PDF file - Glatt

Times
No. 33 · January 2013
SPECIAL
Pharmaceutical
Services

Glatt Pharmaceutical Services –
advanced solutions for solid dosage forms
1. Glatt – a brand for integrated process solutions for solid
dosage forms
When it comes to fluidized bed technology, Glatt has assumed a
pioneer role and is the worldwide leader in integrated process solutions.
Glatt offers a unique expertise and product spectrum and
a comprehensive support service for pharmaceutical and related
powder-processing industries. The support service starts with the
product development for solid dosage forms and extends to the
required process technologies, optionally even covers the planning
and installation of the plant required for said technologies.
Glatt is split up into four areas of expertise:
• Process Technology Pharma
• Pharmaceutical Services
• Process Technology Food, Feed & Fine Chemicals
• Process & Plant Engineering.
Process Technology Pharma is the original and top-selling area
of expertise of the Glatt brand. It includes the core business of fluidized
bed systems for which Glatt has assumed a pioneering role
and is considered a worldwide leading supplier.
Technologies
Services
Pharmaceutical Services develops and produces solid pharmaceutical
dosage forms. The core areas here are multiparticulates
such as pellets and micropellets as well as granulates and the
dosage forms resulting from them.
Process Technology Food, Feed & Fine Chemicals develops,
plans and distributes fluidized and spouted bed systems for the
food, feed and chemical industries.
Process & Plant Engineering plans, installs and realizes projects
in plant construction worldwide. Its spectrum of expertise ranges
from the expansion or reorganization of existing production
plants to the construction of new ones – in part or as a whole.
The company, which was founded by Werner Glatt in 1954, is
made up of 14 branches and subsidiaries worldwide. In 2011, it
employed 1,400 people and achieved total revenue in the hundreds
of millions (in euros).
2. Glatt Pharmaceutical Services’ area of expertise – who we
are and where we come from
From an organizational standpoint, Pharmaceutical Services
represents the business unit within the Glatt Group which focuses
on the development and production of solid dosage forms. One
specific area of expertise is multiparticulate forms such as pellets
and micropellets and the dosage forms that result from them. We
make our experience and know-how of more than 50 years available
as a service to our customers.
Published by:
79589 Binzen, Germany
Formulations
List of contents
page
Glatt Pharmaceutical Services –
advanced solutions for solid dosage forms 2
Thoughts on modern qualification 9
CPhI Madrid 10
TTC 184: Fluid bed processing 11
TTC Program 2013 12
Phone: + 49 (0) 76 21 / 664 535
Fax: + 49 (0) 76 21 / 664 798
E-mail: bianca.nowak@glatt.com
Website: www.glatt.com
Glatt Pharmaceutical Services Europe:
A look into the Technology Center in Binzen, Germany
Glatt has always made it possible for interested customers to test
the Glatt technologies on a practical level. Product quality and
process safety are requirements that need to be proven. They can’t
just be developed and described theoretically at the drawing
table, much less promised or guaranteed. Rather, they must prove
themselves under hands-on conditions. This is why hundreds of
pharmaceutical companies from all over the world have conducted
experimental tests with their formulations at Glatt’s facilities.
During these tests, they examined whether or not Glatt’s
technologies could be successfully utilized for the realization of
their product ideas. Over the years, this has enabled Glatt to
acquire extensive know-how for optimal operation and utilization
of its process technologies. Furthermore, Glatt has gathered a
great deal of knowledge regarding pharmaceutical formulations
and technology platforms. We offer our customers this knowledge
as a service for all the different phases of a product life cycle.
2
Times · No. 33 · January 2013

Experiments require a lab. The “pilot plant” at the headquarters in
Binzen, which for several decades provided valuable services for
the continued development of the company, was slowly going out
of date in the 90s. In addition, the available equipment was no
longer considered state of the art and the spatial conditions were
not presentable to the pharmaceutical clientele any longer. So, in
1994, Glatt decided to build a new pharmaceutical technology
center in Binzen. Glatt’s plant construction department moved
into new spaces so that the buildings and areas they formerly utilized
were now always available to them. One vital question was:
“Should we tear down everything and build it all from scratch or
should we renovate parts of a historic building and integrate them
into the new complex?” The answer turned out to be the latter,
which appears to have been the right decision. After all, many visitors
today enjoy coming across a modern communication center
in a former barn: This is a place with flair and a special atmosphere,
which a modern functional building is not really able to offer.
3. What we stand for and what we offer
Glatt started out as a simple manufacturer of process plants. Over
the years, the concept “one source fits all” increasingly started to
become the focus. Today, for example, Glatt customers can’t only
purchase plants or systems; rather, they have a broad spectrum of
services at their disposal in order to develop and produce pharmaceutical
products. At the same time, our “one source fits all”
approach differs greatly from how typical pharmaceutical contract
manufacturers interpret it. These manufacturers oftentimes deal
with a very broad spectrum of pharmaceutical dosage forms and
offer commercial production of ready-to-use drugs including
packaging.
