B i o P r o c e s s Technical

Single-Use Tangential Flow

Filtration in Bioprocessing
An Approach to Design and Development

Pauline Nicholson and Erik Storm

S
ingle-use (SU) components are Such interest in TFF reflects the
widely accepted in method’s complex nature and
bioprocessing due in part to extensive cleaning requirement.
improvements in component Requirements for higher pressures,
design, a wider range of products, and recirculating flow paths, pumps,
increased scalability. Benefits driving valves, sensors, and so forth also
their increased use include elimination present a challenge for developing a
of cleaning, improved system single-use operation.
flexibility, and reduced risk of Cleaning a TFF cassette and
contamination. system is an essential step in
Nonetheless, companies now maintaining flux rates and
question how far disposables can be minimizing cross-contamination risk
incorporated into bioprocessing unit in a multiproduct system. Such a
operations. Results of the second cleaning procedure demands detailed
annual survey of the bioprocessing and validated standard operating
Photo 1: Automated single-use TFF system
market fo single-use solutions showed procedures (SOPs). Cross-
with “shadow board” design and side access
that >90% of respondents considered contamination risk can be eliminated
filtration well suited for single-use either by dedicating a specific cassette System Design: A system designed
processing, compared with 54.5% for to a specific product type or by specifically for incorporating single-
chromatography and only 24.2% for applying a single-use policy, although use components is an essential
centrifugation. Nearly 72% of survey the latter can present a financial requisite for a successful approach.
participants indicated the purification constraint. Nevertheless, these options Any restrictions in the capabilities of
applications they would be most have been introduced into a range of available components must be taken
interested in using in a single-use TFF applications to prevent cross- into account (e.g., pressure and flow
approach was tangential flow filtration product contamination and have been limitations, sensor performance, and
(TFF). Applications incorporating especially beneficial for contract connectivity). We factored in critical
TFF, in part or fully, also gained high research (CRO) and contract process parameters such as hold-up
scores (59.3% for diafiltration and manufacturing (CMO) operators. For volume, cross-flow velocity, and
65.6% for concentration). other product-wetted components — volume concentration factors (VCF).
including pumps, valves and sensors At the earliest possible stage, we also
— increasing availability of single-use considered controllers and automation,
Product Focus: All Biologics
alternatives that meet acceptable especially their practical aspects such
Process Focus: Downstream performance and cost targets offers as ease of access to replaceable
processing possibility of a total single-use TFF components and manifolds and
system. turnaround time between batches.
Who Should Read: Process The cassette holder and pumps are
development and manufacturing Development Strategy an essential part of the design. The
Our approach to developing a single- central core of this TFF system
Keywords: Disposables, filtration,
use TFF system focused on system (Figure 1) provides a platform on
automation, PAT
design, operating capabilities, and which five single-use manifolds could
Level: Intermediate automation. be attached to form a complete

