Single-Use Continuous Chromatography Systems For Perfusion and Batch Bioreactor-based Processes
Pall’s Cadence BioSMB platform provides a highly flexible multicolumn chromatography system that delivers high throughput and very efficient media utilization when compared to traditional batch, and other continuous chromatography methodologies. This is achieved through a unique single-use eight column system architecture which enables a highly flexible flow configuration through the single-use valve cassette. Additionally, the platform is fully scalable from process development (PD) to commercial manufacture. There are two flow range variants available targeted to perfusion (Cadence BioSMB Process 80 system) and batch (Cadence BioSMB Process 350 system) bioreactor-based processes.
Chromatographic processes developed using batch chromatography can be readily scaled without changing the sorbent, buffer system or product quality assays.
- Highly efficient sorbent utilization
- High productivity
- Unparalleled flexibility
- Less than 30 minute manifold installation
By using up to eight smaller pre-packed columns on the Cadence BioSMB Process systems, the need for column packing skids, large columns, and other support infrastructure is eliminated.
Cadence BioSMB Continuous Chromatography System1. Sorbent Utilization
Batch chromatographic processing typically utilizes only 50% to 70% of available binding capacity in the column. To maximize the use of the available binding capacity the Cadence BioSMB platform provides the ability to overload a given column, with the breakthrough passed directly onto a subsequent column.
- Column capacity is maximized
- Buffer consumption is optimized through improved sorbent utilization
The sorbent utilization benefits can be leveraged to optimize the purification strategy, i.e. run at a shorter residence time than batch but achieve a similar operational binding capacity – increasing productivity (a typical Cadence BioSMB strategy for clinical material production). Alternatively the process can be run at a flow rate similar to that used in a batch process with greatly increased operational binding capacity.2. Achieving Higher Throughput
Essential to the process economics of the Cadence BioSMB platform is the availability of multiple columns for continuous loading. Typically the bottleneck in high titer chromatography is the non-load operations. In batch and two column designs, loading cannot be repeated until the non-load steps are completed. With the Cadence BioSMB systems the process can be configured such that the loading steps are continuous; there is always a column ready to be loaded – this often requires a minimum of four columns.
The Cadence BioSMB Process platform has the ability to process on up to eight columns.3. Flexibility
Furthermore, the flexibility of the valve cassette allows multiple columns to be available in the breakthrough zone to collect overload from one column and wash from another, meaning flow rates can be kept high and constant without exceeding the maximum linear velocity for the columns; further increasing productivity.4. Valve Cassette
While competitive systems use a complex set of valves, the Cadence BioSMB technology uses a compact disposable valve cassette specially designed and patented as a single-use component. This valve system eliminates the need for a difficult cleaning validation process.
Each column used with the Cadence BioSMB Process systems is assigned a series of valves arranged in a dedicated array, resulting in each pump delivering a single fluid throughout the entire process and eliminating gradients or wash steps between buffer switches.
Additionally, throughout the Cadence BioSMB product range, the system hold-up volume is minimized, eliminating many of the uncertainties associated with scaling, validation and process control.5. Scale Up and Scale Down
To complement the Cadence BioSMB Process 80 and Cadence BioSMB Process 350 systems, a bench scale version is available, the Cadence BioSMB PD system.
The Cadence BioSMB PD system uses the same valve technology, flow path configuration and recipe handling to ensure simple scale-down or scale-up. This system is available for flow rates up to 100 mL/min.
The Cadence BioSMB Process 80 and 350 systems are the ideal solution for manufacturing-scale continuous chromatography.
Cadence BioSMB Process 80 System for Perfusion Bioreactor-Based Processes
The Cadence BioSMB Process 80 system, when coupled with the Cadence BioSMB Process 80 perfusion manifold, is targeted for perfusion bioreactor-based processes that will run for longer periods of time. The flow rate capability along with the specifically designed low bio-burden manifold meet the requirements for lower flow continuous processing.
Cadence BioSMB Process 350 System for Batch Bioreactor-Based Processes
The Cadence BioSMB 350 system is targeted for batch bioreactor-based processes up to 2000 L. The flow rate capability and larger bore single use tubing, and cassette manifold meet the requirements for high throughput continuous processing.
The software is designed to provide the operator a clear and easy-to-use interface. It has been developed in accordance with Pall usability standards for the most efficient, error-free user experience.Figure 1 Example - Cadence BioSMB software
The Cadence BioSMB software allows users to create methods either on the system directly or remotely on another PC (using another install) which can then be downloaded to the Cadence BioSMB Process 80 and Process 350 systems.
The software uses a proprietary visualization tool called the circular chronogram (Figure 2). The circular chronogram allows users to know the exact position of the columns within a process cycle at any given time.Figure 2 Cadence BioSMB Process 350 circular chronogram
Methods developed on the Cadence BioSMB PD system, using up to eight columns, are directly transferable to the Cadence BioSMB Process 350 system.
