SEMINAR ON WHO GUIDELINES ON STABILITY STUDY OF SOLID DOSAGE FORM Presented by

Ranjeet kumar M.Pharm 2nd sem Roll no -02 1

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 global standards 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

Stability Study
Stability is defined as the ability of a pharmaceutical product to retain its properties within specified limits throughout 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 dossier submission To select adequate formulations and containerclosure system

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.

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)

WHO STABILITY GUIDELINES

Different climatic zone :
Climatic zone Definition Mean annual temperature measured in the open air/ Mean annual partial water vapour pressure 15 C / 11 hPa Country Long-term Testing Conditions

Temperate climate

21 C / 45% RH

Great Britain, North Europe, Russia, Canada USA, Japan, South Europe,

II

Subtropical & Mediterranean climate Hot and dry climate Hot and humid climate Hot and very humid climate

> 15 to 22 C / > 11 to 25 C / 60% RH 18 hPa > 22 C / 15 hPa > 22 C / > 15 to 27 hPa > 22 C / > 27 hPa 30 C / 35% RH 30 C / 65% RH

III IVA

Iran, Iraq, Sudan

Brazil,Cuba,China, India USA(California,Texas), Maxico

IVB

30 C / 75% RH

Stability study performed on :

Drug Substances (DS) The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form. New Chemical Entity Well-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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Stress testing on finished pharmaceutical product

Selection of batches
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.
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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 result in neither loss of data quality produced nor a significant change in the predicted shelf life.

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 point of 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

Matrixing
Dosage strength (Lot A,B,C) Container size A 15 ml 100 ml 500 ml X X X 50 mg B X X X C X X X A X X X 75 mg B X X X C X X X A X X X 100 mg B X X X C X X X

X = 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. Any available 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
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 studies Minimum four time points, including initial and final e.g.: 0,3,6,9,12 months.
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Storage condition
General case: Study Long term Intermediate Accelerated Storage condition 25C 2C/60% 5% 30C 2C/65% 5% 40C 2C/75% 5% Minimum time period at submission 12 months 6 months 6 months

Any significant 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 from 12 month study of intermediate storage condition. Significant change for a drug substance is failure to meet specification.
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Contd.
Drug Product intended for storage in refrigerator :
Study Storage condition Minimum time period at submission 12 months 6 months

Long term Accelerated

5C 3C 25C 2C/60% 5%RH

If significant change occurs between 3 & 6 months of accelerated study, data on long term study should be submitted. If significant change occurs within 3 months of accelerated study, it is unnecessary to continue further testing.
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Contd.
Drug Product intended for storage in freezer :
Study Storage condition Minimum time period at submission 12 months

Long term

- 20 C 5C

There is no accelerated study for above case.

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Stability Commitment
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 production batches, 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 three

production batches covering proposed re-test period.
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Stability evaluation data

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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Contd.
Significant change:
5% assay variation from its initial value. Any degradation products exceeding acceptance criteria. Failure to meet acceptance criteria with respect to appearance, physical attributes, and functionality test. e.g Appearance Color Hardness Extraction from blister Friability Failure to meet the acceptance criteria for dissolution for 12 dosage units (tablet and capsule).

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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 label

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Testing condition where the stability of the pharmaceutical product has been shown for countries in C. Zs I and II: 25C/60% RH (long term) 40C/75% RH (accelerated) 30C/65% RH (intermediate)

Recommended labelling statement Store below 30C *

for countries in C. Zones III and IVA: 30C/65% RH (long term) 40C/75% RH (accelerated)
for countries in C. Zone III and IVA: 30C/65% RH (long term) for countries in C. Zones I and II: 25C/60% RH (long term)

Store below 30C

Store and transport below 30C Store below 25C

5C 3C -20C 5C

Store and transport in a refrigerator (2C to 8C) ** Store in a freezer and transport frozen (-5C to -20C) ***
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Additional labeling statements

Sr. No Limiting factors Additional labeling statement, where relevant Do not refrigerate or freeze Do not freeze Protect from light

1. 2. 3.

Pharmaceutical products that cannot tolerate refrigerating Pharmaceutical products that cannot tolerate freezing. Light-sensitive pharmaceutical products

4.
5.

Highly hygroscopic pharmaceutical products

Pharmaceutical products that cannot tolerate excessive heat

Store in dry condition

Store & transport always 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 shelflife of up to twenty-four months. However, real time stability 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:
Date of commencement of stability study: Title of Specification Limits 0

Packaging (material and pack sizes): Storage conditions: Name of manufacturer: Manufacturer of API:
Time intervals (months) 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 at the 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. If the 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

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. 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. 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
Current membership : 191 countries

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