Article

Wurster Coating - Scale Up and Scale Out

Vasant Shetty*, Head - Process Technology & Customer Support, Pam Glatt Pharma Technologies Pvt Ltd.

Introduction
Dr. Dale Wurster at University of Wisconsin invented the wurster process way back in 1959. Wurster process gained momentum in Indian Pharma Industry in the recent years because of the opportunities in the generic business. Almost all major companies are venturing into particle coating in wurster. In addition, the process can be done with same ease for both aqueous and non-aqueous applications. The process parameters in the Fluid Beds are controllable precisely, which ensures easier optimization and reproducibility of the product quality. There are number of articles available about Wurster processing, optimization and scale up. Still the same misconception comes repeatedly that "whether the fluid bed process is linearly scalable?" Let us find out why even after 50 years of initial application still same question is surfacing in the mind of R&D scientists. Also, let us try to find out the factors and considerations for the scale up based on all dynamics of Fluid Bed Processing. Currently FDA is focusing on the Quality by Design concept where in one has to build the finished product quality attributes in the design itself. Can we build the quality in the product itself by designing the Formulation and Parameters so that one will get consistent output of a process? Unless we understand the basics, it will be a difficult task. Even to fill the QBR format, one must know how to predict the parameters for commercial scale and the basis for the predictions.

A question always comes in mind "When the scale up activity starts?" For any successful scale up activity, we need a robust formulation with optimized parameters. We need to optimize the process parameters in Lab scale by identifying the key variables and their effect on the output. Unless these variables are identified and the impact is understood, the scale up becomes very painful activity. It is easy to understand the variables in small scale and it requires less time and cost. Once these variables are frozen, we are left with only one unknown factor - "mass effect" due to increase in the batch weight from lab scale to commercial scale. Once the parameters are studied then it will be easier to compensate the mass effect by doing minor changes in the predicted parameter in pilot and commercial level. To have better optimization the formulator must know about how "scale up model works. If the scale up activity starts at the stage of development itself then it will be very easy to scale up and scale out the formulation. Process Considerations during the product development Let us understand some basic considerations one has to look into during the formulation.

Core particles
In some cases, the variability starts from the core. An inert core pellets are used to load drug and subsequent functional coating. It can be drug core itself like extruded and spherodised product or drug layered pellets. Any product development process needs to include in-depth study and considerations of Product and process related variables. In many cases, wrong selection of the core or inconsistency in the core or coating polymer leads to the variability from batch to batch. Controlled release pattern is mainly dependent upon the film thickness on the pellets. If the specification set for the core is not stringent enough and if the average particle size of the core varies, even by 50micron, this will lead to considerable change in the film thickens with same percentage coating. For example, a mass of absolute spherical shape and having a mean size 400micron will have 14% higher thickness in the film thickness compared to the spheres of 350 micron. Similarly, the spheres of 800micron will have 7% thicker film than the spheres of 750micron. For this reason, maintaining the specific surface area with in very narrow margin from lab to commercial and batch-to-batch is very critical. Total surface area available for the coating also changes according to the surface roughness. The pellets with rough surface will have considerably more surface area then a pellet with smooth surface. Moreover, to cover the edges and crevices of the rough pellets one has to make the film thicker. In case of highly friable core as the attrition in the lab model is comparatively low, the surface remains to its original shape, but in pilot or commercial batch the core is been subjected to higher attrition Fig3. It is very critical to maintain the drug pellets as smooth as possible. In one case, the product temperature in the drug loading stage changed during the scale up activity. When the product temperature reduced from 60 to 35C, the overall SR coating required to get the desired release was reduced from 21% to 12% even

