Process Analytical Technology Tools For Monitoring Pharmaceutical Unit .
pharmaceuticsReviewProcess Analytical Technology Tools for MonitoringPharmaceutical Unit Operations: A Control Strategy forContinuous Process VerificationEun Ji Kim 1,† , Ji Hyeon Kim 1,† , Min-Soo Kim 2 , Seong Hoon Jeong 3 and Du Hyung Choi 1, *123*† Citation: Kim, E.J.; Kim, J.H.; Kim,M.-S.; Jeong, S.H.; Choi, D.H. ProcessAnalytical Technology Tools forMonitoring Pharmaceutical UnitOperations: A Control Strategy forContinuous Process Verification.Pharmaceutics 2021, 13, cademic Editors: DimitriosG. Fatouros and Holger GrohganzReceived: 13 April 2021Accepted: 16 June 2021Published: 21 June 2021Department of Pharmaceutical Engineering, Inje University, Gimhae-si, Gyeongnam 621-749, Korea;k89321499@gmail.com (E.J.K.); gihyeon906@gmail.com (J.H.K.)College of Pharmacy, Pusan National University, Busandaehak-ro 63 heon-gil, Geumjeong-gu,Busan 46241, Korea; minsookim@pusan.ac.krCollege of Pharmacy, Dongguk University-Seoul, Dongguk-ro-32, Ilsan-Donggu, Goyang 10326, Korea;shjeong@dongguk.eduCorrespondence: choidh@inje.ac.kr; Tel.: 82-55-320-3395These authors contributed equally to this work.Abstract: Various frameworks and methods, such as quality by design (QbD), real time release test(RTRT), and continuous process verification (CPV), have been introduced to improve drug productquality in the pharmaceutical industry. The methods recognize that an appropriate combination ofprocess controls and predefined material attributes and intermediate quality attributes (IQAs) duringprocessing may provide greater assurance of product quality than end-product testing. The efficientanalysis method to monitor the relationship between process and quality should be used. Processanalytical technology (PAT) was introduced to analyze IQAs during the process of establishingregulatory specifications and facilitating continuous manufacturing improvement. Although PATwas introduced in the pharmaceutical industry in the early 21st century, new PAT tools have beenintroduced during the last 20 years. In this review, we present the recent pharmaceutical PAT toolsand their application in pharmaceutical unit operations. Based on unit operations, the significantIQAs monitored by PAT are presented to establish a control strategy for CPV and real time releasetesting (RTRT). In addition, the equipment type used in unit operation, PAT tools, multivariatestatistical tools, and mathematical preprocessing are introduced, along with relevant literature. Thisreview suggests that various PAT tools are rapidly advancing, and various IQAs are efficiently andprecisely monitored in the pharmaceutical industry. Therefore, PAT could be a fundamental tool forthe present QbD and CPV to improve drug product quality.Keywords: process analytical technology; continuous process verification; quality by design; controlstrategy; quality attributes; critical process parametersPublisher’s Note: MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affiliations.Copyright: 2021 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).1. IntroductionQuality control in the pharmaceutical industry has traditionally depended on statistical process control (SPC) [1–4], which is used to understand the process and desiredspecification limits and to ensure a stable process by eliminating the allocable sources ofvariation. Statistical methods, including control charts and run charts, are used to inspectthe quality of the post-manufacturing finished product and determine the performancesuitability of unit operations in the pharmaceutical manufacturing process [1]. Moreover,most offline analyses and monitoring are conducted to evaluate the quality of the intermediate and finished products during the production batch process. For example, it iscommon to use control charts for monitoring general production processes, thereby ensuring that various aspects of the production process are controlled [5,6]. This traditionalprocess verification is designed to perform process verification on finished batches underpredesigned process conditions. Therefore, a disadvantage of this method is that the qualityPharmaceutics 2021, 13, 919. ://www.mdpi.com/journal/pharmaceutics
