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See all Premium member Presentation Transcript Slide 1: RECENT TRENDS IN STABILITY TESTING OF PHARMACEUTICALS WITH REFERENCE TO ICH GUIDELINES Presented by, SAWRAJYOTI DEKA 1 st M.PHARM DEPT.OF PHARMACEUTICS SRIPMS(COP),COIMBATORE-44Index:: Overview of ICH - Definition, History, Structure, Topics & Formal Working Procedure Definition of Stability Purpose & Types of Stability Pathways of Chemical D egradation ICH Guidelines for Stability Testing Examples Conclusion References Index:What does ICH stand for ?: What does ICH stand for ? The complete name of ICH is the “International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use”. What is ICH ? ICH is a joint initiative involving both regulators and research-based industry representatives of the EU, Japan and the US in scientific and technical discussions of the testing procedures required to assess and ensure the safety, quality and efficacy of medicines.Slide 4: A brief History of ICH 1980s Harmonization of regulatory requirements was pioneered by the European Community, as the European Union moved towards the development of a single market for pharmaceuticals. The success achieved in Europe demonstrated that harmonization was feasible. At the same time there were bilateral discussions between Europe, Japan and the US on possibilities for harmonization. 1989 At the WHO Conference of Drug Regulatory Authorities (ICDRA), in Paris, specific plans for action began to materialize. 1990 The birth of ICH took place at a meeting in April 1990 in Brussels where Representatives of the regulatory agencies and industry associations of Europe, Japan and the USA met.Slide 5: What is the purpose of ICH ? The objective of ICH is to increase international harmonization of technical requirements to ensure that safe, effective, and high quality medicines are developed and registered in the most efficient and cost effective manner. To make information available on ICH, ICH activities and ICH guidelines to any country or company that requests the information, and to promote a mutual understanding of regional initiatives in order to facilitate harmonisation processes related to ICH guidelines regionally and globally. T o strengthen the capacity of drug regulatory authorities and industry to utilise them.Who are the members ?: Who are the members ? The Ministry of Health, Labour & Welfare (MHLW) Japan Pharmaceutical Manufacturers Association (JPMA ) The European Commission (EC) European Federation of Pharmaceutical Industries and Associations (EFPIA) The Food & Drug Administration (FDA) The Pharmaceutical Research and Manufacturers of America (PhRMA)Slide 7: ICH STEERING COMMITTEE Determines the policies & procedures for ICH. Selects topics for harmonization. They meet twice a year. ICH SECRETARIAT Concerned with preparation for, documentation of, meetings of the SC. The Secretariat operates from the IFPMA offices, in GenevaSlide 8: - Stability Testing -Carcinogenicity Testing - Impurity Testing - Genotoxicity Testing - Dose Response Studies - MedDRA - Good Clinical Practice - ESTRI - CTDFORMAL ICH PROCEDURE: FORMAL ICH PROCEDURE Step1 : Consensus building Step2 : Confirmation of six party consensus Step3 : Regulatory Consultation and Discussion Step4 : Adoption of an ICH Harmonized Tripartite guideline Step5 : ImplementationStep 1 : Consensus Building : Step 1 : Consensus Building Steering committee (SC) adopts a concept paper. Under Rapporteur, The EWG prepares an initial draft of the guideline. When the agreement is reached among all 6 party EWG members, then the EWG will sign the step 2 expert signoff sheet . This consensus is submitted to steering committee within a specified time period. If the EWG members are not able to submit within the given time period, a report has to be send to SC The SC may extend the time period (or) abandon the consensus .Step 2 : Confirmation of six party consensus: Step 2 : Confirmation of six party consensus Step 2 is reached when the SC agrees, based on the report submitted by EWG. And the consensus is signed off by the SC as step 2 final document . Step 3 : Regulatory Consultation and Discussion: Step 3 : Regulatory Consultation and Discussion Regional regulatory consultation Regulatory consultation is carried on in 3 region: In European union (EU) its published as draft Committee for Medical Product for