physical stability-ICH Guidlines by Hussain Quadri

Physical Stability of Pharmaceutical as Per ICH Guidelines: 

Physical Stability of Pharmaceutical as Per ICH Guidelines Presented by SHAH HUSSAIN QUADRI Under the guidance of Abdul Bari Mohd Head of the Department Pharmaceutics Lalitha College of Pharmacy

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Agenda What is stability What is the need of stability in pharmaceuticals What is the requirements of physicals stability under Indian drug law Possible changes Emphasis on right practice in stability Factor affecting stability Stages of Drug and Product Development and Stability Testing Types of stability Physical stability of Pharmaceuticals Different Organization regulating stability guidelines ICH Guidelines ICH Q1AR2 Conclusion References

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What is Stability? 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 . Doing Every thing or Doing the Right thing..?

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What is the Need of Stability in Pharmaceuticals KEY ASSURANCE OF QUALITY OF PHARMACEUTICALS 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 . To establish retest period of pharmaceuticals. Transport conditions . Provide an evidence on how the quality of a drug substance or drug product varies with the time under the influence of environmental factor

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Requirement of Stability Testing under Indian Drug Law With reference to Schedule M serial No 16 Quality Control System 16.10:The quality control department shall conduct Stability Studies of the products to ensure and assign their shell life at the prescribed conditions of storage. All records of such studies shall be maintained

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The Possible Changes{Visible & Invisible} L oss of active ingredient Alteration in bioavailability Loss of content uniformity Decline of microbiologica l 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.)

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Why so much emphasis on right practice in Stability 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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Factor Affecting Drug Stability 1- Environmental factors - Temperature - Light - Moisture 2- Drugs or excipients in the dosage form Particle size of drug pH of the vehicle 3- Microbial contamination 4- Trace metal Contamination 5- Leaching from containers

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Stages of Drug and Product Development and Stability Testing Pre-Clinical Studies Clinical Studies Pre-Formulation Formulation Development Scale Up Commercial Manufacturing Distribution & Shipping Post Approvals Changes Market Surveillance

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Types of Stability In Pharmaceuticals Stability of Drug Physical Chemical Packaging Microbiological Physical Stability of Pharmaceuticals

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Physical stability of Pharmaceuticals Physical stability implies that : The formulation is totally unchanged (appearance, organoleptic properties, hardness, brittleness, particle size etc). It is significant as it affects: pharmaceutical elegance drug content uniformity drug release rate .

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Formulation Likely physical instability problems Effects Oral solutions 1- Loss of flavour 2- Change in taste 3- Presence of off flavours due to interaction with plastic bottle 4- Loss of dye 5- Precipitation 6- discoloration Change in smell or feel or taste Physical stability of Pharmaceuticals { ORAL SOLUTION}

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Formulation Likely physical instability problems Effects Parenteral solutions 1. Discoloration due to photo chemical reaction or oxidation 2. Presence of precipitate due to interaction with container or stopper 3. Presence of “whiskers” 4. Clouds due to: ( i ) Chemical changes (ii) The original preparation of a supersaturated solution Change in appearance and in bio-availability Physical stability of Pharmaceuticals { PARENTAL SOLUTION}

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Formulation Likely physical instability problems Effects Suspensions 1- settling 2- caking 1-Loss of drug content uniformity in different doses from the bottle 2- loss of elegance. Physical stability of Pharmaceuticals { SUSPENSION}

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Formulation Likely physical instability problems Effects Emulsions 1- Creaming 2- coalescence 1- Loss of drug content uniformity in different doses from the bottle 2- loss of elegance Physical stability of Pharmaceuticals { EMULSION}

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Formulation Likely physical instability problems Effects Semisolids (Ointments and suppositories) 1. Changes in: a) Particle size b) Consistency 2. Caking or coalescence 1-Loss of drug content uniformity 2- loss of elegance Physical stability of Pharmaceuticals {SEMI SOLIDS}

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Formulation Likely physical instability problems Effects Tablets Change in: a) Disintegration time b) Dissolution profile c) Hardness d) Appearance (soft and very hard) Change in drug re lease Physical stability of Pharmaceuticals {TABLETS}

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Formulation Likely physical instability problems Effects Capsules Change in: a) Appearance b) Dissolution c) Strength Change in drug release Physical stability of Pharmaceuticals {CAPSULE}

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Different regulatory Authorities which regulates guidelines for stability ICH: international Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use WHO : World Health Organization USFDA : united state food drug Administration CPMP: Committee for Medicinal Products for Human Use formerly known as Committee for Proprietary Medicinal Products VICH: i nternational cooperation on harmonization of technical requirements fro registration of veterinary products

What is ICH: 

What is ICH The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe , Japan and the US to discuss scientific and technical aspects of drug registration Mission of ICH ICH’s mission is to make recommendations towards achieving greater harmonisation , thereby reducing or obviating duplication of testing carried out during the research and development of new human medicines. Global Cooperation Group In 1999 ICH made five regions INDIA has joined ICH in 2007 in GCC Region

