The Compulsion to Innovate in the Pharmaceutical Industry: A Snapshot of the Situation

In the years 1996 to 2003 the number of NMEs approved by the FDA thus halved, while the research expenditure in the same period almost doubled. Only roughly one in 5000 researched substances can be developed into a new drug.

At the same time scientists are confronted not only with financing problems, but also with increasing security requirements imposed by the authorities, triggered last but not least by frequently occurring undesired effects of preparations that have been market launched.

The recall of the COX2 inhibitors Vioxx is cited as a current example. The high security requirements and the compulsion to achieve consistent data increase the complexity of clinical studies though. More studies and studies with a higher number of participants are required, which in turn can lead to longer development times.

One possibility of moderating the innovation compulsion and evading the cost-intensive development of new molecular entities is the galenic improvement of the existing products and delivery forms.

In recent years interesting approaches have been developed in the field of drug delivery systems to improve, for example, the bio-availability of well-known molecular entities or to adapt their release kinetics to circadian rhythms. Innovative delivery forms for transdermal, pulmonary or nasal administering are cited as further examples.

This trend is certainly strengthened due to the growing proportion of bio-pharmaceuticals among the new substances, these products frequently being proteins or peptides that as a rule cannot be administered enterally. In this case patient-friendly alternatives for injection are required.

In the case of the 21 new substances approved by the FDA in 2003 only 6 were in fact of a bio-technological origin, though it is expected that the proportion of such products will grow rapidly in the next few years to over 40 %.

The progress in the fields of biotechnology, in particular in pharmacogenetics or pharmacogenomics will lead to a rapidly growing number of new possible target structures for a specific drug therapy, i.e. the proportion of complex molecular entities and at the same time the demand for new administering methods will therefore continue to increase.

Strategies for control of the development costs and the “time to market”

In this situation it is becoming increasingly necessary for innovative companies to enter into strategic alliances and cooperation agreements to control the development cost and the time up to market entry.

This type of collaboration is absolutely normal in the field of molecular entity development: Thus up to 40 % of the new substances in the pipelines of the top ten pharmaceutical companies are licensed and in particular in the field of biotechnical products numerous new strategic partnerships are published year after year.

There are many good reasons for entering into such alliances with suitable machine suppliers as partners also, and of already cooperating closely during the product’s development.

In this way it is ensured at an early stage that the manufacturing or packaging technology selected will deliver the required product quality and in the further development phase that it is also transferable to production scale without any change in principle to the processes.

Due to general cost pressure the later post-approval production will become ever more important in the life cycle of the drug anyway. Future developments of pharmacogenetics with its vision of patient-specific therapy give rise to the expectation that batch sizes will continue to fall, frequent product changes will take place and hence the demand for highly flexible production lines will increase.

After all, FDA’s PAT initiative is not the first time that it has become clear that conventional pharmaceutical production, in which the individual batches wait on average 50 % of their production time for intermediate or final clearances by quality control, has no future.

We have tried to illustrate by way of the following example what such cooperation with a machinery manufacturer such as Harro Hoefliger Verpackungsmaschinen GmbH might look like, which, in relation to the delivery form and the requirements that follow from this, is fully in compliance with the previously described trend.

Cooperation by way of the example “Powder for Inhalation”

Asthma and COPD (chronically obstructive bronchial diseases) are increasing all over the world and require the improvement and further development of existing therapies. At the same time the alveolar area of our lungs with an area of roughly 80 to 100 m² and an easily surmountable membrane between the alveolar wall and the blood circulation system is an ideal target organ for administering many systemically acting substances.

While the therapeutics on the market are principally used in the form of dosing sprays, in the case of new developments powders for inhalation as galenic formulations are increasingly encountered. These powders are usually made available predosed in modern inhalers (Dry Powder Inhalers, DPI’s), for example, as blister strips with 60 and more individual pockets.

