Bioprocess Systems

For preparation of plasma factorsand biopharmaceutical APIs

32

Pharma Specialist at Bosch

At Robert Bosch Packaging Technology GmbH, Pharmatec in Dresden is the competence center for pharmaceutical process systems and plants for the production of liquid active substances or medicinal products. In addition, Pharmatec develops and manufactures complete systems for generation, storage and distribution of high purity media for pharmaceu-tical use and the biotechnology industry.

Since 1993, Pharmatec has been one of the technology leaders in this segment of plant construction and benefits greatly from the integration in the Bosch family. Its technological expertise and method competence in research, development and project management provide a resilient foundation to meet the requirements of ”Industry 4.0” with all its options.

The enormous advantages of this far-reaching networking and online integration of industrial production processes makes Pharmatec, together with Robert Bosch Packaging Technology GmbH, beneficial to the pharmaceutical and biotech sector – with fully developed and modern solutions for the production, handling, filling and packaging of pharmaceutical active substances or medication.

Line competence under a single roof: Pharmatec Bosch Packaging Technology

Product life cycle at Bosch

In the interests of its customer companies, Robert Bosch Packaging Technology GmbH has high service requirements: Over the entire product life cycle, we therefore offer all plan-ning and production phases linked together with one another as well as with After Sales Service and Support Offering.

During consulting and project development, customer requirements are in the foreground, which are analyzed based on the planned pro-duction processes and coordinated with the customer.

Project management is the responsibility of a Pharmatec Project Manager who serves as a central contact person. He synchronizes the activities of all project partners in the frame-work of scheduling and technical planning.

For the production process, Pharmatec engi-neers implement the detailed plant concept for production. They inspect the design of all system components, coordinate suppliers and service providers until, after the first complete assembly, all functional tests have been com-pleted.

Assembly on-site by highly qualified specialists also includes the integration of the systems in the technical infrastructure as well as repeated extensive testing up to acceptance by the customer.

For quality assurance, in each Pharmatec pro-ject all work steps from planning up to final inspection are documented extensively and transparently – including endoscopic recor-dings of the welding seams, test reports, inspection reports and material certificates.

After Sales Services are available to the cus-tomer after commissioning for the entire life cycle of his plant. Apart from technical support, this also covers the instruction and advanced training of operating staff and consultation ser-vices for operation or conversion of the plant.

Page 4 Blood plasma fractionationPage 5 Preparation of plasma factorsPage 6 Upstream: Cell growth and reproductionPage 8 Downstream: API productionPage 9 API manufacturing Page 10 Purity to the highest standards

Contents

Blood plasma fractionation

4

Pooledplasma

Effluent I

Fraction I

EthanolEthanol Ethanol Ethanol Ethanol

FibrinogenProthrombin

Factor VIIFactor IX

Factor VIII ofWillebrand factor

Effluent II+III

Fraction II+III

Immunoglobulins

Effluent IV.1

Fraction IV.1

a 1-proteinase inhibitorAntithrombin

Effluent V

Fraction V

Albumin

Cryo-poorplasma

Cryo-precipitate

Thawing

Blood plasma is an indispensable raw material for many pharmaceuticals, including blood clotting products and medicines for treating autoimmune diseases or infections as well as monoclonal antibodies for cancer treatment and highly developed vaccines.

Blood plasma fractionation plays an important role in manufacturing these products, as it comprises separating therapeutic proteins from human plasma followed by purification and concentration.

This process requires a highly controlled infra-structure throughout all phases of production, on the one hand because the raw material is provided by donors and its availability is limited, and on the other hand because high technical requirements must be combined with particu-larly protective process conditions to ensure efficient processing of the blood plasma.

API manufacturing

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The manufacturing of active biopharmaceutical ingredients is divided into two phases. Growing and gradual cultivation of a cell culture and biomass reproduction in fermenter systems are carried out in the upstream process.

The so-called harvest forms the interface to the subsequent downstream process. This includes the depletion, inactivation, extraction and purification of the raw culture, whereby, apart from centrifuges and filtration systems, chromatographs or chemical separating pro-cesses are also used.

The ultra-clean biological active substances thus created serve, after multiple bioanalytical tests, as the basis of modern medication.

Preparation of plasma factors

Upstream: Cell growth and reproduction

Downstream: API production

Two stage nanofiltration system with two filtration circuits, automatic integrity testing and CIP/SIP

5 6 7 8

Blood plasma fractionation

Pilot fermenter

API manufacturingLarge-scale system for continuous fermentation

Pilot fermenter: Modularsystem for laboratory and small industrial batches

The process for preparing plasma factors is technically sophisticated and presupposes a perfectly tuned infrastructure. After all, the four complex process steps involve the efficient processing of valuable donor material to partly highly potent pharmaceutical active substances.

Thawing Blood plasma processing begins with hand-ling deep-frozen plasma bags. The plasma is gently thawed and collected for further pro-cessing at precisely controlled temperatures. A proportion of the proteins (cryoprecipitate) is already precipitated during this step, which is processed to different coagulation factors via centrifugation or filtration procedures.

Fractionation Useful proteins are contained in the remaining plasma elements which can be extracted, for example, using the multistage Cohn fractio-nation process. Ethanol is added to the plasma in increasing concentrations as the tempera-tures fall. Immunoglobulins and albumins are extracted in this process along with additional coagulation factors.

