your partner in
BIOPROCESSING
www.parker.com/dhsingleuse
Issue One
INSIDE
TANGENTIAL FLOW
FILTRATION
at a glance
NORMAL FLOW
FILTRATION
GRAVIMETRIC
BIOREACTOR MAINTENANCE
FLUID TRANSFER
& STORAGE
INTELLIGENT
LABORATORY SYSTEMS
SENSOR
TECHNOLOGY
2www.parker.com/dhsingleuse
www.parker.com/dhsingleuse
3
8
Contents
13
Features:
16
Together, we can provide cell culture
harvest. Straight out of the box.
8 Risk Management
Controlling supply chain and process risk in biomanufacturing
Normal Flow Filtration
Solutions
Tangential Flow
Filtration Solutions
Gravimetric Biorector
Maintenance
Intelligent Laboratory
Systems
Sensor Technology
Fluid Transfer
& Storage
Events Calendar
19
39
47
52
56
63
72
13 Square Pegs in Round Holes
Understanding bioprocess variation ensures facility fit during technology
transfer
16 Out of the Box
Introducing the new HarvestClear™ Complete Filtration System
for clarification of small-scale bioreactors
Pre-conditioned and ready straight from the box, our new integrated solution for cell
culture harvest provides automated, fast and cost-effective clarification of bioreactor
outputs up to 20 L.
22 Protecting your cell culture
Parker Hannifin Corporation
domnick hunter
Process Filtration - North America
tollfree 877 784 2234
phone +1 805 604 3400
dhpsales.na@parker.com
www.parker.com/dhsingleuse
Minimizing the risk of mycoplasma contamination
during
The system can
increase filter throughput by up to 35% by allowing walk-away operations
and increasing safety levels through automation.
mammalian cell culture
The launch marks the first of our integrated, application-specific solutions combining
42 Preparing your productSciLog
for the
vial and sensor leadership with Parker domnick hunter filtration expertise.
automation
Overcoming obstacles in final ultrafiltration steps
67 Understanding leachables and extractables
Improvements in single-use bioprocess product testing
4www.parker.com/dhsingleuse
HarvestClear™
Complete Cell Culture Harvest System
Parker Hannifin Manufacturing Ltd
domnick hunter
Process Filtration - Europe
phone +44 (0)191 4105121
dhprocess@parker.com
www.parker.com/processfiltration or www.scilog.com
Parker Hannifin Oy - Koivupuistontie 18-22, FI-01510 Vantaa
Phone: +358 (0)20 753 2500 - email: lifescience.finland@parker.com
www.parker.com/dhsingleuse
5
Welcome
Parker’s acquisition of SciLog Inc. in August
2012 marked the birth of a new global
supplier of bioprocessing solutions. SciLog’s
innovative single-use automation and control
technologies have since been combined with
the filtration expertise of Parker domnick
hunter, Parker’s lead division in the
biopharmaceutical sector. The reborn Parker
domnick hunter is now focused on integrating
technologies into bioprocessing solutions
combining filters, bags and tubing, and sensors
into customized single-use systems that
meet the specific needs of our customers’
applications.
Another important aspect of our offering is
expert local support. With multiple laboratory
facilities around the world and customer
support centres in 49 countries, we strive to
deliver consistent and quality support
wherever
our
customers
choose
to
manufacture biopharmaceuticals.
To help demonstrate how we can create
complete single-use solutions for our
customers’ applications we decided to produce
this magazine. We wanted to highlight
how our innovations can help improve the
productivity and simplicity of our customers’
processes as well as produce a resource to
At the centre of our system design philosophy help our customers develop and optimize their
is ‘Open Architecture’.
Our customers are processes. We hope you find it useful.
free to choose any supplier’s lenticular, virus
reduction, tangential flow filtration or normal
flow filtration components to integrate into
their system, an approach which means
Jennifer Johnson
our customers can enjoy all the benefits of
Editor
automation without ever having to compromise
on their process. We will fit our solution to
our customer’s process; we do not expect our
customers to fit their process to our equipment.
Publisher: Editor: Designer:
Contributors:
Distribution and Marketing:
Parker domnick hunter
Jennifer Johnson
Michelle Gray
Juliette Schick, Gregg Larson, Dean Pighin, Todd Kapp,
Andrew Kelly, Karl Schick, Nick Hutchinson
Jennifer Johnson
Together, we can
create your single-use solution.
The addition of single-use innovator SciLog to filtration specialist Parker domnick hunter,
marked the birth of a new global solutions provider for the biopharmaceutical industry.
Our complementary bioprocessing technologies can be integrated into
application specific, single-use solutions that shorten product development
times and improve productivity.
Find out more at www.parker.com/dhsingleuse
Your Partner in BIOPROCESSING is published by Parker domnick hunter. Parker domnick hunter has a continuous policy
of product development and although the Company reserves the right to change specifications, it attempts to keep customers
informed of any alterations. This publication is for general information only and customers are requested to contact our
Process Filtration Sales Department for detailed information and advice on a products suitability for specific applications.
All products are sold subject to the company’s standard conditions of sale.
6www.parker.com/dhsingleuse
www.parker.com/dhsingleuse
Europe: phone +44 (0)191 4105121 - email: dhprocess@parker.com
North America: toll free 877 784 2234 - email: dhpsales.na@parker.com
phone +1 805 604 3400
RISK
MANAGEMENT
Controlling
supply chain
& process risk in
biomanufacturing
Ensuring patients receive the
lifesaving pharmaceuticals they
need, when they need them is of
paramount importance to any
biopharmaceutical manufacturer.
With the industry still at a relatively
early stage of its development,
few molecules if any are
manufactured at a large number
of global locations.
Biomanufacturers need to put
into place all kinds of strategies
to mitigate risk and ensure their
products are available for patients.
Imagine the scenario whereby an
insulin production facility is forced
to shut down or production was
to cease limiting the availability
of insulin to diabetics around the
world. Of secondary importance,
though still to be considered, is the
resulting loss of sales for the
manufacturer and a resultant
drop in share price.
8www.parker.com/dhsingleuse
www.parker.com/dhsingleuse
9
‘Open Architecture’ Approach
Prevents Supply Chain Disruption
Parker domnick hunter’s ‘Open Architecture’ system design
philosophy allows complete customization so our customers never
need to be tied to a single components supplier. ‘Open Architecture’
also helps address any legacy issues allowing the continued use
of validated filters while still benefiting from the implementation
of automation and better documentation. Parker domnick hunter
systems fit our customer’s processes, not vice versa.
required throughout the single-use
component’s lifecycle from its
design and manufacture, through
its distribution, installation,
use and disposal.
Manufacturing Process Risks:
Risks to manufacturers can be
categorized in many ways.
The adoption of single-use
technology in the manufacture of
biopharmaceuticals has changed the
profile of risk that producers face.
For example, the risk of product
cross-contamination between
batches in multi-product facilities
has been dramatically reduced as
have risks from failed cleaning and
steaming regimes. However, the use
of single-use technologies has
created the need to have greater
oversight of supply capability and
quality risks throughout the
supply chain.
10www.parker.com/dhsingleuse
Let’s consider how
biopharmaceutical manufacturers
can mitigate against both supply
chain and manufacturing
process risks.
Supply Chain Risks:
Biomanufacturers can mitigate
supply chain risks in a number of
ways. Firstly they can qualify more
than one supplier. Parker domnick
hunter’s ‘Open Architecture’
approach to the design of its
single-use automated systems
allows customers to utilize filters
- be they cross flow, normal flow,
lenticular or virus reduction - from
their suppliers of choice. Single-use
technology solution providers like
Parker domnick hunter put great
effort into selecting new and
managing existing suppliers. Parker
domnick hunter takes the additional
precaution of approving second
suppliers of components. We put
site contingency plans in place to
minimize the disruption caused by
unforeseen circumstances and can
manufacture products at multiple
locations. Managing quality
throughout this extended supply
chain is an additional challenge
biopharmaceutical manufacturers
face. Assessing risks to the end-user
of the pharmaceutical is inherent to
ISO standards such as ISO 9001 &
13485. Quality risk management is
Minimizing processing risks is also
critical to biomanufacturers. Parker
domnick hunter launched the
PROPOR MR filter last year which
provides maximum protection
against mycoplasma
contaminations of cell cultures,
with a class leading typical log
reduction value (LRV) of greater
than 10, while maintaining high
flow rates for faster batch processing
which decreases the risk of further
contamination.
Unlike a typical membrane
structure, the PES membranes used
in Parker domnick hunter sterilizing
grade and mycoplasma retentive
filters feature a unique design
whereby their most critical retentive
layer is set back from the surface,
protecting it from damage and
providing greater confidence of
filter integrity.
Overmolded single-use assemblies
from Parker domnick hunter avoid
operators having to perform the
time consuming activity of
tie-wrapping tubing together.
Overmolding protects the
process from contaminations and
minimizes risks to operators from
being exposed to potent biological
molecules such as hormones.
Perhaps most critically though,
Parker domnick hunter’s ‘Open
Architecture’ single-use systems
allow users to mitigate process risk
by implementing automation and
sensing into operations which were
previously manual through easy to
learn and use software. Our unique
pre-calibrated single-use sensing
technology not only eliminates
contamination risks during offline
calibration but also enables process
reproducibility with reliable,
certified single-use sensor
performance. SciLog sensors
can be gamma-irradiated or
autoclaved and are suitable for
use in cGMP environments.
Automated systems reduce
variability between operators
and also feature ‘human-like’
control strategies that maximize
filtration performance and adverse
event detection and shutdown
algorithms to ensure when the
unexpected happens your process
is protected.
www.parker.com/dhsingleuse
11
Overmolded manifolds
prevent risk of leakage
Process Manufacturing
Risk Mitigation
Mycoplasma - a common contamination in
mammalian cell culture
retentive area
SciPres sensors
for increased
reproducibility of
filtration operations
®
Square pegs
in round holes
Understanding bioprocess variation
ensures facility fit during
technology transfer
Retentive filtration area set back
from the surface in
our PROPOR range
12www.parker.com/dhsingleuse
By NICK HUTCHINSON
Market development manager
T
he scale-up and transfer of manufacturing
processes is common during the lifecycle
of biopharmaceutical molecules. A lack
of understanding of process variations can lead
to poor process performance and even failures
during such transfers.