Pharmaceutics 2021, 13, 9192 of 45characteristics of intermediate products cannot be confirmed during the manufacturingprocess. Hence, identifying and solving problems that arise during the process requiresa lot of time and results in relatively more high-quality defects. Moreover, there is noassurance that the entire lot conforms to the required specifications, and the method cannotbe applied generally as a solution to all quality defects.The International Council for Harmonisation (ICH) launched continuous processverification (CPV) to overcome SPC limitations, ensure process control, and improve theunderstanding of processes and product quality. Furthermore, ICH described CPV as analternative approach to process validation, in which manufacturing process performanceis continuously monitored and evaluated. In addition, CPV provides more informationabout variability and control, providing higher statistical confidence, improving the assessment of pharmaceutical manufacturing processes and higher assurance of continuouscontrol status.Another strategy introduced by the pharmaceutical industry to improve the understanding of the process and quality control is quality by design (QbD). QbD is definedin ICH Q8 guidelines as “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control,based on sound science and quality risk management.” The development of a QbD-basedpharmaceutical process involves a scientific risk-based systematic method to correlatecritical process parameters (CPPs), input-materials attributes, and critical-quality attributes(CQAs) [3]. In general, QbD tools, including design of experiments (DoE), empirical modeling, and response surface analysis can develop a design space and reveal process variabilityduring the pharmaceutical manufacturing process [7–9]. Unlike the existing quality bytesting (QbT) system, in which the quality test of the finished product is mainly used, theQbD approach enables drug-quality management to enhance the quality of drugs based onscience- and risk-based technology.The US Food and Drug Administration (FDA)’s Center for Drug Evaluation andResearch (CDER) discussed the need for FDA guidance to facilitate PAT implementation,and the FDA published the PAT guidance for innovative pharmaceutical manufacturingand quality in September 2004 [10]. It is recognized as an important paradigm shift ininspecting and approving processes for the continuous process verification of pharmaceutical production processes. This initiative is also implemented by the EMA, and theMinistry of Health, Labor, and Welfare (MHLW) in Japan adopted it immediately [11].Interfacing manufacturing processes with analytical techniques is essential in PAT, as itfacilitates process development according to QbD principles and enables real-time releasetesting (RTRT) [12]. PAT is applied to each unit operation in the manufacturing process;CPPs, which have a significant influence on CQAs, are controlled to present a high-qualityproduct in the market [13–15].PAT in CPV ensures product quality throughout the manufacturing process andenables the automation of transportation between product processes [16,17]. Furthermore,PAT is used as a control strategy for monitoring processes in real time, improving theunderstanding of the process, and RTRT [11,18,19]. The vast amount of informationobtained by PAT enables rapid problem resolution, optimization, and defect detection. Inaddition, in the event of unexpected process changes, PAT can be applied to identify theroot causes of undesired drug product-quality issues. Therefore, appropriate PAT enablesthe timely adjustment of process parameters, ensures good and stable product quality,and shortens the overall manufacturing time. These frameworks provide advantagesthat enable process control quickly and easily and are a trend that has been graduallyadopted and introduced because it contributes significantly to establishing the controltechnology [18–21]. Furthermore, several studies have applied the QbD approach and PATin pharmaceutical manufacturing processes [12,14,16–18].This review focuses on applying PAT to QbD, RTRT, and CPV to improve drug qualityin the pharmaceutical industry. It presents a significant relationship between the processand IQAs with the relevant literature, which could be monitored with PAT framework for
Pharmaceutics 2021, 13, 9193 of 45QbD, RTRT, and CPV. The recent PAT tools are presented with the relevant literature inpharmaceutical unit operations, including blending, granulation, tableting, and coating.Based on unit operations, IQAs measured by PAT, equipment type, PAT tools, multivariatestatistical tools, and mathematical preprocessing are listed along with relevant literature.2. Control Strategy for PAT ApplicationAppropriate control strategies should be applied during the manufacturing processto control variables affecting product quality. A control strategy comes from the understanding of products and processes and risk management. There are various approaches,such as in-process testing, RTRT, and finished product testing [11,14,15]. Traditional control strategies mostly rely on off-line analysis of finished-product testing. In addition,process verification has been performed on batches produced under predesigned processconditions. However, because it is difficult to predict the