Harro Höfliger: Powders require more than engineering expertise

"New Drug Delivery Systems" from Harro Höfliger.

Fig 1: Laboratory analysis of powders with varying flow and dosing behaviours

The majority of pharmaceutical products have to enter the blood stream in order to be effective. They can be taken orally, via the intestine, by injection or infusion. In addition there are other special methods that are grouped under the collective term, "New Drug Delivery Systems". These include, for instance, transdermal therapeutic systems (TTS), whereby the skin absorbs the active pharmaceutical ingredient, or the subcutaneous injection, whereby the drug is administered almost pain-free, using injection equipment.

An alternative method for taking in the active pharmaceutical ingredient is the "micronized powder" method. In this case, a predetermined dose of powder is inhaled into the lungs (pulmonary) or over the nasal mucous membrane (nasal) and distributed in the blood stream.

While the production processes for injections, tablets and infusion solutions are undergoing technical development and are available on the market, the procedural method and its large-scale technical implementation also have to be developed when a New Drug Delivery System is introduced, besides the actual development of the medicament itself and its testing. In this respect, knowledge of the behaviour of the medicament plays just as much a role as the technical know-how for setting up a production machine.

Höfliger has made a name for itself on this very sector during the past 10 years by developing and implementing production methods and possible solutions for its customers, as regards manufacturing and packing pharmaceutical products. At Höfliger, the competence necessary for handling pharmaceutical products is combined with highly technical expertise in the sectors for process, monitoring and control engineering.

If one takes the example for processing different types of micronized powder, it is possible to demonstrate how the obstacles arising during the development of a new procedure can be successfully overcome.

Fig 2: Influence of Particle Size

Core competence – Classifying and processing different types of inhalation powder.

The ability to process micronized powder and the selection for a certain dosing procedure depends largely on the physical properties of the respective powder involved. These properties are defined by its flow behaviour, ability to be compressed, roughness and adhesive behaviour. Expert knowledge on mechanics and electrical engineering is therefore no longer sufficient by any means for bringing powder-filling machines onto the market successfully today.

In addition, the variety of differing drug delivery is increasing tremendously due to the rapid development of the products. It is a fact that the number of patents for inhalable products increased 6-fold, from 1976 to 1999 alone in the USA. This is mainly based on the fact that the nasal and pulmonary forms of intake are far less expensive than the customary injection therapy and cause the patient far less pain.

Fig 3: General Procedure in the Handling of Powder Materials

Apart from this, the argumentation - "No first pass metabolism" and the suppression of the "pulsed absorption profile" speak out in favor of the pulmonary or nasal intake of active pharmaceutical ingredients.

If one takes a closer look at the development of the DPIs (Dry Powder Inhaler), one can determine that due to the place where the powder becomes effective, the size of the particles are becoming progressively smaller in order to enable better absorption by the body. The trend towards continued reduction in the size of the particles and thus a continual reduction in the dosage quantities has a decisive influence on the physical behaviour of the powder.

The distribution of the particles, their size and roughness thus largely determine the flow behaviour which, in turn, is of crucial importance during the transport of the active pharmaceutical ingredient from the inhaling device to the lungs and, to the same degree, also from the dosing unit of the powder filling machine to the device.

Whereas the investigation on the behaviour of a medication drug in the human body is the task of pharmaceutical research, it is the task of those developing the machine to provide installations that are optimally aligned to the process. In the sector for powder-processing machines, this means that the manufacturer of the machine must know exactly what the properties of the powder are, in order to select the optimum dosing procedure to suit it. The focus of a powder-filling machine as regards its function is, therefore, normally on the procedure to be selected.

At Höfliger, the powder in question is therefore examined thoroughly before its filling process is decided on and developed. This, for instance, includes the following investigations:

• Particle size distribution
• Particle size
• Adhesion force
• Particle geometry
• Particle roughness
• Powder density

Partner with Expertise in Powder Handling and Dosing.

