GE Healthcare QuixStand™ benchtop systems Operating Instructions Original Instructions Table of Contents Table of Contents 1 Introduction .............................................................................. 5 1.1 1.2 1.3 2 Safety instructions................................................................. 17 2.1 2.2 2.3 2.4 3 7 Operation overview .............................................................................................. 33 Starting the instrument ...................................................................................... 34 Starting the system .............................................................................................. 36 Constant volume diafiltration .......................................................................... 38 Pressurized feed reservoir ................................................................................. 38 High flow pump tubing (size 18) ..................................................................... 39 Autoclaving .............................................................................................................. 39 Procedures after operation .............................................................................. 39 Maintenance ........................................................................... 41 5.1 5.2 5.3 6 Site requirements .................................................................................................. 25 Unpacking ................................................................................................................. 25 Assembly ................................................................................................................... 26 Connections ............................................................................................................. 32 Spare parts and accessories ........................................................................... 32 Operation ................................................................................ 33 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 5 Safety precautions ............................................................................................... 17 Labels .......................................................................................................................... 21 Emergency procedures ...................................................................................... 21 Recycling procedures .......................................................................................... 23 Installation .............................................................................. 25 3.1 3.2 3.3 3.4 3.5 4 Important user information ................................................................................. 6 Regulatory information ......................................................................................... 8 Instrument ................................................................................................................ 10 Inspection ................................................................................................................. 41 User maintenance schedule ............................................................................ 41 Storing the system ................................................................................................ 41 Troubleshooting ..................................................................... 43 Reference information .......................................................... 49 7.1 7.2 Specifications .......................................................................................................... 49 Ordering information ........................................................................................... 50 QuixStand Operating Instructions 28-9646-70 AA 3 Table of Contents 4 QuixStand Operating Instructions 28-9646-70 AA Introduction 1 1 Introduction Purpose of the Operating Instructions The Operating Instructions provide you with the instructions needed to handle QuixStand in a safe way. This user guide describes how to assemble and use the QuixStand bench top system. Topics include a product description, assembly instructions, operation instructions, and maintenance procedures. Prerequisites In order to operate QuixStand safely and according to the intended purpose the following prerequisites must be met: • You should be acquainted with the use of general laboratory equipment and with handling of biological materials. • You must read Chapter 2 Safety instructions‚ on page 17 of these Operating Instructions. • The system should be installed according to the instructions in Chapter 3 of these Operating Instructions. In this chapter This chapter contains important user information and a general description of QuixStand and its intended use. QuixStand Operating Instructions 28-9646-70 AA 5 1 1.1 Introduction Important user information 1.1 Important user information Read this before using QuixStand All users must read the Safety Instructions in Chapter 2 of these Operating Instructions before installing, using or maintaining the system. Do not operate QuixStand in any other way than described in the user documentation. If you do, you may be exposed to hazards that can lead to personal injury and you may cause damage to the equipment. Intended use QuixStand is a bench top system intended for laboratory-scale filtration of biological solutions using hollow fiber membrane cartridges under the conditions stated in this manual. If you use the system and cartridges in a manner not specified by GE Healthcare, you may impair the protection provided by the system and cartridges. When using any laboratory, pilot-scale, or production cross-flow filtration equipment, the potential exists for personal injury unless you follow established safety procedures. When using GE Healthcare products, you should follow OSHA, federal, state, and local safety regulations for equipment installation and operation. You should follow your company’s safety regulations and good engineering practices. You should follow the specific safety instructions provided in this manual and in the operating guides of any user supplied equipment. Only qualified personnel who are adequately trained and who understand the operating instructions should install, operate, maintain, and inspect the QuixStand system. These Operating Instructions address the needs of scientists, process engineers, and technicians who operate laboratory-scale cross-flow filtration systems. The level of information presented in this guide assumes the user possesses basic laboratory and technical skills, and has the knowledge and documentation to safely operate any user supplied equipment connected to the QuixStand bench top system. If you need assistance with the instructions in this guide, contact GE Healthcare for more information. Safety notices These Operating Instructions contain WARNINGS, CAUTIONS and NOTICES concerning the use of the product, with meanings as defined below. 