Freeze Dryers

Lyophil Technologies

for the Pharma & Biotech Industry

GEA Pharma Systems

GEA Pharma Systems is world leader in providing

advanced processing solutions for solid dosage forms to

the pharmaceutical industry. Based on a dedication to

research and durable quality, GEA Pharma Systems

offers a wide range of solutions, from individual pieces

of equipment to complete integrated plants, by uniting

the state-of-the-art technologies of Aeromatic, Buck,

Collette, Courtoy, Fielder, Lyophil, Nica and Niro.

Product Know-How

GEA Lyophil’s process expertise is based on

experience and innovation secured by R&D. With

over 1,000 units installed worldwide and literally

thousands of tests performed in GEA Lyophil’s own

test area the company has established a solid base of

expertise related to the needs of the pharmaceutical

and biotech industry.

Delivering the Right Solutions

Every GEA Lyophil freeze dryer originates from the

customer’s desire to create a product that will

succeed in the market. In GEA Lyophil, the customer

finds a partner which will assist in meeting that goal.

GEA Lyophil’s range of supplies and services comprises laboratoryfreeze dryers, the pilot range for R&D purposes and smallproduction batches, industrial size freeze dryers, and completefreeze dryer systems including among others Automatic Loading-and Unloading Systems (ALUS®). In addition the company providesservice and retrofitting of existing freeze dryers.

The design and manufacture of freeze dryers and freeze dryingsystems is carried out inaccordance with all cGMP, CE, GAMP4 and21 CFR Part 11 guidelines.

The company’s expertise in freeze drying and

related processes, i.e. isolator technology,

sterilisation and clean-in-place (CIP) covers all kinds

of pharmaceuticals and biotechnology derived

products, for example, hormones, vaccines,

antibiotics anti-infectives, bacteria, sera, enzymes

and diagnostic agents.

Plants Customized for Success

Every pharmaceutical plant and system from GEA

Lyophil is a unique and efficient combination of

proven technology and individual solutions

reflecting the customer’s needs. Based on standard

components, the company supplies plants for cGMP

production configured to meet the customer’s

specific requirements.

GEA Lyophil can deliver: The right size to meet the

customer’s output demands, the right configuration

for their production and process requirements, and

the right technology to reduce contamination risks.

A Partnership in Every Perspective

Working with GEA Lyophil means entering a solid

and professional partnership every step of the way,

from process testing and design to start up and take

over of the new plant ready for production. GEA

Lyophil’s comprehensive after sales program ensures

that return on investment is optimised throughout

the lifetime of the plant.

Process Expertise

3

•

Expertise

4

ProvenTechnology

For more than half a century GEALyophil has designed and manufacturedfreeze dryers for the pharmaceutical andbiotech industry.

During this time the company has remained

dedicated to the development of freeze dryer

technology and has contributed substantially both to

design and process control as shown in the

illustration below.

GEA Lyophil was one of the first freeze drying

companies to deliver Automatic Loading and

Unloading Systems (ALUS®) for freeze dryers and

integrate isolators and CIP-Skids into a complete

system with freeze dryer and ALUS.

1950 1960 1970

1951

First LYOVAC®

Freeze Dryer built

by Leybold

1959

Patent for PRM

(Pressure Rise

Measurement)

1969

Cryomicroscope

1975

Eutectic Monitor

for Resistance

Measurements

1980

Mushroom Valve

as Chamber/

Condenser Valve

1985

Patent

Nitrog

Conde

1952

Application

Laboratory

1960s

Pilot and

Production Scale

Freeze Dryers

1982

Lyo Process

Control

•

Innovation

5

Preventing Sticking Stoppers

Sticking Stoppers may occur while the vials are

closed (stoppered) in the freeze dryer. Stoppering is

achieved by moving the shelves downwards so that

the pressure of the shelves inserts the stopper into

the vials. Sometimes, when the shelves are moved

up again, the stoppers stick to the upper shelf; they

can fall down and cause damage to other vials. GEA

Lyophil prevents sticking stoppers by:

• Optimising the hydraulic stoppering system by

combining the necessary pressure for closing the

vials with an adjusted dwell. This is achieved by an

intelligently-controlled hydraulic system.

• Adjusting the shelf surface to minimize adhesive

forces.

- Achieving a surface finish of the lower side of

the shelves of Ra 2,0.

- Coating of the lower side of the shelves (incl.

FDA approval) to achieve a lotus effect.

This process does not involve any changes to the

stoppers or any additional costs.

Fast Track Projects

In the pharmaceutical industry ‘time to market’ is

critical. To help manufacturers bring new products

to market as quickly as possible GEA Lyophil has

pioneered its Fast Track process for pharmaceutical

freeze drying projects, with or without ALUS®

(Automatic Loading and Unloading System), that

can reduce lead times for plants to less than 9

months.