effect of process parametersduring processing on finished-product quality, there is a limit to effectively controllingthe process. It cannot be determined that all produced lots comply with the requirements.In addition, it is not easy to establish the feasibility of controlling the process variablesof each unit process. Therefore, real-time process control is impossible and inefficient interms of time and cost. The QbD approach has been introduced to overcome this andto improve understanding of product performance, identify critical process parameters(CPPs) during quality risk assessment of the product manufacturing process, and establishappropriate control strategies for each variable [13,22]. The QbD approach is applied for theaccurate and reliable prediction of product-quality characteristics within the design spaceestablished, using each variable, manufacturing environment, and other conditions [12]. Asthis improves the understanding of products and processes, control strategies are appliedto produce products of consistent quality that meet the desired quality attributes [23,24].Introducing process control strategies to minimize the variability of the finished-productquality can justify an approach to quality assurance with an improved level of qualitycompared to finished-product testing using existing compendial standards.2.1. The Effect of the Manufacturing Process on Intermediates during ProcessingAs described above, CPV was introduced in the pharmaceutical industry to producehigh-quality drugs through quality control and quality assurance throughout the druglifecycle. Therefore, in CPV, the quality control and process monitoring of intermediateproducts are recommended by using QbD to identify the quality of intermediate productsthat may affect the quality of finished products and by adjusting process parameters duringthe manufacturing process using the PAT framework. [12,13,22]. Table 1 presents theprocess parameters and quality of intermediate products that need to be adjusted in themanufacturing process, including blending, granulation, drying, coating, and tabletingof solid dosage form based on the risk assessment using the QbD approach. Since theproposed process parameters and quality of the intermediate can greatly influence thequality attribute of the finished product, they should be adjusted by conducting appropriateprocess monitoring through a PAT framework during the manufacturing process [23,24].
Pharmaceutics 2021, 13, 9194 of 45Table 1. Effect of critical process parameters (CPPs) on intermediate quality attributes (IQAs) for the solid dosage ality AttributesJustificationRef-Drug contentBlendinguniformityIf the blending time is long, separation mayoccur depending on the particle characteristics,which may affect the content and contentuniformity of the mixture.[25,26]-BlendinguniformityWhen blending above the optimum blendingspeed, the particles adhere to the wall of theblender by centrifugal force, which may affectthe uniformity of the content of the mixture.[25–29]-Drug contentBlendinguniformityThe order of input of additives has little effecton content and content uniformity because ofthe blending process in the blender. However,the effect of the input of the lubricant mayaffect the content and content uniformity.[26]Environment-Moisture contentDrug contentIf temperature and humidity are not controlled,it may affect the moisture content of themixture, and the content and contentuniformity may be affected depending on themoisture and thermal stability of the drug.[26]Filling level-Drug contentSince the charging rate affects the movement ofthe particles, it can cause blendingnon-uniformity. This can affect the content andcontent uniformity of the mixture.[25–27]-Granule-sizedistributionGranule strengthFlowabilityWhen the amount of liquid increases, thepowder is completely wetted, which impedesthe particle flow in the granulator, which canaffect the particle-size distribution of thegranules by increasing the residence time andtorque value. When the amount of liquid isinsufficient, weak granules are edistributionThe concentration of the binding liquid has adirect relationship with the binding force andcan affect the density and particle-sizedistribution of the granules.[32–34]Drug contentGranule sizeGranule strengthThe binder solvent spray rate is directlyconnected to the size of the granules. If it is tooslow, the process time is lengthened, and it isdifficult to form granules; if it is too fast, amass may be formed. Therefore, it can affectthe granule-size distribution and density.[35–38]Drug contentThe filling level affects the movement ofparticles in the granulator ball, so that finegranules may be generated due to an increasein the number of collisions between thegranules and an increase in strength. This canaffect the content and uniformity of ngOrder ofinputBindersolventamount-Bindersolvent concentration-Bindersolvent sprayrate-High-shearGranulation granulationFilling level-
