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On Demand Tutorial Transcript

Pharmaceutical Coating:- Equipment

Evaluating equipment and processes

On Demand Tutorial Transcript

Pharmaceutical coating: Equipment. Evaluating equipment and processes

Contents Pharmaceutical Coating Equipment & Processes Overview Role of the Coating Technologist Robust and Efficient Film Coating Equipment Specifications Equipment Variables Choosing a Vendor Equipment Design - Formulation and Process Needs Equipment Design - Reliability and Innovation Process Control System Considerations Strategies for Process Control Air Handling Materials Handling Cleaning & Cleaning In-Process Systems Spray System Parameters Spraying Stream Air Consumption for Spray Guns New Developments in Spray Systems Know Your Droplet Size Profile Droplet Size Distribution - 1 Droplet Size Distribution - 2 Robust Film Coating Processes Influence of Baffle Design Summary

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Pharmaceutical Coating Equipment & Processes

This FMC tutorial for scientists at beginning and intermediate experience levels, discusses methods and key questions to be asked when evaluating equipment and processes for Pharmaceutical Coating. Welcome to Pharmaceutical Coating - Evaluating Equipment and Processes, an FMC ondemand tutorial, designed to benefit formulators at beginning and intermediate levels.

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Overview

As you will see from this tutorial, high quality pharmaceutical coating results from careful planning and, to a large degree, making correct and practical decisions about equipment and coating processes. The pharmaceutical coating technologist, whether in R&D, scale-up, or production, makes innumerable decisions which directly impact product success or failure. These important decisions must lead to processes that are better, faster and more economical. With this in mind, we will discuss the numerous aspects of selecting the optimal equipment, including, but not confined to, equipment design, choice of vendor and spray systems. Also, characterizing the coating process, from laboratory, to scale-up, is critical to producing a robust and assured formulation and process. During this tutorial we will discuss the factors which are essential to ensure success in this area.

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Role of the Coating Technologist

Formulations that are optimally designed for a particular tablet core are now more the rule than the exception. Gone are the days when a one formulation fits all approach can be taken, or when the process can be outsourced to obtain coating know-how. Also, in todays competitive environment, knowledge is a valuable resource, and business asset. New formulation development expertise and process knowledge should be shared globally within an organization. This highly competitive environment compresses the timeline to bring new drugs to market. The coating technologist should be looking for FASTER coating processes and, perhaps more importantly, more efficient coating processes. The route to efficiency is not always the most obvious one. For example, increasing the solids concentration within the coating suspension is an easy alternative for enhancing productivity. However, depending on the number of batches to be produced per day, spraying a higher solids concentration may not be the most desirable way to achieve greater efficiency. In fact, utilizing a high solids concentration in the coating suspension can, potentially, increase scaleup or technology transfer issues. Surprisingly, sometimes a lower solids concentration in the film coating suspension can result in a high quality, reproducible coating without the potential loss of material during scale-up, facilitating a smooth technology transfer. In film coating processes, multiple factors must be considered when determining efficiencies. For a more economical process, coating excipients and their costs must be considered, as should the cost of manual processes versus automated processes, and the cost of failure. The cost of one lost batch can quickly negate any savings gained by, for example, running the process faster.

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Robust and Efficient Film Coating

Just like most other pharmaceutical processes, choosing the right combination of formulation, equipment and process conditions is key to obtaining optimal film coating results. These decisions are complex and interrelated, and can pose significant challenges for even the most experienced coatings professionals. We will not be discussing coating formulations during this tutorial as this topic could comprise a tutorial all of its own. However, product formulations and processes should be carefully evaluated and understood before moving on to the stage of evaluating coating equipment.

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Equipment Specifications

Using the correct machine for the job is critical to a successful film coating process You should choose the equipment which best suits the intended purpose, or multiple purposes. For example, must the equipment have flexibility for a number of applications like tablets, pellets or even sugar coating? The equipments intended purposes should include accommodation for special situations, such as higher spray loads if you were to enteric coat. Simple, aesthetic HPMC based coatings are much less susceptible to equipment design issues than a coating intended for a controlled release or enteric application. Questions like, how complicated is your process, or how many sub stages will be needed, and, will color need to be included, must all be addressed prior to setting up equipment specifications. This sounds like an obvious statement, but you would be surprised by how often equipment is purchased without first laying out an adequate set of specifications. Evaluation of machinery costs should take into account the price of purchase as well as costin-use for each specific application. Finally, make sure to involve representatives from production, the technical transfer group and research & development in the ultimate choice of what equipment should be deployed. It takes more time, but they will help to ensure that all necessary perspectives and scenarios are taken into account before final choices are made .