Fast Track from GEA Lyophil is a practical and

proven process that keeps construction and

commissioning time to a minimum. By a

combination of careful project management and the

transfer of many manufacturing processes to the

customer’s site, the need for a FAT (Factory

Acceptance Test) can be eliminated allowing

commissioning times to be reduced dramatically.

GEA Lyophil is the largest supplier to the

pharmaceutical contract manufacturing industry

globally. In recent years more than 20 production

freeze dryers have been delivered by the Fast Track

system, installed and gone into production.

Brilliant but deceptively simple ways to preventsticking stoppers and to shorten lead times.

1980 1990 2000

5

t for Liquid

gen

enser

1997

Delivery of first

ALUS with Isolator

technology to

Pharmaceutical

Industry

1988

Dome Device

and BTM

1989

ALUS®

1997

ISO 9001

Certification

1998

TLC®

1999

Merger with

STERIS

2005

GEA Lyophil

GmbH

2006

VAPOVAC®

and FALCO

compact

Pharmaceutical andBiotech Industry

6

In the aseptic pharmaceutical production as well as in the biotech area,Freeze Drying, or Lyophilization has a key role as the main fill and finishprocess, handling liquid products and formulations in solutions.

Why Freeze Dry?

Freeze dried products retain their original

properties.

By adding water or other solvents they can be

reconstituted easily and very quickly to a usable

solution. There is no need for cooling during storage,

therefore storage costs decrease and handling is

made easier.

•

Applications

7

There is a wide range of substancesfor which freeze drying is used asconservation method:

Antibiotics, Bacteria, Vaccines, Hormones, Vitamins,

Enzymes, Ferments, Peptides, Liposomes, Collagen,

Plant extracts, Liver extracts, Radio-immuno-essays,

Blood plasma, Plasma fractions, Antibodies.

Commonly, water is used as solvent,

but in some cases pharmaceutical products need

solvents based on alcohol. In this case the freeze

drying process and subsequently the design

of the equipment will comply with ATEX guidelines.

GEA Lyophil is able to support its customers in the

installation and operation of a reliable, validated

lyophilization process for pharmaceuticals and

biologicals.Pilot freeze Dryer FCM 2

Product Line

Freeze Dryer

8

GEA Lyophil’s freeze dryer product line comprises laboratory freezedryers, pilot plants for R&D purposes or small production batches,industrial size production freeze dryers as well as complete freezedryer systems consisting of one or multiple freeze dryers plus ALUS®(Automatic Loading and Unloading System) and isolators.

FCM 20

View into chamber

of a FCM 600-D

FCM 80-D and

FCM 500-D with

Transfer Cart

FCM 2

Production SystemsAutomation and highest contamination prevention

The handling of pharmaceutical substances such as

cytostatics creates a high need for operator and product

protection.

A typical Freeze Dryer Production System incorporates

the following components:

• Multiple Freeze Dryers

• Automatic Loading and Unloading Syste (ALUS®)

• Common CIP-Skid

• Isolator or RABS

• SCADA System

Lab UnitsFor Laboratories, Universities and Research Institutes

• Shelf Size 0.1 - 0.3 m2

The smallest Freeze Dryer unit in the product line serves the

following purposes:

• First product development steps

• Preparation of substances for analysis, e.g. biomasses

• Teaching and demonstrating of the freeze drying process

Pilot PlantsFor R & D and Small Scale Production

• Shelf Size 0.4 - 8 m2

GEA Lyophil offers Pilot Plants for the following applications:

• Product development and process cycle optimisation

• Up Scaling of the process for later use in Production Plants

• Small scale production especially by Biotech customers

Production PlantsLarge scale production plants built to customer specifications

• Shelf Size 8 - 58 m2

GEA Lyophil production Freeze Dryers are either non sterilisable

units or steam respectively VHP sterilisable units for e.g.

• bulk drying for intermediate products

• blood plasma and proteins

• diagnostic agents

• sensitive components

•

PlantComponents •

9

Cold Sterilisation as an Alternativeto Steam Sterilisation

VHP Sterilisation for Freeze Dryers

Usually freeze dryers are sterilised by using steam.

GEA Lyophil is the only manufacturer to offer an

alternative: sterilisation by vaporized hydrogen

peroxide. The VAPOVAC Steriliser, which is

connected to the freeze dryer, generates vapour of

hydrogen peroxide, which is lead into the chamber

and condenser of the freeze dryer.

The sterilisation process takes approximately 3 h

depending on the performance of the vacuum

pumps; a much shorter cycle time compared to

steam sterilisation.