38 BioProcess International January 2011

 Figure 1: Central core of single-use TFF system
system. Figure 1 shows the cassette
Diafiltration
holder, pump drives, valve heads, and Buffer Inlet Fed Batch Inlet Peristaltic Pump
the various inlet and outlet flow paths.
The design of this part of the system Control Valve
had to satisfy many requirements to
ensure that the target performance Permeate Valve
could be achieved, but the following Retentate
Return
issues were particularly critical.
Pressures ≤3.5 bar (50 psig) on the Waste
product feed to the TFF cassette are Return
essential to ensure sufficient
transmembrane pressure (TMP)
typically observed in traditional TFF
operations. Such pressures cannot be
reliably achieved with peristaltic
pumps. Single-use systems restricted
WFI
to TMPs of 1–1.7 bar (15–25psig) will
require longer processing times and Sanitization
Recovery Valve TFF Cassette
increased membrane area in cassettes. Buffer at Low Point
Diaphragm Holder
We integrated a diaphragm pump Product Feed Pump
with a single-use detachable head that
could achieve the optimum TMP,
Figure 2: Single-use manifolds for TFF system
thereby maximizing filter efficiency
and minimizing process time and Permeate Manifold
Batch Manifold
cassette size. On lower-pressure flow Pressure Sensor,
Biocontainer, Pinch Clamps, Connection to Batch Feed Flowmeter,
paths, peristaltic pumps met system Connections (2)
requirements. The diaphragm pump to TFF, Cassette
Retentate Manifold Permeate Port
has a working range of 30–1,200 L/h,
which allows the system to support a Multiple Return Lines, Back-Pressure
Valve, Flow Sensors (2), Connections
0.5 to 5-m 2 filter membrane area. to TFF, Cassette Retentate Port
System line size can scale from 0.5 to
0.75 inches depending on TFF
crossflow rate, which allows system
optimization, minimum working Feed Manifold
volume, and fluid linear velocity for Multiple Feed Lines
High-Pressure Pump Head
the full filter-area range. Pressure Sensor
We designed the central core for Three-Way Valve Head to
Recovery Manifold
ease of use and unrestricted access to Recovery Manifold
the system. The design allows quick Biocontainer, Pinch Clamps, Connection to
installation and removal of the various Recovery Valve
single-use manifolds. Five single-use
manifolds are attached to the central
core (Figure 2). Many factors had to valves to supply product, water for braided tubing and a flow sensor. On
be considered in designing them. injection (WFI), buffer, and sanitizing the low-pressure side, pinch valves
• Careful selection and assessment fluids to the single-use high-pressure could open and close return lines.
of construction materials, not only to pump head. Downstream of the pump, The permeate manifold combines
meet flow and pressure requirements braided silicone tubing is used for the two permeate lines from the TFF
but to ensure that target performance feed to the single-use TFF cassette cassette into a single flow path, which
and scalability requirements can be with an area ≤4 m2. An intermediate contains a pressure sensor, a flow
achieved three-way valve enables connection to a meter, and pinch valves.
• Exclusive use of materials with manifold for final product recovery. The batch manifold is the simplest
full specification and certification for For the retentate manifold, precise of all five manifolds. It comprises a
tubing sets control of backpressure is an essential flexible biocontainer of the required
• Special attention on selection, requirement achieved by working with volume and inlet/outlet tubing fitted
attachment, and connectivity of qualified component suppliers to with quick connectors. Fluid paths are
sensors essential for process control. obtain a single-use control valve with opened and closed with pinch valves.
The feed manifold has four low- the required performance. The high- The recovery manifold is similar in
pressure feed lines controlled by pinch pressure side of the valve is fitted with design to the batch manifold and is