ICH GUIDLINES: 

ICH GUIDLINES GUIDELINES { QSEM } Q uality S afety E fficacy M ultidisciplinary Q1:Stability Q1A(R2):stability testing of new drug subs & pro Q2: Analytical Validation Q1B:photostability testing Q3: Impurities Q1C:stability testing of New Dosage Form Q4: Pharmacopoeias Q1D:Braceting and Matrixing Q5: Quality of Biotecnological Q1E:Evaluation for Stability Data Q6: Specification Q1F:Stability Data Package for Reg Application Q7: GMP in climatic Zones III and IV Q8:P D, Q9: QRM, Q10: PQS, Q11: DM&DS

ICH GUIDILINES : 

ICH GUIDILINES Objectives defines stability data package for drug substance and drug product for registration application, Within there region Exemplify the core stability package for new substance & products. General principle of Q1AR2 The purpose of stability testing is to provide evidence on how a drug substance or drug product varies with in time under the influence of environmental factor such as Temperature Humidity Light To established a re test period for the drug substance/shelf life Recommended storage condition

ICH GUIDLINES: 

ICH GUIDLINES Stress Testing : This guidelines help to identify the likely degradation products , to establish the degradation pathway and intrinsic stability of the molecule Carried out at 10c increment 50c….to 70c Humidity 75% RH Selection of Batches :The over all quality of the batches of drug substance placed on formal stability studies should be representative of the quality of the material to be made on production scale

ICH GUIDELINES : 

ICH GUIDELINES Container Closure system Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing Specification These guidelines states the list of test , reference to analytical procedure , and proposed acceptance criteria, include the concepts of different acceptance criteria for release and shelf life specification is addressed in ICH Q6A & Q6B .

ICH GUIDELINES : 

ICH GUIDELINES Testing frequency For products with a proposed shelf life of at least 12 months the frequency of testing at the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed re-test period. First year------------------3 month Second --------------------6 month Thereafter------------------annually through out the proposed re-test period Testing frequency at accelerated storage condition min three point , at 0 , 3 , 6 month

ICH GUIDELINES : 

ICH GUIDELINES THE ZONE CONCEPT

ICH GUIDELINES : 

ICH GUIDELINES 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,. 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, Australian/oceanic Australia, New Zealand. Figi . Society Islands, Marshall Islands, New Caledonia, Papua-New Guinea, Samoa,

ICH GUIDELINES : 

ICH GUIDELINES 1.STORAGE CONDITION {GENERAL CASE} Study Storage condition Minimum time period covered by data at submission Long-term 25°C ± 2°C/ 60% RH ± 5% RH or 30°C ± 2°C/ 65% RH ± 5% RH 12 months Intermediate 30°C ± 2°C/ 65% RH ± 5% RH 6 months Accelerated 40°C ± 2°C/ 75% RH ± 5% RH 6 months

ICH GUIDELINES : 

ICH GUIDELINES 2.Drug products packaged in semi permeable containers Study Storag e condition Minimum time period covered by data at submission Long-term 25°C ± 2°C/ 40% RH ± 5% RH or 30°C ± 2°C/ 35% RH ± 5% RH 12 months Intermediate 30°C ± 2°C/ 65% RH ± 5% RH 6 months Accelerated 40°C ± 2°C/ 25% RH 6 months

ICH GUIDELINES : 

ICH GUIDELINES 3.Drug products packaged in impermeable containers The stability studies for product stored in impermeable container can b conducted under any controlled or ambient humidity condition. 4.Drug products intended for storage in a refrigerator Study Storage condition Minimum time period covered by data at submission Long-term 5°C ± 3°C 12 months Accelerated 25°C ± 2°C/ 60% RH ± 5% RH 6 months

ICH GUIDELINES : 

ICH GUIDELINES 5.Drug products intended for storage in a freez er Study Storage condition Minimum time period covered by data at submission Long-term -20°C ± 5°C 12 months stability commitment submission includes data from stability studies on at least three production batches, a commitment should be made to continue these studies through the proposed re-test period .

ICH GUIDELINES : 

ICH GUIDELINES Evaluation The purpose of the stability study is to establish, based on testing a minimum of three batches of the drug substance and evaluating the stability information a re-test period applicable to all future batches of the drug substance manufactured under similar circumstances. The degree of variability of individual batches affects the confidence that a future production batch will remain within specification throughout the assigned re-test period. Conclusion By applying standard regulation and guidelines in practice of manufacturing pharmaceuticals and dispensing we can achieve the product as per specified under standards.

References : 

References www.goog.co.in www.pharmpedia.com www. ich .org www.fda.gov www.vichsec.org www.whoindia.org www.ema.europa.eu Remington the science and practice of pharmacy p1025

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