6 QuixStand Operating Instructions 28-9646-70 AA Introduction 1 Important user information 1.1 WARNING WARNING indicates a hazardous situation which, if not avoided, could result in death or serious injury. It is important not to proceed until all stated conditions are met and clearly understood. CAUTION CAUTION indicates a hazardous situation which, if not avoided, could result in minor or moderate injury. It is important not to proceed until all stated conditions are met and clearly understood. NOTICE NOTICE indicates instructions that must be followed to avoid damage to the product or other equipment. QuixStand Operating Instructions 28-9646-70 AA 7 1 1.2 Introduction Regulatory information Notes and tips Note: A Note is used to indicate information that is important for trouble-free and optimal use of the product. Tip: A tip contains useful information that can improve or optimize your procedures. 1.2 Regulatory information This section lists the directives and standards that are fulfilled by QuixStand. Manufacturing information Requirement Content Name and address of manufacturer GE Healthcare Bio-Sciences AB, Björkgatan 30, SE 751 84 Uppsala Sweden Name and ID of notified body - Place and date of declaration Uppsala, Sweden, May 2009 Identity of person authorized to sign DoC See EC Declaration of Conformity CE Conformity Directive Title 2006/42/EC Machinery Directive (MD) 2006/95/EC Low Voltage Directive (LVD) 2004/108/EC ElectroMagnetic Compatibility (EMC) Directive International standards 8 Standard Description Notes EN 61010-1, IEC 61010-1, CAN/CSA-C22.2 no. 61010-1 Safety requirements for electrical equipment for measurement, control and laboratory use QuixStand Operating Instructions 28-9646-70 AA Introduction 1 Regulatory information 1.2 Standard Description Notes EN 61326-1 EMC emissions and immunity requirements for measurement, control and laboratory use Harmonized with 2004/108/EC EN-ISO 12100-1, 12100-2 Safety of machinery – Basic concepts, general principles for design Harmonized with 2006/42/EC EN-ISO 14121-1, 14121-2 Safety of machinery – Principles of risk assessment Harmonized with 2006/42/EC CE marking The CE marking and the corresponding Declaration of Conformity is valid for the instrument when it is: • used as a stand-alone unit, or • connected to other CE-marked instruments, or • connected to other products recommended or described in the user documentation, and • used in the same state as it was delivered from GE Healthcare, except for alterations described in the user documentation or explicitly authorized by GE Healthcare. Regulatory compliance of connected equipment Any equipment connected to QuixStand should meet the safety requirements of EN 61010-1/IEC61010-1 or relevant harmonized standards. Within the European Union, connected equipment must be CE-marked. QuixStand Operating Instructions 28-9646-70 AA 9 1 1.3 Introduction Instrument 1.3 Instrument A typical setup for a QuixStand system includes all the components needed for crossflow filtration with hollow fiber cartridges (Figure 1-1). 10 11 1 2 12 13 3 14 4 15 16 17 5 18 6 19 7 8 9 20 Figure 1-1. Typical QuixStand setup. Table 1-1. Parts in Figure 1-1. 10 Part Description 1 Back pressure valve 2 Retentate outlet 3 Reservoir cap, gasket and clamp 4 Feed reservoir (1,000 ml shown) 5 Permanent reservoir attachment 6 Lower manifold 7 Pump cover QuixStand Operating Instructions 28-9646-70 AA Introduction 1 Instrument 1.3 Part Description 8 Pump controls 9 Pump inlet 10 Outlet pressure gauge 11 Support rod cap (not visible) 12 Upper manifold assembly 13 Tightening knob (not visible) 14 Upper permeate outlet (Normally used to collect permeate during a run) 15 Support rod 16 Xampler cartridge (Size 4M shown) 17 Lower permeate outlet (Normally use to drain permeate after a run) 18 Sanitary connection 19 Inlet pressure gauge 20 Pump outlet The main components of a QuixStand bench top system are: • Lower manifold • Support rod • Reservoirs • Upper manifold • Peristaltic pump (optional) 1 2 3 Figure 1-2. Close up of pump. QuixStand Operating Instructions 28-9646-70 AA 11 1 1.3 Introduction Instrument Table 1-2. Parts in Figure 1-2. Part Description 1 Pump display and keyboard 2 Cover to pump mechanism 3 Bottom part of pump mechanism The following sections describe these and other key components. Lower manifold The lower manifold consists of a polysulfone manifold with a stainless steel top plate. The polysulfone block has channels and six ports that direct the flow of process fluid. The six ports use sanitary connectors to connect the reservoir, hollow fiber cartridge, feed tubing (to and from the pump), pressure gauge, and a drain/sample valve. Four rubber bumpers mounted on the bottom of the base support the base assembly. Support rods The support rod slips into the lower manifold and supports the upper manifold. The upper manifold slides up and down along the support rod and locks into place at a height that matches the cartridge in use. Two support rods are included also allowing you to match the rod to the length of the cartridge. When a QuixStand model includes a carrying case, the system uses a two-piece rod so that the rod fits in the case. A quick connect coupling enables you to assemble the rod. Reservoirs QuixStand systems include a 400 ml and 1,000 ml reservoirs. The reservoir holds the process solution, feeds the solution to the recirculation pump, and collects the retentate stream. The feed reservoir of choice is connected to the sanitary connector located on the lower manifold. The system includes a reservoir cap, gasket, and clamp. The cap has two barbed inlet ports that enable you to connect tubing to the cap. The cap’s two ports allow recirculation of the retentate stream back to the reservoir and allow additional feed solution or diafiltrate to be introduced into the reservoir during processing. The cap fits both reservoirs. The sanitary clamp holds the reservoir cap and silicone gasket in place. Two polysulfone downcomers are included with each reservoir. The downcomer is associated with the retentate return line to minimize aeration and foaming of sample in the feed reservoir. The two reservoirs supplied with the QuixStand system are graduated to indicate the nominal volume of fluid in the system. The exact volumes will depend on the size of the cartridge, the lumen diameter of the hollow fibers, and the size and length of the tubing used. For the most accurate volume measurements, you should measure the feed volume prior to processing and collect the permeate in a graduated vessel. 