Cadence BioSMB Process 80 and 350 Complete Hardware Systems
Each Cadence BioSMB Process 80 and 350 system has the following architecture
|2.7/1.3/2.1 m (106/51/83 in.)
Height without alarm tower: 1.9 m (75 in.)
|Flow Rate Range PROCESS 350||30-350 L/h|
|Flow Rate Range PROCESS 80||5 - 80 L/h|
|Inlets||8 (7 usable + 1 for system use as second pass)|
|Outlets||6 (5 usable + 1 for system use as second pass)|
|Number of column
|Number of pumps||7|
|4 bar (58 psi)|
|Air supply||6 bar (87 psi) with integrated pressure regulator|
|Electricity supply||3 phase 400 V – 32 A – 50 Hz
(other voltages available)
Cadence BioSMB Pump Modules
If a complete Cadence BioSMB Process 80 or Process 350 system is purchased, then it is possible to buy a Cadence BioSMB Process 80 or Process 350 pump module respectively to increase the flexibility of the main system.
The pump module can be exchanged easily, requiring a mechanical changeout of the module and a switch in the software. The mechanical swap of the two pump modules typically takes less than an hour. This modularity allows the system to run either from 5 L/h - 80 L/h (Cadence BioSMB Process 80 pump module) or 30 - 350 L/h (Cadence BioSMB Process 350 pump module).
If a Cadence BioSMB Process 80 pump module is used then the Cadence BioSMB Process 80 manifold set must be used, and if a Cadence BioSMB Process 350 module is used then a Cadence BioSMB Process 350 manifold set must be used.Figure 3 Cadence BioSMB Process 80 pump module
Cadence BioSMB Process 80 and 350 Platform - Single-Use (SU) SystemTable 2
|Hose and connectors
|Silicone braided tubing ID: ⅜ in. with
HFC39 connectors for internal connections
and sanitary connection clamp 3/4 in. for upstream and
|Hose and connectors
|Silicone braided tubing ID: 1/4 in. Kleenpak®
Presto sterile connector for external connections.
HFC39 connectors for internal connections
(NOTE: The process 80 manifold is available
with sanitary connection connections in place of the
Kleenpak connectors. Contact Pall for more details)
|Pressure||7 pressure transmitters (1 after each pump with
integrated pressure switch)
0 to 5 barg/72 psig
(NOTE: Maximum operating pressure for system
is 4 barg/58 psig)
|Flow||7 ultrasonic non-invasive flowmeters
(1 after each pump)
|Air||7 integrated with flowmeters|
|Conductivity||4 sensors (on outlets 1-4)
Range: 0 μS/cm – 150 mS/cm,
accuracy of 2% measuring range
Built in temperature compensation
|pH||4 sensors (on outlets 1-4) Range of 2-10,
accuracy of 0.15 pH unit
|UV||4 UV-VIS sensors each with wavelengths in
280 nm as standard
|Process pump||4 piston diaphragm single-use
The single-use pump heads are Quattroflow♦
sanitary diaphragm pumps, 4 pistons with
polypropylene (PP), ethylene propylene diene
monomer (EPDM)/PP compound diaphragm
and EPDM valves
|Gamma irradiation dose||25 kGy|
Process wetted components materials of construction
|Tube||Platinum cured silicone|
|Fittings||Polycarbonate, polypropylene, polyphenylsulfone|
|Valve diaphragm||Fluoroelastomer (FKM)|
|Pump head||Polypropylene, EPDM/PP compound|
|UV-VIS sensor windows||Quartz|
Continuous Biomanufacturing Implementation Now and in the Future
Cadence BioSMB Process 350 SU SystemsTable 4
The Cadence BioSMB Process 350 SU system is comprised of four separate manifolds; inlet manifold, valve cassette manifold, column manifold and outlet manifold. These can be purchased individually, the manifolds are supplied individually double bagged and gamma irradiated.
|BIOSMB-IT-8||Cadence BioSMB Process 350 inlet tubing set|
|BIOSMB-OT-8||Cadence BioSMB Process 350 outlet tubing set|
|BIOSMB-CT-8||Cadence BioSMB Process 350 column tubing set|
|BIOSMB-VB-8||Cadence BioSMB 8 mm Process 350 valve cassette|
Cadence BioSMB Process 350 SU system manifold
*Second pass and column tubing not shown.
Cadence BioSMB Process 80 SU SystemsTable 5
The Cadence BioSMB Process 80 SU system is comprised of one single manifold. The system is supplied double bagged and gamma irradiated.
|BIOSMB-PF-5||Cadence BioSMB Process 80 SU system
comprising inlets, valve cassette, outlets and
column connectors only. Other connectors are
available on request.