Virus inactivation The proportion of pathogens that may potenti-ally exist in the blood plasma is already con-siderably reduced by fractionation. In the interests of patient safety, however, complete and reliable elimination or inactivation is neces-sary. At least two virus inactivation steps are stipulated by legislation for the production of

plasma products. Pharmatec systems implement these requirements using thermal methods which are subject to stringent process control.

Final purification Following separation of the desired plasma frac-tions, individual proteins are isolated using ad-ditional precipitation processes and chromato-graphic purification steps and concentrated by means of ultrafiltration or cross-flow filtration. The active substance gained from these proces-ses is then available for further pharmaceutical processing following additional quality controls.

A prerequisite for the efficient cultivation and reproduction of cell cultures in fermenter systems is a controlled environment whose parameters can be regulated precisely to ensure the best possible influence on the quality of the end product.

Fermentation Pharmatec provides a wide range of solutions for cell cultivation, which can be combined in numerous ways due to their modular design. All fermentation systems enable substrates, gases and additives to be precisely supplied at controlled temperatures and stirring rates. This allows the targeted level of cell growth to be achieved in the fermenter, enabling efficient product formation at maximum bio-logical activity. The scaling options range from small bioreactors to plants for industrial cultivation of large call volumes.

Harvesting A wide range of technologies is required to ensure efficient, contamination-free separa-tion of the extracted raw culture. In the case of extracellular base products, a purification phase is required in the first step to separate the detritus (cell debris) before the extracted cell material is concentrated using tangential cross-flow filtration. Microfiltration, ultrafiltra-tion and diafiltration system are available for this process. In intracellular raw cultures, the product must first be extracted from the cells by means of centrifugation and cell disruption.

In focus: Continuous fermentation on a large scaleDimensioning of fermenter systems is generally not limited, even though container sizes in the hectoliter range prevail. The shown sample system for dialysis fermentation is based on a media preparation volume of 6 000 liters in a system designed for addition of liquid and powder components and combined with a dedusting and exhaust air cleaning option.

The integrated cleaning circuit comes with a separate CIP pump. The preparation system further includes a 200 liter pre-fermenter, a dialysis fermenter with 2 000 liters capacity and seven storage vessels for lye, antifoam and sub-strate, which hold between 10 and 200 liters. The largest volume represent the two dialysis storage vessels – each with 10 000 liters.

The harvesting module consists of vessels for harvesting (200 liters) and permeate (205 liters) with connected ultrafiltration and separation.The flexible, phase-oriented process control is based on standard industrial interfaces. It is interconnected with a process control system and a recipe management for cleaning of the system.

After the ”harvest”, the raw cultures from the upstream process run through several purifica-tion procedures during which they are finally refined to the active substance. The systems from Pharmatec permit the seamless integra-tion of different technologies and procedures from other manufacturers in accordance with established industry standards.

Chromatography When purifying proteins, several different purification methods are often used consecu-tively. Affinity chromatography is the central method used for accumulating biologically active protein in this process. Pharmatec integrates this technology in customized configured systems, in order to supply com-plete and ready-to-use installations.

Virus inactivation Thermal virus inactivation for depleting poten-tially contained pathogens can be integrated as an intermediate step during purification.

Filtration The concentration of the proteins is carried out with different filtration technologies de-pending on the requirements profile. The most frequently used systems are ultrafiltration or cross-flow filtration. The filtration modules can be permanently integrated in the system or designed as individual mobile systems.

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Purity to the highest standards CIP system for a biotechnical process system with two independent

cleaning circuits for active and inactive substances

Mobile CIP system for condi-tioning of cleaning media for flexible use with different process or filling units

CIP system on stainless steel platform with three tanks for cleaning of mobile storage vessels

Cleaning and sterilization of process systems is of crucial importance in pharmaceutical and biopharmaceutical production. These important auxiliary processes guarantee trouble-free procedures with consistently high product quality. The requirement-oriented design of cleaning facilities also has a strong influence on operating costs.

During the design and layout of CIP/SIP sys-tems, engineers from Pharmatec focused not only on the technical parameters but always on cost-effectiveness. The modular system concept allows efficient and professional project execution within the shortest period of time. All CIP systems have reliable self-cleaning functions and can also be sterilized in place (SIP) on request.

Smaller units can be configured as mobile systems, while larger plants with several vessels are permanently integrated into the infrastructure. This allows for the preparation or intermediate buffering of larger quantities of cleaning media. Different CIP programs can be selected, depending on the vessel type,

product and batch quantity, which enable relevant parameters such as rinsing times, pressure or temperature to be set as required.

Inactivation Pharmatec plants for the thermal inactivation of biologically and chemically contaminated production waste water operate within a varia-ble temperature range of between 80 °C and 135 °C, depending on the level of bacterial contamination. Intelligent control systems ensure the complete decontamination of the waste water with as little energy used as possible.

Pharmatec GmbHA Bosch PackagingTechnology Company

Elisabeth-Boer-Straße 3D-01099 DresdenGermanyTel. +49 351 282 78-0Fax +49 351 282 78-662www.pharmatec.de PA

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