During R&D phases only small quantities of
biopharmaceutical product are needed but the
requirements increase as the product enters
clinical trials. Non-GMP pilot plant studies can
be used to assess how the process will perform
at larger scales and mitigate the risk of process
failures during cGMP manufacture. Subsequent
increases in cGMP production-scale are likely
to be required as the molecule progresses
through clinical trials and into commercial
manufacture.
→→
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13
Increases in scale may involve
transferring products between a
sponsor’s manufacturing sites while
a significant proportion will choose
to transfer the process to a contract
manufacturing organization (CMO).
Additional transfers will be required
should the product sponsor change
their CMO or bring the process back
in-house which can happen depending
on their experiences and changes in
manufacturing strategy.
The biopharmaceutical industry strives
for consistency between production
runs no matter what the scale or
location of the process. The continued
difficulty in linking the molecular
structure of large proteins to their
efficacy and safety means the
industry must maintain that the
“process is the product”. A change in
the process implies that the resultant
product cannot be assumed to be
the same as that for which data was
generated during clinical trials. It
should be recognized, however, that
within defined limits process variability
is a fact of bioprocessing life.
Despite the fact that many well defined
scaling criteria and models exist it is
not unusual to see some differences
in process outputs between processes
operated at different scales and in
different locations. The pH of a
chromatography elution pool at the
process scale may differ from the
laboratory and pilot scales due to
14www.parker.com/dhsingleuse
differences in systems designs and
hold-up volumes. An ultrafiltration
step may take more or less time for the
retentate to reach specifications limits.
We may be able to assess the risk
and conclude that these changes are
within design limits and therefore will
not impact patient safety but this lack of
complete certainty when products are
scaled or transferred creates problems
for engineers attempting to fit an
existing process to a new facility or
scale of operation.
A typical approach to modelling
processes and predicting facility fit uses
average values derived from historical
datasets. This is then considered to be
the most likely scenario. However, that
a given bioprocess with its inherent
variation conforms perfectly to typical
values is actually a relatively unlikely
outcome. The impact of this is that
individual process steps developed for
the ‘average process’ may not be well
designed for the actual process.
Consider a cell culture process
producing a recombinant protein
with seven recovery and purification
steps and each step giving a 90% yield.
Should each step including the cell
culture give as little as a 2% deviation
from the expected yield, the difference
in overall process yield can deviate
from the predicted value by around
±15%. Imagine the impact of having
this additional volume of product. If
the normal and cross flow filtrations
are sized on protein mass or volume
per square metre of membrane we
can add in contingent area, however, if
these turn out to be unexpectedly low
we run the risk of exacerbating the
problem by having excess area
which contributes to product losses
through
hold-up
volumes and nonspecific binding.
The solution is to develop more
sophisticated decision-support tools
to enable the process variability within
process limits that we are able to
measure and understand, to be factored
into calculations for facility fit models.
Such tools have been developed by
collaborators working
with the Department
of
Biochemical
Engineering
at
University
College
London in the UK
and
have
integrated
stochastic
simulation with multivariate analysis
to detail how sub-optimal facility fit
can be alleviated by alternative process
configurations. The objective, therefore,
is to allow managerial decisions to
be made between the risk of process
disruption due to poor process fits and
the implications on Cost of Goods of
mitigating against every eventuality.
'The Process
is the Product'
How
then
should
we design those unit
operations towards the end of our
process such as formulating cross flow
filtration or final bulk filtration steps? It
is common to build safety factors into
design calculations without trying to
cover every processing eventuality yet
relatively little consideration is given
to how these safety factors are derived
and the impact of these on process costs
versus the risk of poor process fit,
disruption or even failure.
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15
HarvestClear™ Filtration System for
harvest of small-scale bioreactors
Figure 1:
HarvestClear™ bioreactor
harvest process
FilterTec™
The system provides analysis of
throughput volumes and system
pressure parameters in order to
provide comparative performance
data for optimum system selection.
The FilterTec™ controller can be
operated at constant pressure or at
constant speed. In addition, the
FilterTec™ incorporates the patented
R/P Stat Mode (Pg 21), an innovation
which allows up to 30% more filter
throughput.
The clarification of batch and fed-batch bioreactor systems can pose a practical challenge to
biopharmaceutical manufacturers due to high cell densities. The HarvestClear™ Filtration
System is an automated single-use system designed to optimize clarification of 1L to 20L
high density bioreactor outputs, while reducing hands-on time and increasing operator safety.
Here we describe this fast and easy system, which is ready-to-use straight from the box, its
features, and its use in clarifying 1L to 20L of high density fermentation batches of Chinese
Hamster Ovary (CHO) cells.
HarvestClear™ has been designed to provide automated, fast and cost-effective clarification
of bioreactor outputs of 1L to 20L straight from the box.
When correctly sized and controlled,
single-use normal-flow filtration
(NFF) systems can provide the
biopharmaceutical manufacturer with
high-quality, rapid and cost-effective
clarification of small-scale bioreactor
outputs. The Parker domnick hunter
HarvestClear™ Filtration System is
designed for single-use clarification
of 1-20L bioreactor outputs from
discovery to development-scale.
Automated systems prevent manual
errors while allowing walk-away
operations and higher levels of safety.
SciLog automated pumping and
single-use sensor technologies have
16www.parker.com/dhsingleuse
been combined with the filtration
expertise of Parker domnick hunter in
the HarvestClear™ Filtration System.
This new system offers a fast and
cost-effective alternative to traditional
time consuming, and sometimes messy
techniques, such as centrifugation or
coarse filtration. With plug-and-play
functionality, it is immediately usable
without the requirement for any initial
flushing. The full system is shown in
Figure 1 connected to a bioreactor and
a bioprocessing container to collect
filtrate. The filtration system consists of
a sterile single-use filtration manifold
containing a 5 micron PROCLEAR GF
prefilter followed in series by the
0.2 micron PROPOR HC, high-capacity
sterilizing-grade membrane filter. The
product descriptions of these filters are
shown in Table 1. Upstream from each
of the pre-flushed filters is a SciLog
SciPres® pre-calibrated pressure sensor
for monitoring pressure at the filter
inlets. These filtration manifolds are
controlled by a SciLog FilterTec™
laboratory-scale monitoring and
control system. When the collection
container is mounted on a
WeighStation™ connected to the
FilterTec™ controller, the system offers
gravimetric control.
NFF trials of this system were
performed in conjunction with a large
biopharmaceutical manufacturer on
the output stream from single-use,
bioreactors used to grow Chinese
Hamster Ovary (CHO) cells for
research purposes. The typical viable
cell concentration of the bioreactor
output used for testing was 7 x 107 cells
per millilitre. The key system
performance criteria were speed of
processing and ensuring that filter
blockage did not occur mid-batch.
Subsequent scale-up testing
conducted using large-scale MURUS
capsule PROCLEAR GF and
PROPOR HC filter products provided
confirmation of the initial results and
were used to establish approximate
sizing guidelines for systems of this
type which are shown in Table 2.
Table 1: Filter Product Descriptions
‘Automated
systems prevent
manual errors
while allowing
walk-away
operations and
higher levels of
safety’
•Pharmaceutical-grade,
glass-fibre depth media
prefiltration product.
PROCLEAR
GF
•Designed to provide
exceptionally high
dirt-holding capacity and
low extractable levels
making it well-suited
to biopharmaceutical
applications.
•Pharmaceutical
sterilizing-grade, high
capacity polyethersulphone
membrane filter.
PROPOR HC
Sterilizing-Grade
Filter
Bioreactor
Prefilter
By GREGG A LARSON - PRODUCT Manager, SINGLE-USE
Container
•Designed to provide
assurance of sterile
filtrate without
compromizing on filtration
system capacity.
Table 2: HarvestClear™ Filter Manifold Sizing Guidelines
Bioreactor Output
(litres)
PROCLEAR GF 5 µm
(Prefiltration)
PROPOR HC 0.2 µm
(Sterilizing-Grade)
1 - 5L
10¨
10¨
5 - 10L
20¨
10¨
10 - 20L
30¨
10¨
The HarvestClear™ filtration system
provides plug-and-play functionality
for clarifying the outputs from small
bioreactors, allowing immediate use
without the need for initial flushing.
The sterile, pre-flushed, pre-sized
manifolds in the system save time
and effort.
The automation in the FilterTec™ controller, coupled with feedback from the in-line SciPres® pressure
sensors, allows walk-away bioprocessing, with reduced risk of product loss, as well as an increase in
product yield and operator safety.
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17
Normal Flow
Filtration
Solutions
Together, we can start processing your cell
culture harvest. With no hanging around.
HarvestClear™
Complete Cell Culture Harvest System
Pre-conditioned and ready straight from the box, our new integrated solution for cell
culture harvest provides automated, fast and cost-effective clarification of bioreactor
outputs up to 20 L.
The system can increase filter throughput by up to 30% by allowing walk-away operations
and increasing safety levels through automation.
The launch marks the first of our integrated, application-specific solutions combining
SciLog automation and sensor leadership with Parker domnick hunter filtration expertise.
filtration sensors
automated systems
www.parker.com/dhsingleuse
Europe: phone +44 (0)191 4105121 - email: dhprocess@parker.com
North America: toll free 877 784 2234
- email: dhpsales.na@parker.com
phone +1 805 604 3400
www.parker.com/dhsingleuse
19
A complete range of normal flow filtration (NFF)
solutions from laboratory to production-scale
designed to safely automate NFF operations while
improving overall filtration yield.
R/P Stat
Method
FilterTec™ Plus expands upon the FilterTec™’s
capabilities to allow for simultaneous testing
of up to three identical filters at the same rates
or three different filters at the same pressure.
SciLog FilterTec™
Laboratory-Scale NFF System
FilterTec™ automatically adjusts and
documents filter back pressure
and filtrate to optimize filtration
parameters and maximize filter
throughput. The system can also
be used as a filter evaluation tool.