12 QuixStand Operating Instructions 28-9646-70 AA Introduction 1 Instrument 1.3 Hollow fiber cartridges You order hollow fiber cartridges separately from the QuixStand system. Consult our cartridge selection guide, Selecting Hollow Fiber Cartridges and Systems, for a list of cartridges and cartridge specifications such as membrane pore sizes, fiber lumen diameters, cartridge lengths, and membrane areas. Valves QuixStand systems include a precision back pressure control valve (also called a tubing pinch valve). The back pressure control valve is installed on the retentate line near the upper manifold. QuixStand systems use various drain valves. Systems QSM-02S and QSM-02SP include a non-sanitary, threaded, nylon sampling/drain valve. Systems QSM-03S, QSM-03SP, QSM-04SA, and QSM-04SAP include a sanitary, autoclavable, stainless steel sampling/ drain valve (Figure 1-3). Figure 1-3. Non-sanitary nylon drain valve (left) and sanitary, autoclavable stainless steel valve (right) Pressure gauges Each QuixStand system includes two 0 to 2 barg (0 to 30 psig) pressure gauges to monitor feed and retentate pressures. Non-sanitary QuixStand systems (models QSM02S and QSM-02SP) use gauges with threaded fittings. Sanitary—but not autoclavable— QuixStand systems (models QSM-03S and QSM-03SP) use stainless steel gauges with 0.75-inch sanitary fittings. Sanitary, autoclavable QuixStand systems (models QSM- QuixStand Operating Instructions 28-9646-70 AA 13 1 1.3 Introduction Instrument 04SA and QSM-04SAP) use stainless steel pressure gauges with 1.5 inch sanitary fittings (Figure 1-4). Figure 1-4. Pressure gauges with threaded (left), 0.75 inch sanitary (middle), and 1.5 inch sanitary (right) fittings. Upper manifold The upper manifold has channels and ports to direct the flow of process fluid out of the hollow fiber cartridge and back to the feed reservoir or collection vessel. The manifold has three ports (sanitary connectors) to allow you to connect a hollow fiber cartridge, retentate pressure gauge, and retentate line to the manifold. A knob on the back of the upper manifold enables you to loosen and adjust the position of the manifold on the support rod. You can match the height of the manifold to the height of the cartridge you are using. Peristaltic pump (optional) Some QuixStand models include a Watson-Marlow peristaltic pump. QuixStand systems with a P in the model number (QSM- 03SP for example) include a pump. Read the supplied Watson-Marlow pump user guide before using the system and peristaltic pump. Submit the warranty registration for the pump directly to the pump manufacturer using the card provided. 14 QuixStand Operating Instructions 28-9646-70 AA Introduction 1 Instrument 1.3 Accessory kit QuixStand systems include an accessory kit containing clamps, gaskets, o-rings and adaptors useful for operating the system (Figure 1-5). Figure 1-5. QuixStand accessory kit. QuixStand Operating Instructions 28-9646-70 AA 15 1 1.3 Introduction Instrument QuixStand system flow path The standard flow path for the QuixStand system includes a feed reservoir, peristaltic feed pump, hollow fiber cartridge, valves and pressure gauges. 2 1 P 3 4 5 Recirculation Reservoir 8 P 7 6 Figure 1-6. QuixStand bench top system flow diagram. 16 1 Diafiltrate port 2 Backpressure valve 3 Retentate 4 Permeate 5 Hollow fibre cartridge 6 Inlet pressure gauge 7 Sampling/Drain valve 8 Peristaltic recirculation pump QuixStand Operating Instructions 28-9646-70 AA Safety instructions 2 Safety precautions 2.1 2 Safety instructions This chapter describes safety compliance, safety labels, general safety precautions, emergency procedures, power failure and recycling of QuixStand. 2.1 Safety precautions Introduction Before installing, operating or maintaining the system, you must be aware of the hazards described in the user documentation. Follow the instructions provided to avoid personal injury or damage to the equipment. The safety precautions in this section are grouped into the following categories: • General precautions • Flammable liquids • Personal protection • Installing and moving the instrument • Maintenance QuixStand Operating Instructions 28-9646-70 AA 17 2 2.1 Safety instructions Safety precautions General precautions WARNING If you overpressurize the system with compressed air during integrity testing, system components can rupture causing bodily harm. To avoid the rupture of a system component due to over pressurization with compressed air, use a pressure regulator to limit the pressure of your compressed air supply to the maximum operating pressure of your system. WARNING Wear the appropriate personal protection devices when testing the system. WARNING If the system leaks, it can release potentially hazardous process fluids or cleaning fluids causing bodily harm. To prevent leaks and the release of potentially hazardous process or cleaning fluids, limit feed pressure to the maximum operating pressure of your system. WARNING Mishandling potentially hazardous process and cleaning/storage solutions can cause bodily harm through exposure to skin, eyes, and respiratory system. To safely handle potentially hazardous process and cleaning/storage solutions, read the MSDS for the solutions you use. Follow the handling and safety instructions on the MSDSs and use the personal protection equipment required by your company, local, state, and federal laws. Notices NOTICE Starting the optional peristaltic pump with the voltage selector set to the incorrect voltage can result in pump motor damage. To prevent pump motor damage, ensure the voltage selector switch is set to the proper voltage (110V/60 Hz or 220V/50 Hz) before starting the pump. NOTICE Failure to open the pump head and relieve the pressure on the tubing in a peristaltic pump when the pump is stored can accelerate tubing wear. To prevent premature wear, open the pump head and relieve the pressure on the tubing when the pump is not being used. 18 QuixStand Operating Instructions 28-9646-70 AA Safety instructions 2 Safety precautions 2.1 NOTICE Failure to carefully plan the installation of the system can result in equipment damage or poor performance. To avoid equipment damage, carefully plan the installation of the system in reference to the effects of a power failure and utility connections. Read the installation instructions in this manual. NOTICE Hollow fiber cartridges are strong and safe, but mishandling can damage the membrane fibers or cartridge housing connectors. Follow guidelines in Operations section to prevent damage to the hollow fibers and cartridge housing connectors. Using flammable liquids WARNING An adequately dimensioned ventilation system shall be installed when flammable or noxious substances are used. Personal protection WARNING Wear the appropriate personal protection devices and clothing when operating and cleaning the system. Basic personal protection devices include protective clothing and safety glasses. Use additional protective devices (fume hood, respirator, etc.) if the nature of your product or your company’s safety regulations require it. WARNING Wear protective glasses at all times when in vicinity of instrument. Installing and moving the instrument WARNING Use tubing clamps on all hose barb connections, particularly connections to the feed ports for leak-free connections at high pressure. Failure to do so may lead to unexpected leaks that my lead to bodily harm. QuixStand Operating Instructions 28-9646-70 AA 19 2 2.1 Safety instructions Safety precautions WARNING The system must be connected to a grounded mains socket. WARNING Do not block the rear panel of the system. The mains power switch must always be easy to access. WARNING Failure to wet the o-rings before you install barbed, hollow-fiber cartridges into end adaptors can result in deformation and improper seating/sealing of the o-ring. This can also cause unexpected leaks of potentially hazardous fluids and result in bodily harm. To prevent leaks and damage, wet the o-rings with water before each use. WARNING Using tubing not designed for peristaltic pumps in the peristaltic pump can cause the tubing to fail prematurely, exposing the operator to potentially hazardous process or cleaning fluids. To prevent the premature or unexpected failure of the tubing, use special, heavy-duty tubing intended for use in peristaltic pumps. System operation WARNING Ensure that the retentate valve is open before starting the feed pump. Failure to do so can cause the feed pressure to reach excessively high levels causing leaks, bodily harm, and damage to the cartridge. Maintenance WARNING Disconnect the power cable, the compressed air supply, and decompress the system before inspecting or maintaining the system. Failure to do so can result in bodily harm from the accidental starting of the pump or unexpected release of pressure. WARNING Decontaminate the equipment before decommissioning to ensure the removal of all hazardous residues. 