Normal-flow filtration is used throughout downstream processes for biologics including depth, sterile, and viral filtration applications. Because of its ubiquity in large-scale biomanufacturing, using the most efficient normal-flow filter media area and type can lead to significant cost savings. To determine the most effective media type and area, developers use a scaled-down process model is used in bioprocess laboratories to minimize material requirements. Constant–flow-rate filter evaluations involve direct scale-down parameters that match manufacturing-scale process conditions. This type of evaluation can be time consuming, labor intensive, and complicated because of a lack of specialized laboratory-scale equipment. Clearly an integrated and semiautomated system would facilitate the efficient evaluation of filter media for manufacturing-scale bioprocesses.

PRODUCT FOCUS: BIOLOGICS

PROCESS FOCUS: DOWNSTREAM PROCESSING

WHO SHOULD READ: ANALYTICAL AND PROCESS DEVELOPMENT PERSONNEL

KEYWORDS: SCALE-DOWN, FILTER MEDIA, MABS, SCALE-UP, PERISTALTIC PUMPS, DIAPHRAGM PUMPS, AUTOMATION

LEVEL: INTERMEDIATE

Genentech Inc. and PendoTECH collaborated on developing an integrated filter-sizing system that addresses several disadvantages of the equipment commonly used. Those disadvantages included poor integration of multiple components from different sources (including pressure sensors, signal conditioning, data acquisition, balances, and pumps), continuous operator monitoring, and decreased portability of most systems due to their numerous components. In addition, peristaltic pumps have been the primary scale-down model for constant-flow filter-sizing applications. Such pumps require frequent calibration and can have difficulty maintaining flow rates at high back-pressures. Screening multiple media types from different vendors can require a range of flow rates because of varying scaled-down areas available. That requires multiple peristaltic pumps to supply needed flow rates, further reducing system portability and increasing laboratory space requirements for process development.

System Development and Specs



Several requirements shaped development of our filter-sizing system to address those disadvantages of existing equipment used for such applications. Genentech desired the following characteristics of its new laboratory-scale system to efficiently perform normal-flow filter sizing and screening experiments:

• Can be easily purchased from one vendor with direct technical support

• Can control four independent filtration trains

• Can monitor and record three pressures from each train

• Should automatically stop a filtration train when a target volume or maximum filtration pressure is reached

• Uses high-precision pumps that eliminate the need for table-top balances to measure flow rate

• Operates at pressures ≤40 psig and flow rates of 1.0–20 mL/min

• Is controlled by a simple, graphical user interface (GUI) with user-friendly data retrieval and manipulation

• Offers real-time trending of process values

• Can be moved (portability) easily.

PendoTECH had worked on many systems for filter sizing and offers customized systems for process control solutions and/or data acquisition through its PendoKIT program. We used that program as the building block for developing our control system. It was designed to simultaneously record data from as many as 12 pressure sensors (through high-resolution analog inputs), control four pumps (through relay control and analog outputs or digital control), record data from four optional balances (through Recommeded Standard 232), and connect to a PC through two data ports (also RS232). Pressure sensors, pumps, and balances were arranged to enable four independent filtration trains, each capable of controlling one pump, measuring three pressures, and reading one balance if needed.

PendoTECH follows the good automated manufacturing practice (GAMP) lifecycle in development of its automated systems to manage the process from user requirements to system build. Based on Genentech's needs and additional requirements from the vendor, we finalized a design specification and put the system into production after extensive real-world testing. The standardized normal-flow filter screening system design included a control module and pump module (Photo 1).

The entire control module is housed in one box with electrical connectors on its back panel designed to interface with sensors, pumps, and other instruments. At the core of the control module is a dedicated, programmable, high-performance microcontroller that uses firmware stored in radom-access memory (RAM) with a battery back-up. Embedded firmware in the control system stores process parameters entered from the GUI, controls pumps, reads sensors and scales, and monitors process conditions. This control system has a keypad and liquid crystal display (LCD) primarily used to enable nonstandard configurations.

We included a PC-based GUI (Photo 2) in our specification for user friendliness, and it allows complete control of the pump module. The GUI operates from a local PC and can be operated from outside a laboratory through remote-desktop applications. Through the GUI, users specify key process parameters such as maximum filtration train pressure, maximum differential pressure across each filter, and volumetric end-points for each filtration train. When a given set-point is reached, the corresponding pump automatically stops. For example, an audible alarm sounds when a pressure limit is reached, and the GUI highlights the affected filter and stops its corresponding pump automatically. The GUI records experiment-specific information such as filter names, filtration train names, and experimental notes. It can display real-time experimental data such as flow rate, differential pressure, flux, and filter permeability. Full manual pump control is also possible through the GUI. These functions (and more) are distributed across six easily accessed tabs that users can select.

Photo 1: