The document discusses stability testing of pharmaceutical products. It defines the purpose of stability testing as providing evidence of how a product's quality varies over time under the influence of factors like temperature, humidity and light. There are two main types of stability studies: stability studies and accelerated stability studies. Stability studies involve testing products under various storage conditions like long term, intermediate and accelerated conditions over minimum time periods to establish a product's shelf life.

1. STABILITY STUDIES
K.KRANTHI KUMAR M.Pharm.,M.B.A.,(Ph.D)
Asst.Prof
Department of Pharmaceutics
SKU college of Pharmaceutical Sciences
S.K. University
Anantapur
Andhra Pradesh

2. To gather information during Preformulation stage to produce a stable
product. To determine maximum expiration date. To get an idea of
storage condition. To determine the packaging components. To
establish retest period of pharmaceuticals. To establish Transport
conditions.
The main concept of stability testing of pharmaceuticals is to find
out the product shelf life.
The Purpose of stability testing is to provide evidence how quality
varies with time under influence of - temperature - humidity – light.
This stability studies are 2 types
1.Stability studies
2.Accelerated stability studies
There are different stages in stability studies

3. STAGE 1-Early stage stress-and accelerated testing with drug
substances
STAGE 2-Stability on pre-formulation batches
STAGE 3-Stress testing on scale-up batches
STAGE4-Accelerated and long term testing for registration purposes.
STAGE5-On-going Stability Testing
STAGE 6-Follow-up Stabilities.
Q1A(R2)-Stability Testing of New Drug Substances and Products.
Q1B- Stability Testing : Photo stability Testing of New Drug
Substances and Products.
Q1C- Stability Testing for New Dosage Forms.
Q1D- Bracketing and Matrixing Designs for Stability Testing of New
Drug Substances and Products.
Q1E- Evaluation of Stability Data.
Q1F- Stability Data Package for Registration Applications in Climatic
Zones III and IV.
Q5 C-Stability testing of biotechnological /biological products

4. Degradation pathways
Physical degradation
1.Loss of volatile constituents
2.Loss of water
3.Absorption of water
4.Crystal growth
5.Polymorphisam
6.Colour changes
Loss of volatile constituents:-medicinal agents like iodine camphor
menthol have tendency to evaporate from the product during storage.
Similarly nitroglycerine tablets may loose its potency owing to
volatilization of the medicament.

5. Loss of water:-loss of water from the product leads to decrease the
weight, increase concentration of drug &increases potency.efferescent
substances borax, caffeine losses water. Emulsions &semisolids
exhibits cracking.
Absorption of water:- Absorption of water from atmosphere increases
weight of the product,dilites the dose decreases potency.
Crystal growth:-fluctuation sin the ambient temperature causes crystal
growth. When the solutions storage conditions are changes it
becomes super saturation and crystal growth occurs.
Polymorphism:-it exhibits significance change in physicochemical
properties like solubility,dissolution,melting point.
Colour change:-it indicates photochemical decomposition of the
active ingredients

6. .
Chemical decomposition
1.1.hydrolisis
2.Oxidation
3.Environmental control measurements
4.Miscellaneous reactions
a.Isomerisation
b.epimerisation
c.Absorption of Co2

7. Statistical Considerations and Evaluation
A stability protocol should describe not only how the
stability study is to be designed and carried out, but also the
statistical method to be used in analyzing the data. An
acceptable statistical approach to the analysis of stability
data and the specific features of the stability study that are
pertinent to the analysis. Generally, an expiration dating or
retest period should be determined based on statistical
analysis of observed long-term data.
Expiration Dating Period for an Individual Batch
The time during which a batch may be expected to remain
within specifications depends not only on the rate of
physical, chemical or microbiological changes, but also on
the initial average value for the batch.

8. The expiration dating period for an individual batch is
based on the observed pattern of change in the quantitative
attributes (e.g. content uniformity,assay,degradation
products) under study and the precision by which it is
estimated.
Bracketing:-
It is design of a stability schedule such that only samples on
the extremes of certain design factors(strength ,container
size,/fill) are tested at all time points as in a full design. the
designs assumes that the stability of any intermediate levels
is represented by the stability of extremes tested. The use of
reduced stability testing, such as a bracketing design, may
be a suitable alternative to a full testing program where the
drug is available in multiple sizes or strengths.

