Pharma Times - Vol. 42 - No. 11 - November 2010 33

IntroductionDr. Dale Wurster at University of

Wisconsin invented the wurster process wayback in 1959. Wurster process gainedmomentum in Indian Pharma Industry in therecent years because of the opportunities inthe generic business. Almost all majorcompanies are venturing into particle coatingin wurster. In addition, the process can bedone with same ease for both aqueous andnon-aqueous applications. The processparameters in the Fluid Beds are controllableprecisely, which ensures easier optimizationand reproducibility of the product quality.

There are number of articles availableabout Wurster processing, optimization andscale up. Still the same misconceptioncomes repeatedly that "whether the fluid bedprocess is linearly scalable?" Let us find outwhy even after 50 years of initial applicationstill same question is surfacing in the mindof R&D scientists. Also, let us try to find outthe factors and considerations for the scaleup based on all dynamics of Fluid BedProcessing.

Currently FDA is focusing on the Qualityby Design concept where in one has to buildthe finished product quality attributes in thedesign itself. Can we build the quality in theproduct itself by designing the Formulationand Parameters so that one will getconsistent output of a process? Unless weunderstand the basics, it will be a difficulttask. Even to fill the QBR format, one mustknow how to predict the parameters forcommercial scale and the basis for thepredictions.

Wurster Coating - Scale Up and Scale OutVasant Shetty*,Head - Process Technology & Customer Support, Pam Glatt Pharma Technologies Pvt Ltd.

*E-mail : vasant.shetty@acg-world.com, prcess@acg-world.com

A question always comes in mind "Whenthe scale up activity starts?"

For any successful scale up activity, weneed a robust formulation with optimizedparameters. We need to optimize the processparameters in Lab scale by identifying thekey variables and their effect on the output.Unless these variables are identified and theimpact is understood, the scale up becomesvery painful activity. It is easy to understandthe variables in small scale and it requiresless time and cost. Once these variables arefrozen, we are left with only one unknownfactor - "mass effect" due to increase in thebatch weight from lab scale to commercialscale. Once the parameters are studied thenit will be easier to compensate the masseffect by doing minor changes in thepredicted parameter in pilot and commerciallevel. To have better optimization theformulator must know about how "scale upmodel works.

If the scale up activity starts at the stageof development itself then it will be very easyto scale up and scale out the formulation.

Process Considerations during theproduct development

Let us understand some basicconsiderations one has to look into duringthe formulation.

Core particlesIn some cases, the variability starts from

the core. An inert core pellets are used toload drug and subsequent functional coating.It can be drug core itself like extruded andspherodised product or drug layered pellets.

Any product development processneeds to include in-depth study andconsiderations of Product and processrelated variables. In many cases, wrongselection of the core or inconsistency in thecore or coating polymer leads to thevariability from batch to batch.

Controlled release pattern is mainlydependent upon the film thickness on thepellets. If the specification set for the core isnot stringent enough and if the averageparticle size of the core varies, even by50micron, this will lead to considerablechange in the film thickens with samepercentage coating. For example, a mass ofabsolute spherical shape and having a meansize 400micron will have 14% higherthickness in the film thickness compared tothe spheres of 350 micron. Similarly, thespheres of 800micron will have 7% thickerfilm than the spheres of 750micron. For thisreason, maintaining the specific surface areawith in very narrow margin from lab tocommercial and batch-to-batch is verycritical.

Total surface area available for thecoating also changes according to thesurface roughness. The pellets with roughsurface will have considerably more surfacearea then a pellet with smooth surface.Moreover, to cover the edges and crevicesof the rough pellets one has to make the filmthicker. In case of highly friable core as theattrition in the lab model is comparatively low,the surface remains to its original shape, butin pilot or commercial batch the core is beensubjected to higher attrition Fig3. It is verycritical to maintain the drug pellets as smoothas possible.