Pharmaceutics 2021, 13, 9195 of 45Table 1. ntermediateQuality Attributes--Chopperspeed--Massing time--Mill screensizeNozzle ule densityFlowabilityGranule strengthThe speed of the impeller determines the stateof the granules. Accordingly, the porosity anddensity of the granules may be affected, andthe particle-size distribution and flowability ofBulk/apparent/true the granules may be affected. In addition, asdensitythe impeller speed increases, it may affect theGranule-sizegranule growth due to coalescence, so it maydistributionaffect the granule size.[30,35,41–45]Granule-sizedistributionSince the chopper speed plays a role inbreaking the mass of granules, it can affect theBulk/apparent/true density of the granules, the particle-sizedistribution, and the flowability of thedensitygranules.Flowability[30,37,41,46]The massing time is a factor that determinesthe main physical properties of the granules.Depending on the massing time, the strengthof the granules and the density of the granulescan be affected, and thus, the flowability andparticle-size distribution can also be affected.Excessive massing time can result in granuleBulk/apparent/true growth by coalescence, which can affectdensitygranule size. Accordingly, it may affect theFlowabilitycontent uniformity of the granules, which mayaffect formation of nGranule strengthDrug tyThe mill screen size can affect the physicalproperties of the granules, such as the densityand flowability of the granules, due to a largeBulk/apparent/true correlation with the particle-size distributionof the granules.density[35]Granule sizeGranule-sizedistributionFlowabilityThe nozzle position affects the spray angle ofthe binder solvent, which can affect theagglomeration and growth of the granules, butthe effect is negligible. In addition, the size ofthe nozzle hole affects the distribution of thebinder solution. However, this has little effectwhen adjusted with other process tyWhen the amount of liquid increases, thepowder is completely wetted, which impedesthe particle flow in the granulator, which canaffect the particle-size distribution of thegranules by increasing the residence time andtorque value. When the amount of liquid isinsufficient, weak granules are stributionThe concentration of the binding liquid has adirect relationship with the binding force andcan affect the density and particle-sizedistribution of the granules.[52–57]Binder concentrationJustification
Pharmaceutics 2021, 13, 9196 of 45Table 1. ality AttributesJustificationRefThe binder solvent spray rate is directlyconnected to the size of the granules. If it is tooslow, the process time is lengthened and it isdifficult to form granules; if it is too fast, amass may be formed. Therefore, it can affectthe granule-size distribution and density.[53–60]Higher temperature increases fineness due torapid drying, and lower temperature causesgranules to agglomerate, resulting in harderand larger granules. This can affect the density,flowability and particle-size distribution of theBulk/apparent/true granules. The flow of particles is determineddensityaccording to the air-supply flow rate, and if itGranule-sizeis too high, the degree of blending due todistributionprocess loss may be lowered, which may affectFlowabilitythe density, flowability, and particle-sizedistribution of the granules. The air-supplyhumidity determines the size of the granules,which can affect the particle-size distributionof the granules.[52,53,59,61]Binder sprayrate-Air arent/truedensityGranule sizeGranule-sizedistributionGranule sizeGranule-sizedistributionThe position of the nozzle affects the sprayangle of the binder solvent, which can affectthe agglomeration and growth of the granules,but the effect is zedistributionThe nozzle type affects the way the binder issprayed into the fluidized-bed of the particles,which can affect the particle-size distributionor density of the tyGranule densityMoisture contentIt can be determined according to the heat andmoisture stability of the drug. If the dryingtime is short or the granules are not sufficientlydried due to the low drying temperature, themoisture content of the granules may beaffected. If it is too high, fines may occur dueto over-drying, which may affect theflowability and density of the particles.[59,61]-Moisture contentDrug contentIf the temperature and humidity are notmanaged, it may affect the moisture content ofthe granules, and the moisture and thermalstability of the drug may affect the content andcontent uniformity of the granules.[59,63]-Granule-sizedistributionWhen the binder solvent viscosity is high,there is a risk of granule mass, which mayaffect the size and particle-size distribution ofthe f the amount of liquid inside the granulatorincreases, the powder may become excessivelymoistened and impede the flow of the inside.This increases the residence time and can thusaffect the size and particle-size distribution ofthe granules.[65–69]-Nozzle ityTwin-screwgranulationLiquid tosolid ratio-
