Hot melt coating processes have been firmly established in the food industry for many years. However, the majority of the production machines which are used for this purpose fail to meet pharmaceutical manufacturers’ high cleanability requirements. A technology specifically for hot melt applications in this sector has now been developed in response to the growing interest among pharmaceutical producers in fat, wax or polymer-based coatings of this kind. This GMP compliant device for heating and feeding hot melt coatings integrates all functional components in a heatable monobloc, which is designed to ensure good access to all components. The system thus satisfies all the requirements for pharmaceutical grade cleaning. Cross-contamination is demonstrably avoided. No further obstacles remain to the approval of hot melt coating formulations in the pharmaceutical industry. This article explains both the potential and the engineering challenges associated with the processing of pharmaceutical hot melt coatings (HMC).

Suitable for the food and pharmaceutical industries
Fat-based coatings have been used for some time now in the food industry, for example for the food acid, salt or aromatic spices contained in cake mixes or mixed spices. Natural raw materials like palm fat or Carnauba and beeswax are generally chosen for these formulations.¹ Organic fat or wax coatings are considered to be both economical and extremely efficient because no liquids need to be evaporated. Unlike aqueous alternatives, the melt contains no solvents and solidifies directly on the product without evaporating. The entire spray for coating the product is applied to the particles, leading to a significant reduction in processing times and energy costs.² Against this background, hot melt coatings are also a highly attractive option for the pharmaceutical industry. Numerous pharmaceutical manufacturers and research institutes are therefore starting to look more closely at the properties and potential applications of melt coatings. Among other things, hot melt coatings can be used as moisture barriers for hygroscopic products in the same way as in the food industry. They are also ideal for masking the taste of bitter API particles.^3,4,5 Their behavior in connection with sustained release tablets has moreover been the subject of various studies.^6,7,8

Risks and opportunities of hot melt coating processes
Despite the intensive development activities of the last few years, melt coatings have yet to gain widespread acceptance throughout the pharmaceutical industry. For a long time, the technology was not fully mature either from a pharmacological point of view or in terms of the apparatus design. For one thing, the fats which are processed in the food industry are inferior in quality to what is stipulated for pharmaceuticals. The properties of natural products are inherently prone to instability.⁹ For another, the highest levels of plant safety are necessary to handle the hot fats. To protect the operator adequately, the heated components must be continuously insulated and clad.¹⁰ This insulation automatically complicates access to the individual components.

This is probably the biggest challenge for hot melt technology in the pharmaceutical industry, where optimal access to components is essential for a GMP compliant cleaning validation. However, the large systems which are common in the food industry are difficult to access and hence not suited for use in pharmaceutical production. The obligatory swab test,¹¹ for instance, is only possible on the hidden inner surfaces of a food plant with a great amount of effort and expense.

The potential and the economic efficiency offered by the hot melt process are nevertheless appealing. Several manufacturers of pharmaceutical excipients are therefore pushing ahead with ongoing research into hot melt coating techniques. In the meantime, quite a few synthetic fats and ready-to-use coatings with the necessary stability and reproducibility can be purchased.^12,13 Progress has also been made with respect to the equipment and the system design, and the processes are now better adapted to the pharmaceutical industry’s GMP requirements. The pharmacologists carrying out the research are very keen to scale up their laboratory findings to real production conditions.¹⁴ One hot melt technology which was specifically developed for use in the pharmaceutical industry is described in Figure 1. The focus is on the processing and apparatus requirements which must be satisfied in order to comply with GMP regulations.

Functional hygienic design
The avoidance of cross-contamination is one of the basic principles described in the German Ministry of Health’s guide to good manufacturing practices in the pharmaceutical industry.^15,16 This presupposes a system concept which is conducive to thorough and efficient cleaning. Product and detergent residues must be ruled out in keeping with the criteria of acceptability. It must be possible to validate the cleanliness of all product-contacted surfaces.¹¹ Machines for pharmaceutical production, including all product-contacted inner surfaces, should therefore be readily accessible to the operator. Since hot melt devices must be continuously heated and insulated, ensuring optimal accessibility represents the biggest and most important design challenge.