In one case, the product temperaturein the drug loading stage changed during thescale up activity. When the producttemperature reduced from 60 to 35ºC, theoverall SR coating required to get the desiredrelease was reduced from 21% to 12% even

Article

Fig 1 - Diagram of Wurster Process 1 Fig 2 - GPCG 1.1, Lab Model

Pharma Times - Vol. 42 - No. 11 - November 201034

though all parameters in the SR coating keptsame. This is mainly due to smooth surfaceof the drug pellets when processed at lowtemperature. When the drug loading wasdone at higher temperature, the surface ofthe drug-loaded pellets was rough andporous due to the spray drying effect Fig4.To cover these pores one has to apply morecoating. But when the drug loading was doneat lower temperature, the surface becamesmooth due to reduced spray drying andhigher moisture on the core surface.

keep more rigorous fluidization to havehigher drying efficiency. One must keep inmind that the inlet air volume is not to drythe product, it has to be used to get therequired fluidization pattern. The requireddrying efficiency must be maintained byadjusting the temperature.

Once the fluidization pattern is decidedand maintained in the lab model, for the scaleup process the same pattern must bemaintained.

For a highly water-soluble substrate, itis not recommended to keep high moisturein the initial stage. Static charge developsonly once the pellets are coated withpolymers. Therefore, the humidity can beincreased after initial coating.

Fluidization Air Temperature: Theinlet air temperature is the last parameter tobe set as per the product requirement. It willdepend on the spray rate, type of solventmedia, tackiness of solution and have directimpact on the product humidity andtemperature.

Batch Size: One has to use optimumbatch size for the development after initialfeasibility study. The utilization must beabove 20% of working capacity for non-functional coating and above 40% for thefunctional coating.

Column Height: There is no basic ruleto set the column height. The height will varydepending on the particle properties. Shape,flow, Bulk Density, and size have impact onthe flow behavior. The column must notcreate barrier for the particle movement andat the same time, the air from the up bedzone must not be diverted towards down bed,which happens if the column height is toohigh or batch load is too low. Ideally, flowstudy must be conducted to check themaximum flow of the material inside thewurster column by fluidizing the mass andstopping the fluidization and measuring theheight of the bed inside and outside thecolumn.

Spray Rate: In the wurster typicallybinary nozzle are used. The dropletformation, contact, spreading, coalescenceand evaporation happen almostsimultaneously during the process Fig5. Theatomisation air used for the formation ofspray mist also contributes to the evaporationwhich results in increase in the dropletsviscosity. Some time excessive atomisationair pressure leads to spray drying of portionof spray, especially in case of solvent basedcoating. The spray rate depends on thesolution properties as well as the coreparticles. The spray rate has to be setaccording to the drying efficiency, tackinessof the solution. To coat smaller particles weneed to keep the droplet size small to avoidagglomeration either by reducing he sprayrate or increasing the atomisation sirpressure.

At the beginning of the coating, thespray rate must be kept low to avoidsolublising the core or seepage of the drugor coating polymer in to other layer. Oncethe initial barrier formed the spray rate canbe primed up to the optimum level. It isevident that the as the particle becomesbigger it can take up more droplet withoutagglomerating. So normally, when the buildup is too high we may require to ramp up thespray rate in a regular interval. However, for

Fig 3 - Effect of fluidization on Sugar Spheres 1

Fig 4 - Effect of the Porous surface of core on the SR Film 1

Uncoated core pellet SR coated core pellet

Air Distribution Plate (ADP): One hasto select suitable base plate to get consistentfluidization at minimum attrition. The velocityand height gain is critical. The smaller particlerequires lesser air volume to achieve acertain height than the bigger particles.Nevertheless, the air velocity or differentialpressure at the air distribution plate must bealmost same. Therefore, when we deal withsmaller particle to create the resistance atthe ADP to have better distribution of the airwe have to use the plates having lesseropening area. This factor is very critical tohave more even airflow in all wurster in thecommercial models, where we have to dealwith multiple wursters.

Fluidization Air Flow: Based on theproduct property we need to keep thefluidization. For a non-aqueous coating, abubbling type of fluidization in the down bedis recommended to minimize the particlefriction and generation of static charges,whereas for aqueous application one can

Fluidization Air Humidity: Inlet airhumidity is one of the most critical factorsthat have an impact on the productmovement as well as release profile.Although lower humidity in the air willenhance the drying capacity of the air evenat low temperature, it will cause excessivestatic charge in the product. The effect of thehigher or lower Humidity is unpredictable. Forsome the higher humidity may retard therelease, for other it may increase the release.The required specific or absolute humiditylevel must be set at the initial stage ofdevelopment itself, to eliminate the staticcharges and process variability. Too highabsolute humidity will lead to depression inthe air temperature below the dew point,which will result in the condensation of watereither on to machine or substrate surface.Once the inlet humidity is set then we haveto optimize other parameter to get therequired release profile.

