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CONTENTS Definition Objectives Of Stability Study Application Of Stability Studies In Pharmaceuticals Factors Affecting Drug Stability Design Of Stability Program The Role Of Stability Testing Requirements Of Stability Testing Under Indian Drug Laws ICH Stability Guidelines Different Steps Involved In Stability Study Conclusion References


DRUG STABILITY DEFINITION :- Drug Stability refers to the capacity of a drug substance or product to remain within established specifications of identity, strength, quality, and purity in a specified period of time. Stability is officially defined as the time lapse during which the drug product retains the same properties and characteristics that it possessed at the time of manufacture. The stability of a product is expressed as the expiry period or technically as shelf life.


OBJECTIVES OF STABILITY STUDY To gather information during preformulation stage to produce a stable product. To determine maximum expiration date. To gate an idea of storage condition. To determine the packaging components. The retest period of pharmaceuticals. Transport conditions.


APPLICATION OF STABILITY STUDIES IN PHARMACEUTICALS Chemical degradation of active drug may reduce the quality of therapeutic indices like 5-flurouracil, carbamazepine etc have very small therapeutic range, slight degradation of drug may produce sub therapeutic concentration. After degradation a drug may produce more toxic product(s) which may be more toxic than the parent product. Instability of drug product reduce bioavailability. This may be caused by physical or chemical instability. Instability of a product may change the physical appearance of the product.


FACTORS AFFECTING DRUG STABILITY Storage time Storage condition Type of dosage form Container and closure system

Why so much emphasis on right practices in STABILITY TESTING?: 

Why so much emphasis on right practices in STABILITY TESTING? The ideal production environment - Regulations and Controls - GMP GLP The ideal formulation The non-ideal shipment and storage environment Transport Wholesalers Retailers Patients Mishandling

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The storage facilities currently available in the retail drug outlets and pharmacies include:- A refrigerator, mostly of 165 litres size . Freezer compartment of the same refrigerator. Open shelves [storage at ambient temperature and light of the outlet). Covered cupboards/drawers that do provide protection from light at ambient temperature of the outlet. Air-conditioning, but only of 10% outlets, providing an environment of <30°C.

The Possible Changes (invisible and visible): 

The Possible Changes (invisible and visible) L oss of active ingredient Alteration in bioavailability Loss of content uniformity Decline of microbiological status Loss of pharmaceutical elegance and patient acceptability Formation of toxic degradation products Loss of package integrity Reduction of label quality Modification of any factor of functional relevance (dissolution, release, etc.)

The Role of Stability Testing: 

The Role of Stability Testing Provides evidence on how the drug substance or product quality varies with time under environmental conditions during distribution Helps to recommend storage conditions, including establishment of shelf life, expiry date or retest period Key to assurance of quality of pharmaceuticals


REQUIREMENTS OF STABILITY TESTING UNDER INDIAN DRUG LAWS Schedule M, Serial no.16(June 1988) Quality control department shall control the quality and stability of finished product The quality control department shall have the following principle duties: (Viii) - “to establish shelf life and storage requirements on the basis of stability tests related to storage conditions

WHO TRS 823 of 1992 (16.17 to 16.20): 

WHO TRS 823 of 1992 (16.17 to 16.20) Quality Control department should evaluate the quality and stability of finished pharmaceutical product and, when necessary, of starting materials and intermediate products. Quality Control department should establish expiry dates and shelf life specifications on the basis of stability tests related to storage conditions

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Stability study should be determined prior to marketing and following any significant changes in processes, equipment and packaging material etc. A written program for ongoing stability determinations should be developed and implemented.

Original ICH Stability Guidelines: 

Original ICH Stability Guidelines Q1A Stability testing of new drugs and products October 1993 Q1B Stability testing: photostability testing November 1996 Q1C Stability testing for new dosage form November 1996 Q5C Stability testing of biotechnological/biological drugs November 1995

Q1- Stability Guidance document: 

Q1- Stability Guidance document Guideline number Year ofpublication Q1A 1993 Q1A(R) NOV. 2000 Q1A(R2) FEB. 2003

Other ICH Stability Guidelines: 

Other ICH Stability Guidelines Q1D Bracketing and Matrixing Designs for Stability Testing February 2003 Q1E Evaluation of stability data February 2003 Q1F Stability Data Package for Registration in Zones III and IV February 2003(withdrawn June 2006)

Applicability of these Guidelines: 

Applicability of these Guidelines ICH New Drugs and Products WHO Existing Drugs and Products USFDA Comprehensive, covers- IND, NDA, ANDA CPMP Existing drugs VICH New Drugs and Products

Design of stability program: 

Design of stability program The design of the stability program for the finished product is based on the knowledge of the drug substance and experience gained from clinical formulation study & stability study. It should state the storage condition and the rational change in the dosage form.

Different steps involved: 

Different steps involved Selection of batches Test procedure & test criteria Specifications Storage test condition Testing frequency Packaging material Evaluation Statements & labeling

Selection of batches: 

Selection of batches Selection of batches should be done as per the guidelines

Test procedure & criteria: 

Test procedure & criteria It must cover those features which are susceptible to change during storage & likely effect quality, safety & efficacy. Analytical procedure should be fully validated and that should be stability indicating The testing not only include chemical & biological stability but also loss of preservative, physical, organoleptic properties & also microbiological attributes. Preservative efficacy testing should be done on stored sample.