The Glatt area of expertise Pharmaceutical Services, however, interprets
the expression “one source fits all” completely differently.
We focus on a service spectrum for the area of solid dosage forms.
Formulation Portfolio and Focus on Core Competences
know-how
experience
technical capabilities
pellet +
micropellet
products
i.v., i.m.
creams
liquids
lzo's
granules
coprecipitates
adsorbates
tablets
mini
tablets
coated
tablets
matrix
tablets
ophthalmics
oral films
plasters
aerosols
Glatt Pharmaceutical Services in Binzen, Germany
Where there had previously been an “old pilot plant,” a modern
pharmaceutical technology center was now being built. In the beginning,
however, it wasn’t quite clear yet how the new spaces
would specifically be utilized later on. Some of the questions
being asked were: “Will we be conducting only technical, non-
GMP experiments?” or “Should we maybe also produce clinical trial
material under GMP and just switch from the non-GMP status to
the GMP status? Is that even possible?” In the end we decided to
permanently run our technology center under GMP conditions.
These conditions allow for, on the one hand, technical experiments
to be conducted and, on the other hand, clinical trial material,
registration batches and commercial bulk goods to be
produced.
All GMP-relevant systems and the number of employees started
pretty much at zero. In 1998, the time had finally come: The Regional
Commission Freiburg approved the new site and granted its
pharmaceutical manufacturing permit. Lastly, in 2006, the approval
from the US Food and Drug Administration (FDA) followed,
which meant a considerable expansion of opportunities for us in
the international environment. Today, we also have the permission
to process controlled substances.
This is how, over the years, a pilot plant grew into a complete business
unit: Glatt Pharmaceutical Services.
focused portfolio
focused experience
focused technical capabilities
Glatt Pharmaceutical Services: pharmaceutical dosage forms portfolio
Our core competence lies in the development, optimization and
production of bulk products for clinical trials, registration and, in
the case of selected products, for marketing. We closely combine
our pharmaceutical services with the level of competence and the
services of a worldwide leading pharmaceutical plant manufacturer.
Glatt is therefore able to offer the entire service program, from
the formulation development to the production technology and,
optionally, even the ready-for-use plant. Pharmaceutical developers
and manufacturers benefit from the know-how and the support
of the plant construction team, and vice versa. Thus, to Glatt,
“one source fits all” represents a concept of integrated process
solutions that go beyond business unit boundaries, with a seamless
support system for the customers.
It’s been a while since Glatt has been involved only in the pharmaceutical
sector. Increased demand for the refinement of products
in other industry segments opened up new markets. Customers
from the food, feed and fine chemical industries benefit from our
experience as part of the pharmaceutical industry. On the other
hand, pharmaceutical companies can revert back to technologies
that were originally developed for different applications and markets.
The synergies between our inter-divisional plant business
and pharmaceutical services offer our customers a unique competence
and service spectrum. By utilizing and offering innovative
process technologies, we are making it possible for our customers
to develop and produce cutting-edge pharmaceutical products.
Times · No. 33 · January 2013
3

We would like to enable our customers to produce excellent, innovative
and user-friendly pharmaceutical products. In order to do
so, we employ our expertise for formulation and process development.
Our primary focus lies in the challenging cases that are in
development and finding innovative approaches to deal with
them. One of our core competences is the development and production
of multiparticulates such as pellets and micropellets.
Oftentimes, these systems involve a guided and controlled release
of pharmaceutical substances or the taste masking of substances
that taste bad. From these pellets and micropellets we then produce
the desired application form such as capsules, tablets and
mini tablets, oral disintegrating tablets (ODT), sachets, stick packs
and oral liquids.
Pellet and Micropellet products
oral suspension sachets / stick pack ODT's
< 500 µm
MUPS
< 800 µm
fixed dose
combinations
Some of Glatt Pharmaceutical Services’ core competence drug products
capsule
We possess special technologies for processing drugs that are
hardly soluble in water and therefore hard to absorb into suitable
dosage forms. We also work with sustained release tablets of varying
textures and consistencies.
Even in the early development stages, we strive to achieve stable,
reproducible and economical processes. We choose the most suitable
formulation and production technology for each individual
product from the broad Glatt technology spectrum. Here we also
utilize our vast inter-divisional competence in order to find optimal
solutions for our customers.
We continuously receive tasks that are new to us as well and for
whose solution we must now find suitable technologies. Particularly
when new technologies need to be developed and used, we
benefit greatly from our colleagues in the process technology area
of expertise. In close collaboration with engineers, designers and
control systems experts we develop and realize new technical
solutions. Shorter paths and reaction times are possible because
we all work at the same site. This enables us to find quick and
comprehensive solutions for our customers. This special collaboration
is only possible through the combination of experts in pharmaceutical
pilot construction and pharmaceutical development
and production. In other words: “One source fits all.”
