Liquid pharmaceutical and biotechnology experts engineering for a better world
Liquid pharmaceutical and biotechnology experts
engineering for a better world
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GEA is a leading international supplier of integrated process
systems for the production of liquid products for the
pharmaceutical and biotechnological industries. That extensive
portfolio of products, technologies and services includes
complete plant and components for the manufacture of
• insulin
• monoclonal antibodies
• blood-derived products
• vaccines
This includes systems and plant for the production,
preparation and storage of media and clean utilities, fluid
management, fermentation, cell cultivation and purification.
As a competent manufacturer of complete process lines for the
life science industries, GEA is a full-service provider of
solutions that meet your exact requirements and
specifications.
From planning, development and installation to qualification
and maintenance, our experienced engineers will collaborate
with your project team to supply innovative and efficient
process solutions for your applications.
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Drug production and the manufacture of active pharmaceutical ingredients (APIs)
demands the very highest product quality and purity standards, as well as
validated manufacturing processes. As a supplier of sterile process plant with
many years of experience, GEA can draw upon the comprehensive theoretical
knowledge and expertise of its engineers to provide modern, bespoke and cost-
effective process technology to manufacture new medicines according to cGMP
guidelines and US FDA, SFDA and EMA requirements.
The process lines provided by GEA have a proventrack record in API production, includingfermentation, clarification, separation,homogenization, crystallization, concentration,lyophilization and fractionation. Our standalonemachines or package units guarantee a high yieldof valuable substances and operate trouble-free,efficiently, reliably and economically throughout along service life.
Based on established standards, our project teamswill devise project documentation that’s specificto your individual requirements and competentlydeliver the project on time, on budget and to theagreed level of quality.
Offering a comprehensive range of services andproject management, we guarantee successfuloutcomes and a tailor-made solution for yourapplication.
Liquid pharmaceutical and biotechnology experts
Why GEA?
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Industrial Fermentation
Media preparation includes formulating, mixing,
sterilising and storing the fermentation medium.
The fermentation medium comprises the
compounds and micronutrients required for the
growth of the micro-organism (along with water and
oxygen, if necessary). Any medium for large-scale
fermentation applications should maximise the
growth of the micro-organism, enhance the
production and rate of formation of the desired end-
product and minimise the formation of undesired
byproducts.
Sterilisation is essential to prevent contamination:
air is sterilised by membrane filtration whereas the
medium is usually heat sterilised. Any nutrient
component that is heat labile is filter sterilised and
then added to the prepared medium. The fermenter
may be sterilised together with the medium or
separately.
Inoculum build up is the preparation of the seed
culture in amounts sufficient to be used in the large
fermenter vessel. This involves growing the pure
stock culture in several consecutive fermenters,
thereby reducing the time required for the growth of
micro-organisms in the large fermenter and
increasing productivity.
The fermentation process involves the propagation of the
micro-organism and the production of the desired product, and
can be categorised depending on various parameters: aerobic,
done in the presence of oxygen; or anaerobic, done in the
absence of oxygen.
The fermentation process can also be divided into three basic
principles, namely batch, fed-batch or continuous, depending on
the feeding strategy of the culture and the medium into the
fermenter. Each of these processes has its own advantages and
disadvantages. In a batch operation, the medium and the
culture are initially fed into the vessel. After that, no
components are added apart from oxygen (in an aerobic
process) and acid or alkali for pH adjustment. The fermentation
is allowed to run for a predetermined period of time and the
product is harvested at the end.
In a fed-batch system, additional nutrients are added while the
fermentation is in progress. This extends the time of operation
and the productivity/product concentration of the process. The
required products are harvested at the end of the production
cycle, as per batch fermentation.
In a continuous process, fresh medium is continuously added
and the product — along with the culture — is removed at the
same rate, ensuring that constant concentrations of nutrients
and cells are maintained throughout the process. Harvesting
can be done by filtration, thereby increasing the overall cell
density and productivity (perfusion culture).
Downstream processing includes the recovery, purification and
concentration of the product in a pure state. Product recovery is
done in a series of operations, including cell separation by
settling, centrifugation or filtration, product recovery by cell
disruption (for intracellular products) and extraction.
Finally, the effluents are treated by chemical, physical or
biological methods for inactivation prior to release to the
environment. Equipment and expertise to complete these
processes is also available from GEA.
In biotechnology applications, fermentation describes a process in which micro-organisms that are cultured on a large-scale under aerobic or anaerobic conditionsconvert a substrate into a useful product. Any industrial fermentation operation can bebroken down into three main stages: media preparation, the fermentation process(upstream) and downstream processing.