Not until a powder has been defined and classified can the selection of one or several suitable dosing systems be made. Once the selection has been made, further steps towards developing the optimum production process can be taken. Here it is decisive that the pharmacist has authoritative involvement in the development and also plays a role in deciding what steps should be taken next.

These are, for instance, questions as to whether experiments with differing dosing procedures should be undertaken or whether experimental set-ups should possibly be designed and installed. Depending on the complexity of a development project of this kind, the step-by-step procedure (see Fig. 2) is of decisive advantage, as opposed to ordering a machine to be developed straight away. This process clearly focuses on dialogue and communication with the pharmacist.

As already mentioned, the output of the machine is restricted to the flow behaviour of the powder. A simple sum in economics underlines the significance of the powder dosing station: Let us suppose that a selling price of Euro 45.00 can be reached for one device. The device contains 30 single doses, each having a filling quantity of 13 mg, i.e. 390 mg. Euro 45.00 à 30 doses = Euro 1.50 per dose. A nominal output per machine of 2.700 inhalers per hour, is equivalent to a turnover of Euro 121,500/ hour. Correspondingly, the focus lies on the powder in the starting phase of a new project.

The respective dosing procedure is selected by taking the classification of the powder as a basis. As a basic rule, a differentiation is made here as regards dosing.

Whereas colloquially, we only use the term "dosing", the experts differentiate between filling and dosing. The term "filling" is used for a container (blister cavity, plastic cartridge, etc.) being filled with the product. If this is carried out 100%, the filling volume of the container represents the filling quantity. Here one should consider the ambient variables (incl. temperature, humidity) and the properties of the powder (incl. the degree of compaction), which have to be kept constant.

Fig 4: Development Process

Although it sounds simple in theory to produce constant conditions, problems often occur here in practice:

• Tolerances in the powder production process
• Variations in the room humidity
• Uneven distribution of the powder density
• Variations in the moisture of the powder, etc.

Even at the stage of producing the powder, these parameters have to be kept within very tight tolerances, which however, does not automatically mean that the powder density can change during the subsequent filling procedure.

Fig. 5: Process Optimization

Höfliger has got the Solution.

This is dependent, for instance, on the time between the production and filling and on the mechanical treatment of the powder during the filling procedure. Using constructive means, influence can thereby be brought to bear at an early stage.Sensor technology can therefore be employed to keep the powder filling height in the dosing container almost constant, or the flow velocity can be influenced by the geometrical arrangement. By observing the effects of possibilities like these, the degree of efficiency of a plant can be increased consider-ably.

To ensure the appropriate dosing procedure, Höfliger not only analyses the powder, but also tests its dosing capability. For this purpose, there are differing dosing systems available for selection and if necessary, new testing equipment can be set up. The respective powder undergoes a "sample-dosing" procedure at the powder laboratory, thus enabling the result of the analysis to be documented.

When dosing the powder, the dosing volume of the dosing tool determines the filling quantity. Flow behaviour, especially in the case of inhalant powder, is largely influenced by the adhesion force between the powder particles (van der Waals forces).

Once the adhesion forces have been determined qualitatively, the dosing system can be selected. Here, too, Höfliger employs modules that are available in differing kinds of dosing technology systems. These are selected to suit the powder container and the performance of the machine. Once the appropriate procedure has been found for filling the powder using this structured method, process technology can begin with the technical development of the plant on a large-scale.

Fig 6: Laboratory analysis of a powder sent by the customer for studies on the OMNIDOSE Table-top-device

Since it is extremely important to control the dosing result in the automatic filling process, besides the exact dosing itself, different controlling systems are used.Since the dosing quantities are becoming smaller and smaller alongside fast technological development in the field of control technology, Höfliger is continually developing new control systems with its partners. For instance, there is a brand new method for determining the proportion of active ingredient in the product container.

Work is also being done on an alternative controlling system for gravimetric measurement. This system is to enable a 100% control of the product volume. For this purpose, weighing cells are already being implemented today. However, they are only used for in process control, as the procurement costs of these weighing units for 100% control are often unjustifiable, economically speaking.