As well as constant pressure
and constant flow operations, all
SciLog NFF systems feature the
patented R/P Stat Mode, a novel
method that delivers a higher degree
of filter capacity utilization when
compared to other NFF procedures.
The R/P Stat Mode enables constant
pressure or constant rate NFF via
a pump PID loop including inline
pressure sensors. This is done by
selecting three simple process
variables including inlet pressure and
minimum flow rate. By using the R/P
Stat method, as the membrane begins
to foul, the system dynamically adjusts
the flow rate which allows up to 30%
more filter throughput depending on
process fluid and application.
Air and Gas Filtration
←← Sterile
TETPOR AIR PTFE range of
←←
gas filters offer exceptional
filtration performance in
cartridge or capsule format
while providing high levels
of biosecurity removing all
airborne bacteria, viruses
and bacteriophage.
Dead-end filtration by R/P Stat Method
Integrity Testing
Porecheck 4 provides water
intrusion, pressure decay
and bubble point testing of
membrane liquid and gas
filters while Valairdata 3
offers aerosol challenge
testing for quick and
accurate testing of
sterile gas filters.
18 16 -
Pump Rate (ml/min)
←←
Pharmaceutical Liquid Filter Range
The PROPOR range of PES membrane
filter range and PROCLEAR prefilter
range are ideal for all normal flow
filtration applications including
mycoplasma removal, sterilization,
bioburden reduction and
general clarification.
up to 30%
enhancement
in filter yield
←←
SciFlex® NFF is a proven platform for use in
discovery to production-scale applications.
The onboard sensors and automation
eliminates the need for constant
monitoring allowing for
walk-away operations.
Const. Rate Region
Const. Pressure Region
- 25
- 20
14 12 -
Pressure (psi)
NFF Semi-Automated
Bioprocessing System
←←
←← SciLog SciFlex
®
SciLog FilterTec™ Plus
Laboratory-Scale NFF System
- 15
10 -
Pump Rate vs Time
Pressure vs Time
864-
- 10
-5
200
200
400
600
800
1000
-0
1200
Time (sec)
1
www.parker.com/dhpbiopharm
20www.parker.com/dhsingleuse
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21
Minimizing the risk of
mycoplasma contamination
during mammalian
cell culture
By ANDREW KELLY - PRODUCT MANAGER, FILTRATION
Summary
A mycoplasma contamination event can have a major harmful impact
on a biopharmaceutical manufacturer. The loss of a cell culture due to
a contamination incurs significant costs that can be attributed to both
the initial bioreactor set-up and to the subsequent decontamination.
Production facility throughput and, in the worst cases, the ability of the
manufacturer to supply patients with medicines may be affected.
Mycoplasma are extremely small in size and lack a cell wall giving
the cells some flexibility that enables them to penetrate the 0.2 micron
filters used to ‘sterilize’ cell culture media. The filtration of cell culture
media with 0.1 micron filters alongside the effective screening of cell
lines for infection and adherence to GMP principles of contamination
control will minimize the risk of bioreactor contamination.
22www.parker.com/dhsingleuse
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23
M
ycoplasma is the common
name given to the Mollicutes
class of bacteria. They have
an extremely small size and lack a
cell wall. This latter characteristic
engenders a degree of flexibility in
the cells which, when combined with
their small size, can allow them to
contaminate cell cultures through
sterilizing-grade, 0.2 micron filters.
Contamination with mycoplasma
can have severe deleterious effects
on mammalian cell cultures as the
contaminating species competes
with mammalian cells for key media
components leading to modified
protein production and altered
cell growth characteristics. In
biopharmaceutical manufacturing,
cell cultures from bioreactors in which
a mycoplasma contamination has
been detected are discarded to
protect patient safety. Sources of
contamination include cross
contamination from a previously
infected cell culture, laboratory or
manufacturing personnel and raw
materials used in the manufacture
of cell culture media. These raw
materials can be animal-derived
nutrients or animal-free components
such as plant-derived peptones.
Traditional analytical methods for
mycoplasma detection can take many
days to complete thereby increasing
the risk of a contamination spreading
throughout a manufacturing facility.
Mycoplasmas are potentially
pathogenic or ‘disease-causing’ and
the U.S. Food and Drug Administration
requires mycoplasma safety testing
to be performed on bioreactors
containing mammalian, avian and
insect cell cultures prior to their
harvesting and the transference
of the impure product pool to
purification suites.
The risk of contaminations by
mycoplasmas can be minimized by the
quarantining and testing of all new
mammalian cell cultures, the
adherence to aseptic cell culture
procedures in the laboratory and
good manufacturing practice in
manufacturing. In addition appropriate
precautions should be taken with raw
materials used in manufacturing. These
can be supplied in a pre-sterilized form
or alternatively can be screened for
mycoplasma contamination prior to
being used.
Methods that prevent the infection of
mammalian cell cultures with
contaminated cell culture media
components include the heat
sterilization or sterile filtration of media
prior to inoculation. Heat sterilization
is often not a viable option for the
sterilization of mammalian cell
culture media because these media
typically contain heat-labile
components that would be destroyed
by the heat-sterilization process.
Sterilization of cell culture media by
filtration is, therefore, common practice
within the biopharmaceutical industry.
Photo Typical
Mycoplasma bacteria
T
Photo
Parker domnick hunter
PROPOR MR MURUS
single-use disposable
filter capsule
24www.parker.com/dhsingleuse
he culture of
mammalian cells is a
key technology used
in the manufacture of
biopharmaceuticals.
Microbial contamination of
cell cultures is a major cause
of lost production batches
with significant economic
impact for the manufacturer.
The risk of contamination
can be controlled by
ensuring all components
entering the bioreactor are
free from microorganisms.
Media used for the culture of
mammalian cells commonly
contains heat-labile
components and
consequently cannot be
sterilized at high
temperatures. Filtration
through a sterilizing-grade,
0.2 micron filter can protect
mammalian cell cultures
from contamination by
many microorganisms but
does not protect against
contamination by
mycoplasma species.
C
ell culture media is typically
prepared in an agitated vessel
at ambient temperature.
Powdered basal mediums are dissolved
in water and can be supplemented
with nutrients before tests for pH,
osmolarity and nutrient concentrations
are performed to ensure the made-up
media conforms to specifications.
In this open system the unfiltered
media is at risk from contaminating
organisms including mycoplasma
species.
force for filtration can be supplied by
a pump or by pressurizing the media
preparation tank. Filters are either
steam sterilized prior to use in the
facility or can be supplied in
pre-sterilized, gamma-irradiated
capsule formats. Multiple stage
filtration trains may be required in
which a prefilter is used to protect a
final filter from blockage. The need
for this prefilter can be reduced if a
dual-layer final filter with an integral
prefilter layer is used.
Media that conforms to specification
is then filtered directly into the
bioreactor or alternatively into storage
vessels until it is required. The driving
Media suppliers and biopharmaceutical manufacturers often set a
maximum time limit specification
from the addition of the first media
component to the end of filtration to
reduce the risk of contamination of the
unfiltered media. This time limit will
vary between manufacturers but is
likely to be approximately six hours.
A filter that can deliver high flux rates
without compromising protection from
mycoplasma is, therefore, important.
Upon completion of the media
filtration, conditions within the
bioreactor can be brought into
equilibrium in preparation for the
inoculation of cells from the seed
bioreactor.
www.parker.com/dhsingleuse
25
P
180
Knowledge of the
complete process is
paramount in
designing the optimal
filtration system
160
140
Mass (grams)
arker domnick hunter’s
PROPOR MR solution is a dual
layer, sterilizing -grade
polyethersulphone (PES) membrane
filter which has been developed to
protect cell cultures by removing
contaminating mycoplasma from
cell culture media prior to the
media being inoculated with
mammalian cells.
120
100
PROPOR MR
80
Competitor B
Competitor A
60
Graph 1a - Average
throughput results
for TSB media
40
PROPOR MR filters use a 0.1 micron
rated membrane and have been
validated by bacterial challenge
testing with both the mycoplasma
test species Acholeplasma laidlawii
(ATCC 23206) and the sterility test
species Brevundimonas diminuta
(ATCC 19146).
By using our customers’ feed
streams in the development of
the PROPOR MR solution, Parker
domnick hunter has been able to
ensure that PROPOR MR is capable
of delivering industry leading flow
rates without compromising on
mycoplasma removal assurance.
High flow rates allow the rapid
processing of unfiltered media and
minimize the risk of contamination
occurring in the media preparation
tank.
Graph 1 shows data comparing the
performance of PROPOR MR with
two competitor products. Graph 1a
shows data generated using a Tryptic
Soy Broth filtration while Graph 1b
shows data from a CHO Utility Media.
Both figures show that the PROPOR
MR outperforms competitor products
with respect to flux rates and total
throughput.
0
0
50
100
150
200
250
300
Time (seconds)
350
400
450
500
250
Knowledge of the
complete process is
paramount in
designing the optimal
filtration system
200
Mass (grams)
An integral, high capacity,
prefilter layer has been included in
the PROPOR MR design and has been
demonstrated to reduce customers’
requirements for separate prefilters.
For customers using cartridge filters
this will reduce capital plant costs,
utility requirements and installation
times. Smaller-scale media filtrations
that utilize single-use capsule filter
technology require smaller manifold
designs, fewer connections and lower
disposal costs.
20
150
PROPOR MR
Competitor A
Competitor B
100
Graph 1b - Average
throughput results
for Hyclone CHO
Utility media
50
0
0
50
100
150
200
Time (seconds)
250
300
Product Selection - The right product for your application
Product
Membrane
Main feature
Cost saving benefit
Dual layer
Polyethersulphone
Sterilizing-grade filter
for the effective removal
of mycoplasma species
Minimizes risk of lost batches
due to mycoplasma
contamination
PROPOR SG
Polyethersulphone
Sterilizing-grade filter
with very high flow rates
Faster processing for minimal
batch turnaround time
PROPOR HC
Dual layer
Polyethersulphone
Sterilizing-grade filter
with increased capacity
Economical filtration of
difficult to filter solutions
Glass microfibre /
Polypropylene
Prefilter providing
maximum downstream
protection to
downstream filter
membranes
Maximizes throughput
and flux rates through
downstream filter
membranes
PROPOR MR
PROCLEAR GP
N.B. This table is for guidance only. Filterability can vary from one solution to the next and Parker domnick hunter
recommends that filterability studies are conducted on an individual basis to ascertain the optimal filtration system.