40 BioProcess International January 2011

 Figure 3: Summarized protocol for single-use TFF system trials
used to maximize overall product
IgG (10 g/L) + 10 x Diafiltration:
recovery from the system following BSA (10 g/L) Concentration Five Volumes Concentration
concentration and diafiltration. in 1 M NaCl Buffer Exchange
Sensor Selection and Integration: buffer exchange
Single-use instrumentation played a Table 1: Criteria for selection of single-use instrumentation
key role in this development program,
Accuracy and Capital/
offering the following benefits: Criteria Repeatability Renewable Cost Ease of Use Impact on System Design
• Allows tracking of key process Decision Process What is the ideal Start up time; Signal conditioning;
information determinants requirements blend for the complexity; Stability to irradiation;
user? chance of Materials of construction
• Provides notification when operator error and documentation
processing is not within specification
• Enables automated control of Table 2: Parameters measured in single-use and traditional TFF system trial
processing to optimum conditions Parameter Single-Use Stainless Steel
• Facilitates fully automated process
Volume concentration factor 19.3 16.5
sequences.
To reach our decision on specific Final protein concentration 193 g/L 165 g/L
components, we assessed them on five Final conductivity 17 mS/cm 17 mS/cm
specific criteria (Table 1). Instrument Recovery: initial gravity drain 89% 72%
calibration and validation also was Recovery: first buffer flush 98% 96%
important because they minimize Foaming Minimal Minimal
performance qualification studies and
further calibration before use.
The pool of potential instruments a protein solution and protocol TFF system. So we confirmed that the
for single-use applications is still typically found in bioprocessing critical parameters could be monitored
relatively small. For downstream (Figure 3). Two batches (20 and 100 and controlled in a single-use system
processing, instrument suppliers have L) were evaluated in suitably sized and the target performance achieved.
focused on specific process analytical systems with identical flow paths and Also, the curves confirmed that
technologies (PATs) such as those for only slightly larger hold-up volume for recirculation could achieve adequate
measuring temperature and pressure, the 100-L batch. To ensure sufficient mixing in the biocontainer without a
whereas other technologies — such as mixing during diafiltration, we more complex mixing system. The
those to evaluate flow — have received plumbed the buffer line directly into higher concentration trials represented
less attention. For the latter, extensive the retentate line before it returned to a worst-case challenge to the mixing
testing may be required and alternative the biocontainer. Final processed capability. Inadequate mixing would
methods of integration considered to concentrations of the two solutions have prevented achievement of such
maximize system performance. were 200 g/L (for the 20-L batch) and high-concentration factors and result
We worked with a number of 300 g/L (for the 100-L batch). in significant membrane fouling and
qualified suppliers with approved We measured flux (L/m 2/h), rapid decline in flux.
quality systems, good change control volume concentration factor (VCF), We compared these results with
procedures, and compliant materials of conductivity (mS/cm), and those from a previous study on a
construction to obtain the best diafiltration volumes. Figure 4 plots traditional stainless-steel TFF system.
possible technology and ensure that flux against VCF for both the initial In that trial, we processed a 20-L batch
critical process parameters could be and final concentration steps. Results of polyclonal bovine IgG using a
accurately monitored and controlled. show that for both batch sizes, target similar protocol of 10× concentration
We ensured that renewable costs, concentration factors were achieved followed by five buffer volumes
which have been a major limiting during concentration. Moreover, a diafiltration and final 2× concentration.
factor in introducing single-use linear decrease in flux on a semilog Flux, VCF, conductivity, and
sensors, were within a range users scale agrees with the expected diafiltration volume were measured. In
considered to be acceptable. In this relationship and compares with a addition, we measured product recovery
way, we established a high level of traditional TFF system. both after the initial gravity drain and
confidence that our system would Figure 5 shows conductivity plotted after one recirculated buffer flush
achieve target performance and be against diafiltration volume (DF). The (Figure 6 and Table 2).
comparable with a traditional conductivity wash-out profile for both With those results, we concluded
cleanable system regarding batch sizes was comparable to the the following:
concentration, diafiltration theoretical wash-out curve. • Profiles of the flux versus VCF
performance, and minimizing Using those results, we concluded curves are the same for both systems.
renewable processing costs. that the flux drop-off and diafiltration • The single-use system’s VCF of
Operating Capabilities: We washout curves were comparable with 19.3 was slightly higher than the VCF
evaluated our single-use system using those from a traditional stainless-steel from the stainless-steel system.

42 BioProcess International January 2011

Figure 4: Flux versus volume concentration Figure 5: Conductivity versus diafiltration Figure 6: Flux versus volume concentration
factor in single-use TFF system volume in single-use TFF system factor in single-use and traditional TFF system
Initial Concentration Final Concentration

Conductivity (mS/cm)
100 Initial Concentration Final Concentration
160 100-L batch 80 Theoretical Wash-Out Values 100
Flux (L/m2/h)

120 80

Flux (L/m2/h)
60 20-L Batch
80 20-L Batch 100-L Batch 60 Single-Use TFF
40
40
40 20
Buffer Conductivity 20
0 0
1 10 100 0 1 2 3 4 5 0 Traditional TFF
Volume Concentration Factor (VCF) 1 10 100
Diafiltration Volume (DF) Volume Concentration Factor (VCF)

• Both systems achieved high final Automation: Manual TFF systems ultimately could lead to the
protein concentrations (>150 g/L), heavily depend on well-defined distribution of a contaminated
with a slightly higher value for the procedures and operator skills. Good product. Any manual or mechanical
single-use system. manufacturing practice (GMP) manipulation of the sterilized drug,
• Final conductivity values after requires detailed SOPs, training, and components, containers, or closures
diafiltration were similar (17 mS/cm) validation to limit any process prior to, or during aseptic assembly,
and in agreement with the theoretical variations. The regulatory position poses the risk of contamination and
washout performance. regarding operator interventions is thus necessitates control.”
• Both systems gave good product clearly stated in GMP guidelines (1): The PAT initiative encourages
recovery after flushing (>96%), and the “The design of equipment used in wider use of enhanced technology to
single-use system had higher recovery aseptic processing should limit the minimize operator error and improve
both after initial gravity drain (89%) number and complexity of aseptic accuracy and reliability of processes
and after first buffer flush (98%) interventions by personnel ….” (2). This complements the direction of
(attributed to the design features and Describing filtration, the guidelines the GMP guidelines. To ensure
the low-point recovery drain). also state: “…. liquid dosage forms are conformance and minimize
• In both systems, foaming was subject to filtration. Each of these contamination risk, companies can use
minimal, which confirms that mixing manufacturing processes requires preassembled components, pre-
by recirculation in the single-use system validation and control. Each process irradiated assemblies, and automation.
is an acceptable and effective procedure. could introduce an error that A successful approach to automation