Fig 1 - Diagram of Wurster Process 1

Fig 2 - GPCG 1.1, Lab Model

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

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For a highly water-soluble substrate, it is not recommended to keep high moisture in the initial stage. Static charge develops only once the pellets are coated with polymers. Therefore, the humidity can be increased after initial coating. Fluidization Air Temperature: The inlet air temperature is the last parameter to be set as per the product requirement. It will depend on the spray rate, type of solvent media, tackiness of solution and have direct impact on the product humidity and temperature. Batch Size: One has to use optimum batch size for the development after initial feasibility study. The utilization must be above 20% of working capacity for nonfunctional coating and above 40% for the functional coating. Column Height: There is no basic rule to set the column height. The height will vary depending on the particle properties. Shape, flow, Bulk Density, and size have impact on the flow behavior. The column must not create barrier for the particle movement and at the same time, the air from the up bed zone must not be diverted towards down bed, which happens if the column height is too high or batch load is too low. Ideally, flow study must be conducted to check the maximum flow of the material inside the wurster column by fluidizing the mass and stopping the fluidization and measuring the height of the bed inside and outside the column. Spray Rate: In the wurster typically binary nozzle are used. The droplet formation, contact, spreading, coalescence and evaporation happen almost simultaneously during the process Fig5. The atomisation air used for the formation of spray mist also contributes to the evaporation which results in increase in the droplets viscosity. Some time excessive atomisation air pressure leads to spray drying of portion of spray, especially in case of solvent based coating. The spray rate depends on the solution properties as well as the core particles. The spray rate has to be set according to the drying efficiency, tackiness of the solution. To coat smaller particles we need to keep the droplet size small to avoid agglomeration either by reducing he spray rate or increasing the atomisation sir pressure. At the beginning of the coating, the spray rate must be kept low to avoid solublising the core or seepage of the drug or coating polymer in to other layer. Once the initial barrier formed the spray rate can be primed up to the optimum level. It is evident that the as the particle becomes bigger it can take up more droplet without agglomerating. So normally, when the build up is too high we may require to ramp up the spray rate in a regular interval. However, for

Fig 3 - Effect of fluidization on Sugar Spheres 1 though all parameters in the SR coating kept same. This is mainly due to smooth surface of the drug pellets when processed at low temperature. When the drug loading was done at higher temperature, the surface of the drug-loaded pellets was rough and porous due to the spray drying effect Fig4. To cover these pores one has to apply more coating. But when the drug loading was done at lower temperature, the surface became smooth due to reduced spray drying and higher moisture on the core surface. keep more rigorous fluidization to have higher drying efficiency. One must keep in mind that the inlet air volume is not to dry the product, it has to be used to get the required fluidization pattern. The required drying efficiency must be maintained by adjusting the temperature. Once the fluidization pattern is decided and maintained in the lab model, for the scale up process the same pattern must be maintained.

Uncoated core pellet

SR coated core pellet

Fig 4 - Effect of the Porous surface of core on the SR Film 1 Air Distribution Plate (ADP): One has to select suitable base plate to get consistent fluidization at minimum attrition. The velocity and height gain is critical. The smaller particle requires lesser air volume to achieve a certain height than the bigger particles. Nevertheless, the air velocity or differential pressure at the air distribution plate must be almost same. Therefore, when we deal with smaller particle to create the resistance at the ADP to have better distribution of the air we have to use the plates having lesser opening area. This factor is very critical to have more even airflow in all wurster in the commercial models, where we have to deal with multiple wursters. Fluidization Air Flow: Based on the product property we need to keep the fluidization. For a non-aqueous coating, a bubbling type of fluidization in the down bed is recommended to minimize the particle friction and generation of static charges, whereas for aqueous application one can Fluidization Air Humidity: Inlet air humidity is one of the most critical factors that have an impact on the product movement as well as release profile. Although lower humidity in the air will enhance the drying capacity of the air even at low temperature, it will cause excessive static charge in the product. The effect of the higher or lower Humidity is unpredictable. For some the higher humidity may retard the release, for other it may increase the release. The required specific or absolute humidity level must be set at the initial stage of development itself, to eliminate the static charges and process variability. Too high absolute humidity will lead to depression in the air temperature below the dew point, which will result in the condensation of water either on to machine or substrate surface. Once the inlet humidity is set then we have to optimize other parameter to get the required release profile.