Together, we can produce mycoplasma-free
cell culture media....................faster
Validated Faster
Reduced
mycoplasma batch
removal
processing
filtration
costs
Typical LRV >10 for
Acholeplasma laidlawii
Integral prefilter layer
for increased capacity
Industry leading
flow rates
Incorporate PROPOR MR into single-use automated
systems at: www.parker.com/dhsingleuse
The new PROPOR MR mycoplasma retentive filter from
Parker domnick hunter delivers industry leading flow rates
without compromising on mycoplasma retention assurance.
Find out more at: www.parker.com/mycoplasmafree
Conclusion
M
ycoplasma species are capable of penetrating 0.2 micron, sterilizing-grade filter membranes and contaminating
mammalian cell cultures leading to the loss of biopharmaceutical production batches with significant economic
impact. 0.1 micron filtration has, therefore, become commonplace for cell culture media; however, greater membrane
retention leads to slower filtration which can increase the risk of contamination.
PROPOR MR 0.1 micron PES filters combine validated removal of mycoplasma with high flow rates to minimize
contamination risks. Futhermore, an integral prefilter layer allows greater throughput increasing the cost-effectiveness
of the filtration system.
26www.parker.com/dhsingleuse
filtration sensors
automated systems
www.parker.com/dhsingleuse
Europe: phone +44 (0)191 4105121 - email: dhprocess@parker.com
North America: toll free 877 784 2234
- email: dhpsales.na@parker.com
phone +1 805 604 3400
case study
air, gas
& vent filtration
Product Filtration
The high capacity PROPOR HC
sterilizing-grade PES filter was
developed in conjunction with an
insulin manufacturer who was
experiencing premature filter blockage
when filtering a product intermediate.
Initial filterability trials through to
full-scale on-site testing and full
product validation took less than
6 months and guaranteed full batch
processing for the customer. The
product has since been incorporated
very successfully in various
applications at a number of
biopharmaceutical manufacturers.
Total volume throughput (g) vs time (s)
comparison of prefilter membranes
140
140
120
120
100
100
80
0.6 / 0.2
0.45 / 0.2
1.2 / 0.2
60
40
0
0
80
Dual layer
PROPOR HC 0.6 / 0.2
PVDF 0.2
60
40
20
20
250
500
750
Time (s)
1000
1250
Initial filterability trials on discs:
Different prefilter membranes were assessed to determine the
optimum configuration for the PROPOR HC high capacity product.
28www.parker.com/dhsingleuse
Total volume throughput (g) vs time (s)
Volume Throughput (g)
Parker domnick hunter is strongly committed to increasing process
productivity for our customers. Product development in partnership
ensures customer satisfaction and competitive advantage.
Volume Throughput (g)
Collaborative
Product
Development
0
0
250
500
750
Time (s)
1000
1250
Initial filterability trials on discs:
Improvement over incumbent competitor PVDF sterile filter.
www.parker.com/dhsingleuse
29
Reducing filtration system size
Effective filtration
of common buffers
Comparative
testing
has
been
completed on a number of competitive
sterile grade PES membrane products
using a standard range of buffers
that show significant benefits can be
achieved using the PROPOR range.
Buffers chosen for test were:
•1M hydrochloric acid (pH=1)
•1M sodium hydroxide (pH=13)
•50mM tris-buffered saline (pH=8)
•10mM phosphate–buffered saline
•(pH=7)
•50mM phosphate-citrate buffer (pH=5)
•0.1M acetic acid
•10% ethanol
•6M urea
Tests were conducted on membrane disc
and then scaled up to give the
equivalent system size to filter a typical
12000 litre batch in 1 hour.
Comparative Performance of PES Filters
By ANDREW KELLY - PRODUCT MANAGER, FILTRATION
PROPOR SG
PROPOR HC
Competitor A
Competitor B
6M urea
10% Ethanol
0.1 acetic
acid
50 mM
phosphate
10 mM tris
phosphate
50 mM tris
buffered
1M sodium
hydroxide
1M
hydrochloric
PROPOR BR
Competitor C
FORMULATION
BUFFER
TANK
CHROMATOGRAPHY
*For further details please contact Parker domnick hunter.
STERILE
FILTER
FERMENTATION
B
uffers are used throughout the
production of pharmaceuticals
from
cell
culture
and
fermentation to downstream processes
and final drug formulation. Buffer
filtration is essential in protecting
downstream chromatography and
ultrafiltration equipment, controlling
bioburden throughout the process
and producing an endotoxin free final
product. The growing pressure to
maximize throughputs and minimize
production
time
means
the
optimization of buffer filtration stages
has never been more important.
Choice of filter configuration
Polyethersulphone (PES) is widely
recognized as having exceptional
flux rates compared to alternative
30www.parker.com/dhsingleuse
membranes such as PVDF, as well as
being more chemical resistant to
solutions such as caustic. Parker
domnick hunter supplies a choice
of PES based filters for bioburden
reduction or assurance of sterility,
which can be used for a wide range
of buffers, including difficult to filter
buffers such as 6M urea.
PROPOR BR
• For buffers used in chromatography/
diafiltration that only require
bioburden reduction.
• Single layer PES membrane with
integral depth prefilter layer to
extend filter life under high
precipitate loading and deliver
bioburden reductions >log 5.
Conclusion
Product selection
PROPOR HC
• Maximizing throughputs on more
difficult to filter buffers and reducing
system size.
• Dual layer PES 0.2 membrane
incorporating a highly asymmetric
PES prefilter layer to provide capacity
improvement up to 10 times that of a
single layer membrane.
Implementing the use of the appropriate filter from the PROPOR range can
bring significant benefits by:
• Providing a smaller system size and thereby reducing the cost per batch
for consumables.
• Reducing the filtration time for the batch, (by up to 40% in some cases)
creating the opportunity to process more batches per day and relieving
the bottleneck that often occurs in the buffer preparation area.
PROPOR SG
• Accelerated filtration rates to reduce
batch processing time for standard
buffers requiring sterility when used
as additions to fermentations or in
final product formulations.
• Single layer PES 0.2 configured for
maximum flow rates and assured
sterility.
•Validated bacterial retention
Buffers are used widely
throughout biopharmaceutical
production and, in line with
FDA Guidelines on Sterile Drug
Products, it is incumbent on
the user to reduce and control
bioburden within the process.
Whether bioburden reduction or
sterile filtration is required, the
filter must be validated for the
retention of bacteria and this
must be correlated to a nondestructive integrity test.
•High flux rates
Minimizing transfer times of
buffers is key to quick turnaround of buffer batches leading
to increased daily production
capacity on the existing plant.
The use of a high flux filter can
also significantly reduce system
size decreasing filtration
consumable costs.
Relative filtration area
required to process batch
STERILE
VENT
FILTER
The key specification
requirements for filtering
buffers are:
Parker domnick hunter’s PROPOR range of filters have been shown to
outperform competitive products for the filtration of a wide range of
common buffers including 6M urea, which is often more difficult to filter.
•Excellent chemical compatibility
Buffers used in biopharmaceutical processes span a broad
pH range (1-14) and a buffer
filter must be compatible across
this entire range.
Filtration not only ensures this
happens but brings many other
benefits such as:
Process control:
•Guard against coagulation or
precipitation from unforeseen
upsets in upstream processing
•Removal of any remaining
cells so reducing the risk of
endotoxins
Cost avoidance:
•Reduce irreversible resin pore
plugging by contaminating
proteins and cells that may
decrease resin life
•Decrease stress on resin by
reducing the use of cleaning
chemicals
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31
Prefiltration medias and their
applications
Prefilters
suitable
for
use
in
biopharmaceutical applications can
contain different types of filtration
media. The appropriate media to
use will depend on the application.
Typical
prefiltration
media
are
described in the table along with their
properties and when they should be
used.
Optimization of two stage
filtration systems
By NICK HUTCHINSON - MARKET DEVELOPMENT MANAGER
F
iltration is commonly used in
biopharmaceutical manufacturing
in order to control bioburden
within the production process. Filtration
costs within manufacturing facilities
can be optimized by the appropriate use
of prefilters. A correctly selected and
sized prefilter positioned upstream of a
sterilizing-grade or bioburden control
filter can significantly reduce the
required area of these membrane
32www.parker.com/dhsingleuse
filters. The cost of operating a prefilter
and sterile filter with a low membrane
area is generally less than the cost of
operating high membrane area sterile
filters without an upstream filter.
The key filtration
requirements:
• High throughput
• High capacity
• Minimum system size
• Minimum cost
Media
properties
When to
use ?
Polypropylene
Glass fibre
Dual layer glass
fibre / polypropylene
High physical
robustness
High capacity
Greatest retention of
solid particles
Compatible with a broad
range of chemicals
Less chemically resistant
and physically robust
than polypropylene
High capacity
Typically inert
Interactions with
products sometimes
observed
Chemically resistant
and physically robust
Use for aggressive
solutions such as
solvents, buffers and pH
adjustment
solutions when capacity
is not an issue
Use when high capacity
is a priority such as cell
and precipitant removal
steps
Use in situations when a
high level of protection of
downstream membranes
is required
The upper line in Figure 1 is filter sizing
data for the same PROPOR HC
membrane but with the PROCLEAR
GP prefilter operated upstream of the
sterilizing-grade filter. The PROCLEAR
GP combines glass microfibres with
polypropylene to achieve both high
capacity and physical robustness. The
results show that a single 10¨ PROPOR
HC capsule can be used to filter the
entire batch if a 10¨ PROCLEAR GP
capsule is used as a prefilter. This
solution is approximately 25% more
cost effective than doubling the sterile
filtration membrane area as shown in
Figure 2. In many cases prefiltration
will protect the membrane filter to a
greater extent than in this example,
thereby magnifying the cost savings
available to manufacturers.
100
100
90
90
Relative cost of filtration solutions (%)
The role of prefiltration in the
optimization of bioprocess
filtration systems
Proportion of batch filtered (%)
Use of a prefilter to optimize the
sterile filtration of a serum containing
solution.