20 QuixStand Operating Instructions 28-9646-70 AA Safety instructions 2 Labels 2.2 2.2 Labels This section describes safety labels and labels concerning hazardous substances that are attached to the QuixStand. Labels on the instrument The QuixStand system label, located on the bottom of the base plate, and the pump label (if supplied with a pump) on the back of the pump housing, provide key identification and specification information (Figure 2-1). The CE mark for European models is located on the back of the base. Figure 2-1. Typical pump label. XX-XXXX-XX Code No: Serial No Mfg Year: QuixStand XXXXXXXX XXXXXXX 2009 Made in Sweden GE Healthcare Bio-Sciences AB 751 84 Uppsala Sweden Figure 2-2. Example of QuixStand marking label. 2.3 Emergency procedures This section describes how to do an emergency shutdown of the QuixStand system. The section also describes the result in the event of power failure. QuixStand Operating Instructions 28-9646-70 AA 21 2 2.3 Safety instructions Emergency procedures Emergency procedures In an emergency situation, do as follows to stop the run: Step Action 1 Press the Stopbutton on the pump keypad. 2 Disconnect the electrical power cord from the mains socket outlet. 3 Investigate and remedy the reason for the emergency stop. Power failure A power failure will interrupt your process but does not affect the safe operation of the equipment. 22 QuixStand Operating Instructions 28-9646-70 AA Safety instructions 2 Recycling procedures 2.4 2.4 Recycling procedures The equipment shall be decontaminated before decommissioning and all local regulations shall be followed with regard to scrapping of the equipment. Disposal, general instructions When taking QuixStand out of service, the different materials must be separated and recycled according to national and local environmental regulations. Recycling of hazardous substances QuixStand contains hazardous substances. Detailed information is available from your local GE Healthcare representative. Disposal of electrical components Waste of electrical and electronic equipment must not be disposed as unsorted municipal waste and must be collected separately. Please contact an authorized representative of the manufacturer for information concerning the decommissioning of your equipment. QuixStand Operating Instructions 28-9646-70 AA 23 2 2.4 24 Safety instructions Recycling procedures QuixStand Operating Instructions 28-9646-70 AA Installation 3 Site requirements 3.1 3 Installation NOTICE Fittings and connectors are made of plastic and can crack if clamps are overtightened. Do not overtighten sanitary clamps when connecting fittings and components together. System installation requires choosing a location, assembling the system, and connecting the pump to an electrical power supply. 3.1 Site requirements Parameter Requirement Electrical power 100-120 VAC (50/60 Hz) or 220-240 VAC (50/60 Hz) Placement Stable laboratory bench Ambient temperature 5ºC to 40ºC (recommended) Humidity < 90% RH Select a location that includes: • appropriate drains or collection vessels to collect waste and processed fluids, and • electrical power supply. A commonly used location is on a laboratory bench near a sink. The system is lightweight and portable and no special lift and carry instructions are required. 3.2 Unpacking Your QuixStand system arrives partially assembled. All components are packaged in a heavy-duty cardboard box, including the optional peristaltic pump. Remove all parts from the package and set them out on a bench or table. All QuixStand systems include these assemblies and documents: • 400-ml and 1,000-ml reservoirs • Lower manifold • Upper manifold QuixStand Operating Instructions 28-9646-70 AA 25 3 3.3 Installation Assembly • Support Rod • Accessory kit • Full assortment of clamps, gaskets, tubing, and fittings • Operating instructions • EC declaration of conformity Depending upon which model you ordered, your system may also include a pump and various types of pressure gauges and valves. If your system includes a peristaltic pump, you also receive peristaltic pump tubing and a pump user guide. • Check the equipment for any apparent damage before starting installation. • Document any damage carefully and contact your GE Healthcare representative Table 3-1. Equipment included with various QuixStand systems. QuixStand system model No. Pump included Pressure gauge type Drain valve type QSM-02S No Nonsanitary Nylon QSM-02SP Yes Nonsanitary Nylon QSM-02SP/50 Yes, 230 Volt Nonsanitary Nylon QSM-03S No Sanitary 316LSS QSM-03SP Yes Sanitary 316LSS QSM-03SP/50 Yes, 230 Volt Sanitary 316LSS KCQSM-03SP Yes Sanitary 316LSS QSM-04SA No Sanitary 316LSS QSM-04SAP Yes Sanitary 316LSS QSM-04SAP/50 Yes 230 Volt Sanitary 316LSS 3.3 Assembly The main assembly steps include the following: 26 1 Install the support rod and lower manifold. 2 Install a reservoir. 3 Install the cartridge. 4 Connect the pressure gauges, valves, and tubing. QuixStand Operating Instructions 28-9646-70 AA Installation 3 Assembly 3.3 5 Connect electrical power. The following sections describe each step. Consult Figure 1-1 on page 10. Install a support rod and lower manifold Follow these steps to install the support rod and lower manifold: 1 Insert one of the support rods into the hole on the lower manifold. Line up the hole in the support rod with the hole in the back of the manifold and secure the rod in place with the oval head screw. 2 Slide the upper manifold assembly onto the support rod and tighten the knob to hold it in place. 3 Place the support rod cap on the support rod. a) If your system includes an optional peristaltic pump with a flat top, place the pump on the lab bench and place the QuixStand on the pump. b) If your system includes a pump cover, place the pump cover on the lab bench, place the pump under the pump cover, and place the QuixStand on top of the pump cover. c) If you are using your own peristaltic pump, position the QuixStand so that the pump inlet and outlet tubing can be connected without twisting or kinking. Install a reservoir Follow these steps to install a reservoir on the lower manifold: 1 Gather the following parts: a) A 400 ml or 1,000-ml reservoir. b) Two, 1.5 inch silicone gaskets. c) Two, 1.5 inch sanitary clamps. d) Reservoir cap and two downcomers. 2 Place a gasket on the 1.5 inch sanitary flange on the lower manifold. Place the reservoir on top of the gasket and clamp it in place using a sanitary clamp (Figure 3-1). 