Pharma Times - Vol. 42 - No. 11 - November 2010 35

the functional coating as the size build is notthat significant. Only two to three stageramping is enough up to a build of 100%.This will also minimize the variation in theprocess.

It is also critical to select proper sizetube in the pump. The peristaltic pump tendsto generate the pulse. Higher the pump RPMthe magnitude of the pulse is low. Therefore,we have to select smaller ID for the lowerspray rate. Selection of Nozzle insert alsofollows same sequence. Smaller the nozzleinsert, more consistent will be the spray.However, here smaller insert may causenozzle chocking.

Atomisation Air: It is always a question"How much atomisation air Pressure?" Canwe relate it to the spray rate?

If the atomisation air pressure is highthen the mist size will be lower, then thechances of agglomeration will also low.However, if the set Atomisation air pressurein lab model is high, then the process willdemand too high pressure in pilot scale also.Excess pressure will lead to the particleshooting to the filter bag. The atomisation airmust be adjusted to keep enough to avoidagglomeration. During the optimization of thespray rate to achieve fastest possibleprocess, one has to keep the droplet verysmall. Higher the pressure smaller will bedroplet. It is also necessary to understand

that beyond a certainpressure the particle sizereduction will benegligible Fig6.

Product Tempe-rature: Ideally, theproduct temperatureshall be kept at lowestpossible. It will dependon the Glass Transitiontemperature for somepolymer. However, inother cases to getmaximum efficiency wehave to keep the producttemperature as low aspossible. Lower theproduct temperaturelesser will be the static

charge generation but for some polymer likeHPMC we have to maintain high temperatureto minimize the agglomeration by drying ofthe film effectively.

Apart from the above listed parameters,we have to optimize solution viscosity andsolution concentration to have a bettercontrol on the process. Higher the solutionviscosity or tackiness we have to reduce thespray rate. It is a common thinking that,higher solid content will reduce the processtime. However, this is completely wrong if thesolution is viscous and tackier in case ofpolymers like HPMC, Ethyl Cellulose whenthey are in solution form. As we increase thesolid content beyond certain limit for thesepolymers, the spray rate will reducedrastically which results in higher processtime. If the viscosity of the solution is highthen it also makes the process more critical.So solution viscosity must be optimized tomake the process short and smooth.

Design of Experiments: To optimisethe parameter and freeze the parameter onehas to do multiple trails. There are more than20 variables can be listed out in wursterprocess. Some of them are critical some arenot. Some parameters like batch size, sprayliquid viscosity, concentration, airflow, sprayassembly setting, base plate, column heightand dew point are easy to establish. Fix theseeasy to set parameters and reduce thenumber of variables. Perform some trail to

fix some dependent variables likeatm air volume, exhausttemperature and in processmoisture content etc.

Finally do DOE to fix up mostcritical parameters like spray rate,atomisation air pressure/volume,product temperature and Inlettemperature. To minimize thenumber of trials further one canuse statistical tools like Stavex.From the out put of the statisticalanalysis fix up the ranges for theparameter and validate the

process to check the reproducibility andfreeze the parameter.

Once the parameters are freezed at labmodel next step is predicting the parameterfor scale up.

Fig 6 -Atomisation Air Pressure vs. Droplet size chart

Scale up:Second stage of the development is

setting up parameters for the pilot model.Like lab model in the pilot model also havesingle wurster.

The development of the product isnormally done in 5", 6" or 7" wurster with thebatch size 1 to 3 kg. The wurster column andspray nozzle is small. Overall coating zoneis small. The recommended pilot model is18" wurster where the wurster column ismuch larger also the base plate Fig7. Fromthe lab to pilot although there is singe spraynozzle the nozzle is much bigger and canpermit higher spray rate. The batch depthand mass flow density increases. Overall, thecoating zone increases form lab to pilotscale. The overall coating zone will remainsame in pilot and commercial scale exceptthe height of the wurster column. All theprocess variables again show theirsignificance in scale up model also.Nevertheless, once the effect of variables arestudied and understood in lab model it willmake the analysis much easier. Just like thevariables remaining same in pilot scale also,the same process control will apply. Only theunknown factor will be the mass effect.