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that beyond a certain pressure the particle size reduction will be negligible Fig6. Product Temperature: Ideally, the product temperature shall be kept at lowest possible. It will depend on the Glass Transition temperature for some polymer. However, in other cases to get maximum efficiency we have to keep the product temperature as low as possible. Lower the Fig 5 - Schematic diagram of Coating process product temperature lesser will be the static charge generation but for some polymer like the functional coating as the size build is not HPMC we have to maintain high temperature that significant. Only two to three stage to minimize the agglomeration by drying of ramping is enough up to a build of 100%. the film effectively. This will also minimize the variation in the process. Apart from the above listed parameters, we have to optimize solution viscosity and It is also critical to select proper size solution concentration to have a better tube in the pump. The peristaltic pump tends control on the process. Higher the solution to generate the pulse. Higher the pump RPM viscosity or tackiness we have to reduce the the magnitude of the pulse is low. Therefore, spray rate. It is a common thinking that, we have to select smaller ID for the lower higher solid content will reduce the process spray rate. Selection of Nozzle insert also time. However, this is completely wrong if the follows same sequence. Smaller the nozzle solution is viscous and tackier in case of insert, more consistent will be the spray. polymers like HPMC, Ethyl Cellulose when However, here smaller insert may cause they are in solution form. As we increase the nozzle chocking. solid content beyond certain limit for these Atomisation Air: It is always a question polymers, the spray rate will reduce "How much atomisation air Pressure?" Can drastically which results in higher process we relate it to the spray rate? time. If the viscosity of the solution is high then it also makes the process more critical. If the atomisation air pressure is high So solution viscosity must be optimized to then the mist size will be lower, then the make the process short and smooth. chances of agglomeration will also low. However, if the set Atomisation air pressure in lab model is high, then the process will demand too high pressure in pilot scale also. Excess pressure will lead to the particle shooting to the filter bag. The atomisation air must be adjusted to keep enough to avoid agglomeration. During the optimization of the spray rate to achieve fastest possible process, one has to keep the droplet very small. Higher the pressure smaller will be droplet. It is also necessary to understand Design of Experiments: To optimise the parameter and freeze the parameter one has to do multiple trails. There are more than 20 variables can be listed out in wurster process. Some of them are critical some are not. Some parameters like batch size, spray liquid viscosity, concentration, airflow, spray assembly setting, base plate, column height and dew point are easy to establish. Fix these easy to set parameters and reduce the number of variables. Perform some trail to fix some dependent variables like atm air volume, exhaust temperature and in process moisture content etc. Finally do DOE to fix up most critical parameters like spray rate, atomisation air pressure/volume, product temperature and Inlet temperature. To minimize the number of trials further one can use statistical tools like Stavex. From the out put of the statistical analysis fix up the ranges for the parameter and validate the

process to check the reproducibility and freeze the parameter. Once the parameters are freezed at lab model next step is predicting the parameter for scale up.

Fig 7 - 18" Wurster Scale up: Second stage of the development is setting up parameters for the pilot model. Like lab model in the pilot model also have single wurster. The development of the product is normally done in 5", 6" or 7" wurster with the batch size 1 to 3 kg. The wurster column and spray nozzle is small. Overall coating zone is small. The recommended pilot model is 18" wurster where the wurster column is much larger also the base plate Fig7. From the lab to pilot although there is singe spray nozzle the nozzle is much bigger and can permit higher spray rate. The batch depth and mass flow density increases. Overall, the coating zone increases form lab to pilot scale. The overall coating zone will remain same in pilot and commercial scale except the height of the wurster column. All the process variables again show their significance in scale up model also. Nevertheless, once the effect of variables are studied and understood in lab model it will make the analysis much easier. Just like the variables remaining same in pilot scale also, the same process control will apply. Only the unknown factor will be the mass effect. In many cases, one hears comments like "When we scaled up the process we had to change all parameters. None of the predictions came true" or "the process time is much longer than anticipated". If one understands the scale up principle and applies them to predict the same for larger equipment, both this comment will not stand true. As in the lab scale, one has to follow sequential approach to set the parameter for the scale up. Any process starts with defining the batch size. The process parameter will change slightly depending on the batch size.