The VAPoVAC Steriliser offers the following

advantages:

Cost saving:

• Lower investment

costs and lower

operational costs

• Short process time

• Longer service

intervals

Reliable and safe

process

• Kills a variety of germs

• Achieves equal distribution of steriliant

• No toxic residues

• Easy and safe handling

Retrofitting an existing freeze dryer with a

VAPOVAC Steriliser is a good means of lengthening

its life cycle. A few changes to hardware, and some

software adaptation would be necessary – a minimal

effort in time and cost compared to equipping a

non-sterilisable unit with steam sterilisation. After

the retrofit the freeze dryer will meet current FDA

standards and can provide several more years of

service.

Proven modules built together offer thepossibility of choosing either a cost-effective or a highly customised system.Each module and system componentmust meet the strictest requirements andregulatory standards around the world.

Features of the freeze dryers include:

• Choice of configurations, e.g. monoblock, 2-floor

configurations

• Various door configurations, including re-cooling,

slot doors and many more

• Reciprocating and screw compressors systems as

well as LN2 cooling systems

• Automatic CIP (Clean-in-Place) and SIP

(Sterilisation-in Place) systems offer product

protection, prevent contamination and increase the

productivity by allowing a reduction in the number

of staff needed to operate the equipment

• Automatic WIT (Water Intrusion Test) of the

venting filters ensures integrity and increases the

availability of the unit

• Monitored stainless steel stoppering bellow

• Proven vacuum pump system technology

• VHP Technology: a cost saving and

environmentally friendly alternative to steam

sterilisation

• SCADA system for controlling and monitoring of

reproducible and documented processes, meeting

21 CFR Part 11 regulation

SterilizationMethods •

10

The choice of freeze dryer is driven by a variety of

different requirements with regard to:

• Features of the pharmaceutical product

• Manufacturing needs

• Space

Based on proven technology GEA Lyophil designs freezedryers tailored to its customers’ needs. This has resulted ina wide range of different plant configurations someexamples of which are shown on these pages.

2 - Floor Installation

Tailored plantconfigurations •

Freeze Drying

11

Slot Door (Pizza Door) for ALUS

Door-in-Door Design for Loading/Unloading

and Maintenance at the same side

FCM design with

condenser at the rear

side of the chamberFull Size Door

Slot Door (Pizza Door) for ALUS

Door-in-Door Design

Full size Door

Features of the pharmaceutical product

For many customers it is vital to

minimise contamination risks, both

product as well as the operators have to

be protected. In this case a production

system including Freeze Dryer, ALUS and

isolators is the right choice.

Manufacturing needs:

Integration into a pharmaceutical

production line may determine whether

the freeze dryer will be loaded and

unloaded at the same side, or

loaded at one side and unloaded

at the opposite side.

Space:

GEA Lyophil offers different plant

configurations such as single or two-floor

installation when choosing the GT

concept. The compact modular FCM

construction with its small footprint is

ideal for limited space on a single level.

Increase Efficiency

Minimisingcontamination risks

12

Efficient, safe and reliable performance with the

following key features:

• High throughput with loading speed of up to

400/800 vials per minute and unloading speed of

up to 700 vials per minute

• High flexibility for different vial formats

• High safety of operation and stability for all vial

formats, even small ones with a diameter/height

ratio of <3

• Quality sanitary design with rounded corners for

easier cleaning

• Good integration of Freeze Dryer

and ALUS

• Smooth transition of vials from ALUS to Freeze

Dryer by patented design

• No moving parts above open vials for greater

safety

• Frameless operation

• Design complies to zone concept: no machine

drives in vial processing area

• Constant Laminar Air Flow when using a transfer

cart: The LAF unit moves towards the Freeze Dryer

and covers the vials during the loading process

Human intervention in the loading of the freeze

dryer means the highest risk of contamination. The

use of ALUS minimises this risk as the number of

operators in this area can be reduced, therefore less

operator monitoring for contamination is necessary.

At the same time the automated loading and

unloading process is much shorter compared to

manual loading.

GEA Lyophil has designed and manufactured ALUS

since 1989, and was one of the first manufacturers to

develop this technology using permanently installed

systems, as well as automatic guided vehicles (AGV).

ALUS® (Automatic Loading and Unloading Systems)

Freeze Dryer with

ALUS (Conveyor-

Pusher-System)

•

Enabling PAT

13

ThermodynamicLyophilization

A safe, reliable, reproducible process is essential to

ensure that pharmaceutical and biological products

have the specified properties and quality. In fact the

FDA’s PAT (Process Analytical Technology) initiative

demands thorough process understanding, careful

monitoring and control. Also with the continuing

trend towards more process automation; with

automatic loading and unloading systems and in

some cases isolators, in an effort to minimize

contamination risks and meet sterile processing and

validation regulations. This trend depends on

increasingly sophisticated monitoring methods to

control the freeze drying process.

TLC is a process analysing, monitoring and control

tool for Freeze Drying in R+D applications and for

full-scale production.