The Glatt technology centers in Binzen and Ramsey, New Jersey,
USA are hubs for new ideas. This is where experts from various different
disciplines and many countries of the earth come together.
Practitioners converse with researchers and developers, customers
chat with manufacturers.
Our pharmacists who work in pharmaceutical development, production,
quality control and quality assurance speak to our partners’
pharmacists. Together we develop strategies and approaches
for pharmaceutical development. We believe that speaking a common
technical language is an important element for a successful
collaboration.
4. Our customers and their projects – and how we work
Our customers not only come from various diverse parts of the
world; they also come from different companies and company
types. Yet each company should be looked at and treated as individually
as the people who work there. Whether these are international
global players or startups, originator or generic companies,
OTC or animal health companies.
Our specialized know-how can be used on a broad scale, such as
for the development of life cycle management products and pediatric
dosage forms for humans as well as for specific taste-masked
dosage forms intended for animal health.
We handle projects in the spirit of a fee-for-service concept. This
means: We make available to our customers as a service our knowhow,
our technologies and our technical possibilities and are compensated
for doing so. The rights to the product that results from
this and to the technology platforms are regulated individually as
part of development contracts.
We handle projects based on a flexible approach which involves
making project plans available to our customers. The scope of
work suggested by us and the resulting costs then emerge from
these plans. We discuss the plans and milestones and together
decide on the scope, the approach and timelines. The individual
milestone packages can be accessed and ordered separately,
which allows our partners to be very flexible. If necessary, you can
continue or end your project at a sensible point in time.
Glatt Pharmaceutical Services Service portfolio
Preclinical Development
Development
of API
Preclinical
studies
formulation development
process development
Phase I
CTM supply phase I and II
formulation + process optimisation
Clinical Development
scale-up to pilot scale
CTM supply phase III
registration batches
scale up to commercial + validation
launch / commercial supplies
analytical characterisation / compatibility studies / stability studies
Classical milestones of a pharmaceutical development
Phase II Phase III Registration Market
Launch
Our project plans and cost structures are transparent, which is
very important to us and helps maintain a trusting collaboration
in the spirit of partnership. This way, we are able to demonstrate at
any given time which part of the agreed-upon work we have completed
and which part of the developmental budget we have
already exhausted. We work in a goal and result-oriented manner
and find it to be insufficient and not very goal-oriented to simply
“work off” a work package that was outlined once, which is why
we point out to our partners when we believe goal adjustments
are sensible and necessary. We then implement these adjustments
together.
Close to 60 people are employed at the German headquarters for
Glatt Pharmaceutical Services in Binzen. Our slender organizational
structure and the close spatial proximity of everyone involved
create many advantages: They allow for us to work together closely,
to communicate on a personal level with each other and to
4 Times · No. 33 · January 2013

make speedy decisions. We are convinced that the way in which
we work on projects can optimize our customers’ “time to market.”
We are also convinced that an effective speed during the project
development stage has to be based on a distinct quality standard.
For us specifically this means: Speed through quality.
We enjoy working with our partners on a long-term basis. Nevertheless,
from the start of the project, our customers are free to
choose their partners. Selected bulk products are produced in our
pharmaceutical production, either on a permanent basis or until
our partner invests in his or her own production technology.
During this process, we lend a hand in the product transfer to
other production facilities and help with the implementation and
validation of the processes.
5. Our technology platforms and know-how
We systematically apply our expertise and resources in selected
formulation areas. Our field of activity covers solid dosage forms.
Generally our customers approach us with demanding development
cases.
Intelligent and high-quality medicines require a corresponding
process technology. Here, Glatt offers an ideal solution: On the
one hand, process technologies can be delivered as plants and
systems or, on the other hand, Pharmaceutical Services offers
those services that enable an optimal utilization of the technologies
for the customers. We know the process plants, systems and
technology platforms we developed and built better than anyone
else. Our profound understanding of technology allows us to utilize
the plants and processes in an optimal way for our customers.
Due to the fact that we are constantly further developing our
technologies, we are also broadening the application spectrum
and options for new pharmaceutical products.
Product characteristic diagram
500 µm
CPS
matrix
pellets
Batch
process
Micropellets
possible
MicroPx
matrix
pellets
Continuous
process
Micropellets
possible
Wurster
Process drug
layered pellets
Batch
process
Micropellets
possible
Glatt Technologies for different multiparticulate products
Later on, people started using fluidized bed technology for applying
drug substances and coating films starter particles. Today, the
bottom spray or Wurster technology represents a worldwide
established and leading process for the production of multiparticulates.
The powder-layering technology allows for the coating of
particles with powders. Furthermore, fluidized bed processes were
developed that enable the production of pellets and micropellets
without the use of starter pellets. Here, one can choose from batch
and continuous processes. On the one hand, this enables the production
of a variety of product qualities, but also the use of an
optimal technology while taking into consideration economic
factors.
