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PERFECT FIT. GEA pharma Separators in pharmaceutical plants

Contents

Energizing Pharma. Energizing You.

Empowering pharma lines aseptic & pure GEA pharma Separator aseptic GEA pharma Separator pure 3 bowl types for optimal efficiency with every product GEA flexChange 3-in-1 bowl concept A complete range to exactly cover any capacity Technical improvements Hygienic safety

Human blood plasma separators GEA chamber separators for human blood processing GEA hycon – Fully automated one-touch production

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5 6 7 8 9 10 11 12

15 16 18

Single-use processing Efficient cell harvesting in a snap   Process applications Mammalian cells/monoclonal antibodies (mAbs) Insulin Human and veterinary vaccines Starter cultures and probiotic products Recovery of extracellular and intracellular enzymes

GEA Service – for your continued success

GEA pharma machine range GMP-qualified, FAT-tested

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25 26 28 31 35 37

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40 42

2 Perfect fit.

3 Energizing pharma

ENERGIZING PHARMA. ENERGIZING YOU.

Energizing You: We enable every customer to make better pharmaceuticals and biopharmaceuticals with more effi- cient, more profitable processes.

Energizing Pharma: We are safeguarding future generations by providing sustainable solutions for the pharmaceutical industries.

4 Energizing pharma. Energizing you.

Perfect product Ensure optimal processing to make the best pharmaceuticals or biotech products you can. Leading manufacturers and developers achieve this with GEA.

Perfect process Safeguard your operation against hazard and contamination. GEA protects your future with hygiene technology at the forefront of progress.

Perfect efficiency Turn our industry and engineering know-how into high yield, full reliability and maximumm cost-efficiency for your plants and processes.

We are here for your success

GEA serves the complete range of pharmaceutical processing. From biopharma processes to human blood plasma fractionation, from single- use to multiple-use processing.

Pharma lines aseptic & pure5

EMPOWERING PHARMA LINES ASEPTIC & PURE

The complete biopharma separator portfolio

GEA experts have transformed decades of centrifugal separation experience into a new, complete selection of plug & produce pharma separator skids. Infinitely adaptable to every scope of requirements to take pharma operations to the next level.

With the pharma Separator aseptic, GEA offers manufacturers a new level of performance, clean room protection, validation and cleanability.

Included

Hygienic Design Qualification documentSanitizing

ASME BPE design Complete

GMP documentation included

GEA Ribo design Additional certificates for surface, materials and

weldings

Hygienic design General certificates Automatic CIP process

Automatic SIP

GEA Pharma Separator aseptic

GEA pharma Separator aseptic

Equipped for SIP – highest hygienic demands.

6 GEA pharma lines aseptic & pure

Option

Hygienic Design Qualification documentSanitizing

ASME BPE design Complete

GMP documentation available

GEA Ribo design Additional certificates for surface, materials and

weldings

Hygienic design General certificates Automatic CIP process

Free steaming at < 0.5 bar

GEA Pharma Separator pure

The new pharma Separator pure line delivers machines that are equipped exactly to your varying hygienic needs with numerous combination options.

GEA pharma Separator pure

Included

Utmost variability for your processes.

7 GEA pharma lines aseptic & pure

HighSigma clarifier bowl • Self-cleaning • For solids < 5 vol%%

Uncompromised hygienic design, reliability and high yield are essential – but every production task and manufacturing operation is different.

HighVol clarifier bowl • Self-cleaning • For solids < 10 vol%

flexiCon nozzle bowl • Continuous discharge and self-desludging • For solids < 30 vol%

Available in GEA pharma Separators aseptic and pure

3 bowl types for optimal efficiency with every product

Three bowl types with different clarifier areas and solid spaces are available with every GEA pharma Separator aseptic or pure – to make the most of every process variant, processing capacity, viscosity of product and solid content.

8 GEA pharma lines aseptic & pure

One Machine, three interchangeable bowl types. The GEA flexChange concept offers up to three interchange- able separator bowls to produce any product on just one skid.

Turning static process lines into flexible ones. The exchangeable bowls ensure maximum adaptability to different processing goals and needs. The flexChange machine covers any solids content up to 30 vol% with the different bowls. Manufacturers can flexibly adapt to the next product as fast as possible. A single separator skid efficiently delivers optimal yield for each product and capacity.

Including flexiCon nozzle bowl • Continuous discharge and self-desludging • Optimized for solids < 30 vol%

Available in the series aseptic and pure.

GEA flexChange 3-in-1 bowl concept

For customers with regular product change

HighVol clarifier bowl

HighSigma clarifier bowl

flexiCon nozzle bowl

9 GEA pharma lines aseptic & pure

Separator size

High separation performance Dimension Clarifier Nozzle separator

30

100

170

300

500 – 2,200 l/h

1,800 – 3,700 l/h

3,000 – 6,000 l/h

6,000 – 12,000 l/h

750 – 3,300 l/h

2,600 – 6,000 l/h

5,000 – 10,000 l/h

10,000 – 20,000 l/h

Capacity

Four available model sizes for GEA aseptic and GEA pure with any bowl type ensure maximum efficiency of processing.

