Pharmatec GmbHProcessing and Biotechnology systems

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Pharmatec GmbHA Bosch Packaging Technology Company

Elisabeth-Boer-Straße 3 01099 Dresden GermanyTel. +49 351 2 82 78-0Fax +49 351 2 82 78-662www.pharmatec.de

Printed in Germany100 % chlorine free paper

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Upstream and downstream biotechnology units from Pharmatec

Processing and bio-technology systems from Pharmatec

Preparation systems, units for fermentation and purification In the field of biotechnology and processing units, Pharmatec develops, constructs and produces the following: Preparation units for hygienic,

aseptic and sterile processes, with isolation technology

Systems for inactivation and neutralization

Systems for sterile filtration Integration/complementing of

upstream and downstream processes Fermentation systems

(in cooperation with partners) Sterilization units for substrate

solutions Provision of buffers for chromato-

graphy units with fraction collectors Systems to provide buffers and

prepare substrates Harvest lines Filtration systems (nanofiltration,

crossflow and ultrafiltration)

Isolating and purifying substances extracted by means of bioprocessing is a multi-level process which sets high demands in terms of unit technology and process control. As a unit manufacturer, Pharmatec is a global service provider acting as a partner to the pharmaceutical industry. Fermentation media are complex mixtures of different substances where the final product is intra-cellular or in a diluted solution. At 40 % – 90 %, the recon-ditioning costs make up a considerable amount of manuf-acturing costs. The steps of separating out the solid phase, cell disruption, concentration, purification and formulation all come under the heading of downstream processes. The solids can be separated using means such as filtration, centrifugation and sedimentation. Cell dis-ruption can be caused by mechanical methods, by osmo-

tic pressure or using enzymes. Pharmatec delivers units for the preparation of buffer media and integrates units for filtration and add-on chromatography units. For the buffer preparation, the solid or liquid buffer substances are placed in the containers and dissolved in purified water or WFI (water for injection). Using ultrafiltration modules integrated in the unit, the final product is con-centrated before further reconditioning steps and after chromatography steps. During filtration, other compon-ents can be measured in depending on the conductivity and permeate flow. A chromatography unit integrated into the unit is available to further purify the product. The buffer is supplied and the fractions collected using the containers in the processing unit.

Example of a downstream processing unit (1 x 200 l, 4 x 600 l, 1 x 1,200 l)

Contact Pharmatec for the planning, development and production of: Upstream and downstream biotechnology units Preparation systems CIP/SIP units Wastewater deactivation units

The growing amount of active substances which are produced using biotechnology is changing the structure of pharmaceutical production units. Highly complex biochemical reaction mechanisms demand higher and higher levels of purity and thus more efficient purifica-tion steps in the units. Pharmatec’s processing and biotechnology systems are characterized by many years of experience in development and construction, as well as of uncompromising production quality.

Overview of processing systems Preparation units for hygienic, aseptic and sterile processes, with isolation technology Storage systems with transfer pipes Systems for inactivation and neutralization Systems for sterile filtration Transfer and handling systems

Overview of biosystems Integration/complementing of upstream and downstream processes Fermentation systems Sterilization units for substrate solutions Provision of buffers for chromatography units with fraction collectors Harvest lines Filtration systems (nanofiltration, crossflow, ultrafiltration)

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Bioprocess expertise from Pharmatec

Controlling the unit using PLC – at the client’s request Operation with an operating panel or PC (various visualization systems possible) Complies with 21 CFR 11 Can be connected to a higher-level process

controlling system Control in accordance with GAMP Construction avoids dead legs Pipes and fittings laid out to enable complete

evacuation Built entirely in 1.4404 or 1.4435 premium steel

Pharma Biotech procedures

Media Protection and Substrate Preparation

Sterilization

Fermentation

Product Packaging

Sterilization

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Residual disposal

ExpertisePharmatec

Product

Surface roughness < 0.8 µm Welding mainly carried out using orbital welding

technique Unit documentation in accordance with FDA Optional: design in 1.4539 premium steel Optional: Smoother surface thanks to special

treatment such as electropolishing Optional: Additional tests such as video endoscopy,