An integrated system concept for heating, dosing and feeding hot melt coatings has now been developed to reconcile processing requirements with GMP regulations. All components needed for the process have been arranged in a heatable monobloc for this purpose (see Figure 2). The melting container, pump, control valves, compressed air lines and piping together form a functional unit. These components consequently do not have to be insulated individually. Instead, the complete monobloc can be enclosed. The cladding can be removed easily if necessary (see Figure 3).

This design simultaneously allows uniform and precisely controllable heat distribution. If system components or interfaces are allowed to cool down excessively, the liquid melt in the system could solidify, clogging the dosing device and jeopardizing the entire process. Not only is reliable temperature control crucial in order to prevent deposits and coating residues; the cleaning processes must additionally be defined and validated for each specific product. Since hot melt coatings typically exhibit poor conductivity and solubility, a rinse test with deionized water is inadequate; a swab test is a primary requirement.¹¹

Monobloc design with no dead spaces
The monobloc system was designed with no dead spaces in conformity with GMP regulations (see Figure 2). There are no flange connections and all sealing points, gaps and enclosed spaces where product residues could build up have been eliminated. All pipes through which the hot melt flows are straight and have an identical cross-section, meaning they are intrinsically accessible. The valve inlets, too, are freely accessible, so that visual inspections of all pipe connections are a simple matter. The same goes for swab tests on all product-contacted inner surfaces.

Two pharmaceutical grade diaphragm valves (see Figure 2, no. 8) control the product flow from the melting container via the pump to the coating material discharge. The valve seats are set directly into the monobloc and seamlessly connected to the product channels. The valve actuators which operate the membranes pneumatically are secured to the outside of the heating block, which is not a problem for cleaning. The diaphragm principle with no dead spaces was specially developed for pharmaceutical processes and meets all the requirements for cleaning in place (CIP). The valve actuators merely have to be unscrewed for the cleaning validation in order to reveal the product channels. Alternatively, the valve seats can be machined into a conductive, stainless steel plate, which sits on the heating block and can be opened very easily (see Figure 4, no. 8). This provides even better access to the product channels and the cleaning results are even more straightforward to check.

The integration of the functional components in the continuous heating system of the hot melt device is of vital importance here. If the components were all separate, as is generally the case with conventional melt systems, separate pipe and flange connections would have to be installed for each one and each of those connections separately heated and insulated. This kind of complex architecture is widespread in the food industry but would make pharmaceutical grade cleaning extremely difficult. The heatable monobloc therefore plays a key role.

The temperature is decisive
Melting temperatures of up to 120 degrees Celsius are the norm when processing hot melt coatings. The temperature is controlled by means of an electric heater integrated in the device (see Figure 4, no. 6). In the lab scale version up to 50 liters, the heating block is made from solid, conductive stainless steel, so that the heat is uniformly distributed throughout. In the models for higher production volumes, this compact block is hollow and filled with thermal oil to facilitate the distribution of the heating energy.

The hot coating material is fed to the processing machine via a heatable tube. Two interfaces must be thermally bridged by the flexible connection. There are short, unheated connectors both at the outlet of the hot melt device and at the entrance to the spray nozzle. Critical cold spots could form at these two adapter points when the system is heated. To rule out a temperature drop, the tube is pre-heated with compressed air, which is introduced via the heating block, before production starts. A compressed air heating channel has been integrated in the hot melt block for this purpose (see Figure 4, no. 11). The channel coils result in a larger heat exchange surface and the air is accordingly heated more efficiently. The air is also heated more uniformly because the coils produce turbulence. At the end of the coating process, the compressed air is used to drain the tube. Once again, precise temperature control prevents the coating residues from cooling down and solidifying in the tube or, in the worst case, obstructing the nozzle of the processing machine. The purge air thus also plays a central part in the GMP concept for the hot melt device.