The following case study illustrates the
importance of prefiltration in designing a
cost-effective sterilizing filtration system
for a viscous, serum-containing biologic
solution. The lower line in Figure 1 shows
filter sizing data at constant flow for the
high capacity, sterilizing-grade PROPOR
HC membrane filter. A single 10¨ capsule
would only be able to process half the
batch. Doubling the filtration capacity
would enable the entire batch to be
processed; however, this would be an
expensive solution.
Filter media
80
70
60
50
40
20
0.5 µm
PROCLEAR GP
/ PROPOR HC
10
PROPOR HC
30
0
0
2
Time (hours)
4
Figure 1 - Filter sizing data showing the proportion of a batch of a serum
containing biologic solution that can be sterilized using a
10¨ sterilizing-grade PROPOR HC capsule filter with and
without a PROCLEAR prefilter.
This case study illustrates the savings in
filtration costs that can be achieved by
using prefiltration to optimize sterilizing
and bioburden controlling filtrations
in the biopharmaceutical industry.
Where filter cartridges are being used
instead of single-use capsules the cost of
installing additional filter housings
needs to be considered. Manifolding
together an extra single-use capsule can
require additional labour in the facility;
however, suppliers are able to manifold
complete filtration systems together
prior to delivery allowing biomanufacturers to eliminate these
non-value adding activities.
80
70
60
50
40
30
20
10
0
20¨ PROPOR HC
with no prefiltration
10¨ PROPOR HC
with PROCLEAR GP prefiltration
Figure 2 - Relative cost of filter sterilizing an entire batch of a serum
containing biologic solution using either a 20¨ PROPOR HC capsule or a
10¨ PROPOR HC with an upstream PROCLEAR GP prefilter.
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33
Recommended approach for
sizing prefilters in
biopharmaceutical process
Sizing prefilters can be a difficult and
time consuming activity due to the large
number of variables and parameters to
be optimized. Filtration suppliers are
often happy to provide technical support
scientists to conduct experiments on
behalf of customers.
The following points provide some
recommendations for the sizing of
filtration systems that incorporate
prefilters.
1. Establish the requirement for
prefiltration by first sizing the downstream membrane filter.
2. Where possible gather information
about the properties of the process
stream by collating all existing
relevant data and by performing
experiments to determine the
concentration and particle size of
particulates and the viscosity of the
process solution.
3. Select likely prefilter media based on
the properties of the process stream
and whether retention, compatibility
or capacity is likely to be an issue.
4. Based on previous knowledge and
process stream analysis, select the
prefilter grades you expect to be most
effective at protecting the membrane
filter. A 0.2 micron filter is likely to
require a prefilter with a micron
rating of 0.5-0.6 microns, a high
capacity membrane filter with
integral prefiltration layer is likely to
benefit from a prefilter with a more
open pore structure.
5. Use the constant flow sizing
method to compare the capacities
of the grades selected and retain the
filtrate to allow re-sizing of the downstream membrane filter. (Constant
pressure filtration can be used for
prefiltration screening but use low
pressures in the range of 5-10 psig to
mimic likely operating conditions).
6. Additional prefiltration stages should
be considered for process fluid with a
high solids content. In these cases an
initial coarse prefilter that provides
high solids-holding capacity followed
by a finer secondary stage to protect
membrane filtration can provide a
cost-effective solution.
7. Confirm the results at larger scale
using a pleated format to give greater
confidence in the performance at the
final scale.
8. Once the results are confirmed then
scale-up to the production scale.
Conclusion
The use of prefilters to reduce
total
filtration
costs
in
the
manufacture of biopharmaceuticals
can be easily demonstrated. Prefilter
medias should be selected based on
the properties of the process stream to
be filtered. Guidance on the sizing of
prefilters can be provided; however,
it is technically difficult and can be
performed for on behalf of customers
by the technical support groups of
filtration suppliers.
case study
Sizing prefilters
air, gas
& vent filtration
Flexibility in Design
Sterile Vent Filtration
Parker domnick hunter’s ability to quickly adapt our
products to customer applications allows us to meet
specific customer requirements throughout the
biopharmaceutical industry.
The design of a sterile gas capsule
filter from the Parker domnick hunter
TETPOR range was modified to
satisfy a particular need at a global
biopharmaceutical customer.
The capsules were used as vents
on portable stainless steel tanks
transporting intermediate vaccine
product. Removal of the capsule vent,
which was not required, eliminated
customer concerns over the vent
becoming damaged in use leading
to loss of product integrity.
34www.parker.com/dhsingleuse
www.parker.com/dhsingleuse
35
Scaleable
SINGLE-USE
filtration solutions
Effective
Filtration Area
(EFA)
Syringe
Filters
E Size
B Size
A Size
K Size
10¨ Size
cm2
in2
m2
ft2
m2
ft2
m2
ft2
m2
ft2
m2
ft2
TETPOR AIR
14.50
2.25
0.06
0.64
0.12
1.29
0.25
2.69
0.36
3.87
0.77
8.28
HIGH FLOW TETPOR II
14.50
2.25
-
-
-
-
-
-
-
-
-
-
PROCLEAR GF
14.50
2.25
0.05
0.6
0.10
1.07
0.20
2.2
0.27
2.9
0.56
6.0
PROCLEAR GP
14.50
2.25
0.03
0.3
0.06
0.6
0.12
1.3
0.16
1.7
0.34
3.7
PROCLEAR PP upto
14.50
2.25
0.07
0.75
0.14
1.50
0.28
3.01
0.37
3.98
0.79
8.5
PROPOR BR
14.50
2.25
0.05
0.53
0.10
1.07
0.20
2.15
0.26
2.79
0.55
5.92
PROPOR SG
14.50
2.25
0.05
0.53
0.10
1.07
0.20
2.15
0.26
2.79
0.55
5.92
PROPOR HC
14.50
2.25
0.05
0.53
0.10
1.07
0.20
2.15
0.26
2.79
0.55
5.92
PROPOR LR
14.50
2.25
0.05
0.53
0.10
1.07
0.20
2.15
0.26
2.79
0.55
5.92
PROPOR MR
14.50
2.25
0.05
0.53
0.10
1.03
0.19
2.09
0.24
2.58
0.50
5.38
36www.parker.com/dhsingleuse
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37
Tangential
Flow Filtration
Solutions
18www.parker.com/dhpbiopharm
Untitled-1 1
38www.parker.com/dhsingleuse
6/28/2013 1:40:03 PM
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39
A range of tangential flow filtration (TFF) solutions
for use with cassette or hollow fibre filters and in
microfiltration or ultrafiltration applications enables
successful process scale-up from laboratory through
pilot to GMP manufacture.
Delivered as a complete
development system, PureTec®
TFF protein purification system
automatically monitors and
adjusts trans-membrane
pressure (TMP) or cross flow rate
to optimize product yield.
The SciPure® fully-automated
bioprocessing system features a
user friendly interface and menu
driven operation with data
acquisition (21 CFR Part 11) making
it ideal for GMP manufacturing.
Parker domnick hunter is
committed to providing you
with technology that fits your
process rather than forcing
you to adapt your process to
available equipment; that’s
the reason we have our ‘Open
Architecture’ design philosophy.
All SciLog systems, at every
scale, feature ‘Open Architecture’
design so whomever you
choose as your filter supplier,
we will work with you to deliver
a system that exactly meets
your requirements be it semiautomated or fully-automated,
single-use or multi-use. With
‘Open Architecture’ you can
have all the benefits of
automation without having
to compromise on the best
processing solution.
←← SciLog SciFlex
TFF
bioprocessing system
®
SciFlex® TFF is a semiautomated bioprocessing
platform that is ideal for
pilot level TFF processing
and development,
optimizing filtration
speed and maximizing
filter life and efficiency.
Scalable Solutions
R&D
40www.parker.com/dhsingleuse
'Open
Architecture'
←←
←←
SciLog PureTec®
Laboratory-Scale TFF System
SciLog SciPure® GMP-ready
TFF system
Pilot Plant
GMP Manufacturing
1
www.parker.com/dhpbiopharm
www.parker.com/dhsingleuse
41
Often a critical application for ultrafiltration is at the end of the purification
process prior to final bulk filtration.
At this stage excipients are typically
added and the final product
concentration specification as it will
occur in the vial must be met. Given the
importance of the end purification step
it attracts surprisingly little attention in
literature and yet it can present great
challenges to bioprocess engineers.
Overcoming
obstacles in
final ultrafiltration
steps
By NICK HUTCHINSON
Market development manager
Preparing your product
for for the vial
Cross flow filtration can be used
in a range of applications within
biopharmaceutical
manufacturing
processes. Microfiltration technology is
incorporated into perfusion bioreactor
operations for cell retention and can be
used for harvesting bioreactors used to
manufacture extracellularly-expressed
products. In downstream operations
ultrafiltration can play a significant
role in concentrating intermediately
purified product pools, thereby
minimizing
processing
volumes.
Ultrafiltration typically also plays a
key role in enabling product to be
diafiltered
into
solutions
that
permit subsequent chromatography
operations to achieve maximum
separation performance.
42www.parker.com/dhsingleuse
One difficulty is that the final product
specification including the product
concentration, excipient and aqueous
delivery solutions are finalized late
in the drug and manufacturing
development
processes.
This
immediately creates time pressures and
demands flexibility from engineers.
Single-use technologies that can
readily accommodate design changes
are beneficial in such circumstances.
Very often the concentration of the
product entering this step is low and
the volumes to process high which is
determined by the elution conditions
of preceding chromatography and
virus filtration operations. Final drug
dose concentrations can be extremely
high indeed, sometimes exceeding
200 g/L. Some manufacturers will
perform a large number of buffer
exchanges (7-10 diavolumes) in order
to enable complete removal of the
previous product-containing solution
components ensuring these impurities
do not reach patients. These factors
combine to create the need to remove
significant volumes of filtrate and the
most efficient way of achieving this
is often to incorporate large filtration
areas in order that the process
completes in a reasonable time frame
without concentrated product being
cycled
through
high
shear
environments, which in turn, can lead
to product aggregation and the failure
to achieve key product quality
specifications.