10

A complete range to exactly cover any capacity

GEA pharma lines aseptic & pure

No emission into the cleanroom: State-of-the-art Integrated directDrive (IDD) The IDD features a water-cooled motor in a closed housing. No particle emission to the clean room is possible, for high standards of purity and safety.

Fewer spare parts and less wear on moving parts make service operations easy and efficient. The small machine footprint helps reducing costs for expensive cleanrooms. Noise levels are significantly reduced.

Included in the series aseptic and pure.

Technical improvements

Infinitely adjustable during process: GEA flexiCon nozzle bowl Discover the centrifuge bowl that can handle up to 30 vol% solids with optimum separation results, continuous discharge and – a world’s first – seamless adaption during processing!

GEA separators with the new GEA flexiCon nozzle bowl ensure perfect yield and optimum dryness of the product for further processing.

The GEA flexiCon nozzle bowl is also included in the GEA flexChange 3-in-1 bowl concept.

GEA pharma Separators aseptic and pure embody the state-of-the-art expertise of GEA engineering.

GEA flexiCon nozzle separator Handling up to 30 vol% solids with optimum separation results.

Continuous discharge and self-desludging This machine represents the most efficient solution to separate media with high solid content.

GEA Integrated directDrive (IDD) High purity and safety meets easy setup and maintenance.

11 GEA pharma lines aseptic & pure

Securely clean GEA pharma Separators aseptic and pure are equipped for Cleaning-in-Place (CIP). For fully automatic operation, the cleaning cycle is controlled by a programmable logic con- troller. The program sequence for cleaning can be adapted according to the local requirements.

Included in the series aseptic and pure.

Hygienic safety

Pharma separators aseptic and pure offer state-of-the-art hygienic design – essential for the safety of your products and the reliability of your processes.

No gaps, no dead spaces Hygienic design includes excellent cleaning capability, the prevention of dead spaces, easy-to-clean smooth surfaces and an optimum wetting of the surfaces in contact with the product by the CIP media.

Hygienic design, optimal cleaning capacity

Gap-free welded disk spacers The laser-welded disk spacers developed by GEA lead you to the next level of pharmaceutical cleanability: Maximum welding precision leaves no dead spaces in the disk stack, providing the basis for a highly effective CIP and SIP clean- ing. Optionally available for GEA pharma Separators pure.

Included in the series aseptic. Available in the series pure.

Welded disk spacers Leaving no dead spaces in the disk stack.

12 GEA pharma lines aseptic & pure

ASME BPE, GMP and Ribo design ASME BPE conformance certificates and full GMP documen- tation are included as standard with aseptic skids for easiest implementation of your pharma process line.

Included in the series aseptic. Available in the series pure.

All separators in the aseptic series are steam-sterilizable and completely sealed, designed for maximum biosafety and containment.

Automatic SIP, ASME BPE and GMP included in the aseptic series

Steam sterilizing, Sterilization-in-Place (SIP) Sterilization in addition to standard CIP operations prevents cross-contamination of different fermentation products pro- cessed in the same separator.

Included in the series aseptic.

For maximum safety Steam sterilization (SIP) for a secure bio-containment

13 GEA pharma lines aseptic & pure

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GEA pharma Separator series aseptic and pure at a glance

Two separator lines • perfect fit to your process Three bowl types • 2 clarifier bowls, 1 nozzle bowl for maximum yield Four model sizes • a stepless range to cover any capacity Utmost flexibility and efficiency • only pay for what you need ASME BPE compliant design • maximum safety and fast validation IDD (Integrated Direct Drive) • small, efficient, emission-free GEA flexChange concept • fast & flexible processing of varying solid contents Skid configurator • multiple skid variants customized to your needs

GEA pharma lines aseptic & pure

15 Human blood plasma fractionation

HUMAN BLOOD PLASMA SEPARATORS

The clear plasma phase of human blood contains about five percent valuable pharmaceutical substances with important medical applications, e.g. for controlling bleeding or treating infections.

GEA offers two types of human blood Separators for safe fractionation: The chamber separator BKI and the fully automatic clarifier GEA hycon, which is also ideal for the high-efficiency recovery of insulin crystals.

These centrifuges have become a proven global standard with numerous successful installations.

Thanks to extensive options for adjusting speed, separated particle sizes and discharge volumes, the same type of GEA separator can cover all fractionation steps at optimum performance.

The classic solution for all blood plasma fractionation stages is available on a pre-configured skid with an additional in - dependent GEA plasmacool cooling unit to ensure a failsafe process.

The human blood separator BKI 45 can also be configured in a two-room-concept.