Mobile connection and control
The mobile hot melt device is mounted on castors (see Figure 1) and can be flexibly connected to the downstream processing machine (see Figure 5) as required via the trace heated tube. The hot melt device is embedded in the machine’s control environment by means of a digital interface. All functions of the hot melt device have been integrated into the processing machine’s HMI, so that the entire batch process can be centrally controlled using the formulation system– from melting, dosing and feeding of the hot melt to coating the product at the required spray rate. In addition, the control system for the processing machine records all relevant production data of the hot melt device and stores it automatically in the batch documentation.

Dosing piston for feeding the hot melt coating
A dosing piston for feeding the melt is integrated in the heated monobloc as standard (see Figure 2, no. 4). The piston sucks the liquid coating material into the cylinder up to the end position during the return stroke. A linear stepper motor determines the piston’s relative position. The product is fed to the processing machine during the forward stroke of the piston to the zero position at a defined speed. The product discharge (see Figure 2, no. 9) is consequently a function of the piston feed rate. This has the advantage that the piston is pulsation-free and the hot melt is pumped very evenly into the nozzle of the processing machine, where the coating is sprayed onto the product. Due to this volumetric dosing method, the concept is suitable for the pharmaceutical batch process, in which all components of the end product are predefined. All ingredients and components of each formulation are individually weighed. The finished product is weighed again at the end of the batch and a mass balance calculated.

A further benefit of installing a dosing piston is that the dosing system can be cleaned in line with pharmaceutical requirements. Since the piston is movably mounted in the cylinder, it can be fully retracted from the heating block at the push of a button (see Figure 4, no. 4). The cylinder is thus readily accessible and can also be cleaned manually if necessary. The dosing piston is always arranged at an angle, so that all liquids are basically self-draining. On larger machines with a capacity of 50 kg or more, the dosing piston is arranged vertically in the monobloc next to the melting container to save space.

Peristaltic pumps as an alternative
Alternatively, the hot wax can also be dosed and fed by means of a peristaltic pump integrated in the heating block (see Figure 6, nos. 12 and 13). Peristaltic systems are widespread in the pharmaceutical industry because the delivery tube is easy to replace if the product changes and the pump itself does not come into contact with the medium. Unfortunately, however, peristaltic pumps are not pulsation-free, which means the spray rate varies. The peak pulsation must be taken into account when the hot melt is applied and the dose rate adjusted accordingly. To prevent agglomeration, the maximum spray pressure must not be too high. As a result of this constraint, the maximum possible dose rate which can be achieved with a peristaltic pump tends to be less than with a dosing piston.

On top of this, the delivery rate of a peristaltic pump has to be monitored continuously with a mass flowmeter. Since the delivery rate is not proportional to the speed owing to the relaxation rate of the pump tubing, the product flow cannot be determined accurately based on the number of revolutions. A defective tube, for example, will no longer convey any liquid despite the constant speed, which is why it is not enough to check just the mechanical movement of the peristaltic pump. In order to determine the mass flow rate, therefore, the hot melt device must be equipped with a flow sensor. Against this background, feeding the melt with a peristaltic pump is rather more complicated than with a dosing piston, especially as an additional temperature control circuit and heating tube are required to integrate the flowmeter and the sensors have to be insulated.

From the cleanability perspective, though, peristaltic pumps comply with all GMP requirements. A product tube for feeding the hot melt is secured by means of two adapter points each at the pump’s inlet and outlet. It can be removed easily for cleaning and inspection and replaced if necessary.

