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
Process Expertise

GEA Lyophils range of supplies and services comprises laboratory freeze dryers, the pilot range for R&D purposes and small production batches, industrial size freeze dryers, and complete freeze dryer systems including among others Automatic Loadingand Unloading Systems (ALUS). In addition the company provides service and retrofitting of existing freeze dryers. The design and manufacture of freeze dryers and freeze drying systems is carried out inaccordance with all cGMP, CE, GAMP4 and 21 CFR Part 11 guidelines.

GEA Lyophils 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 Lyophils 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 customers 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.

The companys 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 customers needs. Based on standard components, the company supplies plants for cGMP production configured to meet the customers specific requirements. GEA Lyophil can deliver: The right size to meet the customers 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 Lyophils comprehensive after sales program ensures that return on investment is optimised throughout the lifetime of the plant.

Expertise
Proven Technology

For more than half a century GEA Lyophil has designed and manufactured freeze dryers for the pharmaceutical and biotech 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

1952
Application Laboratory

1959
Patent for PRM (Pressure Rise Measurement)

1960s
Pilot and Production Scale Freeze Dryers

1969
Cryomicroscope

1975
Eutectic Monitor for Resistance Measurements

1980
Mushroom Valve as Chamber/ Condenser Valve

1982
Lyo Process Control

1985

Patent

Nitrog

Conde

Innovation

Brilliant but deceptively simple ways to prevent sticking stoppers and to shorten lead times.
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 customers 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.

1980

1990

2000

1988
Dome Device and BTM

1989
ALUS

1997
ISO 9001 Certification

1997
Delivery of first ALUS with Isolator technology to Pharmaceutical Industry

1998
TLC

1999
Merger with STERIS

2005
GEA Lyophil GmbH

2006
VAPOVAC and FALCO compact

t for Liquid

gen

enser

Pharmaceutical and Biotech Industry

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 finish process, 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

There is a wide range of substances for which freeze drying is used as conservation 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

Freeze Dryer
Product Line

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

FCM 80-D and View into chamber of a FCM 600-D FCM 500-D with Transfer Cart

Production Plants
Large 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

Production Systems
Automation 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

FCM 20

FCM 2

Pilot Plants
For R & D and Small Scale Production Shelf Size 0.4 - 8 m
2

Lab Units
For 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

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

Plant Components

Sterilization Methods

Proven modules built together offer the possibility of choosing either a costeffective or a highly customised system. Each module and system component must meet the strictest requirements and regulatory 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

Cold Sterilisation as an Alternative to 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.

Tailored plant configurations

Based on proven technology GEA Lyophil designs freeze dryers tailored to its customers needs. This has resulted in a wide range of different plant configurations some examples of which are shown on these pages.

The choice of freeze dryer is driven by a variety of dierent requirements with regard to: Features of the pharmaceutical product Manufacturing needs Space

2 - Floor Installation

10

Freeze Drying

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. Full Size Door

FCM design with condenser at the rear side of the chamber

Door-in-Door Design for Loading/Unloading and Maintenance at the same side Slot Door (Pizza Door) for ALUS

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.

Full size Door

Door-in-Door Design Slot Door (Pizza Door) for ALUS

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Increase Efficiency
Minimising contamination risks

ALUS (Automatic Loading and Unloading Systems)

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). Freeze Dryer with ALUS (ConveyorPusher-System)

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

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Enabling PAT
Thermodynamic Lyophilization

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

A safe, reliable, reproducible process is essential to ensure that pharmaceutical and biological products have the specified properties and quality. In fact the FDAs PAT (Process Analytical Technology) initiative demands thorough process understanding, careful
Temperature C
40 20

Freeze Drying Cycle

1000

100

Secondary Drying

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.

-20

Unloading

Freezing

monitoring and control. Also with the continuing

10

-40

0,1

-60

0,01

-80 0:00 3:00 6:00 9:00 12:00 15:00 18:00 21:00 24:00 27:00 30:00 33:00

0,001 36:00

Shelf Temperature Product Temperature measured with thermo probes Ice Temperature measured with TLC (or BTM)

Freeze drying cycle 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, noninvasive 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

Chamber pressure mbar

Loading

Primary Drying

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Retrofit
Freeze Drying Expertise

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 Lyophils retrofit expertise enables customers to extend the life of their freeze dryers and to cope with changing requirements and regulations.

On hand throughout the whole life cycle of the plant.

From pre-engineering studies, to the specification of the plant and SAT, (Site Acceptance Test) to qualification and validation support, GEA Lyophils experts remain on hand to ensure that the equipment operates efficiently and reliably within the shortest possible time frame.

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Services

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

Retrofits Retrofits include: Optimisation and upgrading of process control systems including IQ/OQs, 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

Planning
Customer responsibilty

Validation Report Performance Qualification

User Requirements

Functional Specification
Joint tasks

Operational Qualification Installation Qualification Module & Integration Tests

Scada Design (MW & SW)

PLC Design (MW & SW) GxP & Safety Review

Electrical & Mechanical Design

Electrical & Mechanical Construction Practice

GEA Lyophil responsibility

Build PLC. Good Programming Practice & Source Code Review Build Scada. Good Programming & Practice & Source Code Review

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www.geapharmasystems.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
GEA Pharma Systems 2008 Specifications subject to change without notice All trademarks recognized

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 inhouse technology with a thorough understanding of the pharmaceutical industry to help customers maximize their development results.

GEA Lyophil GmbH Kalscheurener Strasse 92, D-50354 Hrth, Germany Tel: +49 2233 6999-0, Fax: +49 2233 6999-10

GEA Pharma Systems

info@gea-lyophil.com