Mixing and Granulation - GEA Pharma Systems

Mixing and GranulationAeromatic-Fielder TechnologiesGEA Pharma Systems

GEA Pharma Systems is world leader in providingadvanced processing solutions for solid dosage forms tothe pharmaceutical industry. Based on a dedication toresearch and durable quality, GEA Pharma Systemsoffers a wide range of solutions, from individual piecesof equipment to complete integrated plants, by unitingthe state-of-the-art technologies of Aeromatic, Buck,Collette, Courtoy, Fielder, Lyophil, Nica and Niro.The High Shear Mixer/Granulator is a multi-purpose processorequally suitable for high speed dispersion of dry powders, aqueousor solvent granulations, effervescent products and melt

Product Know-HowProcess Expertise•For more than forty years, Aeromatic-Fielder has supplied advancedsolids processing plants for blending, granulating, drying, pelletizingand coating to the pharmaceutical industry. This includes smallcapacity systems designed for R & D as well as industrial size plantsfor batch production of pharmaceutical compounds under cGMPconditions.Our plant and process expertise is based on experience and R & D. With plants installedaround the world and literally thousands of tests performed, we have established a solidbase of expertise related to the needs of the pharmaceutical manufacturing industry.Delivering the Right SolutionsEvery Aeromatic-Fielder plant begins with thecustomer’s desire to create a product that willsucceed in the market. In Aeromatic-Fielder, thecustomer finds a partner who will assist him to meetthat goal. Our expertise includes technologies forprocessing Active Pharmaceutical Ingredients using,Blending, Granulating, Drying, Pelletizing andCoating.Plants Customised for SuccessEvery pharmaceutical plant and system fromAeromatic-Fielder is a unique union of proventechnology and individual solutions. Based onstandard components, we supply plants for cGMPproduction configured to meet the customer’sspecific requirements.A Partnership in Every PerspectiveWorking with Aeromatic-Fielder means entering asolid partnership every step of the way, from processtesting and design to specification of the softwarecontrolling your new plant. And our comprehensiveafter sales program ensures that your return oninvestment is optimised throughout the lifetimeof the plant.Safety and the environmentFor full compliance with national, local and in-houseregulations, Aeromatic-Fielder offers a range ofemission control options including solvent recoverysystems, outlet filters and full containment plants.Equipment can be supplied to meet explosion-proofand pressure shock standards as required.3

• Blending • Drying • Granulating • PelletizingProcessTechnologies•The High Shear Mixer/Granulator is a multi-purpose processor equallysuitable for high speed dispersion of dry powders, aqueous or solventgranulations, effervescent products and melt pelletization.Dry MixingHigh Shear mixing consists of a fast homogeneousblending of active powder and the excipients using ahigh-intensity mixing blade.Special featuresEvaluation of blend homogeneity by NIR-TechnologyWet GranulatingThe high shear granulation process combines theactive powder and the excipients with a bindersolution using a high-speed mixing blade andchopper.Special featuresControl of granulation process via in-line focus beamreflection measurementMelt GranulatingMelt agglomeration is a process by whichagglomeration - or size enlargement by which fineparticles are bound together to agglomerates orgranulates - is obtained through the addition ofeither a molten binder liquid or a solid binder whichmelts during the process. Agglomerates are formedby agitation of the mixture. To obtain a stable, drygranule, a cooling to ambient temperature isnecessary to solidify the binder.Dry BondingWhen low amounts of drugs should be administeredvia inhalation, the accuracy of current devices is notprecise enough. Therefore the small drug particlesare bonded to the course surface of lactose particlesin a dry high shear process. This requires specialtechnology - Aeromatic-Fielder’s expertise in thisprocess provides; special impellers giving enhancedshear forces, loading systems allowing a preciselayering of drug and excipient and often specialcontainment devices such as Buck ® split valves orHicoflex.Effervescent productsOne granulate method using waterA very small amount of water is added to start thepre-effervescent reaction by which some of thecarbon dioxide is released during granulation, but bywhich water is also produced as a reaction product,this then acts as a granulation fluid producing morecarbondioxide and also more water. This avalancheneeds to be stopped at a certain point by starting thedrying process and removing the water. This can bedone using a high shear granulator with subsequentfluid dryer by discharging at the end of thegranulation process the material into a pre-heatedfluid bed dryer.4