Case Study:Vaccines
Fermentation ProductsFermentation products can be used for
pharmaceutical, feed and foodstuff, analytical and
home & personal care applications. Commercially
important fermentation products can be
described in four major groups:
• biomass (Baker’s yeast, starter
cultures, animal feed, etc.)
• primary metabolites (amino acids, organic acids,
polysaccharides, ethanol, etc.) and secondary
metabolites (vitamins, antibiotics, etc.)
• bioconversion or biotransformation
products (steroids, L-sorbitol, etc.)
• recombinant products (enzymes,
some vaccines, hormones such as insulin
and growth hormones, etc.).
Whooping Cough VaccineSolution for Beijing Biotech Company
Vaccines are among the 20th century’s most successful
and cost-effective public health tools for the
prevention of disease, disability and death. Vaccination
not only protects individuals, but also entire
communities from diseases spread by person-to-
person transmission. Fuelled by new product
introductions and rising usage in many regions around
the world, the global market for vaccines has
experienced strong growth in recent years, particularly
in Asia.
Beijing Tiantan Biological Products Co. Ltd (Tiantan
Bio) operates as a subsidiary of the National Vaccine
and Serum Institute (NVSI) and is primarily engaged in
the research, development and production of bacterial
and viral vaccines, blood derivates, diagnostic reagents
and various biopharmaceutical products.
Needing a new fermentation system, the company
contacted GEA. After several site visits and a period of
close collaboration, a quote was prepared that
resulted in Tiantan Bio ordering a fermentation system
from GEA in Germany. Detail engineering work soon
began: the system comprises two seed fermenters (50
and 500 L), two 5000 L production fermenters and a
CIP-system.
Now installed and operational, Tiantan can add
Acellular Pertussis Combined Vaccine Adsorbed to its
portfolio of products and help a multitude of people
to life better, safer and healthier lives. As system
integrators and liquid processing specialists, GEA has
the scale, the know-how and the flexibility required to
meet your specific application requirements. Whether
large or small, GEA can add value to any vaccine
production project.
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Utilities and Highly Purified Media
The media and utilities handled are• CIP (Cleaning in Place) preparation and distribution
• clean steam generation and distribution
• DI: Deionized Water generation and distribution
• WFI generation and distribution
• buffer preparation and storage.
The systems are designed according to FDA and ISPE
standards for sterile design and performance using
high quality GEA vessels. The measurement of the
required quality and performance parameters (TOC,
conductivity) is done using state-of-the-art sensors.
Depending on your requirements, we deliver hot or
cold storage systems for pure media with disinfection
methods that are adapted to meet your requirements.
The utility systems are controlled using industrial-
standard PLC/SCADA units and GEA provides the
overall package — from design to manufacturing and
testing — including local installation, start-up and
qualification support. After sales service and
maintenance support complete the overall scope of
supply.
Essential Characteristics• Optimised sterile design
• Entire system can be sterilised
• Diaphragm valve technology
• Tubular heat exchangers
• Sampling systems
• Sterile filter systems
• Constant flow conditions.
Pharmaceutical processes depend on various supporting media and utilities, such as CIP,or basic components such as Water-for-Injection (WFI). GEA provides complete lines byintegrating plant-wide distribution systems to generate these media.
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Complete Processes for Your Applications
SeparationPharmaceutical biotechnology requirements are high, including
aseptic process management, optimum cleaning capability,
closed product handling, reliable compliance with GMP
requirements, gentle product treatment, the efficient recovery of
active ingredients and reliable scale-up. With separators
designed specifically for this sector, GEA stands for reliable
compliance with these requirements.
Since 1893, GEA has been instrumental in advancing mechanical
separation technology. Offering solutions in areas such as
enzymes, hormones, human blood proteins, mammalian cell
culture, pharmaceutical proteins, starter cultures and vaccines,
the company’s technology plays a key role in the recovery of
APIs and optimising production processes and products.
A critical factor underlying the success of the company is its
ability to swiftly translate new developments into marketable
processes and systems that fully meet the complex
requirements of biotechnological procedures. With standalone
machines that guarantee a high yield of valuable substances
and operate trouble-free, efficiently, reliably and economically
throughout a long service life, GEA has developed numerous
innovative improvements to separating processes and brought
them to the global market by applying first-class engineering.
HomogenizationCell Disruption: High-pressure homogenization is widely used
in cell rupture (cell rupturing, cell disruption) applications to
extract intracellular compounds (sometimes without using
solvents or other chemicals to break the cell wall). Being very
effective and efficient, the homogenizers can often maximise
the yield from valuable source material while keeping product
quality at a very high level. GEA homogenizers are fitted with
specifically designed high efficiency valves for optimised cell
disruption at the lowest possible pressure; designed to comply
with FDA and cGMP guidelines, they come with a full
documentation package including materials certification and
traceability, FAT/SAT procedures and IQ/OQ support.
