay,pH,
preservative content ,particulate
matter , sterlity & pyrogenicity
volume
parentrals
Large volume
Parentrals
Appearance ,colour,assay,pH,
preservative content ,particulate

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

30. 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
Example of a
the stability Designextremes tested.
Bracketing of the

31. 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

33. Evaluation Of The Stability Data
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
This guideline is intended to provide
of 0.25.
recommendations on how to use stability data
generated in accordance with the principles detailed in
the ICH guideline ―Q1A(R) Stability Testing of New
Extrapolation and Products
Drug Substances
 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.

34. Stability Data Package For Registration In Climatic Zones
III and IV
A product’s shelf life should be established
according to climatic conditions in which the
product is to be marketed.
Storage conditions recommended by
manufacturers on the basis of stability studies
are meant to guarantee the maintenance of
quality, safety and efficacy throughout the
shelf-life of product.
Temperature and humidity determine the
storage conditions and so they greatly affect
the stability of drug product.
Climatic conditions in countries where the
product is to be marketed should be carefully

36. ICH Topic Q3C (R4)
Guideline for Residual
Solvents
Residual solvents in pharmaceuticals are
defined here as organic volatile chemicals that
are used or produced in the manufacture of
drug substances or excipients, or in the
.
preparation of drug products.
The solvents are not completely removed by
practical manufacturing techniques.
Appropriate selection of the solvent for the
synthesis of drug substance may enhance the
yield, or determine characteristics such as

37. Since there is no therapeutic benefit from
residual solvents, all residual solvents should
be removed to the extent possible to meet
product specifications, good manufacturing
practices, or other quality-based requirements.
Drug products should contain no higher
levels of residual solvents than can be
supported by safety data.

38. Known human carcinogens, strongly suspected
human carcinogens, and environmental hazards.
Not be employed in manufacturing bcoz of their
unacceptable toxicity or their deleterious
environmental effect
If their use is unavoidable – levels should be restricted
Solvent
Conc.limit(ppm) Concern
Benzene
2
Carcinogen
Ccl4
4
Toxic and
environmental hazard
1,2-Dichloroethane
5
Toxic
1,1-Dichloroethane
8
Toxic

39. Non-genotoxic animal carcinogens or possible
causative agents of other irreversible toxicity such
as neurotoxicity or teratogenicity.
Limited use bcoz of their inherent toxicity.
Solvent
Conc.
limit(ppm)
PDE(mg/day)
Chlorobenzene
360
3.6
Chloroform
60
0.6
1,2-Dichloroethane
1870
18.7
Hexane
290
2.9

40. Solvents with low toxic potential to man; no
health-based exposure limit is needed.
Class 3 solvents have PDEs of 50 mg or more per
day.
Less toxic.
No longterm toxicity or carcinogenicity
Eg :
Acetic acid
Acetone
1-butanol
2-butanol
Heptane

41. Eg :
Isooctane
Petroleum ether
1,1diethoxy propane
Trichloro acetic acid
Methyl tetra hydro furan

43. Conclusion
 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

44. References
2. ICH official web site. www.ich .org
http://www.ich.org/products/guidelines
/quality/article/quality-guidelines.html