CX5-14 Film Validation Guide - Thermo Fisher Scientific
CX5-14 film validation guideFive-layer, 14 mil cast filmDOC0017 Revision CNovember 2016
Thermo Scientific CX5-14 filmFive-layer, 14 mil cast filmThermo Scientific BioProcess Containers (BPCs) are built to meetyour single-use upstream and downstream bioprocessing needs.Our films are engineered to meet the most demanding requirementsof your bioproduction processes. Thermo Scientific CX5-14 film isdeveloped specifically for liquid handling, storage, and transportationin the biopharmaceutical industry.Key benefits Good toughness and puncture resistance tomaximize security Highly flexible and stretchable material Non-animal origin formulation High barrier properties maximizing stabilityof content One film for your entire workflow from 50 mL to 2000 L Standard and custom configurations available in 2Dpillow-style with seam or panel ports, and 3D squaretube–style configurations with top– and bottom–panelporting options supplied gamma irradiated and readyto use
ContentsCX5-14 film specifications4Biocompatibility5Physical properties6Mechanical properties7Extractables8
CX5-14 film specificationsThermo Scientific CX5-14 film is afive-layer, 14 mil cast film producedin a cGMP facility. The outer layer is apolyester elastomer coextruded withan ethyl vinyl alcohol (EVOH) barrierlayer and a low-density polyethyleneproduct contact layer. CX5-14 film ismanufactured using non-animalorigin lene10.4PropertyTest protocolAverage valuesPhysical data (post–gamma irradiation, 25–40 kGy)Tensile strengthASTM D8822316 psi16.0 MPaElongationASTM D882476%Yield strengthASTM D8821238 psi8.5 MPa2% Secant modulusASTM D88237898 psi261.3 MPaTensile toughnessASTM D882235 lbf-in2.7 kN-cmPuncture resistanceASTM F130626 lbf116 NSeam strengthASTM F8831 lbf/in54 N/cmO2 transmission rateASTM D3985, 0% relativehumidity (RH) outside, 90% RHinside, 23 C0.024cc/100 in2/day0.37cc/m2/dayCO2 transmission rateMocon method, 0% RHoutside, 100% RH inside, 23 C0.089cc/100 in2/day1.38cc/m2/dayWater vaportransmission rateASTM F1249, 0% RH outside,100% RH inside, 23 C0.023g/100 in2/day0.35g/m2/dayHazeASTM D1003(outside dry/inside dry)70%Glass transition temperatureASTM E1640 19ºF 28ºCFilm gaugeInternal study0.014 in.0.356 mmFilm contact materialNAPolyethyleneTemperature range†Internal study 112ºF to 140ºF 80ºC to 60ºC10-6 Sterility assurance levelANSI/AAMI/ISO 1137:20062.5–4 Mrad25–40 kGyBiocompatibility data (post–gamma irradiation, 50 kGy)Fluid contactsurfaceSchematic cross sectionSchematic 3D viewUSP Class VIUSP 88 PassCytotoxicityUSP 87 PassBacterial endotoxinUSP 85 0.006 EU/mLHeavy metalsUSP 661 1 ppmBuffering capacityUSP 661 1 mLNon-volatile residueUSP 661 1 mgResidue on ignitionUSP 661 1 mgHemolysisISO 10993-4NonhemolyticAppearanceEP 3.2.2.1 PassAcidity and alkalinityEP 3.2.2.1 PassAbsorbanceEP 3.2.2.1 PassReducing substancesEP 3.2.2.1 PassTransparencyEP 3.2.2.1 PassAll tests are run post–gamma irradiation unless otherwise noted. † Sub-zero conditions require proper support and handling.4
BiocompatibilityOverviewBiocompatibility testing was conducted in order to helpensure that the film and other contact surfaces have noadverse effects on any biological material that may becontained within the sample. USP 88 Class VI tests forin vivo reactions to the material, USP 87 tests for in vitroreactions (cytotoxicity), USP 661 tests for assessmentof the physicochemical properties of the film, andUSP 85 tests for the presence of bacterial endotoxins.MethodsFollowing are the test methods used to help ensure thebiocompatibility of the films. The test methods that wereused include: USP 88 Class VI––Acute systemic injection: An extract of the test articlewas prepared for 72 hours at 50 C and was injectedintravenously into an animal model. Signs of toxicitywere monitored.––Intracutaneous reactivity: An extract of the test articlewas prepared for 72 hours at 50 C and injected underthe skin of an animal model, and signs of irritation weremonitored.