Connection to the processing machine
The principle of architectural simplicity also applies to the connection between the monobloc device and the processing machine. The two systems are connected together by a heated tube, through which the hot melt coating is fed into the machine’s nozzle. This special type of connection was developed for a coating technology that manages with a single spray nozzle (see Figure 7) no matter how big or small the processing machine. Systems that work with multiple nozzles will need correspondingly more heatable product feed lines and pumps, which will also increase the time and effort for cleaning. Control and monitoring of the individual nozzle temperatures will likewise be far more complex as regards both the mechanical design and the control system. Conversely, if the spray system has only one nozzle, then only that one component has to be heated and equipped with a temperature sensor. It is sufficient to heat the nozzle spray air to prevent a drop in the melt temperature. The hot spray air is then introduced through two circular gaps, which completely surround the nozzle’s melting channel and heat it reliably up to the mouth.

Liquid spray production
The spray air serves to atomize the coating liquid or melt which is pumped through the circular spraying gap into the process container. To achieve the desired spraying effect, this air is blown into the process through two gaps—one above the spraying gap and one below it. Liquid spray with a defined droplet size is produced depending on the pressure at which the spray air hits the coating liquid. The spray rate is controlled according to the pump output of the hot melt device and is determined by the speed of the dosing piston which feeds the hot melt. The spray air pressure, on the other hand, is a function of the spray rate and the desired size of the coating droplets. The ideal droplet size, in turn, has to do with the size and shape of the product particles which must be coated with the hot melt. If the droplets are too large in relation to the product particles, there is a risk that the product will agglomerate. A finer liquid spray can be obtained either by increasing the spray air pressure or by reducing the pump output. In this respect, hot melt coatings are equivalent to aqueous coating solutions.

Process temperature monitoring
Fat and wax melts are also fairly similar to aqueous alternatives in terms of their viscosity and flow properties. The most crucial difference concerns the transition from the liquid to the solid phase. Whereas solvent based coatings evaporate relatively slowly, hot melt coatings solidify within a very short time as soon as they cool to below the re-solidification temperature. The temperature gradient in the product container should not be too steep for this reason. If the atomized medium cools down too rapidly after it exits from the spray nozzle, isolated droplets will solidify on the particles without fusing into a homogeneous coating. To achieve homogeneous results, therefore, the hot melt must be cooled in a precisely controlled way. Due to the properties of hot melt coatings, only very small process temperature tolerances are permitted. Even slight variations can have a big impact on the quality of the end product. The temperature profile of hot melt coating processes must be controlled very accurately with for this reason. A system concept with a single, centrally arranged spray nozzle makes it easier to monitor the individual steps because the process parameters only have to be measured for this one nozzle.

The product container must be designed so that no more than the tip of the nozzle is immersed into the process rather than the complete nozzle body being in the bulk product area. This prevents product which has already been coated from melting on, and sticking to, the hot nozzle surface. If a central bottom spray system is used, the liquid spray will be directed upwards at the product as it is moved and circulated by the process air. Provided the spray nozzle is completely covered by the product in motion, spray loss will be reduced to a minimum. The flow conditions in the container define the velocity of, and the distance travelled by, the individual particles so that collisions or, worse, agglomeration are prevented. The so-called “air flow bed technology” satisfies all the processing requirements for the application of hot melt coatings.^17,18

Summary and outlook
The biggest engineering challenge associated with hot melt coating processes is simultaneously their biggest potential. Hot melt coatings neither evaporate nor solidify. That saves time, energy, material and money. Cleanability which can be validated is an essential precondition for using this technology in the pharmaceutical industry along with continuous heating of the hot melt device. Even the smallest temperature variations can cause the hot melt to solidify unexpectedly. This will jeopardize the processing result and the time and effort for cleaning will be enormous. Efficient hot melt coatings thus hinge on reliable processes and precise monitoring. Account was taken of all these factors when developing the GMP compliant hot melt device. It is now up to pharmacologists to weigh up the opportunities against the risks. The first hot melt formulations for pharmaceuticals are already available in the market¹⁴ and approvals have been issued for several others. 

Note: All Figures appear in the slider deck at the top of the page.

References

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