Presented By : Guided By :

Ch.Mahesh Babu. Mrs.Mcthel

M.PHARMACY Asst.professor

Dept of pharmaceutics

NIRMALA COLLEGE OF PHARMACY

 Stability
testing is an integral part of
pharmaceutical development.

Theprimary purpose of stability testing is to

provide supporting evidence on stability
behavior of pharmaceutical drug products.

Many factors drive the process of industrial

stability testing for pharmaceutical
development.
 It is an evolutionary concept covering the life
cycle of pharmaceutical product development.

In early discovery phase the primary focus is to

generate stability characteristics of a chemical
/biological entity.

In later stages ,the goal is to establish shelf life

for formulations packaged in final package
intended for commercial introduction.
 Discovery phase
Pre clinical stage
Pre-IND stage
IND stage
Product development stage
NDA stage
Approved product stage
Revised product stage
 DISCOVERY PHASE
To help select the most satisfactory chemical
entity possessing the right pharmacological,
toxicological & pharmaceutical profile.

The pharmaceutical profile is mostly focused

towards the optimum chemical and physical
stability characteristics.

To select the right physical form(base, salt ,ester)

These studies help establish the boundaries with

in which one must operate to design
formulations.
 The development of early dosage form for pre
clinical testing in humans require an extensive
stability evaluation.

Preliminary stability testing on all formulations

must be carried out using stability indicating
assays in accordance with GLPs.

It requires an entrance assay prior to the

initiation of toxicological testing and an exit
assay, must be performed at the end of the
studies.
 Pre-formulation & stability evaluation of
chemical entity is carried out according to ICH
guidelines.
DOSAGE FORM PARAMETERS

SOLID Temperature, humidity,

photo degradation.
solutions pH, ionic strength,
additives

In addition to normal preformulation

evaluations ,forced degradation studies under
highly stressed stability conditions is under
taken.
 Accelerated and normal storage temperature
testing of drug substance and for clinical
formulation must be initiated.

The goal of these studies should be to

generate information to insure that the
clinical formulations are likely to remain
stable during the planned clinical studies.
 Intermediate stability testing is done in this
stage.

Interim stability testing is conducted to

establish the maximum time for which a drug
product can be stored in interim containers
for further processing.
 Formal stability program is established for
generation of stability data for registration
applications.

The stability of drugs should be evaluated in

containers used for marketing.

Care should be exercised in selection of the size,

surface-to volume ratio of the container.
 The goal of the stability evaluation program
during this phase is to confirm or extending
the expiration date.

The commitment in this stage mandates that

any batch that is found out of specification
will be with drawn from the market.
 Most products undergo post approval changes.

They may be internally driven or externally driven.

Internally driven : changing size & shape of dosage

forms, changes in package design and others.

Externally driven : deletion of dyes, formulation

changed and others.
 Establishment of stability testing function
requires an extensive development of
documentation to maximize the compliance
and to minimize the regulatory citations.
 The guidelines in section 211.166 of 21 CFR
states there shall be a written stability
testing program designed to assess the
stability characteristics of drug product.

a written stability testing program is critical

for the establishment of the stability testing
function.
 The stability protocol should record the
purpose for conducting the stability test the
method used, the testing frequency ,storage
conditions and several other factors.

The commitment requires submission of

stability data at periodic intervals as specified
in the application.
 Current good manufacturing practices
mandate that every organization develops a
set of SOPs to describe their operations.

It is almost impossible to develop a stability

management function with out having a
comprehensive set of SOPs
 Regulations require that each person engaged in
the manufacturing processing should have
education or training to enable that person to
perform the assigned functions.
Training shall be in the particular operations that
the employees performs.
Training must be conducted by qualified individual
on a continuous basis with sufficient frequency.
 During discovery phase stability evaluation is
used in the conduct of pre-clinical safety.

This data helps to establish retest period for

drug substances .

Selection of three pilot batches is used for

statistical evaluation.
 Based on the analysis the world is divided in
to 4 climatic zones.
 WORLDWIDE ZONES AND THE
TEMPERATURE AND HUMIDITY
Zone
CONDITIONS
Mean kinetic Yearly average
temperature 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, 30 C 70

moist)
COUNTRIES BELONGING TO
VARIOUS ZONES
Regions Zone I &II Zone III&IV

EUROPE All countries

AMERICA Argentina, Bolivia, Canada, Brazil, Columbia, Cuba,

Mexico, US Jamaica

ASIA Afghanistan, China, Iran, Bahrain , Hong Kong, India,

Nepal, Turkey Oman , Pakistan,
Srilanka,UAE
AFRICA Egypt, Algeria, South Africa, Angola, Benin, Congo,
Libya Uganda, Sudan, Somalia,
Senegal
 Minimum time period
Study Storage condition
covered by data at
submission