Human Use (CHMP). In Japan its translated & issued by Ministry of Health, Labour and Welfare (MHLW). In USA its published as draft guidance in the Federal Register . The regulatory parties exchange information on the comment they have received to arrive at a single Harmonised Guideline.Discussion of regional consultation comments : Discussion of regional consultation comments EWG is resumed after obtaining the consultation result. The draft document generated as a result of step 3 phase is called step 4 Experts Document . The step 4 Experts Document signed by the EWG regulatory parties and the sign off is called as step 4 Expert Signoff . This document is submitted to SC.Step 4 : Adoption of an ICH Harmonised Tripartite Guideline: Step 4 : Adoption of an ICH Harmonised Tripartite Guideline Step 4 is reached on when the SC agrees based on the reports from EWG. The step 4 Final Document is signed off by the SC.Step 5 : Implementation : Step 5 : Implementation The Harmonised Tripartite Guideline immediately moves to the final step of process that is the regulatory implementation. The implementation dates are reported back to the SC and published by the ICH Secretariat on the ICH website.Stability: Stability Stability of a Pharmaceutical preparation can be defined as “the capability of a particular formulation in a specific container/closure system to remain within its physical, chemical, microbiological, therapeutic & toxicological specification throughout its shelf life”. 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. Stability of a product is expressed as the expiry period or technically as shelf life.Purpose of stability testing: Purpose of stability testing 1. Provide a evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light 2. To Establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions 3. Because physical, chemical or microbiological changes might impact the efficiency and security of the final product.Type of stability Conditions To Be maintained during the shelf life : Type of stability Conditions To Be maintained during the shelf life Chemical Retains its chemical integrity and labeled potency Physical Appearance; palatability; uniformity; dissolution and suspendability are to be retained Microbiological Retains sterility; effectiveness of anti microbial agent Therapeutic Drug actions remains unchanged Toxicologic No significant increase in toxicityPathways of Chemical Degradation: Pathways of Chemical Degradation Hydrolysis Oxidation Dehydration Isomerization and racemization Decarboxylation and elimination PhotodegradationSlide 20: Hydrolysis reactions. a) Esters. b) Amides HYDROLYSIS Hydrolysis is the breaking of a molecular bond by reaction with water. Water is common in pharmaceutical products, either as an ingredient or as a contaminant.Slide 21: Example: Hydrolysis of aspirin to salicylic acid and acetic acid. Other examples : procaine, atropine, pilocarpine , procainamide, nicotinamide , chloramphenicol, penicillin G, phenobarbital, etc.Slide 22: Oxidation -Oxidation reaction is a complementary one, its partner is reduction. -One cannot happen without the other. -Oxidation /reduction (redox) reactions involve the transfer of electrons. (or one or more oxygen or hydrogen) Autoxidation:- - This term is used to refer to oxidations that takes place spontaneously under mild conditions. -The majority of the reactions involved are free radical in type with organic peroxides often being intermediate or final products.Slide 23: 1. The first 1 st step is called initiation & takes a period of time called the induction period. The length of the induction period depends on the reaction and the condition. It is promoted by light and the presence of heavy metals which are in trace amounts. R-H R* + * H 2. The second step is propagation hydro peroxide formation occurs R* + O 2 ROO* ROO* + RH ROOH + R* 3. The final step is termination. Reactions occur that break the chain. Termination may take place by coupling (two radicals combine to form a non radical) or due to non availability of oxygen or drug diminishes.Slide 24: Many drugs have been reported to be subjected to autoxidation including. - apomorphine - Cyanocobalamin - ascorbic acid - epinephrine - chlorpromazine - ergometrine - phenothiazine derivative - heparin - hydrocortisone - kanamycin - morphine - neomycin - p. amino bezoic acid - penicillin - Phenylephrine - prednisolone - prednisone - procaine - riboflavin - streptomycin - sulfadiazine - terpenes - tetracyclines - thiamine - vitamins A, D & E - rancidity of oils & fats .Slide 25: Photodegradation The mechanisms for these reactions are generally very complex. Photodegradation generally yields numerous products through complex pathways. Photodegradation is often accompanied by oxidation in the presence of oxygen. Photodegradation of primaquineSlide 26: Isomeric changes: Racemization and epimerization, which are reversible conversions between optical isomers, have been reported for many drug substances. Pilocarpine undergoes epimerization by base catalysis, whereas tetracyclines such as rolitetracycline , and ergotamine exhibit epimerization by acid catalysis. Other drug substances susceptible to racemization include benzodiazepines, penicillins , and cephalosporins .Slide 27: Decarboxylation and Elimination Drug substances having a carboxylic acid group are sometimes susceptible to decarboxylation. 4-Aminosalicylic acid is a good example. Foscarnet also undergoes decarboxylation under strongly acidic conditions, whereas etodolac is susceptible to decarboxylation by acid catalysis as shown below.Slide 28: SHELF LIFE Shelf life is best defined as the time span over which the quality of a product remains within specifications. Shelf-life (also referred to as “expiration dating period”) is defined as t he period of time during which a pharmaceutical product, if stored correctly, is expected to comply with the specification as determined by stability studies on a number of batches of the product. The shelf-life is used to establish the expiry date of each batch. ESTIMATION OF SHELF LIFE 1. Garret and Carper method 2. Free and Blythe methodSlide 29: Garret and Carper method In this, the rate constant ,k values for the decomposition of a drug in solution at various elevated temp., say 40, 50, 60, 70 0 C are determined by plotting conc. v/s time graph. Then the logarithms of specific rates of decomposition are plotted against the reciprocal of corresponding temp. Then the resulting line is extrapolated to room temp. the k value at 25 0 C can be used to determine the time to reduce to 90% potency.Slide 30: Free and Blythe method In this method, the log percentage of potent drug remaining v/s time in days is plotted with data collected at different temperatures. The time for the potency to fall to 90% is read from the graph for each temperature. Then the 1/temp. v/s time in days to reach 90% potency is plotted. Then time to reach 90% potency at 25 0 C is found out by extrapolation.Slide 31: Worldwide zones and the temperature and humidity conditions Zone Mean kinetic temperature Yearly average humidity (%RH) Zone I ( Moderate) 21 ̊C 45 Zone II (Mediterranean) 25 ̊C 60 Zone III (Hot, dry) 30 ̊C 35 Zone IV (Very hot, moist) 30̊ C 70Slide 32: Countries belonging to various zones Regions Zone I &II Zone III&IV EUROPE All countries AMERICA Argentina, Bolivia, Canada, Mexico, US Brazil, Columbia, Cuba, Jamaica ASIA Afghanistan, China, Iran, Nepal, Turkey Bahrain , Hong Kong, India, Oman , Pakistan, Srilanka,UAE AFRICA Egypt, Algeria, South Africa, Libya Angola, Benin, Congo, Uganda, Sudan, Somalia, Senegal ICH GUIDELINES FOR STABILITY: ICH GUIDELINES FOR STABILITY Q1A(R2) Stability Testing of New Drug Substances and Products Q1B Stability Testing : Photostability Testing of New Drug Substances and Products Q1C Stability Testing for New Dosage Forms Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Q1E Evaluation of Stability Data Q1F Stability Data Package for Registration Applications in Climatic Zones III and IVStability testing of new drug substances & products Q1 A(R2), Dated 6 Feb 2003 : Stability testing of new drug substances & products Q1 A(R2 ), Dated 6 Feb 2003 Principle To provide evidence how quality of drug substance or product varies with time under the influence of variety of environmental factors such as temperature, humidity and light. To establish a retest period for drug substance or shelf life for drug product.DRUG SUBSTANCE: DRUG SUBSTANCE Stress testing To identify degradation product To evaluate its susceptibility to hydrolysis Carried out on a single drug substance Photostability is an integral part of this testing Selection of batches Studies carried on atleast 3 primary batches The primary batch should be of