Presentation on theme: "اللهم صلي وسلم على سيدنا محمد"— Presentation transcript:
1اللهم صلي وسلم على سيدنا محمد بسم الله الرحمن الرحيماللهم صلي وسلم على سيدنا محمدSTABILITY STUDY and EXPIRATION DATERaculty of Pharmacyكلية الصيدلةFAlaa Khedr Ph.D.ProfessorFaculty of PharmacyKing Abdulaziz UniversityAbstractThe purpose of stability testing is to provide 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, and enables recommended storage conditions, re-test periods and shelf lives to be established.The choice of test conditions defined in this guideline is based on an analysis of the effects of climatic conditions in the three areas of the EC, Japan and the USA. The mean kinetic temperature in any region of the world can be derived from climatic data.
2Abbreviations API Active Pharmaceutical Ingredient FDC Fixed-Dose CombinationFPP Finished Pharmaceutical ProductGMP Good Manufacturing PracticesICH International Conference on HarmonizationMA Marketing AuthorizationDRA Drug Regulatory AuthorityMCA: Medicine Control AgencyFDA: Food and Drug AdministrationNDA: New Drug ApplicationsANDA: Abbreviated New Drug ApplicationsEU: European UnionEMEA: European Medicinal Evaluation AgencyCPMP: Committee for Proprietary Medicinal ProductsNTA: Notices To ApplicantCDER / CFR: Code of Federal Register
3Applicable guidelines Guidance for IndustryQ1A(R2) Stability Testing of New Drug Substances and ProductsU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)November 2003, ICHQ1E Evaluation of Stability DataJune 2004, ICH
4Objectives Degradation Prod. 4.5% Drug 100% Drug 95.5% + Time (month) 1- The purpose of stability testing is to provide 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, and enables recommended (1) storage conditions, (2) re-test periods and (3) shelf lives to be established.Temp.HumidityLightDrug 95.5%Drug100%+Time(month)Degradation Prod.4.5%2- Safety and efficacy.
5Before starting program execution we should have; DesignBefore starting program execution we should have;Specification of ProductAll SOP’sEquipment & toolsStability ProtocolCompendia& Company SpcsApproved DocsIQ/OQ/PQ,Data LoggerLog sheetsWritten/ApprovedStability IndicatingAnalytical MethodDrug productReference StandardsICH Stress testingDevelopmentValidationRepresent. ChromatogramsPurchase USP / Europ. RSPurchase Potential ImpuritiesStorage cabinetVerifiedBatch size3 batchesSampling protocol
6Before starting program execution we should have; DesignBefore starting program execution we should have;1Stability ProtocolWritten/ApprovedWho doing what? How to do the taskClear interpretation of proceduresStepwise mannerStability protocol is a signed/dated and approved document that describe the exact and clear procedure to start the stability testing of drug. The procedure should be described in a sequential stepwise manner, who doing what, how to do the task.
7Before starting program execution we should have; DesignBefore starting program execution we should have;2Specification of ProductAll SOP’sInfo. Source 1 = Compendia (USP/BP)Info. Source 2 = FDA / ICH guidelines (Limits / general Official Procedure)Info. Source 3 = Supplier of raw materialInfo. Source 4 = Company approved specs of API and PFP
8Before starting program execution we should have; DesignBefore starting program execution we should have;3Equipment & toolsIQ/OQ/PQ,Data LoggerLog sheetsDocumentations are available = IQ/OQ/PQData Logger (calibrated) = Temp., HumidityDocuments = Log sheets of operation, time, dateHow to operate the machine = SOP for machine
9UV HPLC Dissolution Stability Cabinets Karl Fisher Balances 3Equipment & tools+ Data loggers !!!!UVHPLCDissolutionStability CabinetsKarl FisherBalancesCalibrated Glassware
10Stability Cabinets A special cabinet for each condition 3Equipment & tools+ Data loggers !!!!Stability CabinetsA special cabinet for each conditionShould be qualified / calibratedMonitor Temp. / humidity vs time. TimeThree General conditions required.Deep freeze Data loggers
11sensor probe / thermocouple Data Loggers (Types)sensor probe / thermocouple
12Why we use Data Loggers ? How many sensor probe? How to position sensors? To monitor Both, temperature and Relative Humidity along 24 hours.To ensure consistency of the adjusted Temp. and RH.Should be calibrated by supplierAny deviation for NLT 6 hours, we should stop study and repeat using new samples.Ex: Electricity shutdown, or instrument failer, no enough water inside instrument.