One of the prerequisites for substances in powder form being able to get into the alveoli is that they have a particle size of roughly 1 µm to 5 µm. However, on account of the strong adhesive forces between the particles such powders are very cohesive and on account of their poor flow properties are extremely difficult to handle.

This applies in particular, if the single dose to be packaged is in the range 1 mg to 15 mg. If the quantity of drug to be administered is relatively small, the micronized molecular entities can in fact also be applied to a coarse carrier substance such as lactose monohydrate. However, the dosing behavior of such “well-ordered mixtures” is determined largely by the dispersed, micronized molecular entities.

Conventional dosing processes as are used for filling hard gelatine capsules (by dosing tube or tamping plate) or for filling powder into glass vials (auger filler) do not achieve the desired effect. However, the vacuum drum-type doser developed by Harro Hoefliger, with several dosing chambers, each having an effective volume of between roughly 1 mm² and 100 mm², is highly suitable for the dosing of powders with poor flow behavior.

For example, the market-dominating mixtures based on lactose can be dosed in the range 2 mg to 15 mg without difficulty. If the relative standard deviation is calculated as a measure of the uniformity of mass, values of 1 % to 3 % are encountered depending on the dosing behavior. Analogous results have also been achieved for non-mixed micronized molecular entities by making specific modifications to the filling system.

What would a partnerlike collaboration between the pharmaceutical company as the customer and HH as the service provider look like for the development of a powder for inhalation? And how can the path to a stable production process and to appropriate production lines be shortened?

At the center: The powder

It is well known that the behavior of powders is determined by numerous parameters such as the particle size distribution, particle shape, particle density, melting point, hygroscopicity, the tendency to become electrostatically charged etc.. This explains the very varying behavior of different powders and requires knowledge as precise as possible of the materials to be handled.

As an entry into a common project Harro Hoefliger therefore initially offers its customers a powder analysis of the material, which is then invoked as a basis for selection of the most suitable dosing system.

At the same time this analysis already provides valuable indications as to which environmental conditions, e.g. temperature and relative humidity, have to be ensured during the later processing of the powder in the machine or in the production rooms.

The adhesive behavior can already be investigated at this stage on various materials. It will be of importance later when selecting the materials for the construction of parts that come into contact with product.

First dosing attempts: Coping with a lack of the substance

In the initial phase of the development of a drug often only very little substance is available for the first technical tests or filling tests. In this case one of the small laboratory devices (Omnidose TT) developed by Harro Hoefliger provides the possibility of already being able to perform the first dosing tests on the vacuum drum-type dosing principle using just a few hundred milligrammes of substance.

The device can be operated in an isolator to process, for example, moisture-sensitive products, but also to protect the experimenter. Experience to date with this manually operated device has shown that a powder that can be dosed with sufficiently precision in this way can later also be processed well with a high degree of certainty on automated drum-type doser integrated into complete filling lines.

Furthermore, the first galenic improvements can already be assessed on this level, for example, by directly comparing the uniformity achieved in the dosing of different formulations.

The first dosing tests with the Omnidose TT drum-type doser can be performed by the customer in Harro Hoefliger’s air-conditioned Technical Laboratory together with the specialists available there. It is of course also conceivable that the device could be used at the customer's premises for the manufacture of initial small series as samples for clinical or preclinical tests.

Flexibility for clinical studies phase II and phase III

As a rule a somewhat larger filling capacity becomes necessary with the progress of development. At the same time it is helpful, if the powder for inhalation can be dosed into extremely differing target containers in order to finally find the optimized primary packaging medium.

These could be thermoformed blisters, but also special individual containers manufactured by means of injection molding and capsules made of gelatine, cellulose derivates or other polymers. The Omnidose drum-type doser developed by Harro Hoefliger with its integrated linear conveyor system provides the possibility of positioning all the named packaging media under the dosing drum and filling them fully automatically.