pilot scale Should be packed in same container closure system as proposed for storage and distribution Testing frequency To establish the stability profile of drug substance : Testing frequency To establish the stability profile of drug substance For long-term storage 12 month study Testing frequency 0 3 6 9 12 For accelerated storage 6 month study Testing frequency 0 3 6 (initial) (final) If significant change occur Increase the testing by adding sample at final time point Include 4 th time point in study design For intermediate storage 12 month study - Testing frequency 0 6 12 If significant change occur - A 4 th time point can be includedSlide 37: Storage condition Drug substance is evaluated to test Its thermal stability Sensitivity to moisture Table 1 : General case Study Storage condition Minimum time period for data submission LONG TERM 25ºC±2ºC/60%RH±5%RH Or 30ºC±2ºC/65%RH±5%RH 12 MONTH INTERMEDIATE 30°C±2°C/65%RH±5%RH 6 MONTH ACCELERATED 40°C±2°C/75%RH±5%RH 6 MONTH 0 6 12 Significant change 0 3 6 12 Additional testing at intermediate condition Long-term studiesSlide 38: Study Storage condition Minimum time period for data submission LONG TERM 5°C±3°C 12 MONTH ACCELERATED 25°C±2°C/60%RH±5%RH 6 MONTH Table 2 : Drug substance intended for storage in a refrigerator 0 3 6 Significant change Retest period 12 monthSlide 39: For drug substance stored in freezer, the retest period is of 12 month Study Storage condition Minimum time for data submission LONG TERM -20°C±5°C 12 MONTH Table 3 : Drug substance intended for storage in a freezerDRUG PRODUCT: DRUG PRODUCT Stability studies based on Behavior & properties of drug substance The stability study of drug substance Selection of batches Testing frequency Storage condition General case Drug product stored under refrigerator Drug products packaged in impermeable containers act as a barrier to moisture or solvents conducted at controlled humidity condition Drug products packaged in semi-permeable containers aqueous products should be evaluated for water loss, physical, chemical, biological & microbiological activity conducted at low relative humidityStatements & labeling: Statements & labeling The statement should be based on the stability evaluation of drug substance. Specific instruction should be provided for drug substance that cannot tolerate freezing. Terms such as “ambient condition” or “room temperature” should be avoided. Retest period derived from stability information. Retest date should be displaced on container label.Photostability testing of new drug substances & products Q1 B, Dated 6 Nov 1996 : Photostability testing of new drug substances & products Q1 B, Dated 6 Nov 1996 Photostability testing studies include: Test on drug substance. Test on exposed drug product outside the immediate pack. Test on drug product in the immediate pack. Test on drug product in the marketing pack. Light source Option 1: Artificial daylight lamp combining both visible & UV output similar to D65 & ID65. Option 2: Cool white fluorescent & near UV lamp output max. energy emittedProcedure : Procedure Sample exposed to light source/actinometric system Eg: Quinine chemical actinometry 2%w/v aq.solution of quinine monohydrochloride dihydrate Option 1: In 20ml colourless ampoule at 400 nm Option 2: In 1cm quartz cell-(sample) and control wrapped with Aluminium foil Change in absorbance calculated by A = AT-A0DRUG SUBSTANCE: DRUG SUBSTANCE Evaluate the photosensitivity Its used alone or in solution Placed in chemically inert & transparent containers. Variety of exposure condition Information necessary for handling, packaging and labeling To study, identify precautionary measures needed in manufacturing or in formulationPresentation of the samples: Presentation of the samples Physical characteristic of the sample should be taken care Interaction between the sample and any material should be eliminated Small amount of solid sample placed in glass or plastic dish If its liquid sample its exposed in chemically inert and transparent container Analysis of samples Should be performed with the control Sample examined for change in physical property in assay and degradantsDRUG PRODUCT: DRUG PRODUCTStability testing for new dosage forms Q1 C, Dated 6 Nov 1996 : Stability testing for new dosage forms Q1 C, Dated 6 Nov 1996 A new dosage form is defined as a drug product which is a different pharmaceutical