Built-in VersatilityPelletizingTo form granules out of powders a granulationliquid and mechanical energy is needed.Wet PelletizingThis process uses a Niro Rotary Atomiser spray toachieve excellent dispersion of binder liquid throughthe mix, and a special high-speed rotation blade formaximum movement of the product, for moreefficient pelletization. A PTFE container-liningminimises the need for ‘top and tailing’, even with themost cohesive of products. Studies have shown thatthe PTFE liner - unique to Aeromatic-Fielder - canincrease production efficiency by as much as 40%.Alternatively, an extruder may be used, similar tothose used for the manufacture of pellets. In atypical set-up all ingredients are pre-blended in acontainer after dispensing. Depending on theextruder design the liquid can be added in theextruder or mixed separately to the correctconsistency.The material produced by the extruder is now notrounded in a spheronizer (as it would be for pelletmanufacture) but transferred directly into acontinuous fluid bed where it is dried to the desiredmoisture level.Melt pelletizationThis is an exceptionally fast method of producingpellets in a single step. The active material andbinder are mixed in binder form then heated untilthe binder melts. A single batch is processedtypically in just 15-20minutes, and needs no furtherdrying.5

High ShearTechnology•PMA-Standard &PMA-Advanced Using proven standard components, Aeromatic-Fielder can supplyboth simplicity and flexibility in plant design. User-selected processoptions, cleaning equipment, control systems and PAT technologiescombine in a system to meet process requirements exactly. Thisapproach ensures that qualification and validation procedures arekept to a minimum.Impeller & chopper optionsStandard PMA impeller:Standard impeller designed for use with the conicalbowl of the PMA high shear granulator.U-Shaped chopper:Standard chopper for use with the conical bowl ofthe PMA high shear granulator.Through-the-wall configurationThrough-the-wall offers the best option in terms ofcleanliness, maintenance and ATEX. By keeping themotors out of the process room, you are preventingrisk of contamination coming from these difficult toclean items.Maintenance is carried out from the technical area,minimising the need for the maintenance engineerto work in a GMP area. This makes the job easierand again reduces the risk of contamination. ForATEX, the design allows us to classify the technicalarea as safe. This avoids the need for costlyflameproof motors, making the upgrade for workingwith solvents much easier.The frame mounting provides a standard format forthe machine, allowing it to be constructed andinstalled using the same structure. This structuremay be raised using standard modules to achieve thecustomer’s desired height. For some installations itis also possible to mount control panels on thestructure, allowing qualification of the completesystem prior to shipping, significantly reducing theinstallation time on site.M8 impeller:Innovative swept-back design; for improved mixingcharacteristics, faster processing and a more clearlydefined end-point.Multi-bladed chopper:Flush mounted, multi-blade design improves bindersolution dispersion and product movement at slowspeeds.6