Incorporating large cross flow filter
areas into these processes brings
its own challenges. Firstly, this area
represents a point at which
significant yield loss can
occur as the product can
bind to these membranes
and a suitable recovery
step needs to be built into
the process. Yield losses
at this late stage of the
process are particularly
undesirable because they
occur when the greatest
value has been added to
the product by the process.
Secondly, having large filter
areas in the process makes
the fine control required to
achieve accurate product
concentrations
at
low
volumes difficult. If the flux
rate across the membrane
is sufficiently high and
the membrane area large,
excessive over-concentration
and
increased
product
aggregation are real dangers.
That being said, some
level of over-concentration within limits
is frequently required and systems
should be designed to allow subsequent
back dilution with the diafiltration
buffer. Some manufacturers will choose
to use two ultrafiltration systems for
this step. The first set-up has adequate
capacity to process the large volumes
that are anticipated while the second
allows the fine control needed to hit the
final bulk product specification.
The final steps in this operation can be
extremely critical. Membrane rinses
designed to maximize product recovery
must be added back to the concentrated
and diafiltered product in the retentate
container. This is challenging because
the concentration of product in this
rinse is unpredictable and thus the
impact of adding it back into the
retentate pool on the bulk product is
difficult to determine. Excipients may
be added at this point but are frequently
added in low volumes requiring robust
control of dosing into the retentate
container and the avoidance of over
diluting the product pool. Good mixing of the product pool is a pre-requi-
site for this step and it is likely multiple
samples will need to be pulled from the
product pool for protein concentration
determination at 280nm.
The design of final ultrafiltration steps
requires careful consideration given
its critical role in ensuring biopharmaceutical products meet their
specification when delivered to the vial.
These considerations must encompass
process and equipment design and
operational requirements. Failure to
do so results in significant deviations,
difficult and expensive reprocessing
operations and potentially even batch
failure.
Given the importance
of the end purification
step it attracts
surprisingly little
attention in
literature and yet
it can present
great challenges to
bioprocess engineers.
www.parker.com/dhsingleuse
43
case study
publi sh
“We wi ll con tin ue ou r commi tmen t to
t an d
th e latest scien ce, techn olo gie s, ins igh
ceu tic al
pe rsp ect ive s ne ces sa ry for bio ph ar ma
pro fes sio na ls to ma nage an d lead.”
Br ian Ca ine , Publish er
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A large pharmaceutical company needed
a TFF system that could be easily adapted
to perform purification, concentration
and diafiltration operations during a
vaccine manufacturing process.
The customer also had the requirement
that the system can be used for both R&D
and GMP manufacturing applications.
To meet the customer’s requirements for
a flexible system, Parker domnick hunter
supplied a customized SciLog SciPure®
TFF system with ‘Open Architecture’
configuration with different cassettes
and manifold models from different
suppliers.
44www.parker.com/dhsingleuse
•
•
•
•
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Parker domnick hunter’s ‘Open Architecture’ approach to
system design delivered an automated TFF system flexible
enough to be used for both R&D and GMP applications for
a vaccine manufacturer.
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September 2013 | Volume 11 | Number 8
COVERING THE WHOLE DEVELOPMENT PROCESS FOR THE GLOBAL BIOTECHNOLOGY INDUSTRY
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47
MabTec®: Automated
High Density Cell Culture
Process Management,
Optimization and
Documentation
By DEAN PIGHIN, ENGINEERING MANAGER - SINGLE-USE
Cell cultivation is one of the most
critical processes in biopharmaceutical
research today. High-density cell cultures
can create dynamic environments which
challenge your ability to maximize
the optimal growth environment and
cell viability. The demand for a more
intelligent means of producing high yield
cell cultures with automated technology
has grown exponentially.
Protect your entire cell culture
processes with MabTec® - Parker domnick
hunter’s fully-automated high density
cell culture system. MabTec® modules
may be purchased to enhance your
current instrumentation or used as a
Fig. 1 Pre-Programmed Modes
The MabTec® has a pre-programmed mode
for inoculating, transfecting and induction
when used with a laboratory scale.
This pre-programmed mode allows the
user to deliver precise additions without
being physically present, which is ideal
for processes that are scheduled to run
at inconvenient hours or on a repeated
schedule.
48www.parker.com/dhsingleuse
complete optimized system. Each of the
MabTec® modules are engineered to
fit seamlessly with any bioreactor and
enhance its performance.
MabTec® modules are designed to
monitor and automate perfusion,
feeding and recirculation processes.
Combine the three units and the result
is the complete MabTec® system. The
MabTec® system is a complete method
to deliver the highest level of consistent
performance from your bioreactor.
This new advancement in intelligent high
density cell culture automation:
Fig.2 Fed Batch
The MabTec® can be used to automate the
feeding of cell cultures. Automation of this
process greatly reduces the possibility of
human error while reducing operator time.
The MabTec® can be programmed to deliver
a continuous feed for a specified number of
days up to 100. Two modes exist for feeding;
one that monitors levels in the reactor and
makes additions while the other monitors the
reactor and amount of feed media.
• Maintains a steady state bioreactor
weight/volume within +/- 0.5%
• Gravimetrically delivers balanced
nutrient fortification to your cells
• Reduces aggregation of cells in the
perfusion filter
• Provides alarm systems that monitor
critical parameters in real time
• Displays real time data with
easy-to-use graphical user interfaces
Depending on your needs, MabTec®
modules can be purchased separately
and integrated with your current
process as your budget and process
optimization demand.
Fig. 3 Ultra High Density Cell Culture
The MabTec® system is uniquely designed
to provide a complete perfusion strategy.
The user is able to maintain fresh media in
the reactor, remove desired component or
prevent the build-up of waste products, all
without a scale under the bioreactor.
By keeping bioreactor weight maintained to
within 2% and providing a constant stream
of nutrient rich and pH buffered media, the
bioreactor environment becomes ideal for
ultra high density cell cultures.
www.parker.com/dhsingleuse
49
with manual production. The objective
of the experiment is to:
• Demonstrate the feasibility of
replacing a manual fed batch process
with an automated process.
• Verify automated performance results
against manual operations. Automated
results must meet or exceed manual
operations.
• Determine the number of manual
operations.
Results
Initial conditions were extremely similar for all three reactors. % Viabilities for all
three reactors on day five was 98% or better when the switch to automated fed batch
began.
The three runs were not significantly different which was the intended outcome for
the test. The automated MabTec® method was able to reproduce the manual method
exactly and added consistency to the method that was not possible before.
Test scenario
A SciLog MabTec® Method for Manual Bolus Fed-Batch
Versus MabTec® Automated Continuous Fed-Batch
T
The manual feeding method required an
operator to perform 10% bolus reactor
fluid additions daily. Each day’s bolus
media quantity required the operator to
autoclave the media feed container and
prep the media daily. The automated
feeding method was set up to add media
to the reactor in a continuous method that
totalled a ten 10% daily reactor weight
addition. All the media for the automated
process was prepared at one time and
placed on a cart next to the MabTec®.
The run was scheduled for a total of
18 days. The automated method was
allowed to continue for an additional
3 days as this method of processing had
not been tested previously. The reactor
was sampled and tested daily for viable
cell density, percentage cell viablity,
protein concentration, glucose, lactate,
glutamine and ammonium.
By DEAN PIGHIN, ENGINEERING MANAGER - SINGLE-USE
photo: SciLog
MabTec® unit
available from
Parker domnick hunter
50www.parker.com/dhsingleuse
he SciLog MabTec® is
an add-on bioreactor
maintenance system
designed to gravimetrically
manage, automate and
document your bioreactor
feeding or perfusion strategy.
The MabTec® upgrades many
manual processes to walkaway automation with minimal
investment in terms of capital
or time.
Summary
MabTec® combines accuracy
with convenience to provide an
ideal solution for cell
culture feeding strategies.
90-
VCD x10^5 cell/mL
80-
Reactor 1 (Manual)
Reactor 2 (Manual)
Reactor 3 (Automated)
7060-
Graph 1 :
Viable cell
density
50403020Standard
Operating Range
100To be used in results section0
Protein
V14
V17
V18 Scilog
Day 0
Day 1
5
Day 2
Day 3
Day 4
10
Day 5
Day 6
630
670
660
DaysDay 8
Day 7
840
930
880
20
Day 9 Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
1220
1420
1560
1700
1890
2020
2110
mg/L
1470
1660
1870
2120
2270
2260
2360
2410
1370
1570
1800
2020
2330
2160
2360
2440
2430
2500
2520
2470
250020001500-
Reactor 1 (Manual)
Reactor 2 (Manual)
Reactor 3 (Automated)
100050000
Standard
Operating Range
5
10
Days
15
Graph 2 :
Protein
concentration
Extended
Operating Range
20
1201008060Reactor 1 (Manual)
Reactor 2 (Manual)
Reactor 3 (Automated)
4020-
Based on the results, MabTec®
demonstrated the ability to
increase protein production
while eliminating several hours
of manual daily operation.
15
1020
1190
1160
Extended
Operating Range
3000-
Protein Concentration
(mg/L)
Three 10L glass bioreactors were filled
with 4L of media to be used in a
mammalian cell culture. Agitation was
started and maintained at the same rate
for the duration of the run. After 5 days
the culture reached a density point where
a feeding strategy is required.
Percent (%)
Photo: A typical
buffer preparation
and storage
schematic
00
Standard
Operating Range
5
10
Days
15
Graph 3 :
% viable
cells
Extended
Operating Range
20
Introduction
The application flexibility of
MabTec® delivers superior
growth efficiency within
a bioreactor through the
replacement of repetitive
manual operator steps with
an automated solution. The
replacement allows for more
constructive use of operator
time and eliminates the
inadvertent errors associated
T
Conclusion
he viable cell densities produced in the bioreactor fed by the MabTec® was on par with the two manual methods.
