Stability testing

INDEX
Introduction
Advantages
Types
Stability evaluation for different formulations
Shelf life estimation
Overage calculation
ICH guidelines

“A measure of how pharmaceutical product
maintains its quality attribute over a time”

Stability
 The USP defines the stability of a
pharmaceutical product as “ extent to which a
product retains , with in specified limits, and
throught out its period of storage and use i.e its
shelf life, the same properties and
characteristics that it possesed at the time of its
manufacture”.

Stability is used to determine
 quality of a drug substance or drug product

 shelf life for the drug product

 Recommended storage conditions

Why stability testing is necessary-
Chemical degradation may lead lowering of


concentrataion of drug in dosage form

toxic product may form due to degradation of
active ingridients

Advantages of stability studies

 Assurance to the pateint

 Economic consideration

 Legal requirements

Types of stability

 Chemical
 Physical
 Microbiological
 Therapeutical
 Toxicological

Stability evaluation for different
formulations
1.Tablets
 odour
 colour
 assay
 degradation
 products
 dissolution
 moisture
 hardness/friability.

2. Capsules
 appearance (including
 brittleness),
 colour
 odour of content,
 assay,
 degradation products,
 dissolution,
 moisture and microbial content.

3. Emulsions
 appearance (including phase separation),
 colour,
 odour,
 assay,
 pH, viscosity, microbial limits,
 preservative content, and mean size and
distribution of dispersed globules.

4. Oral Solutions and Suspensions

 Additionally for suspensions, redispersibility,
rheological properties
 mean size and distribution of particles should be
considered.

5. Oral Powders for Reconstitution

 moisture and reconstitution time.

6.Metered-dose Inhalations and Nasal Aerosols

 appearance (including content, container, valve,
and its components),
 Dose content uniformity
 labeled number of medication actuations per
container meeting
 aerodynamic particle size distribution,
 microscopic evaluation,
 water content,
 leak rate,
 microbial limits

7.Topical & Ophthalmic and Preparation
(ointments, creams, lotions, paste, gel,solutions and non-metered aerosols
forapplication to the skin)

-Topical preparations
 clarity, colour,odour, pH, resuspendability (for
lotions), consistency,
 viscosity,
 preservative and antioxidant content (if
present), microbiallimits/sterility and weight
loss (when appropriate).

-Evaluation of ophthalmic or (e.g., creams, ointments,
solutions,and suspensions)

 Sterility
 particulate matter, and extractable.

-Evaluation of non-metered topical aerosols

 delivery rate,
 microbial limits,
 spray pattern,
 water content, and particle size

8. Suppositories

 softening range, dissolution (at 37 C)
 Microbial limits.

9. Small Volume Parenterals (SVPs) & Large
Volume Parenterals (LVPs)

 particulate matter, pH, sterility and
pyrogen/endotoxin.

10. Transdermal Patches

 in-vitrorelease rates,
 leakage,
 microbial limits/sterility, peel and adhesive forces, and
 the drug release rate.

11. Freeze-dried Products

 Appearance of both freeze-dried and its reconstituted
product, assay,
 degradation products, pH, water content and rate of
solution.

Shelf life estimation
&
overage calculation

What is shelf life ??

Shelf life (t0.9)
It is defined as the time necessary for the drug
to decay to 90% of its original concentration.

Accelerated analysis for chemical stability

 Based on the principles of chemical kinetics
 Test are carried out at different elevated
temperature that enables prediction of the
effective life of the preparation at normal
temperature

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 = reaction rate constant
A = frequency factor constant i.e maximum
number of collisions at infinite temperature
Ea = Energy of activation
T = absolute temperature (Kelvin)

Arrhenius plot:
 Click to edit Master text styles

Second level

Third level

Fourth level

Fifth level

1.According to the Garrett and carper “the
k value for decompostion of a drug in
solution at various elevated temperature are
obtained by plotting some function of
concentration against time”.

Accelerated breakdown of a drug in solution at various
elevated temperature

2. The log of specific rates of
decomposition are than plotted aginst the
reciprocal of the absolute temperature and
the resulting line are extraplotted to room
temperature

Predicting drug stability at room temperature by Arrhenius
plot

3. Free and Blythe suggested a similar
method in which the fractional life period is
plotted against reciprocal temperature, and
the time in days required for the drug to
decompose to some fraction of its original
potency at R.T is obtained.

Log plot of t90 against reciprocal temperature

4. The log % of the drug remaining is
plotted against time in days and the time
for the potency to fall to 90% of the
original value i.e t90 is read from the graph.
The log time to 90% is then plotted against
1/T and the time at 25 degree c gives the
shelf life of the product in days

Time in days required for drug ptency at fall 90% t90 are than plotted on a log
scale

Limitations of accelerated analysis
 Carried out only at final package container
 Prediction is not possible at all climatic
conditions
 Limited to the product formulations
 Only apply to the those which degrade with
increase in temperature

Long term stability studies

 Second level
 Third level
 Fourth level

Fifth level

Overage

It is over loading the dosage form with more
drug than 100% (i.e 110% or more) to give more time to get 90%
potency i.e. shelf life is longer.

Rational
 Shelf lives are usually a maximum of 5 years and it takes a
product up to 2 years to reach customer
 Reduced shelf lives are seen in liquid products e.g,
antibiotics and ophthalmics because they are unstable in
presence of moisture
 Some drugs are inherently unstable e.g, vitamins. Therefore,
they are over loaded.

 Second level
 Third level

Fourth level

Fifth level

ICH guidelines…………………

 ICH stands for International Conference on
Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human
use.

Objective
 Harmonization of registration application
within the three regions of the EU, Japan and
the United States.

 ensure and assess the safety, quality and
efficacy of medicines.

The zone concept-

The whole world is divided into 4 climatic
zones in order to harmonize and simplify
stablity testing:

Stability Studies are preformed on

Drug Substances Drug Products

 Stress Testing
 Selection of Batches
 Container Closure System
 Specification
 Testing Frequency
 Storage Conditions
 Stability Commitment
 Evaluation
 Statements/Labeling

Drug substance General case

Minimum time period
Storage condition covered by data at
Study submission
Long term 25°C ± 2°C / 60% ± 5% 12 months
r.h or
30°C ± 2°C / 65% ± 5%
r.h.

Intermediate 30°C ± 2°C / 65% ± 5% 6 months
r.h.
Accelerated 40°C ± 2°C / 75% ± 5% 6 months
r.h.

Drug substances intended for storage in a freezer

Study Storage condition Minimum time period
covered by data at
submission

Long term -20°C ± 5°C 12 months

Drug substances intended for storage in a refrigerator

covered by data at
submission

Long term 5°C ± 3°C 12 months

r.h.

Drug product general case

covered by data at
submission
Long term 25°C ± 2°C / 40% ± 5% 12 months
r.h. or
30°C ± 2°C / 35% ± 5%
r.h.

Intermediate 30°C ± 2°C / 65% ± 5% 6 months
r.h.
r.h.

Storage in refrigerator
covered by data at
submission
Long term 5°C ± 3°C 12 months

r.h.

Stability testing

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