Transcript stability testing protocols according to united states

Presented By :
Ch.Mahesh Babu.
M.PHARMACY
Guided By :
Mrs.Mcthel
Asst.professor
Dept of pharmaceutics
NIRMALA COLLEGE OF PHARMACY
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Stability testing is an integral part of
pharmaceutical development.
The primary 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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Establishment of stability testing function
requires an extensive development of
documentation to maximize the compliance
and to minimize the regulatory citations.
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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”.
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a written stability testing program is critical
for the establishment of the stability testing
function.
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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.
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Current good manufacturing practices
mandate that every organization develops a
set of SOP’s to describe their operations.
It is almost impossible to develop a stability
management function with out having a
comprehensive set of SOP’s
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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.
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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.
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Based on the analysis the world is divided in
to 4 climatic zones.
WORLDWIDE ZONES
AND THE 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
COUNTRIES BELONGING TO VARIOUS
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
Bahrain , Hong Kong, India,
Oman , Pakistan,
Srilanka,UAE
AFRICA
Egypt, Algeria, South Africa,
Libya
Angola, Benin, Congo,
Uganda, Sudan, Somalia,
Senegal
Study
Storage condition
Minimum time period
covered by data at
submission
Long Term
(Ambient)
25º C ± 2º C
60%RH ± 5%
12 months
Intermediate
(controlled)
30º C ± 2º C
60%RH ± 5%
6 months
Accelerated
40º C ± 2º C
75%RH ± 5%
6 months
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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
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Option 1:
In 20ml colourless ampoule at 400 nm
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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
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Evaluate the photosensitivity
Its used alone or in solution
Placed in chemically inert &
transparent containers.
Variety of exposure condition
Confirmatory testing
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Information necessary for
handling, packaging and
labeling
To study, identify
precautionary measures
needed in manufacturing or in
formulation
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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 accelerated storage
6 month study
◦ Testing frequency
0
3
6
(initial)
(final)
If significant change occur
◦ Increase the testing by adding
sample at final time point
◦ Include 4th time point in study
design
For intermediate storage
12 month study
- Testing frequency
0
6
12
If significant change occur
- A 4th time point can be
included
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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”.
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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
of particle.
Oral powders
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,creams,l
otions,pastes,gels,solutions.
Appearance,clarity,colour,homgeneity,
odour,ph,resuspendibility,viscosity,par
ticle size distribution,assy,degraation
products,preservatives,microbial limits,
weight loss.
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,pyrogeni
city,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
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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
month
6th month