3 Push the two downcomers into the holes on the bottom of the reservoir cap. QuixStand Operating Instructions 28-9646-70 AA 27 3 3.3 Installation Assembly 4 Place a gasket on the top of the sanitary flange on the top of the reservoir. Place the reservoir cap on top of the gasket and secure it in place with a sanitary clamp. Figure 3-1. Rod and reservoir installed on base assembly (left) and cap installed on top of reservoir (right). Install a cartridge Cartridges with housing size 3M, 3X2M, 4M, and 4X2M use sanitary connectors to connect to the upper and lower manifolds. Cartridges with housing size 4 use a hose barb/o-ring arrangement to connect to the upper and lower manifolds (Figure 3-2). The following two sections describe how to install these two types of cartridges. Figure 3-2. Cartridge with sanitary connector (left) and cartridge with hose barb connector (right). Installing cartridges with sanitary connectors Follow these steps to install a cartridge with sanitary connectors at its ends: 1 28 Gather these parts: QuixStand Operating Instructions 28-9646-70 AA Installation 3 Assembly 3.3 a) Cartridge size with 3M, 3X2M, 4M, or 4X2M housing. b) Two, ½-inch silicone gaskets. c) Two, fractional sanitary clamps. 2 Raise upper manifold so that distance between upper and lower manifolds exceeds cartridge length. 3 Place a gasket on the lower manifold. 4 Place the end of the cartridge on the gasket in the lower manifold and secure with a sanitary clamp. 5 Place a gasket on upper end of cartridge. 6 Loosen the upper manifold and slide it down to mate with gasket and upper end of cartridge. 7 Tighten upper manifold hand knob to secure it in place. 8 Secure the end of the cartridge to the upper manifold with a sanitary clamp. Tip: Two types of 1-inch (nominal) gaskets are included with QuixStand systems. The gaskets have similar outside diameters but different inside diameters. When installing the sanitary pressure gauges on models QSM- 03S and QSM-03SP, use the gaskets having a larger nominal inside diameter. The larger inside diameter prevents interference with the pressure gauge’s diaphragm. Installing cartridges having hose barb connectors Follow these steps to install cartridges with 3/8 inch hose barb end fittings: 1 Gather these parts: a) Cartridge with size 4 housing. b) Two, ½ inch silicone gaskets. c) Two, fractional sanitary clamps. d) Two, cartridge-to-manifold adaptors. e) Two, long tube standoffs. f) Two, hose barb O-rings. g) Two, short tube standoffs. 2 Raise the upper manifold so that distance between upper and lower manifolds exceeds the cartridge length. 3 Clamp the hose barb adaptors to the upper and lower manifolds using the silicone gaskets and sanitary clamps. QuixStand Operating Instructions 28-9646-70 AA 29 3 3.3 Installation Assembly 4 Push a long tube standoff onto each cartridge hose barb (Figure 3-3). 5 Push an o-ring onto each cartridge hose barb and seat it against the standoff. 6 Push a short tube standoff onto each cartridge hose barb and seat it against the o-ring. 7 Wet the o-rings with water, and with the standoffs and o-rings in place, use a twisting motion and firmly slide the lower end of the cartridge into the lower manifold adaptor. 8 Slide the upper manifold assembly down to mate with the upper end of the cartridge and press firmly. 9 Tighten upper manifold hand knob to secure it in place. 2 1 4 2 3 4 5 Figure 3-3. O-ring with long and short standoffs (left) and installation of a cartridge into adaptor (right). 30 1 Adapter 2 Short standoff 3 O-ring 4 Long standoff 5 Cartridge QuixStand Operating Instructions 28-9646-70 AA Installation 3 Assembly 3.3 Connect the pressure gauges, valves, and tubing After installing the cartridge, connect the pressure gauges, valves, and tubing following these steps: 1 Gather the following parts: a) Two pressure gauges. b) Drain/sample valve. c) Tubing supplied with the system (size 17 or 18). d) Accessory kit. e) Supplied clamps, gaskets, tubing, and fittings. 2 Attach one pressure gauge to the lower manifold and one pressure gauge to the upper manifold using the ¾-inch silicone gaskets and sanitary clamps (Figure 1-1). For models QSM-04SA and QSM-04SAP, position and clamp adaptors (fractional sanitary fitting to 1.5-inch sanitary fitting) between the manifolds and the pressure gauges so that the pressure gauges are positioned upward. 3 Attach the drain valve to the drain port located on the left side of the lower manifold using a silicone gasket and sanitary clamp. 4 Install a length of tubing between the upper manifold and one of the hose barbs on the reservoir cap. (This is the retentate line.) Ensure you slide the tubing pinch clamp on the hose before installation. Secure the tubing at both ends with tubing clamps to prevent leaks. 5 Install the sanitary-connector-to-hose-barb adaptors on the pump inlet port and pump outlet port on the lower manifold using silicone gaskets and sanitary clamps. Install a length of tubing from the reservoir outlet port, through the peristaltic pump head, and on to the feed port. (Read the Watson-Marlow pump user guide to learn how to install the tubing in the pump head.) Secure the tubing on the hose barbs using tubing clamps. 6 Visually check the feed tubing upstream and downstream from the peristaltic pump and ensure it is not pinched or held incorrectly. If necessary, loosen the tension on the tubing and reposition. 7 Install a length of the tubing to the drain/sample valve hose barb using a tubing clamp. 8 Install lengths of tubing from the upper permeate port on the side of the cartridge to an appropriate collection vessel. QuixStand Operating Instructions 28-9646-70 AA 31 3 3.4 Installation Connections 3.4 Connections Connect electrical power The optional peristaltic pump motor can operate at 100-120 VAC (50/60 Hz) or 220-240 VAC (50/60 Hz). Ensure the voltage selector switch on the back of the pump is set to the proper voltage before plugging it in. Consult the Watson-Marlow pump user guide if you need help in setting the pump motor to the proper voltage. Connect the pump’s power cord to a fuse-protected, electrical outlet of the proper voltage. Final checks Before using the system, check the flexible tubing to ensure it sits properly in the pump head. Finally, check the tightness of all tubing clamps and sanitary clamps. 