9. Bracketing design is applicable to most types of drug
products, including immediate- and modified-release oral
solids, liquids, semi-solids, injectables. Certain types of
drug products, such as metered-dosed inhalers (MDIs), dry
powder inhalers (DPIs) and transdermal delivery systems
(TDSs).Where a range of container/fill sizes for a drug
product of the same strength is to be evaluated, bracketing
design may be applicable if the material and composition of
the container and the type of closure are the same
throughout the range.

10. An example of bracketing design where both strengths and
container/fill sizes are bracketed in one protocol and “X”
denotes the combination of strength and container/fill size
to be placed on stability study. In this hypothetical situation,
the capsule dosage form is available in three different
strengths made from a common granulation and packaged
in three different sizes of HDPE bottles with different fills:
30 counts, C1; 100 counts, C2; and 200 counts, C3. 300
counts.The surface area/volume ratio, dead space/volume
ratio, container wall thickness, and closure performance
characteristics are assumed to be proportional among the
three container/fill sizes for each strength of the capsules.

11. Batch 1 2 3
Strength 100mg 200mg 300mg 100mg 200mg 300mg 100mg 200mg 300mg
Contain
e/closer
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
Sample
stability
X X X X X X X X X X X X
Matrixing:- Matrixing is a statistical design for stability
testing that requires experimental stability data to be
obtained from all forms of the drug product but permits
only a fraction of the total number of samples to be tested at
any specified sampling point according to a specific
sampling design The use of reduced stability testing, such as
a Matrixing design, may be a suitable alternative to a full
testing program where multiple factors involved in the
product are being evaluated..

12. Batch 1 2 3
Strength 100mg 200mg 300mg 100mg 200mg 300mg 100mg 200mg 300mg
Contain
e/closer
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
C
1
C
2
C
3
Schdule
s
T
1
T
2
T
3
T
2
T
3
T
1
T
3
T
1
T
2
T
2
T
3
T
1
T
3
T
1
T
2
T
1
T
2
T
3
T
3
T
1
T
2
T
1
T
2
T
3
T
2
T
3
T
1
TIME
POIN
TS
(min)
0 X X X X X X X X X X X X X X X X X X X
3 X X X X X X X X
6 X X X X X X X X X
9 X X X X X X X X X X X X X X X X X X
1
2
X X X X X X X X X X x x X X X X X X X
1
8
X X X X X X X X X X X X X X X X X X X X X X X X X X X
2
4
X X X X X X X X X X X X X X X X X X X X X X X X X X X

13. Matrixing design is applicable to most types of drug
products, including immediate- and modified release oral
solids, liquids, semisolids, injectables.
Matrixing designs can be applied to strengths with identical
or closely related formulations.
1.Capsules with different strengths made different fill plug
sizes.
2.Tablets with different strengths manufactured by
compression varying amount of same granulation.
3.Oral solutions with different minor changes in excipients.

14. TIME POINTS(MONTHS) 0 3 6 9 12 18 24 36
S
T
R
E
N
G
T
H
S1 BATCH-1 T T T T T T
BATCH-2 T T T T T T
BATCH-3 T T T T T
S2 BATCH-1 T T T T T
BATCH-2 T T T T T T
BATCH-3 T T T T T
“ONE-HALF REDUCTION”
TIME POINTS(MONTHS) 0 3 6 9 12 18 24 36
S
T
R
E
N
G
T
H
S1 BATCH-1 T T T T T T
BATCH-2 T T T T T T T
BATCH-3 T T T T T T T
S2 BATCH-1 T T T T T T T
BATCH-2 T T T T T T
BATCH-3 T T T T T T
“ONE-THIRD REDUCTION”

15. Examples of Matrixing designs on time point for a product
in two strengths(S1,S2).the term one-half reduction, one
third reduction refer to the reduction strategy initially
applied to fully study design.
Ex:-on half reduction initially eliminates one in every two
points from the fully study design and a one third reduction
initially removes in in every three. In the examples show
in reduction are less than one-half & one-third due to the
inclusion of full testing of all factors combination at some
time points. These ex include full testing at the initial final
and 12months time point. the ultimate reduction is
therefore less than one-half(24/48) or one third (16/48)and
is actually15/48 or 10/48.