X-ray test Optional: Compliance with delta-ferrite content

pursuant to BN2

Example of a bioprocessing unit (2 x 1,000 l)

Harvesting

Product Purification

Integration of filtration systems (UF/NF)

Integration of separators

Integration of chromatographs

Integration of buffer/ processing vessels

CIP

CIP

ExpertiseBoschbusiness union

Upstream and downstream biotechnology units from Pharmatec

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Preparation systems from Pharmatec

Preparation system expertise from Pharmatec

Some of the main components of a preparation system are: Pressure-resistant processing

containers in accordance with guidelines on pressurized devices, with or without double wall

Magnetic mixers with frequency regulator

Sterile ventilation and product filters with certified integrity

Pumps: circulation, metering, vacuum or transfer pumps

Valves Calibrated meters Automation system and process

control Integration of preparation isolators

Example of a preparation system (preparation vessels 3 x 500 l, 1 x 50 l; buffer vessel 1 x 125 l; CIP vessel 150 l)

Preparation systems with RAPS (Restricted Access Barrier Systems)Pharmaceutical processing units are becoming more and more complex, and set extremely high demands for operator safety, protection against contamination and product protection, not only in the field of bioproces-sing. Despite the degree of automation in the field of preparation, manual interventions are absolutely neces-sary to implement formulations. Processing units to produce cytostatics or other products which inhibit cellular growth often require manipulation when adding active substances and solid or liquid substances in extremely small pre-weighed quantities. In this case, precise doses can only be added manually. The ideal solution for a method which is very safe, protects the operating staff and protects the product from contami-nation is “Restricted Access Barrier Systems”, or RAPS for short, or isolators. Both companies have a long tradition of the combination and connection of Pharma-tec processing units with Bosch isolator systems, proce-dural calculation, and expertise in cleaning and sterili-zing complex isolator/unit systems.

Example of a preparation isolator

Pharmaceuticals are substances or preparations which are designed for use on or in the bodies of humans or animals. The fundamental rules for their quality and the substances and processes used in manufacturing them are clearly defined and described in international laws. These sets of rules are used as a principle in planning and project plan-ning for sterile preparation systems. The high standards set down for cleanliness and sterility when manufacturing pharmaceuticals reveal the obvious value placed upon processing units of this type in the pharmaceutical industry. Pharmatec has made this high status the focus of its core business and can provide complete production units for manufacturing parenteral or oral products all over the world. Due to the variety of different processing steps and technological procedures, concepts for preparation lines vary; Pharmatec engineers adjust them to fit custo-

mers’ requirements perfectly. Procedural processes for the manufacturing of the above products often start with the introduction of raw and auxiliary materials, with liquids or solids being measured out extremely precisely using weighing systems or flow rate metering. Mixing processes with high-performance mixers which are gentle on the product; temperature control procedures with extremely close tolerances and very high precision, and sterilization programs, secure the long-term future of the company’s processing expertise in pharmaceuti-cal unit construction. To maintain values such as the pH value, conductivity, concentration and density, which are critical to the process, process engineers and auto-mation engineers create special program flows which are turned into GAMP-compliant automation systems to fulfill the customer’s wishes.

Processing and Biotechnology systems | 9

CIP/SIP units from Pharmatec

Mobile CIP systems from Pharmatec

CIP/SIP biotechnology units from Pharmatec are individually adjusted to customers’ requirements. Pharmatec develops, constructs and manufactures CIP/SIP units for: cleaning buffer preparation

systems, fermenters, filling machines

single vessel (mobile or fixed) or complex multi-vessel units closed-loop or single-use cleaning

systems complete integration into the

processing units to be cleaned

Pharmatec’s services: Advice and planning, all the way down to putting together one or more CIP unit sy-stems, including the supply and return lines to the processing units and piping to be cleaned. To automate the process, validated software modules are used to create a greater degree of standardization. The start- up and qualifying costs are reduced thanks to effective project planning. At the same time, the high reliability of the tried and tested fast-track module increase the units’ availabi-lity, allow them to be inspected safely, make troubleshooting easier and thus contribute to the safety and reproducibility of the procedures.

