this content takes important information about stability & stability study of pharmaceutical products including guidelines,climate zone,testing conditions,sampling plan,extension of shelf life,re test,current trends in stability study etc.

1. Presentation on: stability study of pharmaceutical products
Presented To:
Department of Pharmacy
Northern university
Bangladesh
Supervised by:
Dr. Harun AR Rashid
Associate professor &
Head
Department of Pharmacy
Presented By:
Md.Mohsin &
Khadija Tut Tahera
NORTHERN UNIVERSITY
B A N G L A D E S H

2. Contents
stability
Stability study
Types of
stability
Pharmaceutical
degradation
Testing
conditions
Climate zone
Guidelines
Types of
stability testing
Activation
energy
Shelf life
prediction
Limitation of
accelerated
study
Current trend
in stability
testing

3. Stability
.
Stability of pharmaceutical product may be defined as the
capability of a particular formulation in a specific
container/closure system to remain within its physical,
chemical, microbiological, therapeutic and toxicological
specification.

4. Stability study
Stability testing/study is termed as a complex
process because of involvement of a variety of
factors including
1
stability of the active
ingredients
3
heat and moisture
conditions
encountered
during shipment,
storage and
handling.
4
type of dosage
form
5
interaction
between active
ingredients and
excipients
2
container/closure system
used for packaging

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

6. Ultimate achievement
Assurance to
the patient
Economic
considerations
Legal
requirement

7. THEARAPEUTICAL
STABILITY
PHYSICAL
STABILITY
TOXICOLOGIC
STABILITY
MICROBIOLOGICAL
STABILITY
CHEMICAL
STABILITY
Stability

8. PHARMACEUTICAL DEGRADATION
1. Physical
degradation
2. Chemical
degradation
3.Microbiological
degradation
TYPES OF PHARMACEUTICAL DEGRADATION

9. FACTORS AFFECTING PHYSICAL DEGRADATION
PHYSICAL
DEGRADATION
Polymorphic
changes
Crystal
growth
Absorption
of H2O
Loss of H2O
Loss of
volatile
components
Color
changes

10. chemical degradation
Hydrolysis oxidation Decarboxylation Isomerization Polymerization

11. MICROBIAL DEGRADATION
MICROBIAL
DEGRADATION
EndotoxinPyrogen

12. What happens if drug is degraded?
Lowering of concentration/potency
Active to toxic product
appearance
Reduction in bioavailability

13. TYPES OF STABILITY TESTING
stability testing
Real-Time stability
testing
Accelerated stability
testing
Retained
sample/ongoing stability
testing

14. GUIDELINES
guidelines
ICH
FDAWHO

15. Climate zone
Four climatic zones can be distinguished for the purpose of worldwide
stability testing, as follows: ICH Stability Zones
Zone Type of Climate
Zone I Temperate zone
Zone II Mediterranean/subtropical zone
Zone III Hot and dry zone
Zone IV Hot humid/tropical zone
Zone IVb ASEAN testing conditions
hot/higher humidity

16. Testing Conditions
Long Term/Real-Time stability testing
Climatic Zone Temperature Humidity Minimum
Duration
Zone I 21ºC ± 2ºC 45% RH ± 5% RH 12 Months
Zone II 25ºC ± 2ºC 60% RH ± 5% RH 12 Months
Zone III 30ºC ± 2ºC 35% RH ± 5% RH 12 Months
Zone IV 30ºC ± 2ºC 65% RH ± 5% RH 12 Months
Zone IVb 30ºC ± 2ºC 75% RH ± 5% RH 12 Months
Refrigerated 5ºC ± 3ºC No Humidity 12 Months
Frozen -15ºC ± 5ºC No Humidity 12 Months

17. Testing Conditions
Accelerated and Intermediate Testing Conditions
Climatic Zone Temperature Humidity Minimum Duration
Accelerated
Ambient
40ºC ± 2ºC 75% RH ± 5% RH 6 Months
Accelerated
Refrigerated
25ºC ± 2ºC 60% RH ± 5% RH 6 Months
Accelerated Frozen 5ºC ± 3ºC No Humidity 6 Months
Intermediate 30ºC ± 2ºC 65% RH ± 5% RH 6 Months

18. Sampling Frequency
For Long term testing, during first year sampling should be done
every three months, during second year, sampling should be done
every six months and after two years, sampling should be done once
a year.
Accelerated testing should be done at least six months and it
suggests sampling points of 0, 3, 6 months.

19. Testing parameters of different dosage forms
Tablets Capsules Oral solutions,
suspensions and
emulsions
Topical &
Ophthalmic and
Preparation
Powders and granules for
oral solution or suspension
Metered-dose
Inhalations and
Nasal Aerosols

20. Examples of testing parameters contd
Suppositories Freeze-dried
Products
Transdermal Patches
large volume
parenterals (LVPs)
Small volume
parenterals (SVPs)

21. ACCELERATED STABILITY TESTING AND ACTIVATION ENERGY
Activation energy is the energy that must be overcome in order for a
chemical reaction to occur. Activation energy may also be defined as the
minimum energy required to start a chemical reaction. The activation
energy of a reaction is usually denoted by Ea.