product type, but contain the same active substance as included in the existing drug product. Eg: Different administration route (oral to parenteral) Specific delivery systems (immediate release tablet to modified release tablet)Bracketing & matrixing design for stability testing of new drug substance & product Q1 D, Dated 7 Feb 2002 : Bracketing & matrixing design for stability testing of new drug substance & product Q1 D, Dated 7 Feb 2002 A full study design is one in which samples of every combination of all design factors are tested at all time points. A reduced design one in which sample for every factor combination are not tested at all time points . BRACKETING Bracketing is the design of a stability schedule such that samples on the extremes of certain design factors are tested at all time points.Slide 49: Capsules of different strengths made with different fill plug sizes from same powder blend, Tablets of different strengths manufactured by compressing varying amounts of same granulation, and Oral solution of different strengths with formulations that differ only in minor excipients (eg: colourant, flavourings). Bracketing cannot be applied when different excipients are used among strengths. Bracketing can be applied to study of container closure system. Characteristics of the container closure system include: container wall thickness, closure geometry, surface area to volume ratio, headspace to volume ratio, water vapour permeation rate.Slide 50: MATRIXING Matrixing is the design of a stability schedule such that the selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. 3 rd month 6 th monthEVALUATION OF STABILITY DATA Q1E, Dated 6 Feb 2003 : EVALUATION OF STABILITY DATA Q1E, Dated 6 Feb 2003 Data evaluation for retest period or shelf life estimation for drug substance or product intended for room temperature storage How to use stability data generated according to Q1A(R2). When and how a retest period or a shelf life can be extended beyond the period covered by long-term data. Q1E provides recommendations on : significant change Accelerated condition NO YESIf No: If No The retest period or shelf life depend upon the long-term data and accelerated data . change with time & variability Long-term and accelerated data If no : The product remains within the proposed retest period. if yes: Statistical analysis used in establishing a retest period NO YES Data amenable to statistical analysis NO YES If no: Should not be more than 6 month beyond the period covered by long-term data. i.e. 12 + 6 if yes: Should not be more than 12 month beyond the period covered by long-term data. i.e. 12 + 12If YES: If YES The retest period or shelf life depend on intermediate condition and long-term condition. significant change NO YES Intermediate condition If no : Statistical analysis used in establishing a retest period if yes: Should not exceed the period covered by long-term data. Data amenable to statistical analysis NO YES Can be up to 3month beyond the period covered by long-term data. i.e. 12 + 3 If no: if yes: Should not be more than 6 month beyond the period covered by long-term data. i.e. 12 + 6Physical parameters to be evaluated: Physical parameters to be evaluated Sl. No. Dosage forms Physical parameters 1. Solutions Change of Colour Change of 0dour Clarity Appearance( precipitation, cloudiness) pH 2. Suspensions Appearance( precipitation, cloudiness) pH Colour, 0dour Redispersibility 3. Tablets Appearance Friability Hardness Colour, 0dour Dissolution Moisture adsorption 4. Hard gelatin capsules Moisture Colour Appearance(shape) Brittleness Dissolution pHSlide 55: 5. Soft gelatin capsules Moisture Colour Appearance(shape) Brittleness Dissolution pH Precipitation Cloudiness 6. Emulsions Appearance(phase separation) pH Colour, 0dour Precipitation Cloudiness 7. Creams and Ointments Appearance and Clarity Colour, 0dour Homogenicity pH Resuspendibility (for lotions) Consistency Weight loss(plastic containers) Particle sizeSTABILITY DATA PACKAGE FOR REGISTRATION APPLICATIONS IN CLIMATIC ZONE III AND IV Q1F: STABILITY DATA PACKAGE FOR REGISTRATION APPLICATIONS IN CLIMATIC ZONE III AND IV Q1F This guideline defined the storage conditions for stability testing in countries located in Climatic Zone III (hot and dry) and IV (hot and humid). Stability storage conditions for Zone- III & IV countries Product Types of study Accelerated Long