Pharmatec’s mobile cleaning centre is designed as a CIP unit and automatically carries out procedural steps in the cleaning of important components which come into contact with products in processing units and filling and packaging machines. The unit is designed as a mobile unit which is ready for immediate operation.

Components: Tank, 500l, for cleaning solution/rinsing water CIP supply pump with built-in frequency converter CIP return pump with built-in frequency converter Measuring pumps for adding alkaline and acidic cleaning agents Electric/steam heated exchanger Chassis (approx. 2,500 x 1,200 x 2,000 mm [L x W x H]) Pipes, valves Pressure reduction and sterile filter for compressed air Metering and regulating devices Control cabinet with power section and unit control Electrical and pneumatic installation Control system with operating system External interface

Conceptual diagram of CIP unit Compact, modular unit structure Tried and tested standard compo-

nents used from selected suppliers Design with little or no dead space

makes it easy to clean yourself Optional: SIP design (for inline

sterilization)

Example of a four-vessel CIP unit (4,000 l RW-model; 3 x 2,000 l pre-rinsing water, acid, leach)

CIP – Cleaning in PlaceSIP – Sterilization in PlaceDIP – Drying in Place

CIP return

Shell-and-tube heat exchanger

CIP supply

Metering pump

Detergents

CIP tank

Item to be cleaned

Mobile CIP unit

Processing and Biotechnology systems | 11

Wastewater inactivation units from Pharmatec

Inactivation units from Pharmatec

Biotech procedures to produce active substances are widespread in the pharmaceutical industry. One important link in the production chain is disposing of production waste. The law sets down regulations on this point to minimize risks to people and to the environment. For inactivation, a wide temperature range is available, from 80 – 135°C, which can be selected depending on the type and concentration of the bacteria to be inactivated. Thanks to the construction of the unit and the controls, which are adjusted to it, the wastewater is kept in the unit in liquid form above boiling (at normal pressure).

Pharmatec develops, constructs and produces inactivation units which can run continuously. Thermal inactivation of wastewater

contaminated with biological materials Treated wastewater fulfils all legal

requirements (safety level BSL 1, BSL 2, BSL 3)

Lower energy use than with units which do not run continuously

Example of an inactivation unit which runs continuously (2,500 –4,000 l/h)

Thanks to the adjustable volume flow at which the wastewater is conducted through the unit, the inactiva-tion level can be adjusted to the quantity of wastewater occurring at any time. This minimizes energy-sapping starting-up and switching-off procedures. The heat maintenance section is designed as a coil and also acts as the base of the unit. Above it come three heat exchangers (heater, recuperator, cooler). To detect any leaks, the base stands in a basin equipped with liquid sensors.

Biosafety level (BSL) classification

When dealing with biological agents such as viruses, bacteria and fungi, corresponding safety regulations must be complied with in accordance with the law on genetic engineering. Depending on the biosafety level, the danger of infection due to contact with the biologi-cal agents must be avoided by using appropriate sealant systems (e. g. double mechanical seals with isolating pressure vessels), (de-)aeration, sampling systems and sterile barriers.

BSL 1 Risk level: Very little or no risk to individuals or the

population. Potential risk: Humans or animals are not expected

to fall ill.

BSL 2 Risk level: Moderate risk to individuals, low risk to

the population. Potential risk: Humans or animals may fall ill, but

there is no serious danger to lab personnel, the population, livestock or the environment. Contacts in the lab can lead to successful infection but effective treatment and prevention measures exist. There is limited risk of spreading.

BSL 3 Risk level: High risk to individuals, low risk to the

population. Potential risk: Humans or animals are expected to

become seriously ill, but it is not usual for the infec-tion to spread from one infected host to the next. There are effective treatment and prevention measures.

BSL 4 Risk level: High risk to individuals and the population. Potential risk: Humans or animals are expected to

become seriously ill, but it is not usual for the infec-tion to spread from one infected host to the next. There are effective treatment and prevention measures.