Micronization involves reducing the particle size of liquid
pharmaceutical products using dynamic high-pressure
homogenization to make a dispersion of active ingredients
more stable for enhanced clinical effectiveness. Optimised
particle micronization and homogenous distribution means
that API bioavailability and drug tolerance is improved.
Membrane FiltrationMembrane filtration offers tremendous separation and
purification opportunities to the pharmaceutical and
biotechnology industries, resulting in significant advancements
in both product development and quality. GEA specialises in
cross-flow membrane filtration — microfiltration, ultrafiltration,
nanofiltration — and reverse osmosis. Along with our process
experience, we offer a wide range of both polymeric and
inorganic membrane systems to provide the best possible
solutions to our customers in the biotechnology industry.
Membrane filtration for cell harvesting or biomass recovery is
an important step in any fermentation process, especially when
manufacturing bulk intermediates such as antibiotics.
Membrane filtration can successfully replace separation
methods such as rotary vacuum filters or centrifugation in
many plants by significantly improving product yields and
reducing operator involvement and maintenance costs.
Membranes are also a standard part of industrial enzyme
manufacturing lines to concentrate the enzymes prior to further
downstream processing.
Freeze DryingGEA is one of the market leaders in pharmaceutical freeze
drying/lyophilization. With more than 55 years of development,
engineering and manufacturing experience and a pedigree of
more than 1000 freeze dryer installations worldwide, GEA is a
reliable supplier of high quality aseptic production solutions.
ISO 9001-certified and fully compliant with cGMP, GAMP and
other relevant guidelines, GEA supplies a comprehensive range
of products and services, comprising laboratory freeze dryers
for pilot scale, R&D and small production batches, industrial
freeze dryers and complete freeze dryer systems. These include
vial conveyer systems, Automatic Loading and Unloading
Systems (ALUS®), integrated isolators and CIP skids with
integrated freeze dryers.
Our expertise includes innovations in shelf, chamber, slot door
and condenser design, novel technology to avoid sticking
stoppers, minimise footprint and energy usage, VHP™
sterilisation technology to save costs and reduce cycle times,
and a fast-track approach to full project execution — from
signed contract to SAT in less than 9 months. GEA offers a
complete programme of high quality products associated with
all aspects of aseptic manufacturing and integrated solutions, in
addition to efficient service for the pharmaceutical, healthcare
and biotech industries.
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GEA and Blood
GEA supplies plant and components for fractionation,
concentration, pre- and post-virus inactivation,
purification and buffer production, storage and
distribution. In addition, depending on the application,
plasma may need to be frozen to –30 °C within 60
minutes; GEA can supply equipment to accurately
maintain such extreme low temperatures.
An essential part of high-quality blood plasma
production is an integrated CIP/SIP system. GEA
provides efficient cleaning and sterilisation processes
that meet your individual demands and ensure that
sterile media is delivered to the right place at the right
time. We offer a wide range of cleaning options, from
mobile, independent cleaning systems to CIP satellites
fed with conditioned cleaning solutions.
We integrate GEA’s proven hycon separators to enable
fully automatic discharge, which saves time and makes
the process safer for both the product and the operator.
Designed for CIP and SIP applications, sterile handling
is guaranteed during the entire fractionation process
under cooled conditions.
Whatever it is you need your process plant for — from
the fractionation and manufacture of products such as
immunoglobulins or human albumins to Factor
VIII/Factor IX — our wide range of plant concepts will
provide for any task to be performed and take account
of any requirements or conditions.
The processing of blood must meet the very highest requirements to ensure clinicalexcellence. GEA is a specialist in this field, using its experience and expertise to unitevital GEA technologies to create complete processing plants for blood and plasmaprocessing, including controlled precipitation, centrifugation and filtration forsolid/liquid separation, thermal and chemical inactivation, ultrafiltration/diafiltration,nanofiltration, chromatography and precise temperature control. The company hassuccessfully planned and built plants for plasma fractionation all over the world.
Essential Process Requirements
• Gentle thawing of the plasma by precise temperature control and regulated stirring
• Appropriate conditions for solid/liquid separation by centrifugation or filtration
to separate the plasma fractions
• Special filtration techniques to obtain eluate for the manufacture of Factor IX
• Exact temperature control for the precipitation of all fractions
• Optimised sterile design
• Compliance with emission regulations when dosing the precipitation medium.