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Equipment Variables

These variables apply not only to purchasing new equipment, but also to upgrading or improving the performance of existing equipment. Well discuss each of these areas in greater detail, but first, some general comments. The choice of equipment is, obviously, a major financial decision. Choose a vendor who offers both the required machine design and the required flexibility. Of course youll want to consider vendors with whom youve already had a positive experience, but dont limit yourself to these vendors alone, especially if they dont offer the best designs and flexibility for your needs. Its important to explore the options with several vendors. Understanding your companys culture and how it relates to the required degree of automation is also important. For example, some companies encourage the use of automation and, for their own reasons, some companies do not. Within companies that discourage automation there is no point in purchasing a sophisticated, automated system. Validation packages can also be quite extensive and youll have to decide whether or not to source the validation package from the vendor. Its important to evaluate whether your organization has the internal expertise to deal with the IQ, OQ aspects of the new coating equipment. Often, it can be far more efficient to source the validation package from the vendor to ensure full and up-to-date compliance with regulatory requirements. There are also materials handling considerations, such as, will the equipment capabilities fit within the parameters of your facility? In addition, what are the options for spraying systems? As you can see, there are a considerable number of items to review during the process of choosing the most appropriate film coating equipment for your application.

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Choosing a Vendor

This is, by no means, an all inclusive list but generally, all of these companies sell good quality products. Evaluate each of your potential vendors carefully, including their reputation, (if unknown) technology and what they have to offer in terms of your particular product and coating process. Always run trials on each piece of equipment under consideration, utilizing your most challenging film coated product. This will help to ensure that all the major issues related to your product and processes are addressed. Questions that should be answered during these trials are: What is the coating machines performance when a sub-optimal batch is run? Can data be provided to prove the cleaning system can be validated when coating an insoluble product with an insoluble polymer? Can the software you are going to purchase be demonstrated during the trials? What is the validation package and specifically what will you have responsibility for from a maintenance perspective? In your discussions with the equipment vendors, clearly define what is to be achieved during your coating equipment trial. This means defining what is acceptable in terms of process times, quality, tablet appearance, cleaning process and time. Request that this information be documented so you can compare and contrast with your expectations, your current manufacturing capability, as well as any additional trials you may run.

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Equipment Design - Formulation and Process Needs

By now, the pharmaceutical coating technologist should have a well-defined product formulation and process. This will help to determine the exact requirements necessary for the coating equipment. When evaluating equipment design the coating professional must consider a host of additional factors, such as are identified here. Examples of questions which should be answered are: What will the coating solution viscosity be? Will it be compatible with the spray system? Will the spray gun beard significantly if an acrylic (or other sticky) polymer is utilized? How much turbulence will there be in the drum due to the design of the inlet and exhaust air plenums? Will this create any significant spray drying or cleaning issues? Has the correct mixer and vessel been defined for the operation? Is containment necessary? Is cleaning likely to be difficult? How so? These same questions need to be addressed whether one is sourcing new equipment or upgrading existing equipment. We encourage you to design a check-list of the many questions to be answered during equipment evaluation. Such a checklist will be enormously useful in evaluating the advantages and disadvantages of various equipment alternatives.

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Equipment Design - Reliability and Innovation

Where does innovation fit in the equipment evaluation? With the conservative nature of the pharmaceutical industry, the basic design of film coating equipment has remained virtually unchanged for close to 50 years. The picture on the left shows the typical design of a fully perforated drum. This concept continues to work very well. It has demonstrated high coating efficiencies, with spray going directly onto the product at percentages in the high 90s. Modifications have focused primarily on automation of the system, cleaning processes and validation. Contrast this with the diagram on the right-hand side. This film coating equipment design shows an interesting variation on the perforated drum from a German company, Bohle. Bohle claims their design, in which the drum is elongated, increases the number of spray guns and, therefore, will coat more efficiently. That claim is based on the idea that the tablets spend more time under the spray zone, which will improve the coating uniformity. How important this is in actuality? It could be important if you had an active ingredient in the film coat. It could also be important if it contributed to additional processing objectives. You will find it quite challenging to prove, to your satisfaction, that the vendors claims are true and that unique but, expensive equipment advantages are required to meet formulation and processing requirements.