3.5 Spare parts and accessories For correct up to date information on spare parts and accessories, visit www.gelifesciences.com/ 32 QuixStand Operating Instructions 28-9646-70 AA Operation 4 Operation overview 4.1 4 Operation 4.1 Operation overview Instructions for using hollow fiber cartridges are provided in the user guide supplied with the cartridges. The actual operation of this system will vary considerably depending upon your process and product objectives. If you need assistance with application information, contact your GE Healthcare representative. NOTICE Do not allow ultra filtration cartridges to dry out. Dropping cartridges during handling or subjecting the cartridge to pressure surges during use can damage the hollow fibers or housing. Tip: Plot the recirculation rate for a given cartridge type (housing size and lumen size) as a function of the pump speed to assist in data interpretation. To do this, attach a flexible tubing line from the retentate outlet of the cartridge to a graduated cylinder. Using a stop watch, measure the flow rate through the cartridge at several pump speeds. Target pump recirculation rates for Xampler™ cartridges are provided in Table 4-3 on page 37. QuixStand Operating Instructions 28-9646-70 AA 33 4 4.2 Operation Starting the instrument 4.2 Starting the instrument WARNING Using tubing not designed for peristaltic pumps in the peristaltic pump can cause the tubing to fail prematurely, exposing the operator to potentially hazardous process or cleaning fluids. To prevent the premature or unexpected failure of the tubing, use special, heavy-duty tubing intended for use in peristaltic pumps. WARNING If you start the feed pump with the retentate valve closed, the feed pressure can reach excessively high pressure causing leaks, bodily harm, and damaging the cartridge or cassette. To prevent leaks or damage to system components, ensure the retentate valve is open before starting the feed pump. NOTICE Starting the optional peristaltic pump with the voltage selector set to the incorrect voltage can result in pump motor damage. To prevent pump motor damage, ensure the voltage selector switch is set to the proper voltage (110V/60 Hz or 220V/50 Hz) before starting the pump. Pump operation Before operating the optional peristaltic pump, you should read the pump manufacturer’s user guide supplied with your QuixStand system. 1 4 2 6 7 3 5 Figure 4-1. Pump control panel for optional Watson-Marlow peristaltic pump showing the Start and Stop buttons, other control buttons, and the display. 34 QuixStand Operating Instructions 28-9646-70 AA Operation 4 Starting the instrument 4.2 Table 4-1. Parts in Figure 4-1. Part Description 1 Display 2 Start key 3 Stop key 4 Up arrow 5 Down arrow 6 Mode 7 Pump direction button Pump controls Read the user guide supplied with the Watson-Marlow peristaltic pump before operating the pump. The pump control panel includes six control buttons and a display (Figure 4-1). The control buttons perform these basic functions: • The control panel display indicates the pump speed in revolutions per minute (rpm). • When the pump is running, pressing the Up Arrow button increases the pump speed. Pressing the Down Arrow button decreases the pump speed. You can adjust the speed on the display while the pump is stopped or running. Typically you should start the pump at a very slow speed and increase the speed slowly. • Pressing the Pump Direction button reverses the direction of rotation of the pump head when the pump is stopped or running. • Pressing the Start button starts the pump. • Pressing the Stop button stops the pump. • When stopped, the display continues to show the current setting for operating speed and direction. When started, the pump returns to the displayed speed and direction. NOTICE Failure to open the pump head and relieve the pressure on the tubing in a peristaltic pump when the pump is not in use can accelerate tubing wear. To prevent premature wear, open the pump head and relieve the pressure on the tubing when the pump is not being used QuixStand Operating Instructions 28-9646-70 AA 35 4 4.3 Operation Starting the system 4.3 Starting the system Initial start-up Follow these steps to start-up the QuixStand system: 1 Close sampling/drain valve, secure cartridge in upper and lower manifolds, and ensure the pump tubing is correctly positioned and tensioned within the pump head. 2 Confirm flexible tubing is connected from the retentate outlet on the upper manifold to one of the tubing barbs on the reservoir cap. If the process solution tends to foam, ensure there is a retentate downcomer pressed into the reservoir cap for the retentate line. 3 Direct the flexible tubing from the upper permeate line to a collection flask. If you choose not to use the lower permeate line, close off the lower permeate port by adding a short piece of tubing secured with a tubing connector or cable tie wrap and clamp the tubing closed with a pinch clamp. 4 Remove the sanitary clamp from the reservoir cap and slide the reservoir cap to one side. 5 Add the feed solution to the reservoir. 6 Reposition the reservoir cap on the silicone gasket and clamp it in place using the sanitary clamp. 7 Open the backpressure tubing valve (turning counterclockwise), several turns. 8 Before staring the pump it is important to check the rotation direction of the pump. The direction should be from the bottom of the reservoir to the filter cartridge. 9 Start the pump on slow speed, and wait about 30 seconds for the pressure to build up. The pressure gauges on the sanitary and autoclavable system versions are mechanically dampened and respond slowly. Slowly increase the pump speed. The inlet pressure will build up, while the outlet pressure gauge may still read zero. 10 Apply backpressure by slowly closing the backpressure tubing valve. 11 Watch the inlet pressure gauge. If the pressure rises too high, lower the pump speed. Xampler cartridge specifications The cartridge selection guide available from your GE Healthcare representative describes the specifications and recommended operating parameters for GE Healthcare cartridges. For convenience, the specifications and recommended operating flow rates for Xampler cartridges are provided below (Table 4-2, Table 4-3) 36 QuixStand Operating Instructions 28-9646-70 AA Operation 4 Starting the system 4.3 Table 4-2. .Xampler cartridge specifications Housing size Lumen diameter (mm) Membrane area (ft ) Hold-up volume lumen (ml) Shell (ml) Permeate port (inches) 2 2 (cm ) 3M 3×2M 4,4M 4×2M 0.5 140 0.15 2 9 1/4 0.75 120 0.13 3 8 1/4 1 110 0.12 3 5 1/4 0.5 290 0.31 5 14 1/4 0.75 260 0.28 6 14 1/4 1 110 0.12 3 5 1/4 0.5 650 0.7 8 45 3/8 0.75 460 0.5 10 40 3/8 1 420 0.45 12 30 3/8 0.5 1400 1.5 20 75 3/8 1 850 0.9 30 50 3/8 1 Table 4-3. Xampler cartridge nominal feed flow rates Housing size Lumen diameter (mm) Shear sensitive (ml/min.) Low fouling (ml/min.) High fouling (ml/min.) 3M, 3×2M 0.5 60 120 250 0.75 100 200 400 1 150 300 600 0,5 300 600 1200 0,75 400 800 1500 1 600 1200 2500 4,4M, 4×2M 1 -1 -1 -1 Shear rates for shear sensitive = 2000 sec ; low fouling = 4000 sec ; high fouling = 8000 sec Flow rate/pressure values determined with water will vary from experimental solutions due to changes in temperature, viscosity and degree of suspended solids. QuixStand Operating Instructions 28-9646-70 AA 37 4 4.4 Operation Constant volume diafiltration 4.4 Constant volume diafiltration The QuixStand system is ideally suited to achieve constant volume diafiltration as the pump will pull a vacuum on the feed reservoir and draw in diafiltrate solution at a fixed rate. Follow these steps to complete diafiltration: 1 Attach tubing from your diafiltrate solution to the hose barb on the reservoir cap. 2 Turn on the pump to circulate the process solution through the cartridge and draw diafiltrate solution into the feed reservoir. 3 If the diafiltration solution causes foaming in the feed reservoir, ensure the second downcomer is attached to the bottom of the reservoir cap and extends down below the fluid level in the reservoir. 