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SEMINAR
ON
WHO GUIDELINES ON STABILITYSTUDY OF SOLID DOSAGE FORM
Presented by
Ranjeet kumarM.Pharm 2nd semRoll no -02
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Introduction
The world health organization(WHO) is a specialized agency
of the united nation created to
give worldwide guidance in
the field of health to set globalstandards for health, to
cooperate with governments in
strengthening national health
programs and to develop and
transfer appropriate health
technology, information and
standards.
WORLD HEALTH
ORGANIZATION
Current membership : 191
countries
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Stability Study
Stability is defined as the ability of a pharmaceuticalproduct to retain its properties within specified limitsthroughout its self life.
Purpose : To recommend storage conditions
To recommend retest period
To assign shelf life
To review the product quality
To fulfill the regulatory requirement for dossiersubmission
To select adequate formulations and container-closure system
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Parameters for stability testing of
solid dosages form :
Physiochemical properties
Tablets:
Dissolution (or disintegration), water content and
hardness/friability.
For coated and colour tablets additional tests may require
for texture and colour stability
Capsules:
brittleness, dissolution (or disintegration), water content,
and level of microbial contamination.
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Contd.
Powders and granules for oral solution or suspension:
Water content
Reconstitution time.Chemical properties :
Assay
Degradation
Container closure system properties :Functionality tests (eg. Extraction from blister)
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WHO STABILITY GUIDELINES
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Different climatic zone :
Climatic zone Definition
Mean annualtemperature
measured in theopen air/
Mean annual partial
water vapour
pressure
Long-term TestingConditions
Country
I Temperate climate 15 C / 11 hPa 21 C / 45% RH
Great Britain, NorthEurope, Russia,Canada
IISubtropical &Mediterranean climate
> 15 to 22 C / > 11 to18 hPa
25 C / 60% RHUSA, Japan, SouthEurope,
III Hot and dry climate > 22 C / 15 hPa 30 C / 35% RHIran, Iraq, Sudan
IVA Hot and humid climate> 22 C / > 15 to 27
hPa30 C / 65% RH
Brazil,Cuba,China,India
IVBHot and very humidclimate
> 22 C / > 27 hPa 30 C / 75% RH
USA(California,Texas),Maxico
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Drug Substances (DS)
The unformulated drug substance that may subsequently be
formulated with excipients to produce the dosage form.
New Chemical EntityWell-known Chemical Entities
Drug Products (DP)
The dosage form in the final immediate packaging intended
for marketing and represents controlled and documented
determination of acceptable changes of the drug substance or
drug product
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Stability study performed on :
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Stress testing on finished pharmaceutical
product
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Data from 3 primary batches required.
Two of three primary batches should be atleast from pilot
scale batches and the third one can be smaller if justified.
Stability studies should be performed on each individual
strength and container size of product unless bracketing and
matrixing is applied.
Selection of batches
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Test procedure
Stability study is very time consuming
process so minimize the time there are
well-accepted procedures, namely
bracketing and matrixing (B&M).These are
procedures for reducing the number of
samples of product tested for stability
which, when correctly applied, should resultin neither loss of data quality produced nor
a significant change in the predicted shelf
life.9
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Bracketing.
The design of a stability schedule such that only samples
on the extremes of certain design factors (e.g., strength and
package size) are tested . The design assumes that the
stability of any intermediate level is represented by the
stability of the extremes tested.
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Matrixing
Matrixing is the design of a stability
schedule such that a fraction of the total
number of the sample are tested at any pointof time. In subsequent sampling points, a
different set of samples of the total number
should be tested. The design assumes that
the stability of each subset of samples tested
represents the stability of all samples at a
given time point.11
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Matrixing
Dosage strength (Lot A,B,C)
Container size 50 mg 75 mg 100 mg
A B C A B C A B C
15 ml X X X X X X X X X
100 ml X X X X X X X X X
500 ml X X X X X X X X X
12X= sample is tested; X= sample is not tested
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Container Closure System
Stability testing should be conducted on the
dosage form packaged in the container
closure system proposed for marketing. Anyavailable studies carried out on the
pharmaceutical product outside its
immediate container or in other packaging
materials can be considered as supporting
information, respectively.
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Testing Frequency
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Long term studies
First year every three months. 0, 3, 6, 9, 12
Second year every six months: 12, 18, 24
Third year and longer annually: 24, 36, 48, 60
Accelerated studies
General minimum three time points: 0,1,2,3 and 6 months.
Intermediate storage condition studiesMinimum four time points, including initial and final e.g.:
0,3,6,9,12 months.
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Storage condition
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General case:
Anysignificant change
occurs during 6 month accelerated study,additional testing at intermediate storage should be conducted. The
initial application should include a minimum of 6 months data from12 month study of intermediate storage condition. Significantchange for a drug substance is failure to meet specification.
Study Storage condition Minimum time period at
submission
Long term 25C 2C/60% 5% 12 months
Intermediate 30C 2C/65% 5% 6 months
Accelerated 40C 2C/75% 5% 6 months
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Contd.
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Drug Product intended for storage in refrigerator :
Ifsignificant change
occurs between 3 & 6 months ofaccelerated study, data on long term study should be submitted.
If significant change occurs within 3 months of acceleratedstudy, it is unnecessary to continue further testing.