The development and production of pellets and, in particular, of
micropellets with a size of 100 to 500 micrometers, requires a very
specific technical know-how and a particular technology.
Varying drug release kinetics can be achieved by using specific
formulation approaches. A variety of options is realizable with pellets
and micropellets, including the quick release of the agent to
the delayed, modified or pulsatile release, from the enteric resistant
to the taste-masking form.
Immediate, sustained, zero order release
Extruded
matrix
pellets
Batch
process
Procell
pellets
Continuous
process
—— Micropellets
possible
Glatt MicroPx Technology
Many years ago, fluidized bed
technology made a splash in the
pharmaceutical industry and became
known as an innovative
drying technology. Over time it
turned into a fluidized bed granulation
process, which, for
example, enables the production
of particularly porous granulate
structures. These types of granulate
qualities are particularly suitable
for substances that are very
difficult to dissolve in water. The
porous structures, which are
achieved by the fluidized bed
granulation process, make it
easier for the physiological liquids
to penetrate the tablets
and granulates and to quickly
dissolve them.
Drug release
Delayed, pulsatile release
Drug release
Time
Time
Drug release profiles achievable with Glatt formulation and process technologies
Modified release dosage forms allow the patient a more comfortable
intake of a medication as it has to be taken less frequently, no
more than once or twice daily. Even the number of side effects
that may occur due to plasma peaks of the active, can be reduced
through optimized drug releases and plasma levels.
Times · No. 33 · January 2013
5

When high-dose pharmaceutical medicines are to be processed
into micropellets with the greatest possible active substance ratio,
it can be quite difficult to find a suitable process. Traditional pelletization
processes such as extrusion, for example, are not suitable
for these kinds of small particles.
Selected Glatt technologies for multiparticulates processing (from left to right):
Glatt Wurster (bottom spray) Technology, Glatt CPS Technology, Glatt MicroPx
Technology
The classic Wurster fluidized bed technology can be applied when
low-dose medicines are to be formulated into pellets or micropellets.
Technical refining, particularly on the spray systems, enables
substance layers and functional coatings to be applied even to
very small starter pellets without the individual particles agglomerating
among one another. Starter pellets with a size of approximately
100 micrometers can be optimally processed this way. A
process effectively achieving a high level of product quality in a
reproducible manner requires great understanding of process
technology and the composition of the pellets and micropellets.
Taste masked antibiotic micropellets for a pedriatic drug product – manufactured
with Glatt MicroPx and Wurster fluidized bed technology
Glatt is able to offer a unique fluidized bed process that is particularly
suitable for the production of highly loaded micropellets with
a size of 100 to 500 micrometers: The Glatt MicroPx Technology.
Due to their composition, shape and stability, micropellets that
are produced this way are particularly suitable to be coated with
functional coatings. The technology works particularly well when
producing taste masked micropellets for use in pediatrics and animal
health.
Drug load of MicroPx and Wurster Pellets
Scale up with Glatt Wurster Technology: from a few grams up to some hundred
kilograms
MicroPx continuous
fluid bed pelletization
MicroPx batch-wise
fluid bed pelletization
Particularly in the context of an increase in scale starting at a small
scale of just a few hundred grams to large-scale production of several
hundred kilograms, it is important that all process parameters
and their interplay are analyzed and understood in a timely
manner. We thoroughly inspect and optimize the formulations
and processes to ensure that the corresponding large-scale processes
work safely and in a reproducible manner. To do so, we use
modern, computer-assisted tools for “design-of-experiments studies”
(DoE). Planned quality, or “Quality by Design” (QbD), plays an
important role today and is being increasingly called for by regulatory
authorities.
Max. spray rate (g/min)
17
16
15
14
13
12
11
17
16
15
14
13
12
11
95 - 97 % drug load 89.1 % drug load
Manufacture of high drug loaded pellets: A comparison of the production strategy
of MicroPx continuous technology with Wurster batch process
The active ingredient core, which contains the pharmaceutical
drug, can be coated with functional coatings that are capable of
achieving a variety of effects. The effects range from taste masking
to enteric resistance or from the extended release form to pulsatile
drug release. An endless number of options can be realized.
However, in order to achieve a high-quality end product, some
preparation work is necessary. Pharmaceutical additives that bring
about the mentioned effects must be optimally harmonized with
a suitable production process.