––Intramuscular implantation: The test article wasimplanted into the muscle tissue of an animal model,and the resulting tissue sections were examined grosslyfor signs of infection, necrosis, discoloration, andhemorrhage. USP 87 Cytotoxicity: An extract of the test articlewas prepared for 24 hours at 37 C in E-MEM cell culturemedium and cultured with L-929 mouse fibroblast cells.The resulting cell culture was monitored for morphologicalchanges and loss of viable cells. EP 3.2.2.1 Plastic containers for aqueous solutionsfor parental infusion: Testing is done to characterizethe suitability and functionality of the materialsused in the construction of polyethylene-basedBioProcess Containers.ResultsA summary of biocompatibility testing is shown in Table 1.Table 1. Summary of biocompatibility testing.TestResultsUSP Class VIUSP 88 PassCytotoxicityUSP 87 PassBacterial endotoxinUSP 85 0.006 EU/mLHeavy metalsUSP 661 1 ppmBuffering capacityUSP 661 1 mLNon-volatile residueUSP 661 1 mgResidue on ignitionUSP 661 1 mgAppearanceEP 3.2.2.1 PassAcidity and alkalinityEP 3.2.2.1 PassAbsorbanceEP 3.2.2.1 PassReducing substancesEP 3.2.2.1 PassTransparencyEP 3.2.2.1 PassConclusionSamples manufactured from the CX5-14 film were tested forbiocompatibility per USP and EP protocols. There were nosigns of toxicity, irritation, inflammation, or cytotoxicity. USP 661 Physiochemical test for plastics: Anextract of the test article was prepared for 24 hours at70 C and analyzed for non-volatile residue, residue onignition, heavy metals, and buffering capacity. USP 85 Bacterial endotoxin testing: Limulusamoebocyte lysate (LAL) testing quantifies thepresence of bacterial endotoxins on a sample aftergamma irradiation.www.thermofisher.com/sut5
Physical propertiesOverviewPermeability gases and water vapor are important propertiesof the film. Resistance to the transmission of oxygen,carbon dioxide, and other gases is important in controllingthe pH and chemical properties of a single-use container’sfluid content. Resistance to the transmission of watervapor is also important to the control of the concentrationof a container’s fluid content. Factors that affect a film’spermeability characteristics include film composition, filmthickness, temperature, and relative humidity (RH).Methods Sample preparation: Test articles consisted of10.8 x 10.8 cm (4.25 x 4.25 in.) swatches. The filmwas always oriented so that the inner layer of the filmwas exposed to relative humidity. Water vapor transmission rate: Test articles wereconditioned at 23 C and analyzed for water vaportransmission rate using a MOCON Permatran-W 700test system per ASTM F1249. The film was oriented sothat the inner layer of the film was exposed to 100% RHwater vapor and the outer layer of the film exposedto 0% RH N2 gas. These conditions simulate theworst-case scenario and represents a higher watervapor transmission rate than ambient conditions(approximately 0% outside RH). Final water vaportransmission rates were recorded when thesystem equilibrated. CO2 transmission rate: Test articles were conditionedat 23 C and analyzed for CO2 transmission rate usinga MOCON Permatran-C 4/41 test system per ASTMD3985. The film was oriented so that the inner layerof the film was exposed to 100% RH CO2 gas and theouter layer of the film was exposed to 0% RH N2 gas.These conditions simulate the worst-case scenario andrepresent a higher CO2 transmission rate than ambientconditions (approximately 0% outside RH). Final CO2transmission rates were recorded when thesystem equilibrated.6 O2 transmission rate: Test articles were conditionedat 23 C and analyzed for O2 transmission rate using aMOCON OX-TRAN 2/21 test system per ASTM D3985.The film was oriented so that the inner layer of the filmwas exposed to 100% RH O2 gas and the outer layerof the film exposed to 0% RH N2 gas. These conditionssimulate storage conditions, with the inner layerrepresenting fluid contact (100% RH) and the outerlayer representing atmospheric contact (0% RH). FinalO2 transmission rates were recorded when thesystem equilibrated.ResultsResults for the above transmission rate testing protocols areshown in Table 2.Table 2. Summary of data for transmissionrate testing.TestTest conditionsResultsWater vaportransmission rate0% RH outside,100% RH inside, 23 C0.023 cc/100 in2/dayCO2 transmission rate0% RH outside,100% RH inside, 23 C0.089 cc/100 in2/dayO2 transmission rate0% RH outside,90% RH inside, 23 C0.024 cc/100 in2/dayConclusionBPCs manufactured from the CX5-14 film were tested forgas and water vapor permeability. These results show thecapability of the BPCs to resist loss of water vapor andtransmission of CO2 and O2, thus showing their suitability foruse in storing solutions where pH, chemical stability, andchemical concentration are a concern.