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TFF Vendors • single-use diaphragm pump TFF. However, some further
— BPI Editors • 1,200 L/min maximum flow challenges of automation must be
The following companies are involved in • 0.5 and 0.75 inch tubing addressed to give additional benefits
tangential-flow filtration. diameters in the future, especially regarding
Pall Corporation ([Link]) • 3.5-bar maximum pressure scalability.
products include the Cadence single- • ~1-L working volume Flow Rates: Single-use, high-
pass system, PallSep vibrating • full automation. pressure pumps capable of flow rates
membrane filtration technology, and We were aware that CMOs and from 1,200 L/h to 4,000 L/h are
Kleepak capsules other users of multiproduct systems available, but cost may be a hindrance.
Millipore ([Link]) offers considered fast turnaround between Further developments in pump
Mobius disposable TFF assemblies, the batches extremely beneficial because technology are likely to make higher
Cogent M1 TFF system, and Pellicon it helps reduce operating costs. Our flow rates possible at an acceptable
cassettes and modules
system design emphasis on ease of use cost and enhance the scalability of
GE Healthcare ([Link]. and careful consideration of a three- TFF systems.
com) cross-flow offerings include dimensional structure were essential Tubing Diameters: Our TFF system
Unicorn automated control systems and
ingredients to successful included flexible tubing with 0.5- and
Uniflex (pilot–production) and MidJet
development. For example, 0.75-in diameters. For larger cassette
(laboratory) products
incorporation of a “shadow board” installations, the higher flow rates
SciLog ([Link]) offers the
design permitted full access to necessary to maintain cross-flow
PureTec TFF system and a compact
components from one side. Where velocities generate linear velocities in
AccuTec manually controlled TFF unit
possible, we implemented single-use 0.75-in tubing that exceed the
TangenX ([Link]) provides
sensors that were precalibrated and maximum recommended of 2 m/s.
Sius disposable TFF cassettes and TFF
did not require recalibration before Polymeric tubing with diameters ≥1-in
membranes
use, thereby minimizing downtime. is available, but the components for
must focus at the earliest stage of Our trials confirmed ease of use. these diameters are substantially
development on a basic design. It is Installation of manifolds, a cassette, higher in cost because the quantities
not possible simply to take a and connections to peripheral supply manufactured are relatively small.
traditional system and make it from such as product and buffers was Some components may need to be
plastic materials. That would achieved in ~10 min (range 6–11 custom-made and will have associated
inevitably result in a system that is min). Potential for automation was costs of machining or molding.
difficult to manage and limited in built into the design of the single- TFF Cassettes: Cassettes ≥5 m 2 for
performance and reliability. use feed manifold. It contains single or multiuse are available, but
One feature we designed into our multiple feed lines to allow simple their application are restricted by
automated system was ease of use. We transfer from a manual to automated current limitations in flow capacity
also ensured that the system was operation without having to and tubing diameter. Developments of
designed and built in accordance with rearrange the system before or fully disposable cassette capsules are
good engineering practice (GEP) and during a process run. well advanced and will simplify
that necessary expertise and Initial trials showed performance processes, reduce capital costs, and
experience in systems engineering was similar to that of traditional reusable provide greater flexibility on system
available (3, 4). We paid special systems. Further performance and size and scale-up.
attention to sensor selection and application testing are in progress to Sensors and Instrumentation: For
performance (a vital consideration provide necessary documentation and automating single-use TFF at current
when developing an automated material certifications. The system has scales, sensors and instrumentation are
system). The increasing availability of been designed for customization to available for most parameters, albeit
single-use sensors for critical meet specific user requirements. For limited in type and performance. If
parameters such as pressure, flow, some applications, a standard system assessment in larger scale systems is a
temperature, and conductivity, has may be suitable and would offer the limitation, then alternative methods
made automation possible for single- benefit of lower manufacturing costs may be possible (e.g., flow rate using
use TFF processes. and expedited delivery. gravimetric methods or tachometers on
Taking into account those factors displacement pumps). Present
and working closely with component Future Challenges technology for measuring pH is
suppliers, we developed a prototype We met two major challenges in significantly limited, and no cost-
automated version of this single-use developing our single-use TFF system: effective single-use device is available for
TFF system. Photo 1 shows key performance comparable with that of a measurement in the ultraviolet range.
features of this system, including traditional TFF systems and a high Other Single-Use Technologies: For
• 20-L feed biocontainer level of automation. Availability of other upstream and downstream
• 10-L recovery biocontainer automated systems will undoubtedly bioprocessing unit operations, single-
• 0.5–5 m 2 TFF cassette drive wider application of single-use use technology is either unavailable or