Fig 6 -Atomisation Air Pressure vs. Droplet size chart

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This is true here also just like nay other process. One has to set and validate the process for any change in the batch size. Keep the batch size within the recommended occupancy. For GPCG1.1, the working volume is 2.4 liter where as FBE 125 it is 84 liter, i.e. 35 times. If some one wants to keep the occupancy level same in pilot also then the batch size has to be increased by 35times. Recommended working volume for non-functional coating is above 20% and for functional coating, it will be above 40% of the machine capacity. Following equation can be used to calculate the batch size.2 B = V x D, where B = Batch size in kg V = Rated volume of the product container D = Un tap density of the product in g/cc

Following equation can be used to calculate to predict the spray rate in pilot model.2 S2 = S1 x V2 / V1, Where V2 = Air Flow for scale up model V1 = Air flow at Lab model S1 = Spray Rate in Lab Model S2 = Spray Rate in Pilot Model For example in the lab model if the spray rate is 15gm/minute for a batch size of 1.2kg and the fluidization airflow is 50 CFM. Then in 18" FBE 125, the airflow must be about 650CFM and the spray rate shall be 15 x 13 = 195gm/min for the batch size of 42kg. The increase in the spray rate must be compensated with the increase in the atomisation air pressure to maintain the droplet size of the spray mist. To keep the droplet size same both in lab as well as pilot model one has to keep the spray rate to atomisation air volume same. It is possible only by measuring the air volumes in both lab model and scale up model. Manufacturers' manuals also can be used Fig 8.

spray gun with higher capacity like HS gun can be used. Any deviation in the spray rate from the scale up factor of airflow shall be compensated by either increasing or reducing the inlet air temperature. Column Height: To fix up the column height, there are no factors, one has to adjust and keep the column height to get maximum mass flow in the wurster column. The mass flow study can be repeated here for different batch volume to fix up the gap. During the process, frequent change in the column height must be avoided. Even if it is required, it has to be adjusted at a fixed and minimum interval for a process. By setting all these said parameters in the pilot model, we left with one variable i.e. mass effect. There may be some deviation in the results form lab scale even after maintaining the parameters as per the scale up calculations due to mass effect. One or the other parameter may have to be changed marginally to achieve desired release profile. The scale up activity starts with preliminary trials with predicted parameter, analyze the results, and take action if required to match the profile. If all the parameter and their effect on the release were understood in the lab scale, it will be easier to analyze the analytical results and vary the parameters to get desired profile. Process validation is recommended to check the robustness of the process before filing the parameters or planning the scale out activity. Scale Out: Once the development and scale up activity completed systematically the scale out will not lead to any surprises. From lab to Pilot, the coating zone increased multifold. However, from pilot to production scale the coating zone or wurster column diameter will remain same. The nozzle is same; the base plate configuration will remain same. The only major change is increase in the number of wurster. There may be two to multiple wurster columns depending upon the machine capacity (Fig. 9). As the capacity of the machine increases, the base plate diameter will increase so the base plate area. Here it is again same calculation for the airflow calculation. Unless the commercial models are designed linearly, it is not possible to scale out the parameters from pilot. It has been calculated adapted successfully some well-known machinery manufacturer, which makes the scale out easier. For the scale out multiply the airflow again in ratio of the base plate area and maintain all other parameter like spray rate per gun, atomisation air pressure and product temperature and humidity similar to the pilot