“Medium” platform“XL” platformFiltrationMaterial filter & shroudProduction filtration is achieved using an easilyremovable material filter that can be cleaned and reused.For vacuum and CIP applications stainless steelmay be utilised.DischargingThrough-the-wall millProduct can be discharged from the high sheargranulator directly into a receiving container, or via asizing mill. This breaks down the granules to producemore even sizing for subsequent processing.The PMA-Advanced features a through-the-wall hingemountedsizing mill, directly connected to the dischargeport, using inflatable seals. For maintenance, cleaningand product changeovers, the seals are deflated and themill hinged away from the port, allowing full access.The TTW mounting ensures the motor and controls arekept away from the clean process area.In addition to the standard mill, CIP and PressureShock Resistant options are available, matching thecontainment and safety credentials of the mainmachine.Concealed hinge mechanismThe cover is mounted on a concealed hinge mechanismallowing the cover to be lifted with the minimum effort,but keeping the counterweight in the technical area.This leads to a more GMP design, reducing surfaces,making cleaning easier. On equipment supplied withthe Pressure Shock Resistant design option the hingeinterlocking system is power assisted to provide safeand comfortable opening to the bowl cover.LoadingGravity loadingSimple open / close ports may be mounted on the coverand used to dispense product into the mixing bowl. Forpotent powders, split-valve technology provides fullcontainment during loading. The PMA-Advanced canalso be delivered with a cone loading port, allowing forthe removal of the powder loading ports from the cover,but giving permanent connection to a Gravity LoadingStation, but also continuous access to open the cover.Vacuum loadingRapid loading can be achieved using vacuumtechnology. Aeromatic-Fielder’s innovative killedvacuumtechnique makes for easy operation andmaintenance, and only requires a standard-sized filter.Binder solution additionNozzleA range of nozzles are available to give the optimumbinder liquid droplet size for an even distributionthroughout the powder mass.PumpThe binding solution required for granulation may bepumped into the mixing bowl using a mechanical orperistaltic pump to deliver the binder liquid to thespray nozzle. Special pumps are available for thedosing of high viscosity binders.Pressure potAlternatively a pressure pot offers fast, high-pressuredelivery of the binder solution, for excellent dispersionof liquid via the binder nozzle spray system. Thesesystems are chosen typically for small scale, R&D-sizedgranulators.Standard Platform Designs (optional)Two standard platforms are available to integrate withthe PMA-Advanced. The “Medium” platform providesroom adjacent to the bowl for the operator to carry outall filling and cleaning operations. The “XL” platformadditionally provides space for other items / operatorson the platform and also provides sufficient space toallow the operator interface to be mounted at theplatform level.Due to the clean lines of this design the bowl/ coverarea can be easily accessed using mobile steps.Additionally we can offer bespoke platform design andconstruction services to provide the optimumintegration within the available plant area.7

Understanding& ControllingYour Process•ControlsIn order to ensure safe, efficient operation of the unit, the systemis controlled through an industrial computer Human-MachineInterface (HMI), with all functions deriving from a plc controller.This design allows the control interface to becompletely washed down during productchangeover. Furthermore the HMI may be upgradedto allow processing with flammable organicsolvents, in an ATEX Zone 1/21 area. Completing theATEX Zone 1/21 upgrade, flammable gases may beprevented from entering the controls enclosure inthe base of the Laboratory PMA-Compactmachines by purging with compressed air.The physical safety of the operator is assured withthe use of safety locks and proximity sensors toprevent access to the bowl and discharge when theequipment is operating.Binder addition and end point determination maybe controlled through the HMI, manual control orfully automated, recipe control for the unit.Data acquisition can be delivered through a 21 CFRPart 11 compliant, on-board data capture devicerecording critical parameters throughout the processand allowing information downloads through anEthernet connection.Aeromatic-Fielder can supply standardised andbespoke SCADA interfaces, utilising software, suchas iFIX from GE Fanuc Automation, to providedata collection, management and recipe drivenprocesses, fully compliant with FDA 21 CFR Part 11.8