GEA chamber separators for human blood processing

Fractionation of human blood plasma can be reliably executed in performance ranges from 60 to 1,000 l/h using cooled GEA chamber separators.

16 Human blood plasma separators

Cooling the process with maximum safety A very narrow temperature range makes it particularly difficult to separate the individual substances from the remaining phase. Using sophisticated technologies, GEA chamber separators safely keep temperature tolerances, at the same time ensuring highest product quality as well as highest plant efficiency.

The permitted temperature range for processing blood plasma and plasma components is merely +2 °C to –7 °C and must be maintained under all circumstances so as not to render the sensitive product unusable. A direct cooling system is integrated into GEA chamber centrifuges for blood plasma fractionation to ensure maximum safety.

One machine type for all fractionation cycles In preliminary fractionation steps, substances such as cryoprecipitate and the prothrombin complex (PPSB) can be separated from the fresh plasma. In further steps, the remaining plasma undergoes several chemical cycles at changing settings for temperature, alcohol concentration and pH in order to deliver individual fractions such as fibrin- ogen, gamma globulin, alpha and beta globulin and albumin.

GEA chamber separators for blood plasma fractionation can be applied to all the different steps of the Cohn fraction- ation process, presenting a particularly economical solution to facilitate efficient plant management as well as future changes in processes or capacities.

Maximum dryness of separated solids Manufacturers need the fractionated solids to be as dry as possible, but without stress on the product. Based on decades of experience, GEA centrifuges ensure unsur- passable and reproducible quality of the product in terms of dryness, product integrity and preservation of product properties.

Careful handling of the product is ensured by the hermetic inlet, which has been confirmed by CFD calculations.

Leukocytes 4.3 – 440 103/μl

Erythrocytes 4.4 – 6 106/μl (men) 4.2 – 5.5 106/μl (women)

80%

70%

60%

50%

40%

30%

20%

10%

0%

Cells

Thrombocytes Leukocytes

Erythrocytes

Plasma

Cells

Proteins Elektrolytes

Water

Albumin

Thrombocytes 140 – 440 103/μl

Clotting preparations Clod-insoluble globulin γ-globulin β-2-globulin β-1-globulin Coeruloplasmin α-2-globulin α-1-globulin

Blood Plasma Plasma proteins

90%

100%

17 Human blood plasma separators

Using ethanol/water at up to –20 °C temperature as a refrigerant, the GEA chamber separators cool the machine bowl during operation so that processed solids are always kept exactly at the pre-selected temperature and iso-electrical value, at no greater tolerance than +/– 1 °C.

For the separation of blood plasma and plasma proteins, GEA offers an optimal solution with the fully automatic clarifier hycon developed by GEA.

The GEA separator hycon enables “one-touch production”. With this separator technology, GEA is a pioneer in the field of fully automated production in clean room applications.

GEA hycon is specially designed for aseptic production environments – a unique cleanroom solution for the final human blood plasma fractionation cycles and also for the automated, high-efficiency recovery of insulin crystals.

GEA hycon – Fully automated one-touch production

Unifying the advantages of self- cleaning and chamber separators

18 Human blood plasma separators

Product area and mechanical elements kept safely apart Whenever centrifuges are installed in clean rooms, special attention must be paid that no particles are emitted to the surroundings and that the machinery can be easily cleaned. To ensure this, the GEA hycon system has been developed as a completely enclosed three-room concept.

The drive section (drive system and motor) and the process room (bowl and solids discharge) are sealed hermetically from each other by gas-lubricated slide ring seals. This precludes contamination of the process room by the drive equipment and thus helps achieve a sterile process.

Automated one-touch production for maximum purity The GEA hycon solution combines consistent separation of product and drive areas with the use of a self-cleaning, fully automatic separator. The centrifuge has a customer-specific solids tank. The separated solids can be collected in a bag, for example, placed in that container. This closed process replaces the conventional manual emptying of the separator bowl.

The advantages of closed handling are significantly better hygiene conditions and, as a result, better sterilizability, pre- vention of cross-contamination, greater batch safety and improved Good Manufacturing Practice (GMP) documen- tation. Cleaning-In-Place (CIP) and Sterilize-In-Place (SIP) were previously not even possible with chamber machines.

The suspended bowl with hood and solids trap is located in a clean room mounted below the separator frame, while the drive units are located in a lower-classified room above. The operating elements are also located outside and thus emission-free for the high-clean room in the adjacent room. The valuable solids are dis- charged fully automatically from the suspended separator bowl at reduced or full operating speed under sterile conditions.