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Process Control System Considerations

There are several things which must be examined when it comes to process control automation. How flexible is the automated system? Its important to determine whether the system can be used for a manual process, and on the other end of the spectrum can it also be used for a complicated multi-stage process if required? Can the automation system be upgraded at a later date? At what likely cost? When thinking about software, also consider whether it will meet and keep up with the ongoing interpretations and implications of the Code of Federal Regulations, Title TwentyOne, Part Eleven especially in terms of security. Will the control system be compatible with existing software systems and with the current factory IT systems it will need to be integrated with upon installation? The automated system should be user friendly without the need for extensive operator training. Finally, dont forget to find out if the system uses pictures and symbols rather than words; the use of pictures would be a very useful attribute in a global operating environment.

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Strategies for Process Control

Now that you have chosen the automation/control system, your next step is to determine how to apply it to the coating process. The most common methodology is to fix the exhaust or tablet bed temperature and vary inlet air temperature. Tablet bed temperature directly influences film formation conditions, but can be difficult to measure accurately. Exhaust air temperature is often used as an approximate measure of bed temperature, but a clear correlation must be established. Challenge your equipment suppliers to develop a standard measurement of temperature. Some processes can be controlled by maintaining a constant inlet temperature. In other cases, the process will be more dependent on the exhaust and bed temperatures. A varying spray rate can also be used. However, use caution, with a varying spray rate as there will be a lag time between the adjusted spray rate and the resulting exhaust temperature; this lag time can negatively impact film formation. Humidity significantly influences the coating process, in fact, it impacts droplet size and characteristics even more than airflow and temperature do. Droplet size and characteristics are key to film coalescence, and thus, the final film properties. Controlling the humidity entering the drum is more important than is routinely recognized, so consider controlling the relative humidity specifications as tightly as you would air flow and temperature.

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Air Handling

This diagram illustrates typical air handling on the inlet side. Options for air handling include the ability to have pre-heaters and pre-filters. For certain moisture sensitive products, a dehumidifier can be added as well. Many choices will depend on the geographic location of the facility, budget, sensitivity of product to moisture and the sensitivity of the process to the humidity of the incoming air. To avoid retrofitting and maintenance charges, evaluate these factors when you are initially sourcing the equipment.

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Materials Handling

Materials handling. Think about how the coating will fit into the production stream. Are the tablets moved via a vacuum process through a continuous production line from blending to tableting to coating, and, finally, on to packaging? How should the tablets be loaded into the pan? Via a vacuum process from the floor above, or manually, from the front or back of the equipment? Plan for loading and unloading methods which are compatible with your process stream. Unloading tablets after they have been beautifully coated is the point at which there is the greatest potential for damage. Automated unloading processes can be utilized but must be monitored to ensure the tablets are not subjected to breakage. Take into consideration the speed at which the tablets will be discharged and the distance which the tablets will fall into a collection bin. Be sure to observe a demonstration of the tablet loading and unloading during the equipment trial. If containment is necessary, will the coating and process equipment be able to handle raw materials and finished coated tablets while ensuring containment?

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Cleaning & Cleaning In-Process Systems

The ability to validate coating equipment C.I.P systems is essential. As the equipment purchaser, you must be fully convinced that the combination of the C.I.P. system design, proper detergent, and the correct cleaning cycle (time and temperature) can be fully validated. With an automated and validated cleaning process, the overall downtime associated with cleaning will be decreased. More aggressive detergents, when combined with high temperatures, are effective in removing very potent actives. However, they should only be utilized in the cleaning process when you are assured, through validation, that they can be removed effectively from the system. Validating that a coating pan is clean can be as difficult as validating the coating process itself. With the emphasis on cleaning validation by the FDA and other regulatory agencies, equipment manufacturers should be able to supply you with data to demonstrate that their C.I.P. system will clean effectively.

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Spray System Parameters

Now, consider spray system parameters such as the spray gun, characterization of the droplet size and distribution, and coating formulation viscosity. Spray guns are different in terms of their atomization efficiency. For example, at a given pressure, the volume of air passing through the gun will be different for any two spray guns. Atomization of the coating liquid depends on the air to liquid ratio and the viscosity of the coating formulation. This will result in different atomizing efficiency and droplet characteristics. The design of the aircap on the spray gun can influence the bed coverage as well as how cleanly the gun runs. The shape of the spray from each type of gun will be significantly different. Now lets look at an example of the difference between spray guns and their atomization

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Spraying Stream

Here you can see the spray stream for two spray guns. Identical conditions are set for both guns, yet resulting droplet characteristics are completely different. On the left is a clean, mist-like spray, which results in more rapid color uniformity; the tablets are less susceptible to over wetting. The right side shows larger droplets and a less uniform spray, far less acceptable from a coating process point of view. An evaluation of the spray gun type and pressure set up is important. It will significantly influence coating quality, process time and coating efficiency. Finally, make sure the droplet size achieved during the development process can be replicated during production.