Study Storage condition Minimum timeperiod at
submission
Long term 5C 3C 12 months
Accelerated 25C 2C/60% 5%RH 6 months
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Stability Commitment
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Commitment required: If the submission includes stability data on at least three production
batches, a commitment should be made to continue these studies
through out the proposed shelf life.
If the submission includes stability data on fewer than three productionbatches, a commitment should be made to continue these studies
through out the proposed shelf life and to place additional production
batches, to a total of at least three, on long term stability
If the submission does not include stability data on production batches,
a commitment should be made to place the first three production
batches on long term stability studies through the proposed shelf life.
Commitment not necessary:Submission includes data on threeproduction batches covering proposed re-test period.
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Stability evaluation data
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Re-test period:Purpose of stability studies is to establish a re-test
period applicable to all further batches of the drug substance
manufactured under similar circumstances. It is based on results of
physical, chemical, biological and microbiological tests from three
batches.
No formal statistical analyses: Do not apply this statistical analysis
for stability data showing little degradation / variability.
Statistical evaluation: Data on a quantitative attribute that changes
with time. Determination of the time at which the 95% one sided
confidence limit for the mean curve intersects the acceptance criterion
etc, The nature of degradation relationship determines whether it
should be converted for linear regression analysis.
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Statement and labeling
Statement:
Storage statement for labeling in
accordance with national/regional
Requirements.
Based on the stability evaluation
Direct link between label storage
statement and demonstrated stability.
Expiration date should be displayed on
container label21
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Testing condition where the stability of the
pharmaceutical product has been shown
Recommended labelling
statement
for countries in C. Zs I and II:
25C/60% RH (long term)40C/75% RH (accelerated)30C/65% RH (intermediate)
Store below 30C *
for countries in C. Zones III and IVA:30C/65% RH (long term)40C/75% RH (accelerated)
Store below 30C
for countries in C. Zone III and IVA:30C/65% RH (long term)
Store and transport below30C
for countries in C. Zones I and II:
25C/60% RH (long term)
Store below 25C
5C 3CStore and transport in arefrigerator (2C to 8C) **
-20C 5C
Store in a freezer and transport
frozen (-5C to -20C) ***22
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Additional labeling statements
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Sr. No Limiting factors Additional labelingstatement, whererelevant
1. Pharmaceutical products that cannottolerate refrigerating
Do not refrigerate orfreeze
2. Pharmaceutical products that cannottolerate freezing.
Do not freeze
3. Light-sensitive pharmaceutical products Protect from light
4. Highly hygroscopic pharmaceuticalproducts
Store in dry condition
5. Pharmaceutical products that cannottolerate excessive heat
Store & transportalways below 30C
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Stability Report
If no significant change occurs during six-month's
accelerated and real time stability testing, the product will
be allowed to place in the market with a provisional shelf-
life of up to twenty-four months. However, real timestability testing should be continued up to the proposed
shelf-life. The manufacturer should have a system of recall
in place so that the sale any batch which does not remain
within the limit of approved product specification be
stopped within twenty-four hours.
The ongoing stability programme should be described in a
written protocol, and results formalized in a tabulated form.
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Stability data in tabulated format :
Product Name:
Batch No.:
Batch Size:
Date of Manufacture:
Packaging (material and pack sizes):
Storage conditions:
Name of manufacturer:
Manufacturer of API:
Date of commencement of stability study: Time intervals (months)
Title of Specification Limits 0 3 6 9 12 24
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Prediction of shelf-life
At least nine months data derived from the product
stored at the maximum recommended storage
conditions, and three months under conditions of
stress for generic products should be available atthe time of registration for consideration of a
provisional shelf-life of 24 months. For products
containing new chemical entities, the data
accumulated over a sufficient period of time,
beyond the initial 12 months to cover appropriate
test periods, should be available
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Calculation of expiry date
The expiry date is calculated from the date of manufacture. Ifthe production batch contains reprocessed material, the expiry
date is calculated from the date of manufacture of the oldest
reprocessed batch. It should also be verified that the batch will
meet the final product specification for the full period of the
allocated shelf-life.
The date of production of a batch is defined as the date that the
first step is performed involving combining the API(s) with
other IPIs. For medicinal products consisting of a single API
filled into a container, the initial date of the filling operation is
taken as the date of production.
Not applicable to biological, vaccines, sera, derived from
human blood as well as medicinals prepared biotechnologically.27
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BIBLIOGRAPHY
1. Stability testing of active substances and pharmaceutical products;Working document QAS/06.179 World Health Organization; 19 April
2006. Accessed on: 20/03/2012, 08.09p.m.
Website Url:
http://www.who.int/entity/medicines/services/expertcommittees/pharmpr
ep/QAS06_179_StabilityGuidelineSept06.pdf.
2. Guidelines on Stability of Pharmaceutical Products, 2007; Working
document; World Health Organization.
Accessed on 25/03/2012, 10.02p.m.
Website Url:
www.dda.gov.np/guidlines/Guidelines_for_stability_testing.pdf.
3. STABILITY; Department of Health, Medicines Control Council; March
2011. Accessed on: 29/03/2012, 09.28p.m.
Website Url:
www.mccza.com/genericDocuments/2.05_Stability_Mar11_v6.doc
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THANK YOU
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Current membership : 191 countries