10
2.5 3.0 3.5
Atomisation Air pressure (bar)
Weight gain (%)
4.0
10
2.5 3.0 3.5
Atomisation Air pressure (bar)
Assay (%)
4.0
Find best processing conditions with process optimization using DoE
Controlled release pellets compressed to MUPS tablets
6 Times · No. 33 · January 2013

We support our customers with more than just the development,
the scale-up and the production of new products. We also help
out when medicines that have already been introduced start causing
problems during regular production. Occasionally, problems
show up very unexpectedly, such as when the quality of the active
ingredient or of additives has changed. Sometimes compositions
and processes are not developed robustly. Minor changes during
the production process or with the ingredients can then be
enough for a potentially shaky system to collapse. A delay in delivery
or, even worse, an off-stock scenario, can be a big problem for
a pharmaceutical company. Glatt Pharmaceutical Services puts
forth its knowledge and experience to help solve these kinds of
problems. To do so, we advise our partners on-site where the problem
occurred. We are able to optimize processes in our research
labs and can then transfer them back over into the production.
Due to the fact that we have a quality control system at our disposal
that is equipped with the most relevant pharmaceutical analytical
techniques, we are able to act quickly and independently.
WURSTER Fluidized Bed Capabilities for Micropellets and Pellets processing
Fluidized bed unit
Mini GPCG 2
GPCG 3
GPCG 5 GPCG 30
GPCG 60
GPCG 120
GPCG 300
Wurster type
Micro
4''
6''
7''
Batch size range (kg)
9''
12''
18''
24''
32''
46''
0.005 - 0,5
0,05 - 0,5
0,5 - 2
1 - 5
2 - 15
5 - 35
15 - 100
30 - 200
60 - 400
120 - 800
micro
scale
laboratory
scale
pilot
scale
commercial
scale
organic solvent based processes
water based processes
HS (high speed) nozzles
Glatt Wurster equipment capabilities at Glatt Pharmaceutical Services Europe
Glatt Pharmaceutical Services Binzen: Quality Control laboratory
In the end, our goal is to achieve reproducible processes and product
qualities at an economic price. This goal can only be reached
if the responsible employees possess the necessary expertise. For
this reason, Glatt offers training programs to train employees with
various different functions for their job.
6. Our technical capabilities
As mentioned previously, the Pharmaceutical Services area of
expertise focuses on solid dosage forms with a core focus on multiparticulates
such as pellets and micropellets. The intermediate
products can subsequently be processed into a variety of pharmaceutical
products such as capsules, tablets and mini tablets, oral
disintegrating tablets (ODT), oral liquids, stick packs and sachets.
For our main fields of activity we offer a plant spectrum ranging
from small to production scale. For example, the Wurster fluidized
bed technology is intended for quantities of five grams up to 800
kilograms under GMP conditions. Similarly, we are equipped for
other pelletization and granulation processes. Our technical
equipment covers a vast scale range and allows us to test the
respective formulations in varying quantities in a hands-on manner
and to lay the groundwork for safe and economic industrial
processes.
Processes with organic solvents are being used more frequently
today in comparison with the last few years and decades. The stability
of functional films that are produced from aqueous dispersions
is usually problematic. For example, the kinetics of the drug
release from film-coated pellets and micropellets can change the
longer the storage time is. On the other hand, films that are produced
from a solution with organic solvents are usually considered
to be less problematic. Glatt offers a broad palette of
processes and plants in varying sizes which allow for safe processing
of organic solvents. These processes and plants are equipped
in such a way that the emission of solvents into the environment
can be kept at a minimum. We therefore also make a direct comparison
of processes that are ”water-based” or “organic solvents
based”. We are interested in robust but also economically viable
processes.
Our customers therefore have a variety of interesting options to
choose from. We are able to develop formulations and processes
on a small scale and then scale them up to the desired scope. Particularly
if the progress of a development project isn’t yet foreseeable,
this method does not require investing in plant technology.
Rather, the tests can be carried out promptly by the experienced
experts of the Pharmaceutical Services area of expertise. The quality
of the formulations and processes is typically evident early on.
Weaknesses can be discovered and rectified early enough and
costly optimization work on a large scale is not necessary. There
are no misguided developments or investments if well-grounded
experimental tests on the desired scale have already been carried
out successfully – before formulations are determined and investment
decisions are made. An investment in a small-scale, wellfounded
development pays off. After all, one or two failed
commercial batches that contain expensive active ingredients cost
more than a well-thought out development of the pharmaceutical
formulation and the process. Time delays that can occur during
the market launch of a new product, for example, are generally
even more expensive.
Times · No. 33 · January 2013
7

Pharmaceutical pellets allowing a controlled release of the drug substance
Glatt offers a unique spectrum of process technologies and corresponding
plants and is therefore able to effectively support its
pharmaceutical customers. The Glatt Pharmaceutical Services sites
in Germany and the US are certified by the local and international
authorities. Clinical trial material as well as registration batches
and commercial bulk products are produced there. Time savings
are an important factor. Clinical trial material can be produced
quickly with a production technology that has been found to be
optimal and is chosen from a broad technology spectrum. Customers
can choose from manufacturing technologies that have already
been introduced but also from innovative and not yet
widely established ones. Investments in one’s own production
technology can be made when the time is right, more specifically,
when a project has made it through the crucial hurdles and when
a process technology has already been intensively tested, used
and optimized in a hands-on environment.