16. Application:-
Knowledge of data variability.
Expected stability of the product.
Availability of supporting data.
Stability differences in the product within a factor or
among factors.
Number of factor combinations in the study.

17. ICH Guidelines
• Quality Guidelines “Q” (chemical and pharmaceutical QA)
• Safety Guidelines “S” (in vitro and in vivo pre-clinical studies)
– covering Carcinogenicity Testing, Genotoxicity Testing,
Toxicokinetics and Pharmacokinetics ….. etc.
• Efficacy Guidelines “E” (clinical studies in human subject)
– Covering clinical safety, Dose Response Studies, Good
Clinical Practices, Clinical evaluation …. etc.
• Multidisciplinary Guidelines “M”
– Covering Medical Terminology, Electronic Standards for
Transmission of Regulatory Information …… etc.
– Important for Stability !
» Guideline M4: The Common Technical Document (CTD)

18. Stability Testing Q1
 Stability Testing in Climatic Zone I and II (Q1A)
 Photo stability Testing (Q1B)
 Stability Testing for New Dosage Forms (Q1C)
 Bracketing and Matrixing Designs (Q1D)
 Evaluation of Stability Data (Q1E)
 Stability Testing in Climatic Zones III and IV (Q1F)
Validation of Analytical Procedures (Q2)
Impurities (Q3)
 Impurities in New Drug Substances (Q3A)
 Impurities in New Drug Products (Q3B)
Pharmacopoeial Harmonization (Q4)
Biotechnological Products (Q5)
Specifications (Q6)
ICH – Q – Guidelines

19. DEFINITIONS
Shelf life (expiration dating period, conformance period)
Self life is the time period during which a drug product is expected to
remain within the approved specification for use, provided that it is
stored under the conditions defined on the container label.
Re-test period
The period of time during which the drug substance is expected to
remain within its specification and, therefore, can be used in the
manufacture of a given drug product, provided that the drug substance
has been stored under the defined conditions.

20. Formal stability studies
Long term and accelerated (and intermediate) studies undertaken on primary
and/or commitment batches according to a prescribed stability protocol to
establish or confirm the re-test period of an API or the shelf life of a FPP.
Stress testing – forced degradation (API)
Studies undertaken to elucidate the intrinsic stability of the API. Such testing
is part of the development strategy and is normally carried out under more
severe conditions than those used for accelerated testing.
Stress testing – forced degradation (FPP)
Studies undertaken to assess the effect of severe conditions on the FPP. Such
studies include photostability testing (see ICH Q1B) and compatibility testing
on APIs with each other in FDCs and API(s) with excipients during
formulation development.

21.  Primary batch (called also exhibit batch)
A batch of an API or FPP used in a formal stability study, from which stability
data are submitted in a registration application for the purpose of establishing a
re-test period or shelf life, respectively. A primary batch of an API should be at
least a pilot scale batch. For a FPP, two of the three batches should be at least pilot
scale batch, and the third batch a production batch.
 Commitment batches
Production batches of a drug substance or drug product for which the stability
studies are initiated or completed post approval through a commitment made in
the registration application.
 Pilot (scale) batch
A batch of an API or FPP manufactured by a procedure fully representative of
and simulating that to be applied to a full production scale batch. (For solid oral
dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full
production scale or 100,000 tablets or capsules, whichever is the larger.)
 Production (scale) batch
A batch of an API or FPP manufactured at production scale by using production
equipment in a production facility as specified in the application.

