1.Prepared By : Alaa R. alfayez Zainab al-mulla

2. Stability Definition These studies provide information about the packaging in that it is not reactive, additive, or absorptive so that the identity,strength, quality and purity of the drug product is not affected, also to provide clearance on stability process flow.To assessment of the stability characteristics of all drug products manufactured / packaged and/orrepacked by Pharmaceuticals companies.To establish and extend the shelf life for products 3. General PrinciplesThe purpose of stability testing is to provide evidence on how the qualityof an active substance or pharmaceutical product varies with timeunder the influence of a variety of environmental factors such astemperature, humidity, and light. In addition, product-related factorsinfluence the stability, e.g. the chemical and physical properties of theactive substance and the pharmaceutical excipients, the dosage formand its composition, the manufacturing process, the nature of thecontainer-closure system, and the properties of the packagingmaterials. Also, the stability of excipients that may contain or formreactive degradation products, have to be considered. 4. Active SubstanceInformation on the stability of the active substance is an integral part of the systematic approach to stability evaluation. For active substances not described in an official pharmacopoeial monograph, stability studies are required. For active substances described inan official pharmacopoeial monograph, which covers the degradation products and for which suitable limits have been set but a re-test period is not defined, two options are acceptable: 5. Active SubstanceThe manufacturer of the pharmaceutical product confirms that the active substance complies with the pharmacopoeial monograph immediately prior to the manufacture of the pharmaceutical product. In this case no stability studies on the active substance are required. The suitability of the pharmacopoeial monograph for the active substance used from a named source of supply has to be demonstrated. 6. Stress TestingStress testing of the active substance can helpidentify the likely degradation products, whichcan in turn help establish the degradation pathwaysand the intrinsic stability of the moleculeand validate the stability indicating power of theanalytical procedures used. The nature of thestress testing will depend on the individual activesubstance and the type of pharmaceuticalproduct involved. 7. Stress TestingFor an active substance the following approachesmay be used:a) When an active substance is described in anofficial pharmacopoeial monograph, andfully meets its requirements, no data are required onthe degradation products if theyare named under the headings purity tests and/orsection on impurities 8. Stress Testingb) For active substances not described in an official pharmacopoeial monograph, there aretwo options: When available, it is acceptable to provide the relevant data published in theliterature to support the proposed degradation pathways; When no data are available in the scientific literature, including officialpharmacopoeias, stress testing should be performed. 9. SpecificationStability studies should include testing of thoseattributes of the active substance that aresusceptible to change during storage and are likely toinfluence quality, safety, and/or efficacy.The testing should cover, as appropriate, the physical,chemical, biological, andmicrobiological attributes. Validated stability-indicatinganalytical procedures should beapplied. Whether and to what extent replication shouldbe performed will depend on the resultsfrom validation studies 10. Storage ConditionsIn general, an active substance should be evaluatedunder storage conditions (with appropriatetolerances) that test its thermal stability and, ifapplicable, its sensitivity to moisture. Thestorage conditions and the lengths of studies chosenshould be sufficient to cover storage,shipment, and subsequent use with due regard tothe climatic zone(s) in which the activesubstance is intended to be stored . 11. Storage Conditions Station 1: (40 C 2 & 75 % RH 5).Station 2: (30 CStation 3: (25 C2 & 65 % RH 2 & 60 % RH 5). 5).Station 5: (30 CStation 4: (2 - 8) C.2 & 35 % RH 5). 