Reliable scale-up

in granulation
How to make the successful leap from laboratory scale
to production scale
Reliable scale-up
in granulation
Granulation is one of the most important unit
operations in pharmaceutical solid dosage
manufacturing. Despite already having been in use for
many years, the choice of the correct technology can
still cause headaches in some situations.
Consequently, for many operators this means running
at less than optimum performance – and particularly
when it comes to scaling up, inaccuracies can creep in
which subsequently become noticeable in production.

However, with a sensible concept it is both possible

to reduce development time and costs, and to
manufacture a better product.

The right steps for a scale-up
Regardless of the particular process step, there is one
golden rule that applies to scaling up. The ratio by
which a plant is scaled up – whether for high shear
granulation, a single pot process, or for fluidized bed
granulation – should never exceed 1:10.
The uncertainties grow if larger increments are chosen.
Here, a scale-up is comparable to a weather forecast –
it‘s usually quite accurate for the next couple of days,
but things become increasingly inaccurate as you look
further ahead to next week, as many different factors
that can influence the weather come more and more
into play.

In terms of high shear granulators, machines

with a capacity of 0.25 to 10 liters have proved
a successful size for galenical development.
This means that, if one has opted for a
6-liter vessel, a scale-up to 60 liters
is possible for e.g. the production of
clinical samples. Production can then
start with 600 liters.

DIOSNA R&D Mixer Granulator

Pitfalls of scaling up in practice
What else needs to be considered? As a rule, two processes are regarded as being similar if there is a geometric,
kinematic, and dynamic similarity between them. When it comes to geometric similarity, it is e.g. the ratio of
the height and diameter of the vessel that counts. Kinematic similarity looks at the ratio of speeds between two
measurement points. Here, it is not the rotational speed that needs to be the same, but the circumferential speed
at the outer ends of the mixing tool (i.e. the tip speed). The dynamic similarity relates to the ratio of forces at two
measurement points.
When describing dynamic processes, it is important that dimensionless parameters like the Froude number and
the Reynolds number are considered. The Froude number has proved particularly useful for the scaling up of
high shear mixers. To achieve comparable granulation results between the individual scale-up steps, the Froude
number should always be kept constant.
However, there are many other parameters that need to be considered during development of the model. DIOSNA
has developed successful scale-up models for decades. These are tested and adapted time and time again with
research and trials. The two examples below show how a well-thought-out scale-up improves product develop-
ment and thus shortens the time-to-market.

Example 1: When are the same raw Example 2:

materials not the same?
In one example, a validated process with mixing
granulators no longer worked as intended, even
though at first glance nothing about the process had
been changed. Moisture, temperature, bulk densities,
and other parameters were still the same. However,
one of the raw materials was now being sourced from
another manufacturer.
During investigations at the DIOSNA technical center, it
was found that this raw material displayed a different
moisture absorption capacity. Based on this, as the first
step the Froude numbers were increased, and changes
were made to the granulating fluid in the laboratory –
after which the process delivered the desired product
again. It was key to the customer that these changes
were minimal, and that no new validation process was
required.
Faster time-to-market
In another example, a customer wanted to improve
the quality of his product and decided to do this by
switching from a low shear mixing process to a high
shear one.
However, this required a fast revalidation of the
process. Within the space of just one week, DIOSNA
was able to develop the necessary model with the aid
of two scale-ups. This paved the way for the results
from the preliminary tests to be translated directly
into production with the active substance, which in
turn meant that validatable results were available in
an extremely short period of time. In addition, the
customer not only benefited from the fast revalidation
process, but also saw an improvement in the quality of
his product.

Scale-up tools In addition, end-point determination is a valuable aid –

although its importance is often underestimated. This
Many R&D departments still employ an empirical defines both the mean value and the distribution of a
approach to scale-ups. One typical test is to see target particle size.
whether the product can be easily compacted in the
hand and whether more liquid needs to be added.
However, results of this type are highly personal and
therefore cannot be validated.
DIOSNA not only has decades of experience
in the production of granulating systems, but also
with scale-ups and the associated validation of
processes. Here, among other things DIOSNA
offers PAT software packages with advanced
analytical tools for statistical data. This data
can also be used for batch reports, data
backup, or for remote assistance.

DIOSNA Granulation Line

in production scale
Conclusions and outlook
In product development, validated results from the
galenical scale need to be translated to production
scale. For this reason, methods that are particularly
suitable for scale-up include flexible modular plants
with interchangeable containers that can replicate a
range of different process steps such as mixing, drying
and coating.
The ability to switch modules without the need for
tools, availability of robust touchscreens, options for
containment or connection of an automatic loading or
emptying system, air conditioning, or operation with
solvent all make it easier to make the transition from
laboratory scale to pilot scale or production scale.
Meticulous logging of the processes and parameters
is also just as important. Software packages that are
compliant with 21 CFR 11 and offer historical data
memory functions featuring audit trails and batch
reporting are a great help here.
The team at the DIOSNA ProcessLab will assist you
in these processes not only with the corresponding
equipment and systems, but also with training courses
designed to ensure that your scale-up is reliable and
a complete success. Our experience has shown that a
well-thought-out development process not only makes
for a better product, but also helps to improve
understanding of the process overall, which in turn
helps to save costs in production and time to market.

Explore the DIOSNA ProcessLab

About DIOSNA
Quality made in Germany
DIOSNA is the partner for processing and the production of solids for the pharmaceutical, food and cosmetic
industries. The product portfolio includes mixers, granulators, dryers, and coating systems for R&D, pilot, and
production scale.
Countless customers worldwide have been appreciating the quality and performance of DIOSNA systems for over
135 years. Thousands of references and machines that have been working reliably for decades prove the success
of our corporate philosophy: To be a dependable and competent partner for our customers over the entire life
cycle of the machines and systems we deliver - in product development, process optimization, project manage-
ment and after sales service.

Contact:
DIOSNA Dierks & Söhne GmbH
Am Tie 23, 49086 Osnabrück, Germany
+49 541 33104-0, sales@diosna.de, www.diosna.com

Author: Andreas Znidar, Area Sales Manager, Diosna Dierks & Söhne
About the author:
Andreas Znidar works as Area Sales Manager for Diosna Dierks & Söhne GmbH, Germany. He holds a degree in Process Engineering and in Business Admi-
nistration, both acquired in Germany at the Berufsakademie Mannheim and the Fachhochschule Nürtingen respectively. Andreas joined Diosna in January
2004, and is known as a highly appreciated process expert for pharmaceutical solid dosage production.
This sponsored content was also published on prozesstechnik.industrie.de in German language on 21st April 2021