46 BioProcess International January 2011

in early stages of development. Areas 2004; [Link]/downloads/Drugs/ Pauline Nicholson is product manager,
where we might see significant GuidanceComplianceRegulatory Information/ single-use systems, 44-23-9230-3372,
Guidances/[Link] pauline_nicholson@[Link].
progress are chromatography and
3 Botterill M, Rawlings B. Applying Erik Storm is process engineer at Pall
depth filtration. Good Engineering Practices to the Design of Life Sciences, 1-508-393-1800, erik_storm@
In chromatography, surface- Single-Use Systems. BioProcess Int. 6(11) 2008: [Link].
modified adsorptive membranes have 18–25.
been introduced to replace resins in 4 Fuller M, Pora H. Introducing
biopurification for applications such as Disposable Systems into Biomanufacturing: A To order reprints of this article,
DNA and HCP removal and protein CMO Case Study. BioProcess Int. 6(10) 2008:
contact Carmelita Garland (carmelitag@
30–36.
adsorption/desorption (5). One main [Link]) at 1-800-382-0808, ext.
5 Warner TN, Nochumson S. Rethinking 154. Download a low-resolution PDF
challenge for wider use of membrane
Int. January 2003: 58–60. •
the Economics of Chromatography. Biopharm at [Link].
chromatography systems is scale-up.
However, recent developments have V.1. Aber Advert A5 Island:Layout 1 9/12/10 15:41 Page 1
shown that these systems can be
scalable using very innovative single-
use designs.
For depth filtration, scalabilty, high
solids capacity, and ease of use are key
requirements. Large, high-pressure
capsule systems show considerable
promise, and recent studies indicate Welcome to the FUTURA…
that they can not only replace existing
stainless-steel filter systems, but also
in some cases offer alternatives to
other technologies such as centrifuges.

A Comparable TFF System

We designed and developed a single-
use TFF system that could perform
equal to or, for some parameters,
As the innovator in biomass
better than a traditional stainless steel
monitoring, we have re-invented
system. We automated the system by
the technology we created to control
virtue of its basic design and with
careful selection and evaluation of and monitor the next generation
single-use instrumentation, resulting of bioreactors including single use
in low hold-up volumes and high and mini-fermenters. The FUTURA
product recoveries. Ease of use was a micro-platform combines increased
key feature achieved by incorporating processor power with intelligent
rapid change-out manifolds and good probe sensing to provide on-line
access to the system. biomass spectra and cell
Further work is now in progress to concentration into a single future
scale up the process for larger batches proof solution.
to enhance further the level of
automation in terms of performance
and reduced costs as well as to develop To find the ideal
FUTURA solution for
a range of stand-alone encapsulated

your bioreactor visit

cassettes for single-use TFF systems.

References
1 Sterile Drugs Produced by Aseptic
[Link]
Processing ­— Current Good Manufacturing
Practice (Guidance for Industry). US Food and
Drug Administration, September 2004;
[Link]/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/
Guidances/[Link].
2 PAT: A Framework for Innovative
Pharmaceutical Development, Manufacturing,
and Quality Assurance (Guidance for Industry).
US Food and Drug Administration, September
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