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GEA and Vaccines
Vaccines are medicines that immunise humans or animals against diseases. The organism to be protected is exposed to small quantities of antigens (vaccines) to achieve immunity.
The vaccine technology market is expected to reach $57,885.4 million by
2019, up from $33,140.6 million in 2014, at a CAGR of 11.8%. Major factors
driving growth in the vaccine technology market include the rising
prevalence of diseases, expanding government initiatives to develop
global immunisation programmes, increasing corporate investment
in vaccine development and rising initiatives by non-government
organisations for vaccinations.
All vaccines, whether live (bacteria or viruses),
inactivated (bacteria and viruses), toxoids or antigens,
are produced using fermentation technology in
fermenters, bioreactors or, in some examples, even
hens’ eggs. GEA is a market-leading supplier of
complete fermentation systems for bacteria, yeast,
mammalian cells and viruses, including
• anaerobic tetanus fermenters with vibrating stirring
systems (up to 1000 L)
• aerobic fermenters for pertussis fermentation with
special stirrers and mechanical foam breakers
• equipment for yeast fermentation and for the state-of-
the-art production of antigens such as Hepatitis B
Antigen (HBsAg)
• viral cell culture systems for polio, rabies and foot and
mouth disease (FMD), for example.
These production lines are complemented with supplementary
tanks for media preparation and harvesting, for example, and
further enhanced by integrating downstream process
equipment such as cell and product separators, homogenizers
for cell disruption and/or filtration units for microfiltration and
ultrafiltration.
The integration of special separators and filter systems enables
cell debris removal and chemical–based virus inactivation.
Further purification steps such as chromatography are managed
by integrating equipment from third-party suppliers.
The final step in vaccine production is formulation, which is
also in GEA’s scope of supply. Inactivation systems for waste
and effluent treatment can also be supplied. Automation is
achieved using PLC or DCS systems, which can be incorporated
into appropriate SCADA or MES infrastructures.
GEA’s Vaccine Technologies• Fermentation
• Mechanical separation
• High pressure homogenization
• Media preparation and formulation
• Freeze drying or novel aseptic spray drying
• Inactivation and waste treatment.
GEA and Insulin
Worldwide in 2011, there were almost 370 million
diabetics. The International Diabetes Federation (IDF)
estimates that, by 2030, there will be in excess of 550
million (10% of all the adults on Earth). World Health
Organization figures suggest that, by then, diabetes
deaths will have increased by two thirds.
GEA produces and supplies process systems for the
production of liquid products for the pharmaceutical
and biotechnological industries, and has a proven
history of successfully installing plant for the
production of insulin, including the engineering,
delivery, commissioning and qualification of entire
ultra-pure media systems as well as various process
equipment and cleaning installations. A worldwide
technology leader in insulin production, GEA is able to
supply the clean utility systems and manage the
integration of all the main processes, including
fermentation, harvesting, chromatography, filtration
and freeze drying.
The biosynthetic production of human insulin is done
using bacteria or yeast cells. Following fermentation,
the biomass is separated (at a constant concentration)
by a nozzle separator, washed, concentrated and
homogenized to release the insulin. The raw insulin is
then treated and precipitated to produce crystals.
Centrifuges and process lines provided by GEA have an
established pedigree in the clarification, separation,
classification, concentration and fractionation steps.
We supply process-specific chamber and nozzle
separators and machinery for use in the subsequent
crystallization stages
With diabetes on the rise and the global insulinmarket estimated to be worth more than $32billion by 2018, demand for GEA technologies forthe production of this life-saving drug is alreadyhigh and set to increase, particularly in newmarkets and emerging economies.
Fermenters from GEA provide
• long-term process sterility
• aseptic sampling, aeration, venting or transfer
• highly accurate temperature control
• stirrers that provide optimum oxygentransfer rates and cell densities
• optimised sterile design.
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GEA is a single-source supplier of production lines
consisting of fermenters, media preparation, buffer
storage, harvesting and cell rupture solutions, and
equipment for the purification, isolation and separation
of cells.
GEA also offers peripheral systems for the production
and distribution of WFI, CIP and freeze drying
technologies, all of which can be installed and
integrated into a state-of-the-art insulin
production facility.
Insulin Crystal Facility for Julphar
Having successfully collaborated in the past to develop a
number of pharmaceutical installations, GEA was the first
choice of single-source solution provider when Julphar
(Gulf Pharmaceutical Industries), the UAE-based insulin
manufacturer and one of the Middle East’s largest
pharmaceutical companies, wanted to discuss a new project.