Mechanical propertiesOverviewThe mechanical properties of a film are important to theintegrity of a BPC and its suitability for use under varyingconditions. The mechanical properties evaluated weretensile strength, elongation, yield strength, secant modulus,tensile toughness, puncture resistance, and seam strength. Tensile strength is the maximum amount of stressthat a material can handle before breaking Elongation is a measure of the ability of a material toresist changes of shape without crack formation Yield strength is the minimum amount of stress ona material at which it begins to permanently deform Tensile toughness is a measure of the ability of amaterial to absorb energy and deform up to thepoint of failure (fracturing) Secant modulus is the measure of a material’selasticity and stiffness Puncture resistance is a measure of the amountof force required to pierce a material Seam strength is a measure the force requiredto rupture a seamMethods Tensile properties: Tensile strength, elongation, yieldstrength, tensile toughness (tear resistance), and secantmodulus testing were based on ASTM D882: StandardTest Method for Tensile Properties of Thin PlasticSheeting. Test articles were placed into the grips of theInstron 5565 equipment’s mechanical test frame andpulled at 50.8 cm (20 in.) per minute. Puncture resistance: Testing was based on ASTMF1306: Standard Test Method for Slow Rate PenetrationResistance of Flexible Barrier Films and Laminates. Testarticles were installed in the Instron 5565 equipment’sfixture. The probe speed was 2.54 cm (1 in.) per minuteand the test article was tested until puncture. Glass transition temperature: Testing was based onASTM E1640: Standard Test Method for Assignment ofthe Glass Transition Temperature by Dynamic MechanicalAnalysis (DMA). Samples were analyzed using the DMAmethod in tension mode: –145 to 50 C at 3 C per minuteusing TA Instruments DMA Q800 equipment. The testwas terminated when the sample yielded. Haze: Testing was based on ASTM D1003: StandardTest Method for Haze and Luminous Transmittance ofTransparent Plastics. Material samples were conditionedfor at least 24 hours at 23 C 2 C at 50% relativehumidity. Values were measured using the Hazemetermethod using Byk Haze-Gard I equipment.ResultsThe results of mechanical testing are shown in Table 3.Table 3. Summary of data for mechanical testing.TestResultsTensile strength (psi)2316 psiElongation (%)476%Yield strength (psi)1238 psi2% Secant modulus (psi)37989 psiTensile toughness235 lbf-inPuncture resistance26 lbfSeam strength31 lbf/inHaze70%Glass transition temperature–28oCConclusionBPCs manufactured from the CX5-14 film were tested toverify mechanical properties. These BPCs proved capable ofresisting the stresses that are incurred during shipping andregular use.www.thermofisher.com/sut7
ExtractablesExecutive summaryBPCs are widely used in biopharmaceutical processes.Buffers, media, and other process liquids are stored in thepolyethylene (PE) BPCs integrated with other componentssuch as filters, tubing, and connectors. Since theseBPCs are used in critical bioprocessing operations, theirinteractions with biopharmaceutical fluids and final drugformulations must be well understood and validated byend users. To ensure the quality of the BPCs, analyticaltesting is conducted for the identification and quantificationof extractables. Extractables are substances that can beforced into solution from the BPCs using