7. Why are we the right partner for
the pharmaceutical industry?
For years now, the number of innovative “new chemical entities”
(NCE) has been declining. Potent medicinal products are available
for many of the important indications. Once the patent protection
has expired, generics companies compete with originators for the
market. Within this context, the importance of life cycle management
for established active ingredients continues to grow. For
example, well-known and previously marketed ingredients are formulated
into new dosage forms. The goal is to make it easier for
patients to use the medicines, to reduce side effects or to make
available special forms for certain age groups such as children or
seniors. The animal health situation is similar to that of the human
pharmaceutical situation.
The medications that are to be developed with life cycle management
in mind are generally more challenging technologically than
a standard tablet with an immediate drug release. Accordingly, the
development of complex formulations and the availability of suitable
process technologies are becoming increasingly important.
But innovative dosage forms can only be developed and produced
if cutting-edge formulation techniques and manufacturing
processes are available.
Many pharmaceutical companies are interested in protected technologies
and technology platforms as they allow them to receive
proprietary rights for their new products and to protect themselves
from their competition.
Glatt has always responded to market changes and trends and
consistently worked on new, innovative processes, not least because
of the close collaboration with many different partners. As
previously mentioned, what was at first a rather simple fluidized
bed technology, used for drying wet goods, has turned into a fundamental
technology, and numerous different and unique specialized
technologies have emerged from it.
The experience and skills from the
various industrial areas continue to
create interesting synergy effects
and make it possible for technologies
to be used in the pharmaceutical
area that were originally
intended for other applications. For
example, the MicroPx technology
was the result of a process that was
originally used for industrial fluidized
bed spray agglomeration of organic
acids from biosynthesis. It wasn’t until a process for the
production of micropellets was needed that a new use for an already
established technology came about. Similarly, the CPS pelletization
technology made its debut in pharmaceutical process
technology in a roundabout way. Initially it was used for the production
of spherical seed pellets that came from misshapen plant
seeds. Today, CPS technology represents an interesting direct pelletization
process for matrix pellets and micropellets. In addition,
we are already testing new applications for which the CPS technology
can be used to realize new effects and qualities in dosage
forms. We enable our customers to utilize our new technologies
during the early development phases. This way they are able to
test if promising new products can be developed with new technologies.
Glatt Pharmaceutical Services employs experts with specific technology
platforms who develop selective dosage forms and technologies.
We focus on a clearly-defined scope of action and, within
this scope, we present our customers with optimal results for their
requirements.
The multitude of available processes makes a diverse range of products
presentable. When we develop new process variations, we
always envision a specific product. Engineers and pharmacists develop
new processes together and bring their individual views
and opinions to the table.
The close collaboration of such diverse areas and specializations in
the course of a pharmaceutical development process is the basis
of our standard “one source fits all.”
Development work with lab scale fluidized bed unit
Norbert Pöllinger, PhD
Head of Technology Center Binzen
Glatt Pharmaceutical Services Europe
8 Times · No. 33 · January 2013

Thoughts on modern qualification
The qualification of GMP-relevant systems moves around in a
stress field between many people with varying functions and
goals. In order to safely cross this stress field, it is primarily and
fundamentally important that all participants have a clear, precise
idea of their expectations. This, of course, starts with the acquisition
of the respective system and the considerations associated
with it: What kind of operations will we be using this system for?
And for what purpose? Which services associated with the establishment
of the system (qualification, maintenance, calibrations)
would we like to purchase (so that we – for whatever reason –
don’t have to take care of them ourselves…)?
What the eventual user expects from his equipment needs to be
defined in writing prior to the acquisition. Naturally, the scope and
level of detail of the user requirement specifications on the one
hand and the complexity of the system to be procured on the
other hand should be in proper relation to each other. But the
more thoroughly and conscientiously the user defines his demands
in terms of performance, execution and documentation
and therefore describes his expectations, the more well-founded
is the basis for all steps that are to follow. This not only helps the
recipient of a newly-acquired system, but also the supplier. When
the user sees that his requirements have been implemented, for
example, in the functional specification of the equipment supplier
for an “off-the-rack device,” this can be easily documented in a way
that will withstand any GMP audit. On the other hand, the logical
business-minded brain demands: The bigger the investment, the
more important a precise and detailed preparation.
Probability
low high
low
Impact
high
more time can be saved during troubleshooting later on and, if
necessary, during required repairs.