13Photostability Cabinets 3Equipment & toolsPhotostability CabinetsAt least one primary batchShould be testedWhy we defined some products to be photosensitive, to which degree ?(use UV-A, 200 watts hours/m2 )Illumination : 1.2 million Lux hoursHumidity range : 40% to 95% ± 2% RHTemperature range : 100c to 500C, ± 0.50C-- Use calibrated machine (candles/inch = ?)3. Exposure time limit = ?(according to the limit of potential degradation products formed, and quinine HCl standard)
14Before starting program execution we should have; DesignBefore starting program execution we should have;4Stability IndicatingAnalytical MethodICH Stress testingDevelopmentValidationRepresent. Chromatograms
15Stability indicating Analytical Method The method is able to discriminate between principle drugand the degradation products and/or impuritiesMethod: Compendial methods are claimed to be stability indicatingRules: ICH stress GuidelinePlus: Photodegradation products & reconstitution testingMonitoring: Peaks of Potential impurities &Degradation products (previously define the cause)
16Example of STRESS TESTING OF BETAHISTINE HCl Rules of Stress testing:-- expose drug subs. To abnormal environmental variables.-- Forced degradation to NLT 90%.-- Do not degraded the drug completely ? To provide selectivity of the method.heatedNaOHHClRepresentative chromatograms of betahistine hydrochloride; heated in solid state [a], boiled in 1M NaOH [b], boiled with 1M HCl [c], extracted from tablet powder exposed to UV light [d], extracted from Betaserc tablets [e], and left to stand in 0.1% H2O2 solution [f].UV lightBetaserc tabletsH2O2
17Analytical Method Performance Chromatographic parameters* of TIA degraded with 1M HCl, (detection; UV at 254 nm, claimed TIA concentration is 250 ng/μL). n = 3.RT (min)(RSD)AreaWidth(min)% Amount± SDK ‘RαAsN12.31(0.14)(0.06)0.8348.60±0.015.151.112039321.37(0.02)694064(0.88)0.707.32±1.029.6811.821.881.3210705328.05(0.27)(0.75)1.0718.55±0.6813.037.57(0.26)1.351.295990929.17(0.15)601828(0.58)0.856.34±1.3313.591.17(0.12)1.041.1915249630.54(0.11)(0.55)0.7318.92±1.2014.271.73(0.08)1.051.2015727632.57(1.20)18284(1.00)0.470.19±0.6615.283.37(0.95)1.1318944833.497442(0.65)0.380.08±0.3415.742.17(0.01)1.03191957* k’ capacity factor; α, selectivity coefficient; R, resolution; and As, peak asymmetry; N, USP plate count.How to present the analytical HPLCmethod PERFORMANCE PARAMETERS
18What are theStability-indicating quality parametersStability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy.For instance, in case of tablets:♦ appearance ♦ hardness♦ friability ♦ moisture content♦ dissolution time ♦ degradants♦ assay ♦ microbial purity
19Before starting program execution we should have; DesignBefore starting program execution we should have;5Drug ProductBatch size3 batchesSampling protocol
20Selection of batches: 5 Drug product How many batches should be tested ?Batch size = ? Product unitWhich Batches should be tested ?When should we repeat stability testing?
21Selection of batches: 5 Drug product How many batches should be tested ?three, using 3 different batches of starting drug substanceBatch size = ? Product unitTwo pilot scale batches, third smaller if justified)Which Batches should be tested ?Stability studies should be performed on each individual strength and container size.When we should repeat stability testing?In case of failed stability ..! Modification?using raw material from different manufacturer,excepients type/ratio changemanufacturing procedure modified.change of package, closure.ApplicationFor ANDA(Pharm. Bioeq) !!
22Container / closure systems: The stability testing should be conducted on the dosage form stored in the proposed containers / closure system for marketing.
