Liquid pharmaceutical and biotechnology experts

engineering for a better world

2

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.

3

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?

4

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.

“

” 5

6

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.

7

8

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.

9

10

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.

11

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.

12

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.”

“

”

Case Study: Insulin

13

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.

14

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.

15

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.

© G

EA G

roup

201

5 (P

harm

a). S

peci

ficat

ions

sub

ject

to

chan

ge w

ithou

t no

tice.

All

trad

emar

ks r

ecog

nise

d.A

ll co

pyrig

hts

rese

rved

. Und

er n

o ci

rcum

stan

ces

shou

ld t

his

docu

men

t or

any

par

t of

it b

e co

pied

with

out

writ

ten

cons

ent.

GEA Diessel GmbHSteven 1, 31135 Hildesheim, GermanyTel. +49 5121 742 0, Fax: +49 5121 742 153

pharma@gea.comgea.com