In many cases, one hears commentslike "When we scaled up the process we hadto change all parameters. None of thepredictions came true" or "the process timeis much longer than anticipated". If oneunderstands the scale up principle andapplies them to predict the same for largerequipment, both this comment will not standtrue.

As in the lab scale, one has to followsequential approach to set the parameter forthe scale up.

Any process starts with defining thebatch size. The process parameter willchange slightly depending on the batch size.

Fig 7 - 18" Wurster

Fig 5 - Schematic diagram of Coating process

Pharma Times - Vol. 42 - No. 11 - November 201036

This is true here also just like nay otherprocess. One has to set and validate theprocess for any change in the batch size.Keep the batch size within the recommendedoccupancy. For GPCG1.1, the workingvolume is 2.4 liter where as FBE 125 it is 84liter, i.e. 35 times. If some one wants to keepthe occupancy level same in pilot also thenthe batch size has to be increased by35times.

Recommended working volume fornon-functional coating is above 20% and forfunctional coating, it will be above 40% ofthe machine capacity.

Following equation can be used tocalculate the batch size.2

B = V x D,where B = Batch size in kg

V = Rated volume of theproduct container

D = Un tap density of theproduct in g/cc

Once the batch size is fixed, the nextwill be the base plate selection. Here onecan refer to the base recommendations formthe machine supplier or they can fix up basedon the experience in the lab model.

Air FlowOnce the batch size is fixed, next is Air

Flow. To fix up the airflow for pilot model onemust know the airflow or velocity at labmodel. From lab to pilot the face velocitymust be kept same. To maintain the samevelocity one must know the base plate areain lab and pilot model.

In addition, it can be expressed in theterm of Fluidization Air Volume. Followingequation can be used to calculate theAirflow.2

V2 = V1 x A2 / A1,Where V2 = Air Flow for scale up

modelV1 = Air flow at Lab modelA1 = Base Plate are for

Lab ModelA2 = Base Plate area for

Pilot Model.

Inlet air temperature and Humidity mustbe kept same as it in lab model

Spray Rate:Many times, query comes stating that

"Can I increase the spray rate in ratio to theincrease the batch size". The increase in thespray rate shall be always in the line ofincrease in the drying capacity rather thanthe batch size. Being said the inlet airhumidity and temperature will remain samefor the scale up model, the drying efficiencyis increased only it terms of air volume. Thespray rate can be increased in the same foldincrease in the inlet air volume.

Following equation can be used tocalculate to predict the spray rate in pilotmodel.2

S2 = S1 x V2 / V1,Where V2 = Air Flow for scale up

modelV1 = Air flow at Lab modelS1 = Spray Rate in Lab ModelS2 = Spray Rate in Pilot Model

For example in the lab model if thespray rate is 15gm/minute for a batch size of1.2kg and the fluidization airflow is 50 CFM.Then in 18" FBE 125, the airflow must beabout 650CFM and the spray rate shall be15 x 13 = 195gm/min for the batch size of42kg.

The increase in the spray rate must becompensated with the increase in theatomisation air pressure to maintain thedroplet size of the spray mist. To keep thedroplet size same both in lab as well as pilotmodel one has to keep the spray rate toatomisation air volume same. It is possibleonly by measuring the air volumes in bothlab model and scale up model.Manufacturers' manuals also can be usedFig 8.

spray gun with higher capacity like HS guncan be used. Any deviation in the spray ratefrom the scale up factor of airflow shall becompensated by either increasing orreducing the inlet air temperature.

Column Height: To fix up the columnheight, there are no factors, one has to adjustand keep the column height to get maximummass flow in the wurster column. The massflow study can be repeated here for differentbatch volume to fix up the gap. During theprocess, frequent change in the columnheight must be avoided. Even if it is required,it has to be adjusted at a fixed and minimuminterval for a process.

By setting all these said parameters inthe pilot model, we left with one variable i.e.mass effect. There may be some deviationin the results form lab scale even aftermaintaining the parameters as per the scaleup calculations due to mass effect. One orthe other parameter may have to be changedmarginally to achieve desired release profile.The scale up activity starts with preliminarytrials with predicted parameter, analyze theresults, and take action if required to matchthe profile. If all the parameter and their effecton the release were understood in the labscale, it will be easier to analyze theanalytical results and vary the parametersto get desired profile. Process validation isrecommended to check the robustness of theprocess before filing the parameters orplanning the scale out activity.