Closed handling of separation media Previously not possible with chamber machines

19 Human blood plasma separators

Supernatant

Solids

Human blood plasma fractionation

1

Fraction II/IIIFraction I

Fraction IIIFraction IV

Cold store Thawing tank (temp. appr. 0 °C) Cryoprecipitate Washing liquid Washing tank (temp. appr. 0 °C) Cryoprecipitate to freeze dryer Buffer Re-suspension tank (temp. appr. 0 °C) Factor VIII concentrate Waste

Fraction IIFraction V

2 A

3

4

5

6

7

8 A

22

9

10

11 A/B

12

10

A/B13

10 10

10 10

A/B

A/B

A/B

A

14

15

18

19

16

22

17

20

B

Options

22

21

22

21

Cryo process

1 2 3 4 5 6 7 8 9 22

Cohn process

10 11

12 13

14

15

Chamber bowl centrifuge hycon (three room concept with closed solids handling)

A

B

Cryo process Cohn process

Alcohol, pH, temperature Protein precipitation (alcohol content = 8 %, temp. = −3 °C, pH = 7.3) Fraction I (Fibrinogen) Protein precipitation (alcohol content = 25 %, temp. = −5 °C, pH = 6.8) Protein precipitation (alcohol content = 40 %, temp. = −5 °C, pH = 5.9) Fraction IV (α- and β-Globulin to waste)

Protein precipitation (alcohol content = 40 %, temp. = −5 °C, pH = 4.8) Fraction V (Albumin) Protein precipitation (alcohol content = 8 %, temp. = −5 °C, pH = 5.1) Fraction III (α-Globulin to waste) Protein precipitation (alcohol content = 25 %, temp. = −6.5 °C, pH = 7.3) Fraction II (γ-Globulin) Waste

16

17 18

19 20

21 22

20 Human blood plasma separators

21 Human blood plasma fractionation

SINGLE-USE PROCESSING

GEA kytero® Separator

GEA’s single-use separation concept transfers acclaimed disk stack separation technology as used throughout the GEA pharma aseptic and pure series – to single-use cell har- vesting and other applications for R&D, pilot plants and small production.

Add more yield to your process kytero® stands for maximum separation efficiency with extremely gentle product handling. This unit creates new ways for processing cell culture fermentation broths with a yield of 98 percent and more. This type of technology is in demand for pilot plants, uni- versity laboratories, and small-scale production with biopharmaceutical manufacturers worldwide, since it is based on the proven technologies of industrial disk stack separators.

No CIP/SIP required All materials in contact with the product – disk stack clarifier bowl, connection tubes and bags – are part of the single-use exchange set and form a closed system that is 100% bio- containment-proof. For every batch a new set is clipped on.

Scale up your success Use the GEA kytero® Separator 500 as R&D and small-batch machine and go into production with the kytero® 2000. The GEA kytero® 500 can process 500 L of input feed in a single batch. Test results from smaller batches can be upscaled to that capacity or transferred to the GEA kytero 2000 for higher capacities. Success is as simple as that.

Efficient cell harvesting in a snap

GEA kytero®: More yield. No CIP/SIP.

22 Single-use processing

Save filtration effort and cost in both clarification steps. The high separation efficiency of the GEA kytero® solution has been tested in cell-based immunoglobulin mAb production at Zurich University of Applied Sciences (ZHAW).

Reduce your dependency on filtration

The results show that facilities can reduce the amount of filter area for cell clarification by 100 % in the primary cla- rification step. Up to 50 % filter area can be reduced in the second clarification step. Apart from the cost of filter ma - terial, this saves considerable space and handling time as well as effort for backup systems, logistics and personnel.

Applications: • Cell harvesting • Gene therapy • e.Coli • many more

23 Single-use processing

Easy operating concept, saving time, space and labor The GEA kytero® solution offers minimum demands on space, time and labor in intensively used pharma produc- tion environments. Set up within minutes and without special tools, the machine operates in a continuous process with fully adjusted components to ensure controlled processing to the parameters set manually or by PLC. All process data are stored and digitally labeled for easy traceability of each batch.

100 percent biocontainment-proof GEA kytero® is equipped with a unique contact-free, no-con- tamination drive system. The revolutionary GEA breezeDrive® has been developed by GEA engineers and drives the bowl without any shafts and bearings or mechanical seals – the failsafe way to ensure an absolutely pure product. This GEA innovation is also appreciated for the very low noise level in the production or lab environment.

Fits into every cleanroom In contrast to conventional single-use solutions, the GEA kytero® skid includes connections, pumps, controls and HMI. The system can be stored outside of the cleanroom and set up for the next batch in only five minutes, with no utilities required other than power supply.

Easy handling – batch-ready in 5 minutes

24 Single-use processing

25

GEA pharma Separator aseptic or pure models cover every cell harvesting, vaccine or insulin production or other bio- pharma process.

From upstream treatment to the intermediate product, from initial tests to global production

PROCESS APPLICATIONS

Monoclonal antibodies (mAbs) are produced on the basis of highly shear-sensitive mammalian cells. These cells must not break during separation and impure the product. GEA pharma Separator skids aseptic offer a solution for effi- cient cell harvesting that minimizes cell shearing. A precisely adjustable ejection system ensures optimal product purity and high yield for mAb manufacturers.

