technology for new drug deliver y systems

7/30/2019 Technology for New Drug Deliver y Systems

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a report by

Ha r ro H f l i g e r Ve rpa c kung sma s c h i n en GmbH

The majority of pharmaceutical products have to

enter the bloodstream 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 therapeuticsystems (TTS), whereby the active pharmaceutical

ingredient is absorbed by the skin, 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 micronised

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 bloodstream.

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.

Harro Hfliger Verpackungsmaschinen GmbH hasmade a name for itself in 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 Hfliger, 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 micronised powder, it is possible to demonstratehow the obstacles arising during the development of

a new procedure can be overcome successfully.

The ability to process micronised 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 forbringing powder filling machines onto the market

successfully today.

In addition, the variety of differing methods of 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

sixfold from 1976 to 1999 alone in the US. 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.

Apart from this, the argumentation no first-pass

metabolism and the suppression of the pulsed

absorption profile speak out in favour of the

Techno logy for New Drug De l i ve ry Systems

Figure 1: Powder Properties

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pulmonary or nasal intake of active pharmaceutical

ingredients.

If one takes a closer look at the development of the

dry powder inhalers (DPIs), it can be determined

that, due to the place where the powder becomes

effective, the size of the particles is 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 and their size and

roughness thus largely determines 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 of 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 aligned optimally 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 Harro Hfliger Verpackungsmaschinen GmbH,

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; and

powder density.

Figure 2: Development Process

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Co r e Competen c e C l a s s i f y i n g and

Pro c e s s i n g D i f f e r en t T ype s o f

I n h a l a t i o n Powde r

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 Figure 2) is of

decisive advantage, as opposed to ordering amachine to be developed immediately. 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 of45 can be

reached for one device. The device contains 30

single doses, each having a filling quantity of 13mg,i.e. 390mg:

45 @ 30 doses = 1.50 per dose.

A nominal output per machine of 2,700 inhalers per

hour is equivalent to a turnover of121,500/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 (including temperature and humidity) and

the properties of the powder (including the degree ofcompaction) that have to be kept constant.

Although it sounds simple, in theory, to produce

constant conditions, problems often occur here in

practice.

These problems can be, for example:

tolerance in the powder production process;

variations in the room humidity;

uneven distribution of the powder density; and

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

Figure 3: Dosing Procedure

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tolerances, which, however, does not automatically

mean that the powder density can change during the

subsequent filling procedure. 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 considerably.

To ensure the appropriate dosing procedure, Harro

Hfliger Verpackungsmaschinen GmbH not onlyanalyses 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 filling quantity is

determined by the dosing volume of the dosing tool.

Flow behaviour, especially in the case of inhalant

powder, is largely influenced by the adhesion forcebetween the powder particles (van der Waals forces).

Once the adhesion forces have been determined

qualitatively, the dosing system can be selected.

Figure 4: Dosing Systems

Figure 6: Powder Filling of Chamber and Compaction for a DefinedPowder Density

Figure 5: Infeed and Device Core Orientation for the Disassembly

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Here, too, Hfliger 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.

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,

Harro Hfliger Verpackungsmaschinen GmbH 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 carried

out 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.

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technology for new drug deliver y systems

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