Once the batch size is fixed, the next will be the base plate selection. Here one can refer to the base recommendations form the machine supplier or they can fix up based on the experience in the lab model. Air Flow Once the batch size is fixed, next is Air Flow. To fix up the airflow for pilot model one must know the airflow or velocity at lab model. From lab to pilot the face velocity must be kept same. To maintain the same velocity one must know the base plate area in lab and pilot model. In addition, it can be expressed in the term of Fluidization Air Volume. Following equation can be used to calculate the Airflow.2 V2 = V1 x A2 / A1, Where V2 = Air Flow for scale up model V1 = Air flow at Lab model A1 = Base Plate are for Lab Model A2 = Base Plate area for Pilot Model. Inlet air temperature and Humidity must be kept same as it in lab model Spray Rate: Many times, query comes stating that "Can I increase the spray rate in ratio to the increase the batch size". The increase in the spray rate shall be always in the line of increase in the drying capacity rather than the batch size. Being said the inlet air humidity and temperature will remain same for the scale up model, the drying efficiency is increased only it terms of air volume. The spray rate can be increased in the same fold increase in the inlet air volume.

Fig 8 - Atomisation air Pressure vs. Volume chart For example, the spray nozzle in GPCG 1.1, consumes 1.2CFM of compressed air. When we scale up to 18" scale up model the air flow was increased as per the base plate ration i.e. about 13 times and so the Spray rate. To keep the atomisation air to spray rate ration same the atomisation air needs to increase by 13times. That means the atomisation airflow must be 1.2 x 13 = 15.6. To get same airflow in pilot and production scale nozzle we need to keep about 4.4 bar pressure. Here as we increase the pressure of the atomisation air the velocity also increases and this is compensated by the longer wurster column and longer expansion chamber. Normally one should restrict the maximum pressure up to 4 to 5 bar. Higher the atomisation air pressure the mechanical stress on the core will be high due to higher velocity. If some one uses higher air pressure in lab model then during the scale up either the spray rate needs to be reduced or the

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Refer to the chart. Here the batch occupancy kept same in all models. Area Model Working Volume lit No. of Wurster Batch Size kg Spray Solution kg Spray rate g/min Spray time Lab GPCG 1.1 2.4 1 1.5 2.7 15 180 Pilot FBE 125C 84 1 52.5 94.5 195 485 Production FBE 500C 367 3 229 412.2 585 705 FBE 800C 597 4 373 671.4 780 861

Acknowledgement:
Dr. Norbert Pollinger - Technology Center Glatt, Binzen

References:
1. Mr. David Jones, Factors to consider in Fluid Bed Processing; Pharmaceutical Technology Apr 1985Dr. Atul M. Mehta, Scale up considera-tions in the fluid bed process for Controlled Release Product. Pharmaceutical Technology Feb 1988.

2.

The batch size increased from lab to FBE 800C by 250 times but the spray time only by 4.8times. Nevertheless, by using the HS spray nozzles spray time can be cut down to to 1/3.

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Summary:
The scale up / scale out activity Fig 9 - 32" Wurster must be the integral part of the development. It is wise to optimize and control the product quality in lab scale than in pilot scale. All variables need to be studied in the lab scale by taking in to the consideration of c o m m e r c i a l equipment. The knowledge on the working 46" wurster model. Here very minute modification in the product temperature may require to nullify the mass effect. Adjust the inlet temperature if required to maintain the product temperature. In the commercial model, again the column height will depend on the batch size and one has to optimize the column height for the product by mass flow study during the 1st trial batch. Process time prediction: Based on the lab data, provided it has been well, the process time for the pilot and commercial scale can be predicted to the near perfect. The prediction will be perfect if it is done from pilot to commercial. of commercial model is must for a formulator. The process must be validated for its robustness in the pilot scale at the 2nd stage the product filing. The scale up is more challenging than the scale out. More the efforts put at the developmental level will reduce the hassles in scale up and scale out. of development before Positions

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