Ranjeet WHO Stability

8/2/2019 Ranjeet WHO Stability

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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



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

Ranjeet WHO Stability

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