22. ARRHENIUS EQUATION
Reaction rates are proportional to the number of collisions per unit time
(of reactant molecules). The number of collisions increases as the
temperature increases. Therefore, the reaction rate increases as the
temperature increases according to Arrhenius equation
K = A e-Ea/RT
logK = logA - (Ea/2.303RT)
K = reaction rate constant
A = frequency factor constant i.e maximum number
of collisions at infinite temperature
Ea = Energy of activation
T = absolute temperature (Kelvin)

23. Estimation of energy of activation
Fig. Arrhenius plot
A graph can be drawn by taking log k on y-axis and reciprocal
temperature (1/T) on x-axis.
A straight line is obtained, the slope of the line is negative and
the magnitude is Ea / 2.303 R.
The intercept corresponds to logA
All the constants in the Arrhenius equation can be obtained from
the graph.

24. Estimation of k value
The reaction is conducted at several
temperatures.
Concentration of reactants is determined.
Appropriate graphs are drawn for the kinetic
data.
Data is processed for all the orders.
The order of the reaction is identified and
from the slopes of the lines, k values are
calculated for all temperatures.
Arrhenius plot for
elevated temperatures

25. SHELF LIFE EXTENSION
To support a shelf life extension, a report must be generated documenting
stability data (for the proposed interval) for three batches which meet all
the following criteria:
Same product /
potency
Same
manufacturing
process.
Same primary
packaging
material
Same
formulation
No significant
change in the
manufacturin
g procedure

26. Re-stability test after registration
Once the pharmaceutical product has been registered, additional stability
studies are required whenever variations that may affect the stability of
the active pharmaceutical substance or pharmaceutical product are
made, such as major variations like the following:
a. Change in the
manufacturing process.
b. Change in the
composition of the
pharmaceutical
product.
c. Change of the
immediate packaging.

27. PHOTOSTABILITY
Photo degradation may be observed as bleaching or as discoloration of products.
The other effects include cloudy appearance of the product, a loss in viscosity of
formulation, precipitation of active principle, alteration in dissolution rate, Although
many drugs are found to decompose when exposed to light.
Light
Source
Xenon
lamps
Tungsten-
mercury
lamps
Natural
Light
Artificial
daylight
tubes
By exposing drug substance to 400
& 900 (FC)of illumination for 4 & 2
weeks to light and another sample
examined protected from light .
e.g. cycloprofen becomes very
yellow after five days under 900
foot candles of light

28. Limitation of Arrhenius relationship for stability prediction
Stability predictions based on Arrhenius equation are valid only when the break
down depends on temperature
The energy of activation obtained in the study should be between 10 to 30
kcal/mole
When degradation is due to Microbial contamination or Photochemical reactions
When the product looses its physical integrity at higher temperatures
When the order changes at elevated temperatures
In case of disperse systems, when temperature is elevated viscosity is
decreased and this may introduce errors in the prediction of stability

29. STABILITY CHAMBER

30. CURRENT TRENDS IN STABILITY TESTING
Current trend, especially amongst the multinational pharmaceutical
companies, is to define conditions for stability testing for global marketing.
For this the companies are orienting their protocols to single set of
conditions that covers extreme environmental conditions. The specific
changes for global testing include increase in duration of accelerated
testing period from 6 to 12 months, and conduct of additional tests at
50°C/75% RH for 3 months.
The concept behind this change is to avoid repetition of stability testing for
other regions and efficient and optimum use of resources as all tests are
done in one laboratory. Moreover testing under combination of three
environmental factors ; temperature, humidity and light, has been reported
to result in stronger deleterious effect on drug substances and products,
than under temperature and humidity conditions only.

31. Reference
1.Stability testing for hot and humid climates, WHO Drug Information Vol 18,
2, 2004, page 113-156
2. World Health Organization :Stability Testing Of Active Pharmaceutical
Ingredients and Finished Pharmaceutical Products; WHO Technical Report
Series, No. 953, 2009 ; Page No.87-123.
3. ICH Q1A: “Stability Testing of New Drug Substances and Products”
http://www.ich.org/LOB/media/MEDIA419.pdf
4.ICH Q1C: “Stability Testing of New Dosage Forms”
http://www.ich.org/LOB/media/MEDIA413.pdf
5.ICH Q1E: “Evaluation for Stability Data”
http://www.ich.org/LOB/media/MEDIA415.pdf
http://www.ich.org/LOB/media/MEDIA427.pdf
http://www.ich.org/LOB/media/MEDIA430.pdf
6.Handbook of modern pharmaceutical analysis, Volume III, page: 445-483

32. Reference
7. Ali J., Khar RK., Ahuja A. Dosage form and design.3rd ed. Delhi. Birla
Publications Pvt. Ltd ( 2008) 100-123
8.International Conference on Harmonization, guidelines Q1A and Q1F,
www.ich.org/
9.CVS Subrahmanyam, Textbook of Physical Pharmacy, Second Edition; 15
May 2000;Page No-51-58,366-426
10. Grimm W. Extension of the international conference on harmonization
tripartite guideline for stability testing of new drug substances and products
to countries of climatic zones 3 and 4. Drug Dev.Ind. Pharm. 1998; 24:313-
325
11.http://www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTechnical
Guides/ucm072919.htm
12. http://www.authorstream.com/Presentation/sachins_patil16-1564811-ich-
guidelines-stability-studies-accelerated/
13. http://apps.who.int/medicinedocs/en/d/Jh1808e/