common solventsand physical conditions that are expected to be moreaggressive than normal conditions of use. The goal of thisextractables study was to supply the worst-case extractabledata to support end users in their validation studies.During the study, high-performance liquid chromatography(HPLC), gas chromatography (GC) and inductively coupledplasma (ICP) separation techniques, and mass-spectrometry(MS) identification techniques were used.ObjectiveThe objective of this study was to provide a comprehensiveassessment of metals, volatile, semi-volatile, and non-volatileorganic compounds that can potentially be extracted fromfluid contact surface of gamma-irradiated BPCs.The selection of the tested solutions has been done tocover a range of worst-case conditions for the extractableanalyses. The intent of this extractable analysis is toprovide qualitative and quantitative information to assesstoxicological risks, and to evaluate the overall safety ofBPCs for long-term storage.Control samples were prepared by filling multiple 20mLheadspace vials with the appropriate extraction sample.Control samples for inorganic extractables testing werestored in chemically resistant Polytetrafluoroethylene(PTFE) vials.Storage conditions Samples and controls were stored in a chamber qualifiedat 60 C 2 C. Chamber qualification, temperature monitoring andcontingency planning were conducted by the testlaboratory's Standard Operating Procedures (SOPs).Time points At 24 hours, 30 days 8 hours, and 90 days 8 hours,one bag containing each of the common solvents wascollected for sampling and analysis. A matching control sample was also removed for each ofthe representative solvents at the same time points. All analyses for organic extractables were completedwithin 7 days of the sample date. All analyses for inorganic extractables were completedwithin 5 days of the sample date.Analytical test methodVolatileextractablesA gradient GC-MS method was used.Table 4. Volatile extractable reference standardsMethodsExtraction solvents: The 5 extraction solvents are waterfor-injection (WFI), 20% ethanol (EtOH), 4 M sodium chloride(NaCl), 3 M sodium hydroxide (NaOH), and 2 M hydrochloricacid (HCl).Sample Preparation: 500 mL BPCs were filled with216 mL of the common solvents listed above using agraduated cylinder and funnels that were rinsed withthe common solvents before RS690Octamethyltetrasiloxane (D4)Aldrich99.6%RS864Octamethyltetrasiloxane (D4)Aldrich98.9%RS655Dodecane (C12)Fluka100.0%RS863Dodecane (C12)Fluka99.9%RS8971,3-ditert-butyl benzeneAldrich97.4%RS8932,4-ditert-butyl phenolAldrich99.5%
ExtractablesSemi-volatile extractablesA gradient GC-MS method was used.Inorganic extractablesTable 5. Semi-volatile extractable reference standards The inorganic extractables analysis was performed byNSF International. Analysis of the below listed metals was yltetrasiloxane (D4)AldrichRS864Octamethyltetrasiloxane anumPhosphorusSodiumVanadiumButylated hydroxytolueneChem biumRS8132,4-ditert-butyl uthGadoliniumLutetiumPreseodymium num hromiumIndiumNickelScandiumTitaniumNon-volatile extractablesA gradient UPLC-PDA-MS method was used.Table 6. Non-volatile extractable reference rityRS800Cyanox 1790Aldrich98.8%RS622Stearic AcidFluka99.7%RS880Stearic AcidFluka99.7%RS805Irgafos 168Aldrich98%RS567Irganox igma100%Total organic carbon (TOC)The TOC conditions listed in the current version of the testlaboratory's internal protocol used.pH testingThe pH conditions listed in the current version of USPGeneral Chapter 791 were used.www.thermofisher.com/sut9