It is important that in this case the actual drum dosing system already complies with the dosing modules to be used later on larger production lines, i.e. that the results gained in this way are also transferable.

As with the manual tests conducted by means of Omnidose TT the offer is also valid in this case of being able to perform test series at Harro Hoefliger’s powder laboratory using for the first tests size parts that already exist. The Harro Hoefliger specialists will be glad to make available to you their experience in the dosing of such powders for the purpose of determining the optimal process parameters.

The data gained in this way can serve the purpose on the one hand of galenic improvement of the formulations and on the other hand can later go into the development and construction of the production machine. As work can be performed in the powder laboratory under controlled climatic conditions, it is already possible at this stage to fill samples for the first orientating stability tests and also to gain time in this way.

In the project example “Powder for Inhalation” the material is filled into preformed blister segments that are fixed flat by means of a vacuum on a carrier and can then be sealed semi-automatically after filling.

Furthermore, being a pronounced manufacturer of specialized machinery Harro Hoefliger is in a position to be able to deal with the special requirements of each individual case and to implement individual solutions. The feasibility in principle of new processes can be tested with the aid of test constructions (“proof of principle”).

Test on a later production line: verum instead of “placebo effect”

From mid-2005 it will also be possible to test at Harro Hoefliger complete production lines under the climatic conditions envisaged for later, using product containing the active pharmaceutical ingredient.

For this purpose an area with several test rooms will be available with a total floor area of approx. 300 m², in which large-scale filling machines can also be set up. A flexible construction of the wall leadthroughs will enable the interlinking of these machines with downline machines, for example, for secondary packaging, which can then be set up in the adjacent assembly area.

The rooms in which powder is handled and dosed are fully air conditioned and can be adjusted by means of adsorption dryers to a relative humidity of 20 %. Regulation of the differential pressure for the environment, air filtration and air change rate are oriented towards the GMP standard for the production of solid dosage forms.

In contrast to the handling and dosing of placebo preparations that were usual up to now and which ultimately cannot simulate all the properties of the “real” product, in tests with verum and under the envisaged climatic conditions critical steps in the manufacturing process become apparent at a very early stage.

For example, the electrostatic (tribo-electrical) charging of the powder can cause great problems. However, this occurs only when relative humidity is below a specific value and will therefore possibly not be noticed in the normal assembly building.

In the present example, the dosing of powders for inhalation, a normal production thermoforming machine can now be modified by docking powder dosing stations onto the filling line for powder in blisters. The modular structure would of course also allow other dosing systems to be integrated in place of the drum-type dosing units used here.

Installation of the line at the Harro Höfliger Technical Laboratory now makes it possible for customers to perform together with the machine manufacturer’s team of specialists detailed tests to optimize the filling and manufacturing process.

The influences of important process parameters such as the dosing time, vacuum, pressure, sealing temperature or even the behavior of different qualities of film can be investigated. It is of course also possible to manufacture samples for the stability test under production conditions.

This also provides a time advantage such as the early gathering of experience in handling the machine, which can include a targeted training course for the later machine operator held by Harro Höfliger personnel.

A further module of the cooperation between pharmaceutical companies and the machine supplier is collaboration in the GMP-compliant qualification of the production lines. For Harro Höfliger this support is an important part of the project, which is based on the FMEA that is elaborated jointly with the customer, and can comprise the drafting of the complete documentation for IQ, OQ and PQ, and if required also in the customer’s document format.

Also with regard to the qualification of the machine it is certainly advantageous, if the FAT can already be performed using “genuine” product and under realistic ambient conditions. The tests gain assertive power. Many an unwanted surprise and therefore lost time can be avoided in this way.

Another advantage of early cooperation with the machine manufacturer is also shown at this stage at the latest: It pays off, if the realizability of the processes on a later production machine has already been thought of at the beginning of the first dosing tests: The dosing principle can be retained throughout, early results of the tests with the Omnidose drum-type filler are usable and the required consistency of the data is ensured.