Shear-sensitive separation of mammalian cells for monoclonal antibodies (mAbs) with optimal purity and yield

Mammalian cells/ monoclonal antibodies (mAbs)

Soft acceleration in the feed system The hydrohermetic feed system developed by GEA guides the cells gently into the separator bowl. It secures a soft and gentle accelaration of the cells. This solution, only available from GEA, has been tested at Bielefeld University on sen- sitive CHO cell cultures and published by the researchers in cooperation with GEA experts.

26 Process applications

Monoclonal antibodies

Cell culture Substrate Aeration

Fermentation Self-ejecting or nozzle separator

Harvest tank

Further processing Waste (solids)

Harvest tank

Depth filtration

Micro filtration

Cell separation Filtration / Purification

27

No airlock in the bowl Thanks to the integrated self-venting function, the hydro- hermetic inlet from GEA also prevents airlock in the centrifuge bowl. This is an important advantage in ensuring continuous, error-free and safe operation under increasingly competitive process conditions in mAb production.

Sensitive speed control The speed of GEA separators can be adjusted to protect particularly sensitive cell products and so always achieve optimal separation results at maximum purity of the product.

Maximum purity The combination of hydrohermetic inlet, bowl overflow and nozzles installed around the bowl has also proven to achieve maximum CIP results. To avoid product contamination from seal abrasion only one double mechanical seal is used. It is made of high-quality silicon carbide and is not in contact with the product.

Economical plug & play GEA pharma aseptic skids With many mAb producers worldwide switching to continu- ous processing and increasing output, state-of-the-art GEA pharma Separator aseptic skids are the right solution for mAb production with maximum success.

Process applications

In the efficient production of insulin, GEA Pharma separa- tor skids make a difference with their unique versatility. One basic type of machine can handle numerous steps in the entire process, with highly suited special solutions avail- able for the remaining steps. This ensures consistently high product quality under fast-changing conditions – a valuable asset for producers in a dynamic market with increasing worldwide demand for life-saving insulin.

One centrifuge type for numerous process steps To obtain insulin proteins from fermented yeast or E.coli bacteria the product is treated in a series of different pro- cess steps, e.g. cell harvesting, cell washing, polishing and removal of unwanted proteins (see process diagrams). GEA  flexicon nozzle bowl separators can be applied to numerous process steps. Since the properties and densities of the solids are different in each step, extensive adjustment

Multiple process steps with just one modular machine

Insulin

options are in place to ensure the handling of proteins with the highest sensitivity at each point.

Suitable for yeast and E.coli processes Each GEA separator for insulin can be converted, at the user’s discretion, to adapt it to different process steps or to ongoing changes in process development. GEA machines are designed for yeast-based as well as E.coli bacteria-based insulin processes.

GEA hycon: A unique solution for crystal recovery In the final crystallization stage, optimal dryness and aseptic handling of the product is of particularly high priority. GEA offers a unique solution for this task: GEA hycon, a closed 3-room centrifuge system specially designed to achieve maximum solids concentrations under aseptic cleanroom con ditions. Automatic self-emptying of the GEA hycon

system eliminates the need for conventional, labor-inten- sive manual recovery of the solid end product. For more information see p. 18.

Improved small-footprint option As an alternative, manufacturers can also rely on GEA for a small-footprint, low-investment option for the crystalliza- tion process, which provides for manual recovery of the dry protein.

For this task, small chamber centrifuges GEA PKB 28 or PKI 45 are available. These models have been specially opti- mized for uncomplicated manual opening of the machines and simple recovery of solids, making the process as fast and fail-safe as possible.

28 Process applications

Insulin based on yeast

Microorganism Substrate Aeration

Fermentation Self-ejecting or nozzle separator

Washing tank

Self-ejecting separator

Water / buffer

Waste

Crystallization tank

Chamber bowl centrifuge

WasteAdditives

Freeze dryer

hycon (two room concept with closed solids handling)

Waste

Additives

Self-ejecting or nozzle separator

Waste Chromato- graphy column

Chamber bowl centrifuge

WasteAdditives

hycon (two room concept with closed solids handling)

Harvest tank

Crystallization tank

Waste

Supernatant

Solids

Options

Cell separation and washing Polishing

Final Purification and Crystallization

29 Process applications

Insulin based on E.Coli

Microorganism Substrate Aeration

Fermentation Self-ejecting or nozzle separator

Homogenizer Self-ejecting or nozzle separator

Water / buffer (washing liquid) WasteWaste

Waste Waste

Self-ejecting or nozzle separator

Self-ejecting or nozzle separator

Water / buffer Water / buffer

Protein folding Precipitation of foreign proteins

Self-ejecting separator

Waste

Freeze dryer

Chamber bowl centrifuge

hycon (two room concept with closed solids handling)

Crystallization tank

Waste

WasteAdditives

Inclusion bodies

Inclusion bodies

Supernatant

Solids

Options

Cell separation Inclusion bodies separation Inclusion bodies washing

Protein purification Insulin crystals concentration

30 Process applications

Vaccines – both live and non-live – are critical to eliminating or reducing the risk of viral infections. Because vaccines can prevent, but potentially also trigger disease, bio-safety is of highest priority at every stage of processing. Any breach in containment and any other risk of contamination must be avoided.