ExtractablesResultsTables 7-16 report the results of extractables testingTable 7. Estimated limits of detection (LODs) forvolatile by headspace GC-MS and semivolatile bydirect inject GC-MS extractablesQuantitation standardVolatilesAnalysisSemiVolatilesAnalysisLOD (μg/mL)Table 8. Estimated limits of LODs for nonvolatileextractables by UPLC-PDA-MSLOD (μg/mL)Quantitationstandard24 hour30 day(WFI, EtOH)30 day(HCI, NaOH, NaCI)90 dayIrganox 1010 (MS)0.951.051.600.46Stearic 52Irgafos 1680.200.550.560.400.278Irganox 1010 (PDA)0.140.100.110.0424 hour30 day90 720.1080.125Butylated Hydroxytoluene0.5090.2022,4 di-tert-butylphenol0.6040.240Table 9. Observed volatile, semivolatile, nonvolatile, inorganic extractables,pH and TOC for WFISolvent and Incubation conditionWFI24 hours, 60 CWFI30 days, 60 CWFI90 days, 60 C10Target compoundsExtracted compoundppmVOCNon Detected .75VOC2,4-Di-tert-butyl phenol0.071, 0.027, ,4-Di-tert-butyl phenol 0.008, 0.008, 8
ExtractablesTable 10. Observed volatile, semivolatile, nonvolatile and inorganic extractables for 20% EtOHSolvent and Incubation condition20% EtOH24 hours, 60 C20% EtOH30 days, 60 C20% EtOH90 days, 60 CaTarget compoundsExtracted compoundppmVOC1,3 – Di-tert-butyl benzene 0.032, 0.032, 0.032SVOC2,4-Di-tert-butyl phenol0.625, 0.576, 0.438NVOCIrgafos 168 Degradanta1.084, 1.099, 1.083MetalsNDNDpH-4.87VOC1,3 – Di-tert-butyl benzene0.024. 0.023, 0.023VOC2,4-Di-tert-butyl phenol0.034, 0.017, 0.017SVOC2,4-Di-tert-butyl phenol0.324, 0.411, 0.391NVOCIrgafos 168 Degradanta1.702, 1.745, 2.162MetalsNDNDpH-5.58VOC1,3 – Di-tert-butyl benzene0.009, 0.010, 0.009VOC2,4-Di-tert-butyl phenol0.014, 0.008, 0.009SVOC2,4-Di-tert-butyl phenol0.706, 0.708, 0.654NVOCIrgafos 168 Degradanta 0.400, 0.400, enyl) hydrogen phosphatewww.thermofisher.com/sut11
ExtractablesTable 11. Observed volatile, semivolatile, nonvolatile and inorganic extractables for 4 M NaClSolvent and Incubation condition4 M NaCI24 hours, 60 C4 M NaCI30 days, 60 C4 M NaCI90 days, 60 CTarget compoundsExtracted .92Table 12. Observed volatile, semivolatile, nonvolatile and inorganic extractables for 3 M NaOHSolvent and Incubation condition3 M NaOH24 hours, 60 C3 M NaOH30 days, 60 C3 M NaOH12Target compoundsExtracted compoundppmVOCNDNDSVOC2,4-Di-tert-butyl phenol1.179, 1.138, DNDMetalsPotassium52pH-14
ExtractablesTable 13. Observed volatile, semivolatile, nonvolatile and inorganic extractables for 2 M HClSolvent and Incubation condition2 M HCl24 hours, 60 C2 M HCl30 days, 60 C2 M HCl90 days, 60 CTarget compoundsExtracted DNDNVOCNDNDMetalsBoron0.74pH-0Table 14. Control sample pH valuespHSolv
Seam strength ASTM F88 31 lbf/in 54 N/cm O 2 transmission rate ASTM D3985, 0% relative humidity (RH) outside, 90% RH inside, 23 C 0.024 cc/100 in/day 0.37 cc/m2/day CO 2 transmission rate Mocon method, 0% RH outside, 100% RH inside, 23 C 0.089 cc/100 in2/day 1.38 cc/m2/day Water vapor transmission rat
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Drying 20 minutes Hang film in film dryer at the notched corner and catch drips with Kim Wipe. Clean-Up As film is drying, wash and dry all graduates and drum for next person to use. Sleeve Film Once the film is done drying, turn dryer off, remove film, and sleeve in negative sleeve. Turn the dryer back on if there are still sheets of film drying.
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