Pharmaceutics 2021, 13, 9197 of 45Table 1. ality yGranule-sizedistributionFlowabilityThe feed rate of the powder affects theresidence time, and due to the low feed rate,the inside of the granulator is not completelyfilled, and the residence time may belengthened. This can affect granule properties,such as the particle-size distribution, densityand flowability of the onRibbon uniformityThe screw speed can affect the residence timeand, accordingly, the particle-size distributionand density of the istributionThe type of screw is affected by the shape andangle of the screw to be engaged or thekneading pattern of the kneader part. Thisaffects the amount of filling inside thegranulator and can directly affect thecompression and crushing of agglomeratedparticles and the distribution of the granules.[65,66,69,75]-Granule-sizedistributionThe feeder amount is directly related to theresidence time and can affect the particle-sizeBulk/apparent/true distribution and density of the granules.density[65,71]Granule sizeGranule-sizedistributionThe residence time of the powder can affect thesize and particle-size distribution of thegranules.[66,72,75]Ribbon g on the type of roller compactor, theprinciple of operation is different, which canaffect the properties of the ribbon and thepowdery properties of granules (roller width,roller diameter). The larger the diameter of theroller, the larger the compression area, so itmay affect the characteristics of the ribbon, but,in general, the diameter of the roller is used asa fixed factor, so the effect on the intermediateproduct is insignificant.[76]Drug contentGranule-sizedistributionFlowabilitySince the roller pressure determines thebonding force of the powder, it is judged to bedirectly related to the density of the ribbon.This may affect granule particle-sizedistribution, flowability and contentuniformity after mill screening.[35,76–80]Ribbon densityDrug contentGranule-sizedistributionFlowabilityThe roller speed is controlled by the screwspeed, and it is judged that it has a directrelationship with the density of the ribbon aswell as controlling the speed of the process.This affects the powder properties of thegranules, which can affect the particle-sizedistribution and flowability of the granules.[35,78,80–84]Feeder rate-Screw speed-Screw typeFilling ionRollerpressureRoller speed-----
Pharmaceutics 2021, 13, 9198 of 45Table 1. ality on densityGranule densityGranule-sizedistributionThe roller gap affects the bonding force of thepowder fed into the feeder, and may affect theribbon density. This affects the powderproperties of the granules after mill screening,which may affect the particle-size distributionand flowability of the granules. As the widthof the roller changes, it is directly related to themaximum pressure of the roller, which canaffect the density of the ribbon and thus thedensity and particle-size distribution of thegranules.-Input speed is directly related to rollerpressure or roller spacing, which can affect theribbon density, particle-size distribution andflowability of the granules.[79,82]-Ribbon DensityGranule-sizedistributionFlowabilityFeed screwspeed-Ribbon uniformityFeed screw speed is a variable that is affectedby roller pressure and roller spacing, and theeffect is negligible.[80]Residencetime-Ribbon uniformityThe residence time of the powder can affect thesize and particle-size distribution of abilityThe size of the granulator can affect thephysical properties of the granules, such as thedensity and flowability of the granules, due toa large correlation with the particle-sizedistribution of the granules.Granule-sizedistributionFlowabilityThe speed of the granulator can affect thepowdery properties of the granules, but theeffect is insignificant.Roller gapFeeder rateMill screensize-Mill speedDrying timeDryingprocess--DryingtemperatureInlet airtemperature--Particle sizeParticledistributionDrug polymorphicformMoisture contentIf the drying time is short, and the result is notfully dried, the moisture content may beaffected. If the drying takes too long, finepowder may be generated due to over-drying,which may affect the flowability anddistribution of the particles.[76,78,88][89–91]If the drying temperature is low, and the resultis not fully dried, the moisture content may beaffected. If the drying temperature is too high,Bulk/apparent/true fine powder may be generated due toover-drying, which may affect the flowabilitydensityand particle distribution of the particles.Moisture contentThe thermal charge of the inlet drying gasreflects its capacity to dry the humid atomizeddroplets, and, therefore, higher inlettemperatures enable higher solventevaporation rates.[92]