In processs measurement position Clean and calibrate position CIP position at end of processEnd-point controlA choice of automated end-point control facilities,with trending for process optimization, is offeredwith all of the system control options - manual aswell as PLC-based. Options include fixed processtime, automatic end-point control based on powerconsumption, and a high-accuracy torque-basedsystem. Both the power- and torque-based optionscan be used to optimize spray rate and wet massingtime, for faster, more uniform granule growth.It is also possible to control in-line the growth of thegranules with FBRM.Power (kW)35Installed power 45kW302533 litres2038 litres15105End pointEnd point00 2 4 6 8 10 12 14 16 18 20 22 24Time (minutes)M8 BladeStandard BladeGranulation comparisonInsoluble activeGranulation graph showing the improvementsgained in a straight walled vessel when using the M8impeller, include reduction in binder solution,reduced granulation time and enhanced end-pointdefinition.Lighthouse ProbeTechnologyGEA Pharma Systems (GPS) has joinedforces with J&M GmbH to create acompact and cleanable in-process opticalprobe for use in powder processingequipment.The result is the novel Lighthouse Probe, whichcan be used with a range of spectroscopictechniques, including NIR and UV/vis, to overcomethe traditional problem of product sticking toobservation windows.The probe is compact and easy to install and makesit possible to take a reliable in process measurementof quality critical product characteristics including:• Material and active content identification• Active content uniformity during highshear blending operations• Moisture content and end-point duringdrying processes• Coat growth during coating processesOptical methods such as UV/Vis or NIRspectroscopy can be very powerful tools foranalysing a range of product characteristics, but inprocesses involving wet and sticky powders it isnecessary to ensure that the system has a clear viewof the product. Conventional windows used inprocess equipment such as fluid bed systems or highshear granulators, have always suffered from therisk of window fouling. The new GPS & J&MLighthouse Probe has overcome this problem.9

ProvenProcess•Sizes &CapacitiesCritically the process geometry of the PMA-Advanced isidentical to the previous model. Modifications to the designhave been made solely to benefit the user and owner interms of ease-of-use, cleanability, process analysis andinstallation. By uniting these new benefits with the provenPMA process technology, Aeromatic-Fielder is providing thelogical solution for your Granulation Needs.Standard options configured into tailor-made plantsThe philosophy behind the design is that a combination of standardisedoptions are built together in order to meet the requirement for a specificduty. Therefore, granulators of equal capacity may be completely differentwith respect to design, configuration and physical size.Production capacitiesPMA150 PMA300 PMA400 PMA600 PMA800 PMA1200 PMA1800Bowl Volume Litres 150 300 400 600 800 1200 1800Typical Weight@ kg 60 120 160 240 320 480 7250.6 g/lMain Impeller kW 11 22 30 30 36 45 75Mixing Impeller rpm 5-260 5-220 5-200 5-170 5-160 5-140 5-120(variable speed)Granulator Motor kW 4.0 7.5 7.5 11 11 15 22Granulator Speed rpm 1000 - 300 1000 - 300 1000 - 300 1000 - 3000 1000 - 3000 1000 - 3000 1000 - 3000Weight (approx) kg 1000 1800 1900 2200 3200 4000 6000Lab / Pilot capacitiesPMA1 PMA25C PMA65CBowl Volume Litres 3 / 7.5 / 10 25 65Typical Weight@ kg 1.2 / 3 / 4 10 260.6 g/lMain Impeller kW 3 5.5 7.5Mixing Impeller rpm 300-1500 50-500 40-400Granulator Motor kW 0.15 1.3/1.8 1.3/1.8Granulator Speed rpm 1000-3000 1500/3000 1500/3000(50 Hz)Granulator Speed rpm 1000-3000 1800/3600 1800/3600(60 Hz)Weight (approx) kg 230 640 66510