23Before starting program execution we should have; DesignBefore starting program execution we should have;6Reference StandardsPurchase USP / Europ. Reference Standard)Purchase Potential ImpuritiesStored in Special Storage cabinet + log book (amount used, when, for what?)Verified (Melting point, IR, HPLC-RT as per USP/BP)
24Major Variables Temperature Relative Humidity Light (Photostability) Stability after Reconstitution (dilution)
25Typical storage condition and study duration [a] General Case (PERMEABLE)[b] Drug Products packaged in IMPERMEABLE containers[c] Drug Products packaged in SEMIPERMEABLE containers[d] Drug Products intended for storage in refrigerator[e] Drug Products intended for storage in freezer[f] Drug Products intended for storage below -20 ºC
26Frequency of sampling (months) Typical storage condition and study duration[a] General Case (PERMEABLE containers to moisture)StudyStorage conditionMinimum time periodFrequency of sampling (months)Long-term252C / 60 % RH 5% RHor302C / 65 % RH 5% RH12 months0,3,6,9,12,18,24Intermediate6 months0,3,6,12Accelerated402C / 75 % RH 5% RH0,1,2,3,6It is up to the applicant to decide the tem/RH for long term.If 302C / 65 % RH 5% RH is the long term, then NO INTERMEDIATE cond.
27Frequency of sampling (months) Typical storage condition and study duration[b] Drug product packaged in IMPERMEABLE containers(to moisture or solvent loss)Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent.Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.StudyStorage conditionMinimum time periodFrequency of sampling (months)Long-term252Cor302C12 months0,3,6,9,12,18,24Intermediate6 months0,3,6,12Accelerated402C0,1,2,3,6
28Frequency of sampling (months) Typical storage condition and study duration[c] Drug products stored in SEMIPERMEABLE containersStudyStorage conditionMinimum time periodFrequency of sampling (months)Long-term252C / 40% RH 5% RHor302C / 35% RH 5% RH12 months0,3,6,9,12,18,24Intermediate302C / 65 % RH 5% RH6 months0,3,6,12Accelerated402C / NMT 25 % RH0,1,2,3,6It is up to the applicant to decide the tem/RH for long term.If 302C / 35% RH 5% RH is the long term, then NO INTERMEDIATE cond.Aqueous-based products packaged in semipermeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability.5% loss of water (after 3 months) is considered significant change.
29Frequency of sampling (months) Frequency of sampling (months) Typical storage condition and study duration[d] Drug products intended for storage in a REFRIGERATORStudyStorage conditionMinimum time periodFrequency of sampling (months)Long-term5 3C12 months0,3,6,9,12,18,24Accelerated252C / 60 % RH 5% RH6 months0,1,2,3,6[e] Drug products intended for storage in FREEZERStudyStorage conditionMinimum time periodFrequency of sampling (months)Long-term-20 5C12 months0,3,6,9,12,18,24[f] Drug products intended for storage BELOW -20 CDrug products intended for storage below -20°C should be treated on a case-by-case basis.
32Example of Failed stability The assay value is still within the limits but the change during stability is more than 5.0%ExampleRelease assay limit: 95.0 – 105.0%Release assay: % (within spec)6-Month assay: 95.5% (within spec)Loss in potency: %.This is a significant change.
34Stability Data and Report attaché Real Chromatogramsattaché RecordsEx: Karl fisher data, tablet weight. .Attaché auto dissolution readingsAttaché Cabinet temp./RH chart data.Batches testedProduct name.Name and potency of active ingredient.Validated Stability indicating assay methodBatch size.Batch number.Manufacturing site.Manufacturing date.Date stability study was started.Date sample(s) was withdrawn from chamber.Date of sample analysis.Storage conditions (e.g., 40C / 75% RH).Container / closure system.Supplier and manufacturer of active ingredient(s).Supplier and manufacturer of container / closure system.Supplier and manufacturer of packaging components, cartons, etc.Cumulative tabulation of all tests result.Literature reviewRecords, reports, and certificatesConclusion, QA approval and Decision
35Additional or New Stability Data is Required if; Change in the route of synthesis of an APIChange in composition of the FPPChange in immediate packaging of the FPPIn case of failed stability, (chemical, instrumental, regulatory)using raw material from different manufacturer,excepients type/ratio changemanufacturing procedure modified.change of package, closure.