The MabTec® also allowed slightly higher protein production than the other two vessels. The switch to an automated process
eliminated thirty manual operations, 15 autoclave cycles and 15 buffer preparations, which equated to several hours of
operator time freed up. The MabTec® has demonstrated its feasibility to replace a manual fed-batch operation.
www.parker.com/dhsingleuse
51
Intelligent
Laboratory Systems
52www.parker.com/dhsingleuse
www.parker.com/dhsingleuse
53
Automated
laboratory systems
Advantages
Application
Product
for safe, walk-away normal flow filtration,
tangential flow filtration, dispensing,
metering and bioreactor maintenance operations.
FilterTec™ /
FilterTec™ Plus
PureTec®
MabTec®
ChemTec™
LabTec®
Automated
Normal Flow
Filtration Systems
Automated
Tangential Flow
Filtration Systems
Automated
Bioreactor
Maintenance System
Automated
Metering
System
Automated
Dispensing
System
•Media filtration
•Buffer filtration
•Bioreactor harvest (Pg 16)
•Final sterile filtration
•Viral filtration
•Chromatography column loading
•Filter evaluation and comparison
•Protein purification
•Concentration
•Diafiltration
•Harvesting & clarification
•Inoculating, transfecting and
induction
•Perfusion
•Ultra high-density cell culture
•Feeding of cell cultures
•Feed scheduling for
chemical reactors
•Chemical metering
•pH adjustments
•Solution weight maintenance
•Preparative chromatography
•Laboratory sample preparation
and dilution
•Final fill finish in small
production runs
•Optimization and automation of
NFF applications
•Incorporates patented
R/P Stat Mode increases
filter throughput up to 30%
(Pg 21)
•Complete TFF application
development system
•Automatically monitors flow
rate to optimize yield
•Pre-programmed modes
for bioreactor maintenance
applications minimize
set up times
•Eliminates bioreactor addition
errors
•Accurate metering by volume
or weight
•Rapid and accurate dispensing
by volume, weight or
weight ratio
•10 pre-set dispensing modes
to save time when switching
from one volume to another
From top left
LabTec® dispensing system,
PureTec® tangential filtration
system, FilterTec™ Plus
multi-filtration system,
FilterTec™ dead-end
filtration system and
ChemTec™ metering system.
54www.parker.com/dhsingleuse
www.parker.com/dhsingleuse
55
Save the Date for
Inform, Innovate and Connect
10TH ANNUAL
E U R O P E A N
S U M M I T
2-3 April 2014 • Clarion Congress Hotel Prague, Czech Republic
Connecting innovations in upstream, downstream, analytics and formulation
to accelerate process development, improve product quality and prepare
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CONFERENCE
ADCs, Bioconjugates and Novel Therapies /
21st Century Manufacturing
CONFERENCE
Cell Culture and
Upstream Development
CONFERENCE
5 Conference Streams to choose from
Downstream Processing:
Capture, Recovery and Purification
Keynote Speakers
Accelerating Product
Development
Tony Coyle, Pfizer
Continuous Processing
Rene Labatut,
Sanofi Pasteur
Implementing FDA
Stage 3 CPV Guidance
Lada Laenen, Genzyme, BPOG
CONFERENCE
CONFERENCE
Next-Generation DSP
Haleh Ahmadian,
Novo Nordisk
Biosimilar Quality and Production /
Analytical Methods for Biologics
Making Subvisible, Visible
Wim Jiskoot,
Leiden University
Formulation and Pre-Formulation
Strategies for Biologics
Future of Biotech
Wolfram Carius,
former Boehringer Ingelheim
NEW NETWORKING TOOL
Innovation in Bioprocessing
Nigel Darby,
GE Healthcare
2014 SPONSORS
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Produced by:
Founding Publication:
Sensor Technology
Brochure available NOW!
REGISTER TODAY - Quote VIP code: CQ3509PARKER
+44(0)20 7017 7481 registration@informa-ls.com www.bpi-eu.com
56www.parker.com/dhsingleuse
www.parker.com/dhsingleuse
57
highlights
disposable
sensor technology
from Parker domnick hunter
Single-use pressure, conductivity
and temperature sensors designed
for incorporation into disposable
purification platforms
Pre-calibration reduces set-up time
and avoids contamination risks
associated with field calibration
5 different connection sizes
(Luer, 3/8¨ Barb, 1/2¨ Barb, 3/4¨ Tri-Clover
and 1¨ Tri-Clover ‘Ladish’)
give full scalability throughout
process development
www.parker.com/dhsingleuse
Individual sensor ID makes each
sensor NIST traceable and suitable for
GMP applications
pressure
temperature
conductivity
Validated for sterilization by gamma
irradiation, autoclave and sodium
hydroxide for extended use in pilot plant
or laboratory applications
Monitoring and controlling pressure
with SciPres® pressure sensors
increases the efficiency and safety of
filtration and purification operations
SciCon® conductivity sensors enable
the user to measure the progress of
diafiltration applications
Temperature control with SciTemp®
temperature sensors helps to avoid
protein denaturation due to
temperature rises because of shear in
pumps and across filtration membranes
58www.parker.com/dhsingleuse
www.parker.com/dhsingleuse
59
Disposable
Sensor
Technology
By KARL SCHICK - Innovation manager
S
ensors designed for incorporation
into
disposable
purification
platforms,
i.e.
single-use
tangential flow filtration (TFF),
single-use normal flow filtration
(NFF) or disposable chromatography
must meet a number of challenging
requirements.
Single-use platforms for downstream
purification typically consist of an
integrated assembly of filter elements
or columns, flexible tubing, plastic
connectors and bags, segments of
peristaltic pump tubing as well as
sensors. Such assemblies are designed
and pre-assembled for a specific
purification process and a given,
maximum process volume. Special
aseptic plastic connectors are used
to hook up to external, single-use
bioreactors and/or buffer solutions.
In the final configuration, all elements
of the purification platform are presterilized, assembled and operated as a
closed system.
60www.parker.com/dhsingleuse
Single-use purification assemblies
are typically custom-manufactured
and gamma-irradiated at 30-40 kGy to
ensure sterility of the integrated
assembly. Alternative sterilization
approaches are available utilizing
“steam-through” connectors as well as
steam sterilized, disposable purification
assemblies. Ethylene oxide sterilization
used less frequently because of
potential contamination by residual
ethylene oxide.
Parker domnick hunter’s family of
disposable
in-line
sensors
for
monitoring conductivity (SciCon®),
pressure (SciPres®) and temperature
(SciTemp®) are pre-calibrated and
come in five different sizes, ranging
from Luer, 3/8¨ Barb, 1/2¨ Barb, 3/4¨
TC to 1.0¨ TC accommodating the
industry’s need for system scalability.
The performance characteristics of the
sensor range are summarized below.
Disposable
Disposable
Disposableflowthrough
flowthrough
flowthroughsensors
sensors
sensors
• •  Temperature
Temperature
•  Temperature
Resolution:
Resolution:
Resolution:
oC
oC oC
0.01
0.01
0.01
• •  Temperature
Temperature
•  Temperature
Range:
Range:
Range:
oCto
oto
oC
oC oC
-10
-10o-10
C
C+150
+150
to +150
• •  Temperature
Temperature
•  Temperature
Accuracy:
Accuracy:
Accuracy:
oC
oC oC
±0.10
±0.10
±0.10
• •  Sensor
Sensor
•  Sensor
Type:
Type:
Type:
Epoxy-Coated
Epoxy-Coated
Epoxy-Coated
Thermistor
Thermistor
Thermistor
®® ®
SciTemp
SciTemp
SciTemp
• • Pressure
Pressure
•  Pressure
Resolution:
Resolution:
Resolution:
0.01
psi
0.01
0.01
psipsi
• • Pressure
Pressure
•  Pressure
Range:
Range:
Range:
00psi
psi
0 to
psi
to60
60
to psi
60
psipsi
• • Pressure
Pressure
•  Pressure
Accuracy:
Accuracy:
Accuracy:
±0.35
@
±0.35
±0.35
@60
@
60psi
60
psipsi
• • Sensor
Type:
Sensor
•  Sensor
Type:
Type:
Piezoresistive
Piezoresistive
Piezoresistive
Sensor
Sensor
Sensor
®® ®
SciPres
SciPres
SciPres
•  Conductivity
• • Conductivity
Conductivity
Resolution:
Resolution:
Resolution:
µS/cm
0.1
0.10.1
µS/cm
µS/cm
•  Conductivity
• • Conductivity
Conductivity
Range:
Range:
Range:
11µS/cm
µS/cm
1 µS/cm
toto200
200
to 200
mS/cm
mS/cm
mS/cm
• • Conductivity
Conductivity
•  Conductivity
Accuracy:
Accuracy:
Accuracy:
33µS
µS
3 (0-100
µS
(0-100
(0-100
µS)
µS)µS)
0.25
0.25
0.25
mS
mSmS
(10-200
(10-200
(10-200
mS)
mS)mS)
• • Sensor
Sensor
•  Sensor
Type:
Type:
Type:
Gold
Gold
Gold
4-Electrode
4-Electrode
4-Electrode
Conductivity
Conductivity
Conductivity
Cell
Cell
Cell
®® ®
SciCon
SciCon
SciCon
Sensor Calibration
CX-ZLLNNNN-MMYY
Maintaining sterility of single-use
purification platforms is of the highest
importance. Thus field calibration of
sensors and insertion of sensors into
a pre-sterilized purification manifold
is not an acceptable option because of
the obvious contamination concerns.
A primary, post-use sensor calibration
is equally unacceptable because of
uncertainty of the in-use sensor
accuracy and precision. However,
secondary
post-use
sensor
performance verification may be useful
to metrology departments provided the
pre-use sensor performance is known
and has been fully characterized.
CX = Pressure Sensor Connector
C1 = Luer
C2 = 3/8"Barb
C3 = 1/2"Barb
C4 = 3/4" TC
C5 = 1.0" TC
Z = Sensor Material Code,
Z = 1, Polysulfone,
Z = 2, Polypropylene
L = Sensor Production Lot Number
N = Sensor Serial Number
M = Month of Sensor Calibration
Y = Year of Sensor Calibration
In this context, sensor characterization
will answer the questions related to
sensor performance after gammairradiation,
steam
sterilization
(temperature >121° C) under pressure
(~20psi) and exposure to high
concentrations of NaOH (1.0 Normal).