22.  Specification - Release
The combination of physical, chemical, biological, and microbiological
tests and acceptance criteria that determine the suitability of a drug
product at the time of its release.
 Specification - Shelf life
The combination of physical, chemical, biological, and microbiological
tests and acceptance criteria that determine the suitability of an API
throughout its re-test period, or that anFPP should meet throughout its
shelf life.
 Mass balance
The process of adding together the assay value and levels of degradation
products to see how closely these add up to 100% of the initial value,
with due consideration of the margin of analytical error.

23. WORLDWIDE ZONES / TEMPERATURE AND
HUMIDITY CONDITIONS
Zone Mean kinetic
temperature
Yearly average
humidity (%RH)
Zone I ( Moderate) 21 ̊C 45
Zone II (Mediterranean) 25 ̊C 60
Zone III (Hot, dry) 30 ̊C 35
Zone IV (Very hot,
moist)
30̊ C 70

24. COUNTRIES AND ZONES
Regions Zone I &II Zone III&IV
EUROPE All countries
AMERICA Argentina, Bolivia, Canada,
Mexico, US
Brazil, Columbia, Cuba,
Jamaica
ASIA Afghanistan, China, Iran,
Nepal, Turkey, Japan
Bahrain , Hong Kong,
India, Oman , Pakistan,
Srilanka, UAE
AFRICA Egypt, Algeria, South Africa,
Libya
Angola, Benin, Congo,
Uganda, Sudan, Somalia,
Senegal

25. 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 IN A REFRIGERATOR
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
STORAGE CONDITIONS FOR STABILITY STUDY
API/DRUG SUBSTANCES TO BE STOTRED AT AMBIENT TEMPERATURES
Study Storage condition Minimum time period
covered by data at
submission
Long term -20 C 5 C 12 months
STORAGE IN FREEZER

26. DRUG PRODUCTS - PACKAGED IN
SEMI-PERMEABLE CONTAINERS
Study Storage condition Minimum time
period covered by
data at submission
Long term 25 C 2 C / 40% 5% r.h.
or
30 C 2 C / 35% 5% r.h.
12 months
Intermediate 30 C 2 C / 65% 5% r.h. 6 months
Accelerated 30 C 2 C / 65% 5% r.h. 6 months

27. Evaluation
 A systematic approach should be adopted in the presentation
and evaluation of the stability information.
 Where the data show so little degradation and so little
variability that it is apparent from looking at the data that the
requested shelf life will be granted, it is normally unnecessary to
go through the formal statistical analysis; providing a
justification for the omission should be sufficient.
 An approach for analysing data on a quantitative attribute that
is expected to change with time is to determine the time at which
the 95% one-sided confidence limit for the mean curve
intersects the (lower) acceptance criterion (95% assay).

28. Visible variability and trend
The simple linear regression analysis yields the
equation:
Y = slope X + intercept
where Y is the assay, X is the time factor
expressed in months, the slope is the degradation
rate and the intercept is the assay at time = 0.
Regression analysis provides two additional
factors: the p-value of the slope and the standard
deviation about the regression line SX/Y

29. Evaluation – Change with Time
 The hypothetical figure in the former slide illustrates
that the extrapolated shelf life is 29 months
(25oC/60%RH) and there is only a 5% chance that this
estimate will be high. Such a plot covers assay values
from 100% down to 95%.
 The majority of degradation processes results in an
essentially linear line in this range of the label claim
thus the method is generally applicable for the
estimation of the expiry date at the studied storage
conditions.

31. The Stability Chambers are designed for an operating range
of 4°C to 70°C Temperature only, 5°C to 60°C
Temperature with Humidity. These units employ a
programmable controller to control the temperature, defrost
and humidity settings. The cabinets use an evaporator coil,
located on top of the cabinet as the heat-removing source.
Through the refrigeration process, heat is captured in the
evaporator, transferred to the condensing unit on top of the
cabinet, and expelled to the surrounding outside air. It is
extremely important to allow a four-inch clearance on the
top, rear, and sides of the unit for the refrigeration process
to function properly.

32. Decision Tree for Data Evaluation for Retest Period or
Shelf Life Estimation for Drug Substances or Products