IntegrationOptimumProcess Efficiency•Current Good Manufacturing Practicesincreasingly require that product is fullycontained during processing to protectoperators and environment. Integratedprocess systems not only offer containmentbut improved productivity throughautomation, increased yield and efficientcleaning procedures.System integrationGEA Pharma Systems specialises in the design andmanufacture of fluid bed and high-shear granulationtechnology and is uniquely qualified to provide state-ofthe-artintegrated high shear mixer-granulator and fluidbed drying technology. Drawing on its world-classexpertise, GPS Pharma Systems offers fully integratedturnkey installations. The service includes: design,installation assistance, commissioning, processvalidation, as well as training, and technical support.Installation, operation qualification and documentationare carried out according to FDA/GAMP guidelines.Integration by designAeromatic-Fielder’s entire range of process equipmentis designed with system integration in mind. A modularapproach allows customers to select standard processmodules to suit project needs. Fluid bed dryers andcoaters can be combined with top-drive and bottomdrivehigh shear mixer-granulators, wet and dry millingfacilities, product handling systems, binder and coatingpreparation units, filtration units, all designed for fullyintegrated systems. Safety, containment, product flowand building requirements are in-built for fullintegration for optimum process efficiency11

DesignCleanability &Maintenance •Process optimisation depends on efficient,effective cleaning. Automation of thecleaning process ensures repeatability,allows validation and minimises downtime.In recognition of the fundamentalrole played in today’s advanced powderprocessing industry by automated clean-inplaceprocedures Aeromatic-Fielder hasdeveloped a unique approach to CIP.Shaft seals provided in a “cartridge” design for easyremoval and replacement.The shaft seal symbolises, the many developmentsthat the PMA has seen over its existence. The PMA-Advanced utilises a cartridge-mounted seal systemthat exhibits excellent performance for efficacy,clean-down and wear-life, without the need to purgecompressed air through the seal and into theprocess. Maintenance benefits include rapidreplacement and condition monitoring.Clean line discharge valveThe circular discharge chute design is based on“quick exit” and clean drop of granule withminimum “hang up” surfaces. The discharge valvehas evolved to ensure the minimum of surfaces areexposed to the product, making it simple to clean,either manually or as part of a CIP recipe.Concealed Services (optional)The Filter system can be mounted in the hingemechanism with exhausted air passing through thecentre of the hinge. This creates a less clutteredworking space with fewer hoses being run in theprocess area to the machine. Furthermore pneumaticpipework for actuators and other similar servicesmay also be run through the hinge.CIP* and WIPAll the high shear granulation systems can besupplied with a wide range of washing-in-place andfully automated cleaning-in-place options. CIPfeatures include a combined vacuum cover sealwhich prevents product leaks, lifting impeller,automated spray head and filter cleaning, andinternal O-ring seals.*CIP patent12

ContinuousImprovementSafety•Improved safety for integrated granulationand drying suitesExtensive safety testing confirms pressureenhancement effects and identifies safe designlimits for integrated systems GEA Pharma Systemsin conjunction with the FSA, the safety specialistcentre in Germany, have carried out an extensive testprogramme involving over 100 test explosions. Thisresearch has shown conclusively that should anexplosion occur during the transfer operation in anintegrated system where a granulator is connecteddirectly to a fluid bed dryer without an explosionisolation valve, the secondary explosion pressures inthe granulator can be significantly higher than inthe fluid bed. These tests have enabled GEA PharmaSystems to gain full EC type approval for a range ofpressure shock resistant integrated systems and 16-bar pressure shock resistant high shear granulators.Safety when using organic solventsThe tests were carried out with hybrid mixtures thatbehave in the same way as pharmaceutical productscontaining organic solvents and showed that thefinal explosion pressure in the granulator isdependent on the volumes of the two vessels andthat the length and diameter of the interconnectingduct is critical in ensuring that the pressure remainswithin safe limits.The tests showed that where the fluid bed isdesigned in accordance with VDI 2263 part 5 (i.e.:for a 10-bar explosion pressure, which the standardconsiders to be adequate for all pharmaceuticalpowders and organic solvent combinations), thenthe granulator must be able to withstand an overpressure of at least 16 bar to provide a range oftransfer duct configurations which are both practicaland safe.Where the fluid bed is required to handle materialswith explosion pressures greater than 10 bar (e.g.:metal powders) - and hence is designed outside ofthe VDI standard - or where the configuration of theinterconnecting duct is outside the safe designparameters, then either the granulator must bedesigned to a higher pressure shock resistance or ahygienic fast acting valve, or some other form ofprotection, is essential. The test program showedthat the pressure enhancement effects are caused bythe difference in the propagation speed between thepressure wave and the flame front. The worst casesare when the pressure in the granulator is able torise significantly before the flame can reach it andignite the pre-compressed material. For the range oftransfer duct configurations to be used with the 16-bar granulator design, the presence of bends andobstructions such as mills was not seen to affect theincrease in pressure.For plant processing powders, or mixtures that arenot flammable at the time of transfer between thegranulator and the fluid bed, then the risk ofexplosion is eliminated and hence a wider range oftransfer duct designs can be used safely. Thisextensive research program has significantlyadvanced the state of the art in safety technology forpharmaceutical plants and confirms GEA PharmaSystems’ commitment to introducing newproducts which are based on soundresearch and developmentusing solid process knowhow and understanding.13