term Solid oral dosage forms , solids for reconstitution , dry and lyophilized powders in glass vials 40 ̊C /75% RH 30 ̊C and 35/70%RH (Zone- III & IV) Liquid in glass bottles, vials, sealed, glass ampoules, which provide an impermeable barrier to water loss 40 ̊C/ambient humidity 30 ̊C/ ambient humidity Drug products in the semi permeable containers 40 ̊C/15%RH 30 ̊C/40%RH Drug products to be indented to be stored at refrigerator temperature 30 ̊C and 35/75%RH (Zone- III & IV) or 30 ̊C ambient humidity for liquid products 5±3 ̊ C with monitoring but not control of humidity Drug products intended to be stored at freezer temperature 5±3 ̊C/ ambient humidity -15±5 ̊ CSlide 57: Design and evaluation of self-emulsifying drug delivery systems (SEDDS) of nimodipine . The ability of self-emulsifying drug delivery systems (SEDDS) to improve solubility, dissolution rate and bioavailability of a poorly water-soluble calcium channel blocker, nimodipine (NM) was evaluated. In vitro dissolution studies indicated that NM loaded SEDDS could release complete amount of NM irrespective of the pH of the dissolution media. NM loaded SEDDS were subjected to various conditions of storage as per ICH guideline for 3 months. AAPS PharmSciTech . Feb 2008 .Modified polysaccharides as fast disintegrating excipients for orodispersible tablets of roxithromycin: Modified polysaccharides as fast disintegrating excipients for orodispersible tablets of roxithromycin Modified polysaccharides co grinded treated agar (C-TAG) and co grinded treated guar gum (C-TGG) were prepared by subjecting pure polysaccharides namely agar and guar gum respectively to sequential processes of wetting, drying and co grinding with mannitol (1:1). Evaluated for particle size distribution, derived properties, swelling index & biodegradability. Friability and Disintegration time as response parameters were used to formulate orodispersible tablets of roxithromycin and were evaluated for wetting time, water absorption ratio and in vitro drug release at salivary pH 6.4 and physiological pH 7.4. In vitro release both at salivary pH and physiological pH was found to be more than 90% within 30 min. Stability studies carried out as per ICH Q1A guidelines suggested the formulations to be stable for a period of 6 months. AAPS PharmSciTech. Jan 2008Effect of unconventional curing conditions and storage on pellets coated with Aquacoat ECD: Effect of unconventional curing conditions and storage on pellets coated with Aquacoat ECD Purpose of this study was to develop storage stable pellets coated with the aqueous ethylcellulose dispersion Aquacoat ECD. The influences of accelerated storage conditions on the release behavior of Aquacoat/HPMC-coated drug pellets were investigated. Unconventionally harsh curing conditions (60 degrees C/75% RH or 80 degrees C) improved the storage stability of Aquacoat-coated pellets at accelerated conditions. Drug Development and Industrial Pharmacy May 2009CONCLUSION:: CONCLUSION: The ICH guidelines represent agreed-upon scientific guidance for meeting technical requirements for registration within the three ICH regions - EU, US and Japan. Each regulatory co-sponsor implements the guidelines according to its national/regional requirements. The ICH guidelines are not intended to be comprehensive guidance covering all aspects of product development and registration. They are intended to be used in combination with any regional requirements. An ICH guideline can be used by industry as a means of reducing testing duplication. Industry and governments in ICH and non-ICH countries can use the ICH guidelines to address technical issues during the product development process. In addition to providing state-of-the-art guidance, the guidelines may well also serve as teaching tools. Harmonised ICH guidelines can reduce duplication in meeting technical requirements, thereby saving financial and material resources.References : References Physical Pharmacy by Alfred Martin , B.I. Publications, 4th Edition, Pg no: 313-316. Stability of drugs & dosage forms by Sumie Yoshika & Valentine J.Stella, Springer Publications, Pg no: 205-224. Handbook of Isolation &Characterization of Impurities in Pharmaceuticals by Ahuja & Alsante , Elsevier Publications, Pg no: 103-105. www.ich.org www.ijpsonline.com (Oct-Dec 2004).Slide 62: THANK YOU You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.