Whether live or non-live vaccines, for human use or for vet- erinary applications, manufacturers can trust the superior separation solutions from GEA to keep hazardous sub- stances contained, maintaining the purity of the product and the safety of the production process without compromise.

Securing biosafety and containment with steam-sterilized systems

Human and veterinary vaccines

Optimized for steam-sterilization and biocontainment GEA centrifuges for vaccines are all available in suitable designs for steam-sterilization – the ideal solution to pre- vent cross-contamination of consecutive batches and to protect the operator when opening the centrifuge. To ensure biocontainment during machine operation, the centrifuge housing is entirely sealed, including feed and discharge sys- tems, impeding any contact between the product and the atmosphere.

31 Process applications

Human vaccines

Microorganism Substrate Aeration

Fermentation Self-ejecting or nozzle separator

Harvest tank

Further processing

Waste

Kill tank

Waste

Kill tank

Harvest tank

Additives

Freeze dryer

Non-Live vaccines • Influenza • Cholera • Bubonic plague • Hepatitis A or hepatitis B • Whooping cough (pertussis) • Tetanus • Diphtheria • Pneumococcal bug • Covid

Live vaccines

• Measles • Mumps • Rubella • Yellow fever • Chickenpox • BCG (= tuberculosis vaccine) • Typhus • Human rotaviruses • Whooping cough (pertussis)

Cell separation Non-Live vaccine processing

Live vaccine processing

Careful product handling Extensive scientific research in cooperation with Bielefeld University has led to the development of particularly gentle hydrohermetic feed and discharge systems on current GEA Pharma separators, ensuring particularly careful handling of the product during the centrifugation process.

Vaccine production – human and veterinary

32 Process applications

Veterinary vaccines: Protection from active viruses Particularly dangerous conditions mark the production of some animal vaccines (e.g. specific live foot-and-mouth disease vaccines) involving a virus activation stage (see diagram). Activated viruses can be highly pathogenic, either immediately or at any point in the future, which makes max- imum protection against the risk of contamination or direct infection indispensable.

To ensure maximum safety, the safety concept from GEA with biocontained machine skids in steam sterilizable design for vaccine treatment has also been tested and published together with a research team at London University.

Whatever the vaccine process, choosing the most eco- nomical machine size makes a huge difference to the efficiency of the pharmaceutical operation. The GEA pharma separator portfolio offers sizes to fit any setup and process. The ideal size can be assessed by upscaling from test runs at GEA test centers or at the customer’s site.

Virus solutionBiomass

Veterinary vaccines

Cell culture Substrate Aeration

Fermentation

Micro filtration

Activation tank

Self-ejecting or nozzle separator

Waste/ Solids

Micro filtration

Poly ethylene glycol (PEG)

Inactivation tank

Self-ejecting or nozzle separator

Waste/ Supernatant

Harvest of product/ Solids

Settling tank

Cell separation Virus activation

Harvesting of PEG-phase

Process applications

– example for food and mouth desease (FMD)

Supernatant

Solids

33

Streamlined production of adjuvants Vaccine production includes the preparation of excipients, such as aluminum hydroxide, which themselves have no pharmaceutical effect, but boost the effect of the pharma- ceutical agent. In a typical reaction, chemicals such as ammonia and aluminum salts produce a high water content aluminum gel.

Fewer wash cycles With GEA separators, the remaining chemicals are com- pletely removed in several wash cycles. The high-precision ejection system on the centrifuges controls output sizes and quantities with reproducible results, minimizes the number of cycles and saves time and money for the manufacturer.

Recovery of aluminium hydroxide

1 Water for Injection/ Additives

2 Precipitation tank Self-ejecting or nozzle centrifuge

5 Washing tank

4 Washing liquid Waste/ Supernatant

6 Harvest tank

7 Further processing

Washing steps: 1/3/5/7

3 Aluminum hydroxide

5 Washing tank

4 Washing liquid

Washing steps: 2/4/6/8

8 Water for injection

34

(adjuvants)

Process applications

Starter cultures are responsible for predictable and reproducible production processes in many industries. Probiotic products are popular with consumers for their beneficial health characteris- tics. All these microbial food cultures can only be successfully harvested if the vitality of the cells is protected and preserved. GEA nozzle centrifuge models achieve this with advanced sys- tems that ensure gentle cell handling and high yields.

