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Nov 15, 2005 (Vol. 25, No. 20)

Optimizing Your Process Unit Operations

Using an Air Diaphragm Pump with an Advanced Control System

  • As the bioprocess industry grows, and more products work their way through clinical trials toward approval, commercial production becomes important to supply the market with product. A safe, reliable, and optimized process that minimizes cost of goods and the risk of jeopardizing the supply chain is an important goal.

    Evaluation of niche and new technology, and analysis of the advantages and flexibility of implementing single-use technology are important in the process development phases leading to commercial production.

    A sanitary and sterlizable air-driven (versus mechanically driven) diaphragm pump with a wide range of flow rates is available for applications where it may provide advantages over existing technology, currently in use in different process unit operations. The pump head is compatible with steam sterilization, and single-use versions are planned that will offer compatibility with both steam and gamma radiation sterilization.

    Air-driven diaphragm pumps have been used for many years in different process industries, particularly for their ability to pump without damaging the contents of the liquid stream. They operate without introducing temporary high pressure gradients and shear that can damage liquid components. In the biotech industry some processes may benefit from the use of a low shear, easily sterilizable and cleanable air diaphragm pump that minimizes high pressure gradients and pinching.

    A peristaltic tubing pump, operating at a speed of 250 rpm with four rollers on its rotor, will pinch the tubing 1000 times each minute. In addition, for sterile processing, pumps other than peristaltic tubing pumps may have issues with maintaining sterility and/or difficulty in cleaning, whereas the air diaphragm pump has one product contact surface that is easily cleaned (or a single use version can be disposed of after use) and the expendable silicone diaphragm.

  • Gentle Handling

    The Magma Advanced Pumping System (Magma APS) consists of a pump control system and different volume pump heads for use in various applications and at different process scales. Applications where the Magma APS can be used include liquid transfer, dead-end filtration, cross flow filtration (or TFF), and mixing.

    To demonstrate the low shear pumping capability of the Magma APS pump head, an experiment was conducted at Kemp Biotechnologies (Frederick, MD). Kemp Biotechnologies specializes in protein expression via the insect cell/baculovirus system and mammalian systems.

    The baculovirus system was chosen for evaluation because insect cells become fragile when infected with the virus, and require gentle handling. Two Sf9 (Spodoptera frugiperda) insect cell cultures infected with recombinant baculovirus were compared. One culture was recirculated through the Magma APS-50 diaphragm pump and one was without recirculation.

    For the experiment the bioreactors were autoclaved sterilized, one with the Magma pump head with two check valves on inch ID recirculation tubing. Each vessel was inoculated with two liters of cells from a shake flask that was infected with the baculovirus 24 hours earlier. The cultures in the bioreactors were temperature controlled at 27C, and dissolved oxygen was controlled to a minimum set point of 50%.

    Recirculation of the culture with the Magma APS was commenced at 0.2 liters per minute (6 vessel volumes per hour). Samples were taken over the following 24 hours, and tested on a Cedex AS20 analyzer.

    Total cell counts and viability were comparable between the control vessel (no recirculation) and the vessel with the Magma pump recirculating at a rate of 6 vessel volumes per hour. The average cell diameter in the culture pumped with Magma Pump with the recirculation tracked higher. The Magma APS flow remained precisely at 0.2 liters per minute throughout the experiment without any adjustments.

  • Control System

    In this experiment a stainless steel pump was used with check valves to control liquid flow in and out of the pump. However, pinch valves controlled by the Magma APS control system and in the future, plastic single use pumps, are other options.

    Besides controlling the pump cycling, the Magma APS control system has added features for process control and optimization. There may be process operations where it is desirable for a pump to shutdown if excess downsteam pressure builds up. The Magma APS has this feature, and it may be particularly useful when using single use technology with tubing, process bags, and plastic fittings that can rupture and leak if over-pressurized.

    Automatic shutdown may be important if handling biohazardous components or valuable intermediate product. Also, as part of the process risk minimization, the system can help offer total process containment (no risk of tubing rupture and leaking from wear).

    The control system has an RS-232 input for connection of a scale. An example of how this could be used is for mixing of two liquids. The Magma APS pump can be connected to a process bag to provide mixing, and the bag is placed in a tank on a scale and filled with liquid. A second liquid is added via a tubing pump, and the control system will shut off an addition pump when the weight set point is reached.

    The pump offers mixing without the requirement of internal impellers, motors, or an external recirculation loop. This weight control feature can also be used to control vessel volume in a diafiltration or perfusion process if the Magma APS pump is used as the recirculation pump in a crossflow filtration (or TFF) process step.

    The control system also has an input for an external pressure sensor (either a stainless steel transducer or disposable sensor). This can be utilized in different applications for process safety, optimization, or testing. A minimum and maximum set-point are entered, and if either of these conditions are met, the control system issues a warning.

    Depending where the sensor is used in the process, the high pressure warning may be used to prevent process over-pressurization, and the low pressure warning may be used to monitor filter fouling in a diafiltration or perfusion process.

    The control system also has a mode that can perform a pressure hold test or filter integrity test. In the pressure hold test mode, the external pressure sensor and pump air hose are connected to the device to be tested, and the control system internal valves and on-board precision pressure regulator are utilized to conduct the test routine.

    The capability to pump against back pressure or a pressurized vessel (such as a bioreactor for additions, etc.) is also important. Pump discharge pressure versus flow data was collected to demonstrate this capability using the Magma APS-50 and water at different vessel pressures.

  • Pneumatics

    Because pneumatics are used versus mechanical energy, compressed air from 30 to 125 psi is required for system operation and depending on the application, a vacuum pump (both either portable or house supply). Because each pump discharge cycle requires a pump filling cycle, intermittent flow from the pump head occurs.

    In some processes this may not matter but in others it may be undesirable. If intermittent flow is undesirable, a duplex arrangement can be used. In the simplex mode even though the flow from one pump may be intermittent, during the pump discharge the flow is steady and non-pulsating.

    This could be important if process requirements do not allow for the rapid pressure fluctuations that can occur when a pressure measurement device is placed downstream of peristaltic pump.

    An example is if a process changes from stainless steel vessels with air driven transfer to process bags, and the pressure cannot exceed a certain value.

    There are two stop modes that can be used depending on the application. For the Smart-Stop, the stop button is pressed once, the pump empties the liquid and momentarily vents the air from the pump head to relieve pressure. This minimizes liquid hold-up in the pump and safely removes air pressure. In the Quick-Stop mode, pressing the stop button twice immediately stops the pump in its current position. It can be useful in certain applications where the liquid hold-up should not be purged.

    The control system monitors pump cycling and will alarm and perform a Quick-Stop if an alarm condition occurs (e.g., loss of air pressure to the system). There is an alarm output signal that can be interfaced to different types of external alarm or notification systems and also a data output feature.

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