12. Product storage Storage condition Testing stationsStability condition Zone Station conditionsTemperature/Humidity (Month)all Room temperature 1 40C 2C / 75% 5%RH Accelerated0, 1, 2,3 and 6all Refrigerator storage 3 25C 2C / 60% 5 %RH 30C 2C / 65% 5%RHIII, IV Room temperature 2 30C 2C / 35% 5%RH0, 3, 6, 9, 12, Long-Term18, 24, 36, 48and 60 I, IIRoom temperature 3 25C 2C / 60% 5 %RHallRefrigerator4(2 8)CIntermediate I, IIRoom temperature 2 30C 2C / 65% 5%RH 0, 3, 6, 9 and 12 13. Testing FrequencyFor long term studies, frequency of testing should besufficient to establish the stability profileof the active substance. For active substances with aproposed re-test period of at least 12months, the frequency of testing at the long termstorage condition should normally be everythree months over the first year, every six monthsover the second year, and annually thereafterthrough the proposed re-test period. 14. Testing FrequencyAt the accelerated storage condition, a minimum ofthree time points, including the initial andfinal time points (e.g. 0, 3, and 6 months), from a 6-month study is recommended. Where anexpectation (based on development experience)exists that results from accelerated studies arelikely to approach significant change criteria,increased testing should be conducted either byadding samples at the final time point or byincluding a fourth time point in the study design 15. For products stored at room temperature.For products stored at refrigerator.for products stored at room temperature (for long term conditions at 25 C60 % RH).For products stored at room temperature in climatic zone III and IV.For products stored at room temperature in climatic zone I and II.For products stored at refrigerator. 16. Type of Placement Batches:A- New product registration.B- Process Validation Batch.C- Formulation Change.D- Annual Commitment Batch.E- Raw material manufacturer changeF- Primary packaging material manufacturer changeG- Reprocessing batch 17. H- Batch size changeI- Manufacturing process changeJ- Stability condition changeK- Machine changeL- Site transfer 18. Product Name/Strength Study Number Purpose of StudyBatch Number Batch Size Date Study StartedDate Manufactured Manufacturer/Site Container/Size/SupplierDate Packaged Packager/Site Closure SupplierStorage Condition Storage Orientation Seal SupplierDrug Substance Manufacturer/Site/Batch NumberApproved/Proposed Expiration Dating Period TestsMethodSpecification Time (Months)SOP#(Low/High) appearance 0 3 69etc. Color Degradation Assay Dissolution Clarity 19. In-use stabilityThe purpose of in-use stability testing is to establish where applicable the period of timeduring which a multi-dose product can be used whilstretaining acceptable quality once thecontainer is opened and the first dose is removed.A minimum of two batches, at least pilot scale batches,should be subjected to the test. At leastone of the batches should be chosen towards the end ofits shelf life. If such results are notavailable, one batch should be tested at the final point ofthe submitted stability studies. 20. VariationsOnce the pharmaceutical product has been registered, additional stability studies are requiredwhenever major variations are made like the following:1. Change in the manufacturing process;2. Change in the composition of the pharmaceutical product;3. Change of the immediate packaging. 21. Stability tests for dosage forms:1. TabletsDissolution (or disintegration, if justified), water content and hardness/friability.For coated and colour tablets additional tests may require for texture andcolour stability.2. CapsulesHard gelatin capsules: brittleness, dissolution (or disintegration, if justified),water content, and level of microbial contamination.3. EmulsionsPhase separation, pH, viscosity, level of microbial contamination, and mean sizeand distribution of dispersed globules.4. Oral solutions and suspensionsFormation of precipitate, clarity for solutions, pH, viscosity, extractables, level ofmicrobial contamination. 22. Stability tests for dosage forms:Additionally for suspensions, redispersibility, rheologicalproperties, mean size anddistribution of particles should be considered. Also,polymorphic conversion may be examined, if applicable.5. Powders and granules for oral solution or suspensionWater content, and reconstitution time.Reconstituted products (solutions and suspensions) should be evaluated as described inOral solutions and suspensions above, after preparation according to the recommendedlabeling, through the maximum intended use period. 23. Stability tests for dosage forms:6. Nasal sprays: solutions and suspensionsClarity (for solution), level of microbial contamination, pH, particulate matter, unit spraymedication content uniformity, number of actuations meeting unit spray content uniformityper container, droplet and/or particle size distribution, weight loss, pump delivery,microscopic evaluation (for suspensions), foreign particulate matter andextractable/leachable from plastic and elastomeric components of the container, closure andpump.7. Topical, ophthalmic and otic preparationsIncluded in this broad category are ointments, creams, lotions, paste, gel, solutions, eyedrops, and cutaneous sprays. 