Gentle cell treatment for highest vitality In order to produce microbial food cultures, the cultivated micro-organisms must be separated from the fermentation broth. A gentle hydrohermetic feed system on GEA separa- tors ensures that the product is processed with a minimum of stress, keeping the living cells safely intact. The nozzles inside the centrifuge bowl are placed near the bowl axis, fur- ther reducing pressure on the cells. The product is thus in an

Starter cultures and probiotic products

ideal condition for downstream processing, e.g. pelletizing, freeze drying and packaging.

Innumerous cultures without technical change Sterilizable separators from GEA are becoming increasingly important for harvesting bacteria in super-multi-purpose processes to avoid cross contamination. Often more than 100 different cultures are handled in one process line. In fact, a single GEA machine can be re-adjusted at the user’s discretion to handle all typical starter cultures and probiotic products in the dairy, food, veterinary food and pharma industries. Multi- purpose operation is easy to manage and can accommodate a wide range of feed concentrations (0.1 – 10 vol%). Different product recipes can be stored in the product panel. All set- tings and modifications are also done on the control panel, no changes are required on the machine.

Enhancing yield and vitality of living cells

35 Process applications

Starter cultures

Microorganism Substrate Aeration

Fermentation Self-ejecting or nozzle separator

Harvest tank

Spray dryer

Lactose

Waste/ Supernatant

Freeze dryer

Pelletizer Cold store

Options

Cell separation Drying / Pelletizing

Safe prevention of contamination In addition to the CIP routines, nozzle separators from GEA are designed to be sterilized with saturated steam. This safely prevents cross-contamination and ensures the purity of changing product types and batches. The pressure-tight product processing zone of the centrifuge and its drive unit are separated by a double mechanical seal.

Reproducible and scalable results The separation results with these separators are highly reproducible and scalable, thanks to automated operation and an ingenious metering piston system. Ejection volumes and concentrations can be set externally, continuously 10 – 100 % and with highest accuracy. All functions are optimally matched in GEA nozzle separators to facilitate production control and product development.

36 Process applications

Enzymes are complex organic protein compounds located in every living cell. They accelerate organic processes such as the breakdown of starch, protein, fat or sugar as catalysts, i.e. without being expended themselves. Low-abrasion GEA nozzle separators provide a simple solution to ensure, at low costs, that both intracellular and extracellular enzymes are separated undamaged and in high concentrations.

Low abrasion and fewer process stops To produce enzymes for industrial use, the liquid phase of the fermentation broth is separated by centrifuging with an added flocculent. This process does not require costly ster- ile handling of the product. However, abrasive particles from the fermented raw materials are often present in the broth and can affect the separation system. This is why special- ized GEA nozzle separators are a superior choice compared

Wear-protected recovery and fewer process stops

Recovery of extra cellular and intracellular enzymes

to standard disk stack models: The external nozzle can be inspected and maintained externally with little effort, saving unnecessary downtime and effort. In the case of especially abrasive particles that cannot be prescreened with sieves before separation, special reinforcements are fitted to wear-sensitive components on GEA separators.

Recovery of extracellular and intracellular enzymes After the initial separation of cells from the fermentation broth, different process variants are used for extracellular and intracellular enzymes. In both cases, succeeding stages of washing and polishing with centrifuges further increase the yield and the purity of the enzymes. The centrifuge solu- tion offered by GEA is perfectly equipped to handle all these process steps. It is possible to use the same machine for different steps with little adjustment effort.

37 Process applications

Extracellular and intracellular enzymes

Microorganism Substrate Aeration

Fermentation Self-ejecting or nozzle separator

Harvest tank

Flocculents

Waste/ Supernatant

Rotary brush strainer

Homogenizer

Water / buffer (washing liquid)

Waste/ Solids

Further processing

Harvest tankSelf-ejecting or nozzle separator

Water / buffer (washing liquid)

Waste/ Solids

Harvest tankSelf-ejecting separator

Waste/ Solids

Further processing

Cell separation Intracellular enzymes

Extracellular enzymes

38 Process applications

GEA Service offers dedicated teams of service experts. Our focus is to help our customers build, maintain, and improve their performance, market presence and competitive edge for the entire life cycle of their plants and equipment. Partnering with GEA gives you the ben- efit of our worldrenowned, customer-tailored service and recommended spares upgrade, moder nization and optimization services. With our support you can be certain that every piece of GEA equipment and technology will operate optimally from day one, and for its com- plete lifespan, to give you maximum return on your investment.

KEEP YOUR PRODUCTION PLANT FIT WITH GEA SERVICE

Beginning of Life Services Getting you started

Lifetime Services Keeping it running

Extended Life Services Constantly improving

Consulting and Enhanced Operations Together with you

39 GEA Service

Machines are available in the aseptic and pure range for all pharma applications and as special solutions for specifc areas of application or production environments.