Pharmaceutics 2021, 13, 9199 of 45Table 1. ality Attributes-Air flow rate--RotationspeedNozzlediameterInlet airtemperatureAir flow rateCoatingsolutioncompositionSpray rateAtomizingair pressureRefParticledistributionThe flow of particles is determined accordingto the air-supply flow-rate, and the air-supplyflow-rate determines the size of the granules.Bulk/apparent/true This can affect the density and particle-sizedensitydistribution. In addition, an increase in the airMoisture contentflow rate causes a higher evaporation rate.[89,93]-CoatinguniformityAs the speed increases, the tablets apparentlytumble through the spray zone rather thansliding flat, so the end exposure is morefrequent, and the coating becomes moreuniform.[94–96]-Coating thicknessWeight gainMoisture contentThe size of the sprayed droplet variesdepending on the nozzle diameter. Therefore,since the amount of the coating liquid to besprayed varies, this affects the moisturecontent and residual solvent.[97,98]CoatinguniformityMoisture contentIf the inlet air temperature is high, the tabletsare excessively dried, and the surface becomesrough. If the inlet air temperature is low, thetablets stick together, and the moisture contentof the tablets increases. Moisture content andcoating uniformity are highly dependent onthe incoming air temperature.[99]Coating efficacyThe air flow rate prevents the sprayed coatingsolution from reaching the tablet. The fasterthe air flow, the lower the velocity of thesprayed droplet and the smaller the dropletsize. Therefore, it affects the coating efficiency.[100]-Coating efficacyAn improper air layer due to worn or unevendrying may cause agglomeration betweenparticles. An increase in air volume causes adecrease in spray density because the sprayarea increases as the droplet size decreases atthe center of the spray.[101]-Coated drugappearanceCoatinguniformityHardnessMoisture contentIn the case of functional coatings, the coatingsolution must contain an appropriatecomposition to deliver the desired effect of thedrug, which affects the efficacy of the finishedproduct. In addition, if the ratio of solidsconstituting the coating solution is high,efficient spraying becomes difficult, thusaffecting the coating efficiency.[102,103]-CoatinguniformityToo high a spray rate cause inadequate drying,twining, and sticking. Therefore, spray ratewill have a significant impact on surfaceroughness and weight gain, thus affecting thecoating uniformity.[96,99]-Coating efficiencyToo high a spray pressure can lead to spraydrying, and too low can cause agglomeration,which can have a significant impact on coatinguniformity.[104–106]--Coating processAir volumeJustification-
Pharmaceutics 2021, 13, 91910 of 45Table 1. ure/timeFeeder speedRotary speedTableting processIntermediateQuality AttributesJustificationRef[107–109]-Coating efficiencyMoisture contentHardnessThe incorrect setting of the curing temperatureand curing time will result in incomplete filmformation. Thus, full film formation occurswhen exposed to a certain curing temperature.The proper setting of curing time is necessaryto achieve complete film adhesion.-Tablet porosity/density/solidfractionDrug contentWeight variationLow feeder speeds can lead to improper diefilling, which can lead to weight changes andchanges in hardness and thickness. Fast feederspeeds can overfill the die cavity and lead toweight variations and hardness and thicknessvariations.[110]Drug contentHardnessWeight variationRotary speed affects compressibility and evenaffects weight variation, which can affect drugcontent. A high rotary speed causes a muchwider distribution of lubrication extentcompared to the results from a low rotaryspeed. This may induce greater variability inhardness between tablets.[111]Tablet appearanceThickness/dimensionsTablet porosity/density/solidfractionHardnessIncreasing compression force causes difficultparticle rearrangement, deformation andfragmentation. Compression force affect tabletporosity, hardness, and density. In addition,depending on the tablet porosi
regulatory specifications and facilitating continuous manufacturing improvement. Although PAT was introduced in the pharmaceutical industry in the early 21st century, new PAT tools have been introduced during the last 20 years. In this review, we present the recent pharmaceutical PAT tools and their application in pharmaceutical unit operations.
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