24. Stability tests for dosage forms:Topical preparations should be evaluated for clarity, homogeneity, pH, resuspendability (forlotions), consistency, viscosity, particle size distribution (for suspensions, when feasible), level of microbial contamination/sterility and weight loss (when appropriate).Evaluation of ophthalmic or otic products (e.g. creams, ointments, solutions andsuspensions) should include the following additional attributes: sterility, particulate matter and extractable.Evaluation of cutaneous sprays should include: pressure, weight loss, net weight dispensed, delivery rate, level of microbial contamination, spray pattern, water content, and particle size distribution (for suspensions).8. SuppositoriesSoftening range, dissolution (at 37C). 25. Stability tests for dosage forms:9. Small volume parenterals (SVPs)Colour, clarity (for solutions), particulate matter, pH, sterility, endotoxins.Stability studies for powders for injection solution should include monitoring for colour, reconstitution time and water content. Specific parameters to be examined at appropriate intervals throughout the maximum intended use period of the reconstituted drug product, stored under condition(s) recommended in labelling, should include clarity, colour, pH, sterility, pyrogen/endotoxin and particulate matter.The stability studies for Suspension for injection should include, in addition, particle sizedistribution, redispersibility and rheological properties.The stability studies for Emulsion for injection should include, in addition, phase separation,viscosity, mean size and distribution of dispersed phase globules. 26. Stability tests for dosage forms: 10. Large volume parenterals (LVPs) Colour, clarity, particulate matter, pH, sterility,pyrogen/endotoxin, and volume. 27. When re-test is done??In general, significant change for a pharmaceutical product is defined as:1. A 5% change in assay from its initial value; or failure to meet the acceptance criteriafor potency when using biological or immunological procedures;2. Any degradation product exceeding its acceptance criterion;3. Failure to meet the acceptance criteria for appearance, physical attributes, andfunctionality test (e.g., colour, phase separation, resuspendibility, caking, hardness,dose delivery per actuation); however, some changes in physical attributes (e.g.,softening of suppositories, melting of creams, partial loss of adhesion for transdermalproducts 28. When re-test is done?4. Failure to meet the acceptance criterion for pH; or5. Failure to meet the acceptance criteria fordissolution for 12 dosage units. 29. Ongoing stability studies The stability of the API should be monitored according to a continuous and appropriate program that will permit the detection of any stability issue (e.g. changes in levels of degradation products). The purpose of the ongoing stability program is to monitor the API and to determine that the API remains, and can be expected to remain, within specifications under the storage conditions indicated on the label, within the re-test period in all future batches.The ongoing stability program should be described in a written protocoland the results presented in a formal report. 30. To support a shelf life extension, a report must begenerated documenting stability data (for the proposedinterval) for three batches which meet all the followingcriteria: Same product / potencySame manufacturingShelf life may be extended as long process.term data become available to justifythe extension Same primary packagingmaterialSame formulation No significant change in the manufacturingprocedure 31. After registration Once the pharmaceutical product has beenregistered, additional stability studies are requiredwhenever variations that may affect the stability ofthe active pharmaceutical substance orpharmaceutical product are made, such as majorvariations like the following:a. Change in the manufacturing process.b. Change in the composition of the pharmaceuticalproduct.c. Change of the immediate packaging. 32. At the market If no significant change occurs during six-months accelerated and real time stability testing,the product will be allowed to place in the market with a provisional shelf-life of up totwenty-four months. However, real time stability testing should be continued up to theproposed shelf-life. The manufacturer should have a system of recall in place so that the saleany batch which does not remain within the limit of approved product specification bestopped within twenty-four hours.