4.5 Pressurized feed reservoir The QuixStand system may be operated with a pressurized feed reservoir. This mode of operation is particularly useful in reaching very high concentration factors (minimizing feed volumes for example). It is important to note that pressurization of the feed reservoir is potentially hazardous and is not recommended unless the following precautions are taken: 1 Limit the pressure of the air or nitrogen source to 1.7 barg (25 psig). Install a pressure regulator. 2 Set these to limit the incoming pressure to 0.7 to 1 barg (10 to 15 psig) in the feed reservoir. 3 When all safety equipment is installed, attach the air or nitrogen line to the tubing barb on the reservoir cap. Tip: 38 Expert users often follow these steps to enable the running of the system to the minimum working volume: Note that this is intended for microfiltration applications and not intended for protein concentration applications. (1) use a downcomer on the retentate return line and attach 3/8-in flexible tubing to reach the bottom of the reservoir base, minimizing air entrainment; (2) proceed with standard operation using the extended downcomer to the minimum feed level possible; (3) leave the pump tubing attached to the base assembly, but disengage the tubing from the pump head; (4) fully close the backpressure tubing valve; and (5) operate the cartridge in a flow-through mode by applying low pressure air or nitrogen as described above. QuixStand Operating Instructions 28-9646-70 AA Operation 4 High flow pump tubing (size 18) 4.6 4.6 High flow pump tubing (size 18) The system is supplied with size 17 and size 18 pump tubing. Use size 18 when high circulation rates are required. 4.7 Autoclaving Some QuixStand system models and components can be autoclaved (Table 4-4). It is important to understand the limitations of the system and/or the pressure gauges before autoclaving. General guidelines for autoclaving include loosening all clamps before autoclaving and ramping the temperature up and down slowly. Consult the GE Healthcare hollow fiber cartridge user guide for complete autoclaving instructions. Table 4-4. Autoclavability of QuixStand systems and components Model number Autoclavable systems Autoclavable pressure gauges No No No Yes Yes Yes QSM-02S QSM-02SP QSM-03S QSM-03SP QSM-04SA QSM-04SAP Tip: Some users check cross-flow systems for leaks by pressurizing the system with compressed air or water under pressure and observing any loss in air pressure over time. Users also check the integrity of hollow fiber cartridges before use by performing either a pressure-hold or air diffusion test. This may also be tested in the segments between the pump and backpressure valve using water pressurised by the pump. Do not exceed 15 psig (1 barg) of air or water pressure. GE Healthcare publishes an integrity testing guide that describes how to complete these tests. 4.8 Procedures after operation The system should be flushed after each use. When you flush the membrane cartridge after use, you simultaneously flush and clean the QuixStand system, thus no further flushing is needed. QuixStand Operating Instructions 28-9646-70 AA 39 4 4.8 Operation Procedures after operation After use, you should wipe down the exterior components of the QuixStand system with water to remove dirt and residual process/cleaning solutions. Wipe the system dry with a clean, lint free cloth. 40 QuixStand Operating Instructions 28-9646-70 AA Maintenance 5 Inspection 5.1 5 Maintenance WARNING To prevent bodily injury, disconnect the power cable, disconnect the compressed air line, and depressurize the system before performing inspections and disassembling the system. 5.1 Inspection The following inspections shall be performed: • Inspect and replace pump tubing as needed. • Inspect flexible tubing connections for secure fit. • Inspect sanitary clamps for tightness. 5.2 User maintenance schedule The system should be flushed before storage. When you flush the membrane cartridge after use, you simultaneously flush and clean the QuixStand system, thus no further flushing is needed. If the last operation you perform with the system is to flush the cartridge with a storage solution, you must then flush the system and holder with DI water or WFI to remove the storage solution. Position an old cartridge or a short piece of flexible tubing with sanitary adaptors in the cartridge position to flush the system with water. After use, you should wipe down the exterior components of the QuixStand system with water to remove dirt and residual process/cleaning solutions. Wipe the system dry with a clean, lint free cloth. 5.3 Storing the system To store the system for more than a few days, clean it as described in the maintenance section. Drain all rinse water from the system. Remove the cartridge from the QuixStand. Blank off open lines or ports in the system and reservoir. Store the cartridge in accordance with the instructions in the cartridge user guide (in general, well-sealed with ultra filtration membranes kept wet) and stored in cool or ambient temperature. QuixStand Operating Instructions 28-9646-70 AA 41 5 5.3 Maintenance Storing the system System disposal When the service life of the unit is reached, flush the system to remove hazardous process fluids. Dispose of the unit in accordance with the government and environmental regulations that pertain to your location. 42 QuixStand Operating Instructions 28-9646-70 AA Troubleshooting 6 6 Troubleshooting Symptom Possible cause Suggested remedy Leaks at the tubing nipple at permeate connection of cartridge. Inside dimension of tubing is too large. Ensure tubing i.d. is sized properly for the connection. Split tubing at barb Check tubing for wear or splitting. Replace tubing if necessary. Tubing clamp incorrectly installed. Ensure the clamp is installed and tight. Process solution leaks from sanitary connections. Clamp is loose. Check and tighten clamp. Gasket worn, damaged, improperly mounted or wrong size Inspect gasket for wear, damage and proper sizing. Replace if necessary. Feed pressure increases from starting values slowly at first, then suddenly very rapidly, exceeding process limit. Blockage or partial blockage of flow path. Flush through to clean blockage. If necessary replace tubing and connectors. Please refer to order information for tubing and connectors. Feed inlet at cartridge is blocked. Switch feed and retentate lines to reverse flow and flush with deionized water (DI) or water for injection (WFI). Fouled cartridge. For feed flow rate versus pressure drop and cleaning of cartridge refer to Operating Handbook - Hollow fiber cartridges for membrane separations. Retentate valve closed or restricted. Open valve. Speed of pump (RPM) is too high. Reduce pump speed. No or low retentate pressure. QuixStand Operating Instructions 28-9646-70 AA 43 6 Troubleshooting Symptom Possible cause Suggested remedy Feed pressure is too low. Pump head is not turning. Check for error messages on pump display, check voltage setting is correct on power supply and power is delivered to the motor. Pump is turning but flow is inadequate. Check occlusion setting on pump (if applicable). Tubing has become drawn inside the pump head and has flattened within pump head. Open pump head and stretch tubing while at the same time closing the pump head. Check to see that the settings are correct on the tubing gates on either side of the pump head for the tubing installed. Refer to Pump Manufacturer's instructions for details if applicable. Air leaking from cartridge or housing during cartridge integrity testing (Cartridge integrity testing employs air on the retentate side of a fully wetted cartridge). 