The TLC has been developed as an in-line, non-

invasive method of:

• Monitoring the primary (main) drying

• Determining the end of the main drying

• Monitoring the secondary drying

• Determining the end of the secondary drying

TLC enables a dynamic control of the drying

process: minor variations – e.g. of the raw product

or the filling height of the vials – will be identified

and the process will be adjusted accordingly.

Advantages

• Applicable for all freeze dryers

• Ideal for sterile processing

• Ideal with automatic loading and unloading

systems

• Ideal when isolator technology is used

• No need for mechanical modifications at the freeze

dryer

• No risk of contamination

• Reproducible measurements

• Direct & accurate lyophilization monitoring and

control

• Monitoring of the complete batch during the whole

drying process

• Enables optimization of the freeze drying process

cycle

• No influence on the product by short measuring

times

• Process data easy to scale-up

• Delivers comprehensive data for better process

understanding

During the freeze drying process, the ice temperatureis the key parameter to monitor and control!

-80

0:00 3:00 6:00 9:00 12:00 15:00 18:00 21:00

Shelf Temperature

Product Temperature measured with thermo probes

Ice Temperature measured with TLC (or BTM)

24:00 27:00 30:00 33:00 36:00

-60

-40

-20

0

20

40

0,001

0,01

0,1

1

10

100

1000

Tem

per

atu

re˚C

Ch

amb

erp

ress

ure

mb

ar

Load

ing

Free

zin

g

Prim

ary

Dry

ing

Freeze Drying Cycle

Seco

nd

ary

Dry

ing

Un

load

ing

Freeze drying cycle

•

Freeze DryingExpertise

14

•

Retrofit

From pre-engineering studies, to the specification of

the plant and SAT, (Site Acceptance Test) to

qualification and validation support, GEA Lyophil’s

experts remain on hand to ensure that the

equipment operates efficiently and reliably within

the shortest possible time frame.

On hand throughout the whole life cycle of the plant.

Professional training of customers’ operators,

preventive maintenance together with excellent

parts availability and application support guarantees

the trouble fee and profitable operation of GEA

Lyophil freeze dryers. GEA Lyophil’s retrofit

expertise enables customers to extend the life of

their freeze dryers and to cope with changing

requirements and regulations.

15

Services

Scada Design(MW & SW)

PLC Design(MW & SW)

Electrical &Mechanical Design

GxP & Safety Review Module & Integration Tests

Installation Qualification

Operational QualificationFunctional Specification

User Requirements

PlanningCustomerresponsibilty

GEA Lyophilresponsibility

Joint tasks

Performance Qualification

Validation Report

Electrical & MechanicalConstruction Practice

Build PLC. Good ProgrammingPractice & Source Code Review

Build Scada. Good Programming& Practice & Source Code Review

Retrofits

Retrofits include:

• Optimisation and upgrading of process control

systems including IQ/OQ’s, e.g.

- In compliance with 21 CFR Part 11

- Adaption from Siemens S5 to Siemens S7

• Integration of new process features

in existing references and revamping of

mechanical components and/or existing freeze

drying plants

- Integrity test

- VHP sterilisation

- New shelf package

- ALUS

- Refrigeration system or comp-onents

Services

Services includes:

• Preventive maintenance contracts

• Spare parts

• 24 h/d 7d/week Hotline

• Operator Training

• Calibration Services

• Qualification Services

• Validation Services

Application Support

Assistance in product cycle optimisation via:

• Cryomicroscopical examinations

• Electrical resistance and temperature measurements

• Residual moisture measurements (Karl Fischer

Method)

• Determination of the eutectic point

• Thermodynamic Lyophilization Control (TLC®)

• Freeze drying test campaigns in own pilot freeze

dryers

www.geapharmasystems.com

GEA Pharma Systems

GEA Lyophil GmbH

Kalscheurener Strasse 92, D-50354 Hürth, Germany

Tel: +49 2233 6999-0, Fax: +49 2233 6999-10

info@gea-lyophil.com

Central Know-How on a Global Scale

Based on a strong commitment to

research and development,

pharmaceutical technology centres in

Belgium, Denmark, Switzerland, the UK,

Singapore, and USA provide global

technical support and know-how to the

pharmaceutical industry. These centres

of excellence give customers access to a range of test facilities and expert

teams with technical and process know-how. Our teams work closely with

our customers to optimise processes and evaluate their products, enabling

them to achieve their process and production goals.

Contracting Profitable Experience

A world leader in supplying

pharmaceutical equipment, GEA Pharma

Systems offers manufacturers all over

the world the opportunity to enter into a

profitable partnership for development

and contract. GPS combine advanced in-

house technology with a thorough

understanding of the pharmaceutical industry to help customers maximize

their development results.

©GEAPh

armaSystem

s2008

Specificationssubjectto

change

without

noticeAlltradem

arks

recognized