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Air Consumption for Spray Guns

This graph looks at the quality of the air passing through two spray guns at various pressure settings typically used in development. For example, a Manesty gun (represented by the blue line) consumes up to four times the amount of air at two point zero bar pressure when compared to a Schlick gun (which is represented by the purple line). This can be quite significant in terms of atomizing efficiency, droplet size and the resultant process performance. The differences are a direct result of the gun designs.

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New Developments in Spray Systems

Spray guns have their share of design issues, but several recent developments have helped improve the spraying process. Here are a few examples: Schlicks gun has an anti-bearding cap. The nozzle prevents bearding because the fan air comes out of the cap on the same plane as the atomizing air. This is important for longer processes, like enteric coating. The LHS IMA system of positioning the guns during spray set up is useful when coating a drug where containment is necessary. Bohle has a gun cleaning system which cleans the nozzle at set intervals during the coating process, preventing bearding. Make sure to check with all of the spray equipment manufacturers to learn about whats new in spray systems and determine whats best for your specific application.

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Know Your Droplet Size Profile

Characterization of the droplet ensures that there will be minimal turmoil during the scaleup/technical transfer process. Using laser systems such as the Aerometrics Phase Doppler, you can obtain droplet size profiles for a given coating suspension through a range of pressures, flow rates and gun to bed distances. In the APD system, droplets are atomized in an area of measurement where the 2 laser beams cross. You can then adjust gun position and settings so the conditions utilized in development can be reproduced in the production environment.

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Droplet Size Distribution - 1

Using laser methodology under typical developmental type conditions, two different coating systems were compared : Lustre Clear from FMC and a commercial HPMC-based formulation. The two coating systems produced completely different droplet sizes. Choosing atomizing pressures should be dependent upon each formulation and should not be set the same for every product being coated. Interestingly, the droplet size profile for the LustreClear was tighter, with less spread.

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Droplet Size Distribution - 2

The same experiment was conducted under production conditions. A similar trend was observed. The overall droplet size and spread is very similar for development and production, leading one to expect similar outcomes in terms of film properties. This is the type of result you want to see. The film forming polymer in LustreClear carrageenan has a shear thinning nature; a lower viscosity at high shear rates. In the high shear environment of the spray nozzle, the actual spraying viscosity of the carrageenan based coating suspension will be lower than for HPMC. This will result in more efficient atomization at the same pressure settings for the HPMCbased coating. We believe that faster spray rates with a more reproducible droplet size can be achieved with the LustreClear formulation.

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Robust Film Coating Processes

Characterizing all aspects of the film coating process is critical to producing a robust and assured formulation and process. It is important to investigate how the tablet will flow in the tablet bed upon scale-up. Conducting test batches at the production level with placebos, followed by tests with mixed placebos and actives allows the tablet size, shape, surface characteristics, coating formulation and pan design interactions to come to light. This will greatly improve the chances of a successful production batch. It is also important to determine actual process variables such as bed temperature, drum speed, spray rate, droplet characteristics, coating end-point and moisture tolerance specifications for the production environment. And finally, consider how the product mixes in the bed depending on drum speed, tablet shape and size, surface characteristics, and baffles. A baffle that will optimize the process must be chosen.

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Influence of Baffle Design

The influence of baffle design can be dramatic. This graph shows the time it takes to achieve color uniformity during the coating process. A pink HPMC-based coating formulation was sprayed on white tablets. Throughout the coating process, tablets were removed and measured for color difference. The color difference gradually declined to the point where no difference could be seen with the naked eye. Tubular baffles, in this case, took about 30 minutes to achieve color uniformity, while plough baffles took longer than 45 minutes. All other parameters were kept the same, indicating that baffle design can significantly influence the time to achieve color uniformity. The same effect was seen when the experiment was conducted in a 48 AccelaCota.

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Summary

In conclusion, we have covered some of the important aspects of film coating equipment and processes by providing knowledge of the coating process from equipment design through cleaning and automation. Use these tools to develop processes that are right the first time, and every subsequent time, as they are transferred into production. Be mindful to choose your equipment vendor carefully, ensure their technology meets your requirements, and know the key processing characteristics which must be evaluated. Know what factors are important to your formulation and process. Clearly define the critical variables and the coating end points. By doing these things you will provide your organization with a more robust and assured film coating process. We hope youve found this presentation useful. If you have any comments or questions please contact the moderator of the FMC TechLounge or your local FMC representative.

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