The Ideal Granule From the Lab to Production — Letting You into the Secret of Successfully Scaling-up

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DIOSNA Dierks & Söhne GmbH

ILUDEST Destillationsanlagen GmbH

Glatt Ingenieurtechnik GmbH

How can high-shear granulation be reliably and securely scaled up from the lab to production? In addition to thorough knowledge of the process, it is helpful to have modular systems that enable the process parameters to be set very accurately.

For some time now, wet granulation using high-shear granulators and its subsequent drying in fluid-bed systems have been some of the most important process steps in the production of solid dosage forms for the pharmaceutical industry. The goal of the granulation process is to obtain a mixture with the desired properties, to make it suitable for further steps such as tableting, coating, etc.

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In addition to the active ingredient, fillers, such as lactose, mannitol or cellulose, binders, such as starch, hypromellose or povidone, and disintegrants also have to be incorporated. Wet granulation can improve flow properties and compressibility, increase bioavailability and enable better homogeneity to be achieved, even with low-dose mixtures.

Granulation Process Affects Product Quality

The primary objective of granulation is to avoid segregation. A correctly configured system is not only a requirement for efficient wet-granulation, but can also help overcome any challenges posed by the active ingredient or the formulation.

Most granulation processes include some or all of the following steps:

• Mixing the raw materials and API

• Spraying the granulation liquid to spread the liquid through the mixture and thus to initiate bridging between the particles

• Granulation phase during which the bridges between the individual particles are formed. The end-point can be a predefined target particle size

• Discharge and transfer to the drying process

Which Parameters Determine the Product Quality?

Many parameters contribute to the success and quality of the final product. The most critical effects partly depend on the properties of the raw materials such as their particle size, structure, density, solubility or stability.

But the actual process also involves some variables. For example, the particle size of the granule is determined by various factors, including the granulation fluid quantity, the method by which it is sprayed (manual addition or spraying by using a spray nozzle) and the spraying rate. The average granule size depends on the specific surface area of the excipients, the moisture content and the liquid saturation of the agglomerate.

Moisture content is a crucial parameter as well, as it causes sticky products to adhere more firmly to the inner walls of the mixer. The filling rate and the speed of the mixing tool and the chopper also play a significant role. The higher the impeller speed the bigger the granules.

When is the Optimum Result Achieved?

Special attention should be paid to determining the end-point. Although there is no general definition of what the granules should look like at the end of wet-granulation, good flowability, compressibility (snowball effect) and the desired resolution profile are crucial aspects, as is homogeneity.

When determining the end-point, the entire process should be considered, including achieving repeatable results. The effects on the subsequent drying, grinding, tableting and coating processes should also be taken into account.

The formulator can define the granulation end-point as a target particle size average or distribution. Evidence shows that once the desired end-point is reached, the characteristics of the granule and those of the subsequent tablets are very similar, regardless of factors in the granulation process such as impeller or chopper speeds or the addition of binding agents.

Very often, power consumption and torque are also considered in order to determine the end-point. They enable decisions to be made on when it is the perfect time for granulation to end. This can be read directly from the user interface of the system. Another possibility is in-line particle measurement by means of a near-infrared or fibre optic spatial filter method.

However, one should be aware that even the best formulation, optimum process conditions and good equipment cannot prevent a certain bandwidth of particle sizes being produced. This is not necessarily a bad thing, since, for example, some larger granules are needed in the tablet in order to ‘bind’ the smaller particles.

The smaller particles, on the other hand, fill any gaps and are thus a requirement for good tableting, since this avoids air pockets forming in the die.

Aspects for Successfully Scaling-up

Granulation should be fast, robust, repeatable and controlled, and should also produce the best output possible. Successful scaling-up therefore requires all parameters to be taken into account. However, in practice, many pharmaceutical manufacturers still do not leverage all the possibilities because they tend not to consider the product properties and process parameters sufficiently.

As a result, unnoticed inaccuracies occur when scaling-up, the effects of which will only become apparent at a later stage, during production or in the quality control stage. Diosna has decades of experience in manufacturing granulation systems (Diosna was the first company in the world to launch a high-shear granulator) as well as in scaling-up and the associated validation of processes.

A smart scaling-up concept not only enables the development time to be shortened and costs to be reduced, but also produces a better product.

Successful Leap into Production

In general, two processes are considered to be similar if they share geometric, kinematic and dynamic similarity. For example, as regards to geometric similarity, the ratio of the height and diameter of the granulating bowl is crucial. Kinematic similarity describes the same ratio of velocities between two measurement points.

It is not the speed that is important, but the peripheral speed at the tips of the mixing tool (tip speed). As such: The faster the mixing tool, the higher the tip speed – which is typically a maximum of seven metres per second – the higher the energy input, and the larger the granules.

In order to describe dynamic processes, it is important to consider dimensionless numbers such as the Froude and Reynolds numbers. The Froude number in particular has proven to be very useful for scaling-up. It is the interplay between the centrifugal and centripetal forces and describes the compaction of the granule on the inner wall.

In order to achieve comparable granulation results between the individual scaling-up steps, the Froude number should always remain the same.

Further recommendations are that the steps between the individual system sizes should not be too large; a maximum ratio of 1:10 has produced good results. In order to be able to maintain the Froude number, small mixers should not be operated too fast. There is one thing that seems to be evident, but keeps causing problems in practice: a consistent quality of the initial substances must be guaranteed when scaling-up and during subsequent operation. Raw materials that look identical on paper may actually have very different properties if they are supplied by different manufacturers.

The aim of the scale-up is to develop a process which will successfully produce a desired product when manufactured at a commercial scale.

Flexible modular systems with interchangeable containers or bowls, which represent different process steps such as mixing, granulating or coating, are particularly suitable for scaling-up. The possibility to change modules without any tooling being required, robust touch screens, options for containment or connection of automatic filling or emptying, air conditioning or operation with solvents all facilitate the transition from the laboratory scale to a pilot or production scale.

Meticulous logging of the processes and their parameters is at least as essential. This is where 21 CFR 11-compliant software packages, with historical data storage, audit trails and batch logging, come handy. Diosna offers PAT software packages with advanced analysis tools for statistical data for this purpose. They can also be used for batch reports, data backup or remote assistance.

There is one final aspect that should be addressed: Ultimately, the success of granulation depends on the machine quality and on the operator's know-how. Diosna has decades of experience with these products and knows every single detail of their specific aspects. This forms the basis for successfully developing recipes and processes, avoiding or minimizing any unpleasant surprises during production.

* M. Benjamin is Head of Pharmaceutical Technical Centre and I. Alsaleh is Area Sales Manager at Diosna Dierks & Söhne

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