Specifications Specification is a list of:- Tests & test attributes References to analytical procedure Acceptance criteria

Testing frequency: 

Testing frequency Long term studies Accelerated studies generally minimum three points e.g.:-0, 3, 6 months Intermediate studies minimum four time points e.g.:-0, 6, 9, 12 months

Storage conditions: 

Storage conditions Storage conditions for different zones type of study – long term/accelerated different product types

The zone concept: 

The zone concept

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Region Zone I and II countries Zone III and IV countries Europe All countries ----------------- America Argentina, Bolivia, Chile, Canada, Mexico, Peru, Uruguay, USA Barbados, Belize, Brazil, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Guyana, Haita , Honduras, Jamaica, Columbia, Cuba, Nicaragua, Dutch Antilles, Panama, Paraguay, Puerto Rico, Venezuela. All of these countries are assigned to CZ IV. Asia Afghanistan, Armenia, Azerbaijan, China, Georgia, Iran, Israel, Japan, Kazakstan , Kirghizia, Korea, Lebanon, Nepal, Syria, Tadzhikistan, Turkey, Turkmenia , Uzbekistan Bahrain, Bangladesh, Hong Kong, India , Indonesia, Iraq (III), Jordan (III), Kampuchea, Qatar, Kuwait, Laos, Malaysia, Maldive Islands, Myanmar, Oman, Pakistan, Philippines, Saudi Arabia, Singapore, Sri Lanka, Taiwan, Thailand, United Arab Emirates, Vietnam, Yemen Africa Egypt, Algeria, Tunesia , Libya, Morocco, Namibia, Ruanda, South Africa, Tunesia , Zambia, Zimbabwe. Angola, Ethiopia, Benin, Botswana (III), Burkino Faso, Burundi, Djibouti, Ivory Coast, Gabon, Gambia, Ghana, Guinea, Cameroon, Kenya, Longo, Liberia, Madagascar, Malawi, Mali, Mauritania, Mozambique, Niger, Nigeria, Senegal, Sierra Leone, Somalia, Sudan, Tanzania, Togo, Chad (III), Uganda, Zaire, Central African Republic. Australian/oceanic Australia, New Zealand. Figi . Society Islands, Marshall Islands, New Caledonia, Papua-New Guinea, Samoa, Tonga.

Storage conditions for General products: 

Storage conditions for General products

Storage conditions for Liquid products packed in semi-permeable containers: 

Storage conditions for Liquid products packed in semi-permeable containers

Storage conditions in accordance with ICH Q1A(R2) & Q1F: 

Storage conditions in accordance with ICH Q1A(R2) & Q1F study Zones I & II Zones III & IV Long term studies 25 0 ± 2 0 C / 60%±5% 30 0 ±2 0 C / 65%±5% Intermediate study 30 0 ±2 0 C / 65%±5% ---------- Accelerated study 40 0 ±2 0 C / 75%±5% 40 0 ±2 0 C / 75%±5% When significant changes occur due to accelerated testing, additional testing at an intermediate condition 30 0 C+2 0 C/60±5% should be significant. According to ICH significant change in drug product are:- A 5% change in assay value from initial. Any degradation product exceeds its set limits. Failure to meet acceptance criteria. The pH value and the dissolution no longer satisfies the requirement.

Standard storage condition for temperature sensitive products: 

Standard storage condition for temperature sensitive products Storage condition Temperature & Relative humidity Refrigerator storage 5 0 to 8 0 C / monitored Freezer storage -20 to -13 0 C Note : freezer storage temperature of -15 0 C+5 0 C was specified in FDA

A Comprehensive Stability Evaluation: 

A Comprehensive Stability Evaluation Physical Chemical Microbiological Toxic Therapeutic


Evaluation A systematic approach should be adopted in the presentation and evaluation of the stability information which covers the physical, chemical & biological parameter. A minimum of 3 batches of drug product should be tested. The analyst must find the batch to batch variability & if it is small than only it is accepted & it can be done by different statistical tests(P value for level of significance for rejection).

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When the data shows so little degradation & so little variability that is apparent from looking the data that the requested shelf life will be granted & it is normally unnecessary to go through the formal statistical analysis. The stability of the drug product after reconstitution or dilution according to labeling should be addressed to provide appropriate and supportive information.


CONCLUSION Stability is an essential quality attribute for drug products. Stability testing is not done for creating data for regulators, but as an assurance to manufacturer itself on the quality of its products. Has to be done on all the products in the market. Structured, systematic and documented stability testing based on right principles can save manufacturers from lot of undue hassles, faced when product is proved to be of inferior quality.


REFERENCES Dr.Ali Javed Khan, R.K.Ahuja Alka , Text book of dosage form design,2004. Lachman Leo, Liberman , A.Hebert , kaing l, The theory and practice of industrial pharmacy, 3 rd edition. Yoshika Sumie , Stellar J, Stability of drugs and dosage forms, 2006. Indian Journal of Pharmaceutical Education, vol-38,dec-2004,page-194-198. Pharma Times, vol-38, no.6, march-2000, 15-18. ICH guidelines. www.who.int www.gmp-manual.com www.vichsec.org www.ich.org

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