The modern qualification process is, of course, not completely separate
from parallel GMP-relevant processes such as process validation,
cleaning validation and most certainly not the
computerized systems validation. Risk analysis forms the basis of
all these. Risk analysis requires that an interdisciplinary team made
up of users, engineers, technicians, equipment suppliers, quality
control, quality assurance and occupational health and safety specialist
gives answers to the central questions: “Does this component,
this function, this process step etc. influence the product
quality, the patient safety, the integrity of GMP relevant data? If
yes, how do we control and document this? If no, how do we
explain this in a comprehensible way?” Admitted: It takes a certain
degree of discipline, consistency and methodological skills in
order to create a detailed risk analysis based on, for example, the
FMECA method (failure mode, effects and criticality analysis). But
it is considerably easier to achieve if one looks at it as a real opportunity
to deepen one’s knowledge and not simply as a tedious
necessity based on regulatory specifications.
A modern qualification does not reinvent the wheel with each
project. Knowledge and experience of each individual user influence
the definition of user requirements, the assessment of potential
risks and the configuration of qualifying tests. The same goes
for statistics and operating figures that were gained from comparable
processes. All this serves the main objective of an efficient,
cost-effective and on-schedule qualification. Even during the design
stage and implementation of the IQ and OQ tests, individual
steps can help work towards this main objective. For example, instead
of an extensive factory acceptance test (FAT), several short
FATs can be carried out for individually completed modules
depending on the progress of the plant construction. The test
reports received as a result can be directly taken into consideration
during the qualification if they meet the requirements of the
Good Documentation Practice (GDP). This way, the user can avoid
repeats during the IQ/OQ of the plant at the eventual site. Precisely
this aspect creates great opportunities for a company such as
Glatt GmbH, where the competence of the plant construction as
the supplier and the target group competence of the pharmaceutical
industry as the buyer are united under one roof if both business
units consistently collaborate with each other closely in
terms of wishes, ideas, expectations and options.
Matrix for risk classification
A modern qualification has to, and is allowed to, cost money, and
that’s a good thing. After all, “Was nichts kostet, ist nichts wert
[What doesn’t cost anything, isn’t worth anything].” (Albert Einstein)
Without a doubt, a successfully carried-out qualification increases
the value of a plant: It increases the dependability of the
working system and, in doing so, the utilizability and therefore the
productivity. It is the investment in the qualification of a plant –
assuming said qualification has been successfully completed –
that allows for it to be used in pharmaceutical production. Qualification
requires the user and the person in charge of the plant to
take a closer look at its characteristics and familiarize themselves
with those characteristics in a detailed way and, as a best-case
scenario, they will be able to truly identify with the plant. In other
words, the stronger the personal commitment as part of the qualification
process is, the greater is the process know-how and the
Verification of P&I diagram
Times · No. 33 · January 2013
9

To sum up: Modern qualification of a GMP-relevant plant puts the
primary focus neither on a lot of paper or writing itself nor on a
quick wrap-up as the most important criteria. First and foremost, a
modern qualification, based on the current GMP regulations and
state of the art, focuses on the work, tests and significant documents
that are truly needed in order to prove that an equipment
will perform and deliver precisely what is expected of it within a
defined framework – not more, but also not less. Risk analysis
helps, as a central instrument, to discuss, determine and document
the required scope of a qualification in a specific and comprehensible
manner.
Dr. Godehard Krämer
Head of Quality Assurance
Glatt Pharmaceutical Services Europe
Performance qualification tests on GPCG 2 lab system
Sources:
1. EudraLex Volume 4: Good Manufacturing Practice (GMP) Guidelines: Part I
“Basic Requirements for Medicinal Products”; Annex 11 “Computerized Systems”,
Annex 15 “Qualification and Validation”
2. ICH Q9: “Quality Risk Management” (EMA/INS/GMP/79766/2011)
3. Wolfgang Rudloff: “Moderne, kostenoptimierte Qualifizierung” [Modern,
cost-effective qualification], Vortrag beim Concept Heidelberg Seminar, 28.
März 2012, Mannheim [presentation at the Concept Heidelberg Seminar,
March 28, 2012 in Mannheim]
CPhI Madrid
Glatt attended this year’s show taking
place in Madrid from October 7 to 11.
Thanks to the Excellence United collaboration
we had the opportunity to share the
booth with Harro Höfliger. For the first
time we exhibited in the P-MEC section of
the trade show. The combination showed
to be good as several times the customers
were able to discuss the different topics
with both companies in one go.
The P-MEC exhibition is dedicated to
machinery and usually directly next to the
outsourcing exhibiton ICSE. These two coexhibitions
of CPhI are steadily growing
and are more focused than the very large
and strongly mixed CPhI, where orientation
and selection is getting more and
more difficult. Located within the
P-MEC/ICSE section, Glatt benefitted from
the total amount of visitors of the CPhI
show. At the Frankfurt event in 2011, this
number summed up to almost 30 000
guests. Given the P-MEC section’s focus
on pharmaceutical equipment and
pharma outsourcing, visitiors to the
Glatt booth showed high involvement and
interest.
Although being in the equipment section
of the exhibition and having a GPCG 2
shown during the fair the focus was put on
the activities of Glatt Pharmaceutical Services.