Long Term 25 C 2 C 12 months

(Ambient) 60%RH 5%

Intermediate 30 C 2 C 6 months
(controlled) 60%RH 5%

Accelerated 40 C 2 C 6 months
75%RH 5%
 To simulate the transportation and shipment
conditions in the stability studies thermal
cycling is done

Testing parameters for those studies should

include not only the chemical analysis but
also physical changes.
Photostability testing studies include:
Test on drug substance.
Test on exposed drug product outside the immediate pack.
Test on drug product in the immediate pack.
Test on drug product in the marketing pack.

Light source
Option 1: Artificial daylight lamp combining both visible & UV output
similar to D65 & ID65.
Option 2: Cool white fluorescent & near UV lamp

output max. energy emitted

 Sample exposed to light source/actinometric system
Eg: Quinine chemical actinometry
2%w/v aq.solution of quinine monohydrochloride dihydrate

Option 1:
In 20ml colourless ampoule at 400 nm
Option 2:
In 1cm quartz cell-(sample) and control wrapped with
Aluminium foil

Change in absorbance calculated by

A = AT-A0
 Photostability testing

Forced degradation Confirmatory testing

Evaluate the photosensitivity Information necessary for

Its used alone or in solution handling, packaging and
Placed in chemically inert & labeling
transparent containers. To study, identify
Variety of exposure condition precautionary measures
needed in manufacturing or in
formulation
 The containers should be tested in all
directions i.e..up right ,inverted ,on the side
positions.

This is done for long term and accelerated

stability testing.

This is to ensure that there are no adverse

effects from any interaction is produced.
For long-term storage
12 month study
Testing frequency
0 3 6 9 12 For intermediate storage
12 month study
For accelerated storage - Testing frequency
6 month study 0 6 12
Testing frequency
0 3 6 If significant change occur
(initial) (final) - A 4th time point can be
included
If significant change occur
Increase the testing by adding
sample at final time point
Include 4th time point in study
design
 According to the section 211.166 of 21 CFR
states that testing of drug products for re
constitution at the time of dispensing as well
as after they are reconstituted.
For reconstituted products two distinct

stability periods are in operation.

First period : long term and accelerated

stability testing prior to reconstitution.

Second period: short term stability after

reconstitution
 Dosage form Evaluation
Tablets Appearance,colour,odour,assay,degra
dation products,dissolution,moisture
and friability.
Hard gelatin capsules Appearance,colour,odour,assay,degra
dation products,dissolution,moisture
and microbial limits
Soft gelatin capsules Appearance,colour,odour,assay,degra
dation products,dissolution,moisture
and microbial limits,pH,leakage.

Emulsions Appearance,colour,odour,assay,degra
dation products, microbial
limits,PH,viscosity,preservative
content and distribution of dispersed
phase globules.
 Dosage form Evaluation
Oral solutions Appearance,colour,odour,assay,degrad
ation products, PH,microbial limits,
preservative content.
Oral suspensions Appearance,colour,odour,assay,degrad
ation products, PH,microbial limits,
preservative
content,redispersibility,rheological
properties, mean size and distribution
Oral powders of particle.
Appearance,colour,moisture,and
reconstitution time.
Inhalations and nasal sprays Appearance,colour,odour,assay,degrad
ation products, dose content
uniformity, microscopic evalution,water
content, leak rate, microbial limits.

Topical,opthalamic,ointments,cream Appearance,clarity,colour,homgeneity,
s,lotions,pastes,gels,solutions. odour,ph,resuspendibility,viscosity,part
icle size distribution,assy,degraation
products,preservatives,microbial limits,
 Dosage form Evaluation

Small volume parenterals Appearance,colour,clarity,

assay,presarvative content,
degradation products,
particulate matter, sterility,

Large volume parenterals Appearance,colour,clarity,

assay,presarvative
content,degradation
products,particulate
matter,sterility,pH,pyrogenic
ity,volume.
Bracketing is the design of a stability schedule such
that samples on the extremes of certain design
factors are tested at all time points.
Protocols for bracketing designs should be endorsed
by the FDA prior to initiation of primary stability
studies (FDA 1998).
Bracketing design is suitable and applicable to
identical or closely related formulations packaged
in different size identical container/closure system.
 MATRIXING
Matrixing is the design of a stability schedule such that the selected
subset of the total number of possible samples for all factor
combinations would be tested at a specified time point.

3rd 6th month

month