Scale Out:

Once the development and scale upactivity completed systematically the scaleout will not lead to any surprises. From labto Pilot, the coating zone increased multifold.However, from pilot to production scale thecoating zone or wurster column diameter willremain same. The nozzle is same; the baseplate configuration will remain same. Theonly major change is increase in the numberof wurster. There may be two to multiplewurster columns depending upon themachine capacity (Fig. 9).

As the capacity of the machineincreases, the base plate diameter willincrease so the base plate area. Here it isagain same calculation for the airflowcalculation. Unless the commercial modelsare designed linearly, it is not possible toscale out the parameters from pilot. It hasbeen calculated adapted successfully somewell-known machinery manufacturer, whichmakes the scale out easier.

For the scale out multiply the airflowagain in ratio of the base plate area andmaintain all other parameter like spray rateper gun, atomisation air pressure and producttemperature and humidity similar to the pilot

For example, the spray nozzle in GPCG1.1, consumes 1.2CFM of compressed air.When we scale up to 18" scale up model theair flow was increased as per the base plateration i.e. about 13 times and so the Sprayrate. To keep the atomisation air to spray rateration same the atomisation air needs toincrease by 13times. That means theatomisation airflow must be 1.2 x 13 = 15.6.To get same airflow in pilot and productionscale nozzle we need to keep about 4.4 barpressure. Here as we increase the pressureof the atomisation air the velocity alsoincreases and this is compensated by thelonger wurster column and longer expansionchamber.

Normally one should restrict themaximum pressure up to 4 to 5 bar. Higherthe atomisation air pressure the mechanicalstress on the core will be high due to highervelocity. If some one uses higher air pressurein lab model then during the scale up eitherthe spray rate needs to be reduced or the

Fig 8 - Atomisation air Pressure vs. Volumechart

Pharma Times - Vol. 42 - No. 11 - November 2010 37

model. Here very minute modification in theproduct temperature may require to nullifythe mass effect. Adjust the inlet temperatureif required to maintain the producttemperature.

In the commercial model, again thecolumn height will depend on the batch sizeand one has to optimize the column heightfor the product by mass flow study duringthe 1st trial batch.

Process time prediction:

Based on the lab data, provided it hasbeen well, the process time for the pilot andcommercial scale can be predicted to thenear perfect. The prediction will be perfect ifit is done from pilot to commercial.

The batch size increased from lab toFBE 800C by 250 times but the spray timeonly by 4.8times.Nevertheless, byusing the HS spraynozzles spray timecan be cut down to ½to 1/3.

Summary:The scale up /

scale out activitymust be the integralpart of thedevelopment. It iswise to optimize andcontrol the productquality in lab scalethan in pilot scale. Allvariables need to bestudied in the labscale by taking in tothe consideration ofc o m m e r c i a lequipment. Theknowledge on theworking ofcommercial model ismust for a formulator.The process must bevalidated for itsrobustness in thepilot scale at the 2ndstage ofdevelopment beforethe product filing.

The scale up ismore challengingthan the scale out.More the efforts putat the developmentallevel will reduce thehassles in scale upand scale out.

Fig 9 - 32" Wurster

Acknowledgement:Dr. Norbert Pollinger - Technology

Center Glatt, Binzen

References:1. Mr. David Jones, Factors to consider

in Fluid Bed Processing;Pharmaceutical Technology Apr 1985-

2. Dr. Atul M. Mehta, Scale upconsidera-t ions in the f lu id bedprocess for Control led ReleaseProduct. Pharmaceutical TechnologyFeb 1988.

Refer to the chart. Here the batch occupancy kept same in all models.

Area Lab Pilot Production

Model GPCG 1.1 FBE 125C FBE 500C FBE 800C

Working Volume lit 2.4 84 367 597

No. of Wurster 1 1 3 4

Batch Size kg 1.5 52.5 229 373

Spray Solution kg 2.7 94.5 412.2 671.4

Spray rate g/min 15 195 585 780

Spray time 180 485 705 861

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46" wurster