The $136 million facility at Ras Al Khaimah in the UAE was to
be one of the largest biotechnological plants in the world for
the production of recombinant human insulin crystals. It was
to have a floor space of 20,000 square metres, including
5,000 square metres of clean rooms and 17 km of clean
piping. It was a truly massive project that, when complete,
would produce 1500 kg of insulin a year.
In the autumn of 2006, GEA began work on the initial
concepts and budget calculations. In 2007, the company
worked on scaling up the systems from laboratory to
production levels and determined important procedural
parameters that would serve as a basis for process equipment
selection. By 2009, all the plans and the engineering for the
production plant had been completed. The project was to
provide all the clean utility systems and to manage the process
integration, including fermentation, harvesting,
chromatography, filtration and freeze-drying.
Ralph Schulze, Head of Pharma and Biotechnology at
GEA, noted: “In autumn 2010, we started working on site.
We had to carefully manage a team of 100 engineers and
fitters, and be very flexible; certain process areas had to be
optimised and modified to meet specific requirements. By the
end of 2011, the main work was completed.” Said Schulze:
“With excellent co-operation from the Julphar technical team,
we were able to complete the project in a very short time
because of our past working relationship.”
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Case Study: Insulin
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GEA and Monoclonal Antibodies (mAbs)
mAbs are known as targeted therapies because they
work by selectively binding to specific proteins on the
surface of cells. Driven by demand, the approval of
new products and the launch of generic mAb drugs,
they have been successfully used to treat cancers,
tumours and other serious diseases, such as
auto-immune disorders. The market size for
monoclonal antibody agents is expected to reach a
value of $141 billion in 2017.
Compared with other biopharmaceutical products,
monoclonal antibodies are large proteins that,
traditionally, necessitate high-volume manufacturing
equipment/systems and facilities.
The cell culture process is done in several steps,
starting with low-volume precultures and successively
cultivating intermediate batches of, for example,
40, 200, 1000 and 5000 L, to the final production
volume of up to 20,000 L. These systems comprise
the vessel, with the stirrer as the core element, and
peripherals such as temperature control systems, CIP
components, aeration and deaeration systems, dosing
systems and automated sensors, actuators and the
operator interface.
Support processes such as media preparation and
harvest systems are also available at GEA. The process
integration of separators and filters for the harvest step
is also within GEA’s scope of service. As mAb
fermentation is a long process, and because of the high
sensitivity of the cells — and the need for operator and
product safety — all system components are designed
according to the latest standards and have the highest
grade of finish quality.
GEA offers production systems for mAbs that are produced instate-of-the-art stainless steel bioreactors by specific cell cultures.
Bioreactors from GEA provide
• integrated CIP/SIP
• high-performance control systems
• high quality components
•qualification and validation
• optimised sterile design
• customised solutions.
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GEA and Pharmaceutical Proteins
Highly Potent Products
GEA can supply specialised equipment when no
standard off-the-shelf system exists, particularly for
toxic or highly potent drugs such as cytostatics or
echo contrast media. With our innovative ideas and
fresh approaches, together with your project team,
we will find a solution that’s tailored to your needs
— from basic engineering to fabrication
and qualification.
Extracellular products: After fermentation, the micro-
organisms are removed by continuously operating
separators. To increase the yield, the solid material is
washed and extracted by centrifugation. The clarified
phases of the two stages are mixed and fed to further
stages of the process, such as precipitation or separation,
for example.
Intracellular products and inclusion bodies: In
intracellular processes, the required product may be
contained in the intracellular liquid or in so-called inclusion
bodies. In contrast to extracellular bioproduction, the
clarified phase leaves the process here and the biomass is
processed. The washed and concentrated biomass is
homogenized — the cells are broken down and the
intracellular liquid or the inclusion bodies are released.
These are separated from the cell fragments, washed and
concentrated in further stages of the process by centrifuges.
For intracellular products derived from the cytoplasm, the
solids are precipitated and removed by continuously
operating separators. Further product concentration may
be done by chromatography.
To keep the process as simple as possible, the biomass is
sterilised directly after fermentation in the fermenter by
heat or by chemical methods.
Proteins with pharmaceutical and analytical applications, such as hormones and enzymes, areproduced by mammalian cell culture or by the cultivation of recombinant yeasts or bacteria.
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We live our values.Excellence • Passion • Integrity • Responsibility • GEA-versity
GEA Group is a global engineering company with multi-billion euro sales and operations in more than
50 countries. Founded in 1881, the company is one of the largest providers of innovative equipment and
process technology. GEA Group is listed in the STOXX® Europe 600 index.
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GEA Diessel GmbHSteven 1, 31135 Hildesheim, GermanyTel. +49 5121 742 0, Fax: +49 5121 742 153