The CompletePartnership •Working with you…Entering a partnership with Aeromatic-Fielder means entering a partnership that doesnot end until you are completely satisfied. From the moment you have specified youruser requirements and until the plant has been put into service and has beenqualified, our trained staff stays with you at every step of the process, working inclose co-operation with your own staff creating the components and systems that willresult in a finished plant.CustomerresponsibiltyUser RequirementsClient VerificationProcess QualificationFunctional SpecificationAeromatic-Fielder /Client VerificationOperational QualificationJoint tasksSoftwaredesignHardwaredesignMechanicaldesignInstallation QualificationMechanical equipment buildFAT testingAeromatic-FielderresponsibiltyHardware manufacturingSoftware ConfigurationIntegrated testingBench testing…Every Step of the WayBased on years of experience, equipment qualification will be carried out according toan agreed plan using documents prepared by Aeromatic-Fielder.Our engineers will contribute to a successful qualification of the equipment in closeco-operation with your validation staff.14

Servicefor Life•Project ManagementThe expertise of the Aeromatic-Fielder engineeringteam is available to help customers find theoptimum solution for their individual processingneeds. The company assists with single phases of aproject, or takes full responsibility for design andinstallation of a complete turnkey plant.TrainingOperators of Aeromatic-Fielder equipment canundergo training to help them maximise efficiency,either at the time of installation or periodically asrequired.After SalesRegular maintenance is essential to ensureequipment operates to maximum efficiency. Fullytrained engineers can carry out on-site servicing andcalibration of equipment, either as part of a plannedmaintenance programme or in response to customerneed. Replacement parts can be supplied from stockor manufactured to order.To avoid the expense of equipment replacementAeromatic-Fielder can upgrade existing systems andplant to meet different operational parameters, tocomply with changing regulations, or to modify foruse at another location.15

www.geapharmasystems.comCentral Know-How on a Global ScaleBased on a strong commitment toresearch and development,pharmaceutical technology centres inBelgium, Denmark, Switzerland, the UK,Singapore, and USA provide globaltechnical support and know-how to thepharmaceutical industry. These centresof excellence give customers access to a range of test facilities and expertteams with technical and process know-how. Our teams work closely withour customers to optimise processes and evaluate their products, enablingthem to achieve their process and production goals.Contracting Profitable ExperienceA world leader in supplyingpharmaceutical equipment, GEA PharmaSystems offers manufacturers all overthe world the opportunity to enter into aprofitable partnership for developmentand contract. GPS combine advanced inhousetechnology with a thoroughunderstanding of the pharmaceutical industry to help customers maximizetheir development results.© GEA Pharma Systems 2008 Specifications subject to change without notice All trademarks recognizedGEA Pharma SystemsAeromatic-FielderGEA Pharma Systems AGPO Box 112, Hauptstrasse 145CH-4416 Bubendorf, SwitzerlandTel: (CH) +41 61 936 36 36, (UK) +44 23 8026 7131aeromatic-fielder@geapharmasystems.com