44 Cartridge not wetted properly. Cartridge not been wetted properly. Please read the chapter New cartridge rinsing procedure in the Operating Handbook - Hollow fiber cartridges for membrane separations. For pre-treatment with alcohol please read the document Hollow fiber cartridge preparation instructions. Membrane is not integral. Please contact your local GE Healthcare technical support representative. QuixStand Operating Instructions 28-9646-70 AA Troubleshooting 6 Symptom Possible cause Suggested remedy Water leaking during system integrity testing (System integrity testing employs water on the retentate side). Faulty diaphragm valve. Get valve serviced by GE Healthcare service engineer or replaced. Gasket worn, damaged, improperly mounted or wrong size. Inspect gasket for wear, damage and proper sizing. Replace if necessary. Leakage from process connectors. Check and tighten connectors. Air trapped in the pore structure of the membrane. Air-locked membrane, in which case, water layers trap a pocket of air between inner and outer surfaces of the membrane; effectively reducing the available surface area. This may be observed following autoclaving. Remedy: recirculate cold water (5-15C) on the retentate side with the permeate side closed, very gradually increase retentate backpressure until a stable 20 psig is reached and hold this condition for 10 minutes or until expected permeate flux is reached Note that this does not affect feed pressure or TMP; due to the permeate side being closed, but only raises the absolute pressure on both sides of the membrane; causing the trapped air to diffuse rapidly into the water. Permeate flow is not adequate (microfiltration membrane). QuixStand Operating Instructions 28-9646-70 AA 45 6 Troubleshooting Symptom Possible cause Suggested remedy Permeate flow is not adequate (ultrafiltration membrane). Air trapped in the pore structure of the membrane, or glycerol humectant not properly removed. Cartridge not wetted properly. Please read the chapter New cartridge rinsing procedure in the Operating Handbook Hollow fiber cartridges for membrane separations. For pre-treatment with alcohol please read the document Hollow fiber cartridge preparation instructions. Auxiliary equipment such as manometers and pumps not working properly. Check the function of all auxiliary equipment. Repair/ replace if necessary. Bent tubing. Check that the flow path is not restricted. Liquid viscosity too high. Check the viscosity of the liquid. Viscosity is a function of temperature. (Lower temperature gives higher viscosity.) Let low-temperature liquid reach operating temperature before starting the run. Microbial growth in buffers. The buffer normally becomes opalescent due to microbial growth. Check buffers, especially those with phosphate, for microbial growth. Replace with fresh buffer if necessary. Dimension of tubing is incorrect. Ensure tubing i.d. is sized properly for the connection. Fouled cartridge. Clean the cartridge according to instructions. Split tubing at barb Check tubing for wear or splitting. Replace tubing if necessary. Tubing clamp incorrectly installed. Ensure the clamp is installed and tight. Permeate pressure is dropping. 46 QuixStand Operating Instructions 28-9646-70 AA Troubleshooting 6 Symptom Possible cause Suggested remedy Unexpected passage of target protein to the permeate side. Membrane pore size is too large for target molecule. Select the largest pore size that retains the target molecule (in general choose a membrane 35× smaller than the target protein). For example, either 30,000 or 50,000 NMWC ultrafiltration membranes are recommended for mAb concentration and diafiltration. Unexpected retention of target molecule. Membrane pore size is too small for target molecule. Select the smallest pore size that still allows efficient passage of the target molecule (in general 10 x larger opening than the target protein) For most mammalian cell culture clarification 0.2 to 0.65 micron pore sizes are used. QuixStand Operating Instructions 28-9646-70 AA 47 6 48 Troubleshooting QuixStand Operating Instructions 28-9646-70 AA Reference information 7 Specifications 7.1 7 Reference information 7.1 Specifications Size and dimensions Part Dimensions (W × L × H) Short rod without pump 24 × 34 × 55 cm (9.5 × 13.5 × 22 in.) Short rod with pump 24 × 34 × 70 cm (9.5 × 13.5 × 28 in.) Long rod without pump 24 × 34 × 93 cm (9.5 × 13.5 × 37 in.) Long rod with pump 24 × 34 × 108 cm (9.5 × 13.5 × 43 in.) Weight, approximate System Weight Without pump 12 kg / 25 lbs With pump 18 kg / 40 lbs Construction materials- Wetted parts Part Dimensions (W × L × H) QSM-02S Polysulfone, BioPrene®, Nylon drain valve, 316L SS gauges QSM-03S Polysulfone, BioPrene®, 316L SS drain valve and gauges QSM-04SA Polysulfone, BioPrene®, 316L SS drain valve and gauges All systems supplied with silicone gaskets and O-rings. QuixStand Operating Instructions 28-9646-70 AA 49 7 7.2 Reference information Ordering information Operating parameters Parameter Value Recommended operating temperature 5 to 40°C (41 to 104°F) Maximum temperature, short term 50°C (120°F) Recommended maximum inlet pressure 1.7 barg (25 psig) Operating pH range 1 to 14 Reservoir volume 400 ml, 1,000 ml and optional 2,500 ml Minimum working volume 30 to 50 ml Parameter Value Input voltages and frequency 110-240 VAC, 50-60 Hz Maximum temperature, operating 40°C (104°F) Maximum temperature, short-term (cleaning) 50°C (120°F) Flow rate at 400 rpm 2 liters/min. with size 18 tubing Pump 1.4 liters/min. with size 17 tubing See the Watson-Marlow pump user guide for additional details. 7.2 Ordering information Visit www.gelifesciences.com for ordering and spare parts information. 50 QuixStand Operating Instructions 28-9646-70 AA For local office contact information, visit www.gelifesciences.com/contact GE Healthcare Bio-Sciences AB Björkgatan 30 751 84 Uppsala Sweden www.gelifesciences.com/filtration GE, imagination at work and GE monogram are trademarks of General Electric Company. QuixStand is a trademark of GE Healthcare companies. All third party trademarks are the property of their respective owners. © 2010 General Electric Company—All rights reserved. First published Feb. 2010. All goods and services are sold subject to the terms and conditions of sale of the company within GE Healthcare which supplies them. A copy of these terms and conditions is available on request. Contact your local GE Healthcare representative for the most current information. GE Healthcare UK Ltd Amersham Place, Little Chalfont, Buckinghamshire, HP7 9NA, UK GE Healthcare Bio-Sciences Corp 800 Centennial Avenue, P.O. Box 1327, Piscataway, NJ 08855-1327, USA GE Healthcare Europe GmbH Munzinger Strasse 5, D-79111 Freiburg, Germany GE Healthcare Japan Corporation Sanken Bldg. 3-25-1, Hyakunincho, Shinjuku-ku, Tokyo 169-0073, Japan imagination at work 28-9646-70 AA 02/2010