The group’s area of expertise for the
formulation development and manufacturing
services of solid dosage forms,
showed its expertise in pellets and micropellets.
Based on the current need to find
solutions for pediatric medicine, life cycle
management and line extensions the technologies
for the production of micropellets,
especially MicroPx and CPS arouse
special interest. With these innovative
technologies drug loaded spherical micropellets
below 500 micrometers can be
achieved and used as a good basis for the
application of the desired coating. Be it for
taste masking or controlled release dissolution
profiles. In addition, the coated particles
are still small enough to show a good
mouth feeling for final dosage forms such
as ODT (orally dispersible tablets), dispersible
tablets, stick pack or suspensions.
Overall CPhI is a good opportunity to meet
new and existing customers, present services
and technologies and initiate new
projects. It is the meeting spot of the pharmaceutical
industry and therefore a condensed
opportunity to meet our partners.
Philippe Tschopp
Head of Business Development
Glatt Pharmaceutical Services Europe
10 Times · No. 33 · January 2013

Workshop no. 184
Background
With growing international competition, many
companies have to re-engineer their business
to reach the target of improving yield,
efficiency, market share and (if possible)
profit.
Fluid bed
processing
On the other hand, universities and high
schools are not equipped sufficiently to
provide sound practical education.
Our aim is to fill the existing gap, having
decades of experiences in building and
using production equipment.
What makes us different from other institutions
offering specialized training:
THE UNIQUE HANDS-ON APPROACH
Speakers
Jochen Berger
Ecolab (Schweiz) GmbH, Switzerland
Dr. Jörg Brunemann
HARKE Pharma GmbH, Germany
Dr. Guido Büch
Glatt GmbH, Germany
Dr. Mike Cliff
Consultant Engineering Technologist, UK
Stefan Dietrich
Parsum GmbH, Germany
Dr. Michael Jacob
Glatt Ingenieurtechnik GmbH, Germany
Dr. Caroline Kablitz
Novartis Animal Health, Switzerland
Dr. Atul Mehta
Mehta Consulting LLC, USA
Dr. Tibor Nagy
Gedeon Richter Ltd., Hungary
Dr. Maxim Puchkov
Cincap GmbH, Switzerland
Petra Risse
Glatt GmbH, Germany
Prof. Dr. Agba Salman
University of Sheffield, UK
Lilia Sprich
Glatt GmbH, Germany
Topics
• Principles of fluid bed processing
• Interactions of process parameters with respect to thermodynamic
principles
• Principles of fluid bed drying
• Continuous fluid bed processing
• Online particle size monitoring
• Introduction to particle coating and layering
• Fluid bed spray systems
• Process parameters analysis and process understanding – some industrial
examples
• Excipients for fluid bed processing
• Material handling in the powder processing industries
• Scale up considerations for fluid bed particle coating
• Dry powder coating – process optimization and film formation mechanism
• GMP-conform cleaning
• WIP/CIP for fluid beds
19 - 21 March 2013
To register www.ttc-binzen.de
Times · No. 33 · January 2013
11

Technology Workshops
in 2013
Workshop No. 183
Explosionsschutz
in der
Feststofffertigung
GERMAN LANGUAGE
Tue/Wed 5 - 6 February 2013
Workshop No. 188
Wirbelschicht:
Wartung
& Troubleshooting
GERMAN LANGUAGE
Tue/Wed/Thu 2 - 4 July 2013
Workshop No. 184
Fluid Bed
Processing
Tue/Wed/Thu 19 - 21 March 2013
Workshop No. 185
Granulation
& Tabletting
Tue/Wed/Thu 16 - 18 April 2013
Workshop No. 186
Design and Implementation
of Continuous
Pharmaceutical
Manufacturing Processes
Tue/Wed/Thu 4 - 6 June 2013
Workshop No. 187
Fluid bed:
Maintenance
& Troubleshooting
Tue/Wed/Thu 25 - 27 June 2013
TTC (Technology Training Center)
Regina Bernstein / Ansgar Meermann / Bianca Nowak
Werner-Glatt-Strasse 1, 79589 Binzen, Germany
Phone: + 49 (0) 7621 664 - 308
Fax: + 49 (0) 7621 664 - 798
E-mail: ttc@ttc-binzen.de
Workshop No. 189
Continuous
Particle
Processing
Tue/Wed/Thu 24 - 26 September 2013 · Weimar
Workshop No. 190
Pan Coating
Tue/Wed/Thu 15 - 17 October 2013
Workshop No. 191
Verfahrensoptionen
der Wirbelschicht
GERMAN LANGUAGE
Tue/Wed/Thu 5 -7 November 2013
Workshop No. 192
Matrix and layered
pellet dosage forms
Tue/Wed/Thu 26 -28 November 2013
www.ttc-binzen.de
12 Times · No. 33 · January 2013