Machine type Product throughput depending on the product and process conditions (in l/h)

Applications

Self-cleaning disk stack centrifuges FSC 6* 100 – 200 Pharmaceutical proteins, monoclonal

antibodies (mAb), insulin, starter cultures and probiotic products, extracellular and intracellular enzymes

FSC 15* / PSC 15 250 – 500 FSC 20* 500 – 1,000 pure 30 500 – 2,200 pure 100 1,800 – 3,700 pure 170 3,000 – 6,000 pure 300 6,000 – 12,000 Self-cleaning disk stack centrifuges with nozzle pure 30 750 – 3,300 Pharmaceutical proteins, monoclonal

antibodies (mAb), insulin, starter cultures and probiotic products, extracellular and intracellular enzymes

pure 100 2,600 – 6,000 pure 170 5,000 – 10,000 pure 300 10,000 – 20,000 Steam-sterilized, self-cleaning disk stack centrifuges CSC 6 100 – 200 Aseptic processes, pharmaceutical proteins,

monoclonal antibodies (mAb), insulin, human and veterinary vaccines, starter cultures and probiotic products

CSC 15 250 – 500 aseptic 30 500 – 1,800 aseptic 100 1,800 – 3,700 aseptic 170 3,000 – 6,000 aseptic 300 6,000 – 12,000

GEA PHARMA MACHINE RANGE

40 Machine range

* This design will be offered without polished surfaces and limited GMP documentation.

Machine type Product throughput depending on the product and process conditions (in l/h)

Applications

Steam-sterilized, self-cleaning disk stack centrifuges with nozzles CFC 6 150 – 300 Aseptic processes, pharmaceutical proteins,

monoclonal antibodies (mAb), insulin, human and veterinary vaccines, starter cultures and probiotic products, extracellular and intracellular enzymes

CFC 15 300 – 600 aseptic 30 1,200 – 2,500 aseptic 100 3,000 – 6,000 aseptic 170 5,000 – 9,000 aseptic 300 10,000 – 20,000 Single Use disk stack centrifuges kytero® 500 50 – 150 Mammalian cell cultures

10 – 40 E.coli kytero® 2000 150 – 600 Mammalian cell cultures

30 – 120 E.coli Chamber centrifuges PKB 28 300 – 600 Insulin, pharmaceutical proteins PKI 45 500 – 1,000 BKB 8 100 – 200 Human blood plasma BKB 28 300 – 600 BKI/BKB 45 500 – 1,000 Hyperconcentrator  hycon 500 – 1,500 Aseptic processes, insulin, pharmaceutical proteins,

human blood plasma Solid-wall bowl centrifuge FTC 1* 30 – 60 Technical centers and pilot plants, human blood plasma Other self-cleaning disk stack centrifuges pathfinder GMP FSC 1* / 5* / 8* 15 – 300 Technical centers and pilot plants Scout (4 interchangeable bowls: clarifier, separator, nozzle and chamber bowl)*

150 – 300

FSD 1* 20 – 50

41 Machine range

For manufacturers of pharmaceutical products, GMP- compliant plant qualification is a prerequisite for obtaining and maintaining the ability to design and manufacture according to contract or purchase order specifications.

Good Manufacturing Practice (GMP) qualification GMP-compliant Factory Acceptance Tests (FAT), an import- ant GEA service, take place after the preliminary GMP test in Oelde, Germany. The test includes full documentation and is verified in the form of an installation test (IQ) and a func- tional test (OQ). All GEA centrifuges are assessed according to the quality requirements determined prior to installation and for GMP compliance.

Modular Factory Acceptance Test (FAT) packages The pharmaceutical test bay at GEA offers flexible FAT con- cepts that facilitate approval by regulatory authorities and ensure the faster on-site commissioning of the centrifuge package unit. Depending on the scale and depth of the indi- vidual test, three FAT concepts are available.

GMP-qualified, FAT-tested machines

GEA high-quality production Modular GMP-compliant FAT On-site commissioning

FAT GMPbasic FAT GMPadvanced FAT GMPpremium Duration of the test: 1 day Duration of the test: 2 – 3 days Duration of the test: 5 days GEA supervisors: 1 – 2 GEA supervisors: 2 – 3 GEA supervisors: 2 – 3 Number of participants: max. 2 Number of participants: max. 4 Number of participants: max. 4 PID tests (selective) PID and equipment list test PID and equipment list test Functional test (selective) Dimension test Dimension test Documentation review (spot checks) Control cabinet test Gradient and mounting angle test Concluding discussion Visual inspection Control cabinet test

Documentation review Visual inspection and disassembly Functional test: Test of the basic functions Measurement of the ejection volume Temperature measurement (SIP) Concluding discussion

Documentation review Functional test: Test of the basic functions Measurement of the ejection volume Temperature measurement (SIP) Alarm tests Concluding discussion

Installation tests (IQ) | Surface measurement | Fluorescence test | SIP test | Material mix-up test (PMI) | Functional test (OQ)

Calibrated test instruments | Documentation review | Pure steam use | Pure water use (RO)

42 Unlimited process applications

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