These are the conditions that sensors
will be exposed to when integrated into
downstream, single-use purification
platforms. The Parker domnick hunter
family of sensors has been designed to
provide accurate data after exposure to
such harsh and challenging conditions.
Parker domnick hunter’s approach
to sensor pre-calibration, sensor
characterization and full sensor
performance disclosure has been well
received by the biopharmaceutical
process community.
On request, Parker domnick hunter
provides a sensor material traceability
service
which
includes
sensor
extractable reports, and material lot
certification, as well as product
certificates of compliance.
Sensor Performance
For special sensor applications,
Parker domnick hunter offers a
customer specific sensor calibration
service. For example, oxygen gas
addition to single-use bioreactor bags
requires careful pressure monitoring.
Depending on bioreactor bag size,
excessive gas pressures in the 1-5 psi
range may cause sudden rupture of
the bioreactor. Users of single-use
bioreactors
frequently
request
gamma-stable pressure sensors that
are calibrated at 5.00 psi and capable
of monitoring low-level pressures, in
the 1.00 to 5.00 psi range, with 1.5%
accuracy.
variations from the lot average CF
represent the variances within the
manufacturing tolerances of the
proprietary
solid-state
sensing
element. The sensing element is
covered by a medical grade silicone gel
diaphragm (USP Class VI) capable of
withstanding a 100-hour exposure to
sodium hydroxide solution (1.0N). See
‘Sensor Performance Characterization’.
When connected to SciPres® monitor,
the sensor-specific CF value is used in
a monitor-based correction algorithm
that compensates for the slight sensor
non-linearity. The pressure values
displayed by the monitor as well as
the pressure values communicated by
the monitor’s analog (4-20mA) and
digital outputs represent accurate,
CF-corrected pressure values.
Sensor Performance
Characterization
All Parker domnick hunter sensors,
including the SciPres® pressure
sensors, have been performancetested
under
three
different
conditions. The sensor test protocols
as well as test results are summarized
below:
Post-Gamma Sensor Response:
14 randomly selected SciPres® pressure
sensors were calibrated at 0.00 psi and
30.00 psi prior to gamma-irradiation at
38.4 kGy. Post-gamma sensor accuracy
was determined at 0.00 psi and 30.00
psi of applied pressure, see Table I.
Pre-Calibrated Sensors
In order to implement a sensor
calibration, the sensor is exposed to a
set of known calibration conditions.
The sensor response is stored together
with the calibration value. For example,
the standard factory calibration
procedure for the SciPres® pressure
sensor calls for it to be calibrated at a
0.00 psi applied pressure and at a 30.00
psi applied pressure utilizing digital,
NIST traceable pressure gauges.
Based on the sensor response a sensor
Calibration Factor (CF) and sensor Zero
Offset (PZ) are calculated and stored in
a proprietary sensor memory together
with a unique sensor ID. For each
SciPres® sensor, a sensor-specific
Calibration Certificate is issued and
accompanies the sensor shipment. The
sensor ID code contains the following
sensor–specific information:
A similar problem exists when
overfilling single-use bags causing
an excessive build-up of internal bag
pressure. If not relieved, the pressure
build-up can cause bag rupture.
Incorporating SciPres® sensors into the
bag inlet will not only monitor the bag
pressure but also stop filling operation
when a user-defined pressure level has
been exceeded. SciPres® monitor has
digital alarm outputs that can be used
for this purpose.
Although the SciPres® pressure sensors
have been safety-tested up to 90 psi, the
standard operating range is limited to
60 psi. The SciPres® sensor calibration
certificate includes the specific
calibration points as well as the
sensor-specific calibration factors
(CF). The specific calibration factor
Table I: Post-Gamma Sensor Response
Gamma Irradiation @ 34.8 kGy
Pre-Gamma Test
Post-Gamma Test
NIST
0.00 psi
NIST
30.00 psi
NIST
0.00 psi
NIST
29.99 psi
S4-290006-0408
S4-290008-0408
S4-290011-0408
S4-290013-0408
S4-290017-0408
S4-290018-0408
S4-290020-0408
S4-290021-0408
S4-290022-0408
S4-290023-0408
S4-290024-0408
S4-290025-0408
S4-290026-0408
S4-290027-0408
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
30.00
30.00
30.00
30.00
30.00
30.00
30.00
30.00
30.00
30.00
30.00
30.00
30.00
30.00
-0.01
0.00
0.00
-0.01
-0.02
0.00
-0.01
0.00
0.00
-0.03
-0.02
0.00
0.00
0.00
29.94
29.97
29.97
29.92
30.01
29.96
29.95
29.96
30.03
29.92
29.92
30.01
29.95
29.95
Group Average
Group SD*
0.00
30.00
-0.01
0.01
29.96
0.03
SciPres®
3/4¨ TC
Sensor ID
Applied Pressure
Applied Pressure
SD = Standard Deviation
www.parker.com/dhsingleuse
61
Test Results:
All sensors survived gamma-irradiation
and tested accurately well within Parker
domnick hunter’s established accuracy
limit of +/- 0.35 psi. The post-gamma
data shows a group average of 29.96
psi (for 14 SciPres®, 3/4" TC) with a
standard deviation of +/- 0.03 psi.
Post-Autoclaving Sensor Response:
Six randomly selected SciPres® sensors
(1/2" Barb) were tested after repeated
exposures (3x) to autoclave conditions,
see Table II. The initial, factory
calibration responses are tabulated
under “Pre-Autoclave” heading. The
ambient air vent as well as the
electrical connector of SciPres® sensor
was covered with autoclave tape and
place into a Tuttnauer EZ9 Autoclave.
Table II shows the autoclave conditions
were maintained during the three test
trials.
After each trial, the SciPres® sensors
were allowed to cool to room
temperature and pressure tested at
0.00 psi and 30.00 psi. The SciPres®
response data are listed under the ‘Post
Trial’ columns. All trials were carried
out with the original factory sensor
calibration. No sensor re-calibrations
were made before or during the three
trials.
Test Result:
All of the tested SciPres® sensors
survived autoclave conditions. For the
tested sensors (6), the group average
ranged from 29.99 to 30.11 with an
average standard deviation of +/- 0.06
psi. However, sensor accuracy became
increasingly compromised after two
autoclave
cycles.
For
accurate
performance, SciPres® sensors are
limited to two autoclave cycles.
Sodium Hydroxide Exposure Test:
Six randomly selected SciPres® sensors
(Luer) were tested after a 100-hour
exposure to 1.0 N sodium hydroxide
solution at 22 °C and at 10 psi line
pressure, see Table III. The sodium
hydroxide solution was continuously
re-circulated (150ml/min) through the
sensors using a peristaltic pump. At 25
hour intervals, the exposure test was
briefly interrupted, the sensors were
flushed with distilled water and tested
at 0.00 psi and 30.00psi.
62www.parker.com/dhsingleuse
Test Result:
The data show a stable sensor
accuracy and precision over the
100-hour exposure to 1.0 N sodium
hydroxide solution. For the four
timed exposure tests, the group
averages ranged from 30.06 to
30.08 psi with an average standard
deviation of +/- 0.06 psi. All
sensor responses were monitored
with a digital, NIST-traceable gauge.
sensor-based fluid handling systems
and connectivity (OPC) to a digital
automation system, e.g. Delta V,
are critical steps to realizing the full
benefits of single-use purification
platforms in GMP production.
Parker domnick hunter has made
a commitment to providing precalibrated,
single-use
sensor
technology and associated data
acquisition modules to the biopharmaceutical industry. Parker
domnick hunter’s scalable sensors
provide stable performance after
exposure
to
gamma-irradiation,
steam-sterilization and extended
exposure to 1.0 N sodium hydroxide
solution. The Parker domnick hunter
family of sensors is designed and
manufactured to provide accurate
data after exposure to such harsh and
challenging conditions. Parker domnick
hunter’s approach of sensor precalibration, sensor characterization
and
full
sensor
performance
disclosure has been well received by
the biopharmaceutical community.
Sensor Accuracy & Precision
The SciPres® sensor accuracy, based
on performance data sensor lot of
250 sensors, has been established to
be +/- 0.35 psi for the 0 – 60 psi applied
pressure range. “Out-of-box” sensor
performance has been tested. For
12 randomly selected, factory precalibrated SciPres® sensors. The
“Out-of-Box” accuracy was 30.07 psi
+/- 0.07 psi (NIST test pressure:
30.00 psi) with test results ranging
from 29.96 to 30.19 psi.
The full benefit of single-use
purification platforms, i.e. normal flow
filtration, tangential flow filtration and
chromatography, can only be achieved
through automation. Automated,
Fluid Transfer & Storage
Table II: Post-Autoclaving Sensor Response
Sterilization Temperature: Sterilization Time: Sterilization Pressure: Drying Time: SciPres®
0.50¨ Barb
Sensor ID
257°F (125°C)
30 minutes
19 psi
30 minutes
Pre-Autoclave
Sensor
Average
Sensor
SD*
psi
psi
psi
psi
psi
psi
psi
psi
30.00 psi
NIST 0.00 NIST 30.00 NIST 0.00 NIST 30.02 NIST 0.00 NIST 30.00 NIST 0.00 NIST 30.02
30.00 psi
Post Trial 1
Post Trial 2
Post Trial 3
S3-220221-1007
0.00
29.99
0.01
30.06
0.02
30.04
0.04
30.04
30.05
0.01
S3-220227-1007
0.00
29.99
0.00
30.06
0.02
30.05
0.04
30.06
30.06
0.01
0.02
S3-220229-1007
0.00
29.99
0.02
30.10
0.03
30.06
0.04
30.07
30.08
S3-220230-1007
0.00
29.99
0.01
30.06
0.30
30.24
NR
NR
30.15
0.13
S3-220234-1007
0.00
29.99
0.00
30.05
0.10
30.22
0.05
30.16
30.14
0.09
30.06
0.00
S3-220240-1007
0.00
30.00
0.02
30.06
0.79
30.06
NR
NR
Group Average
Group SD*
0.00
29.99
0.00
0.01
30.07
0.02
0.21
30.11
0.09
0.04
30.08
0.06
SD = Standard Deviation NR = No and/or Erractic Response. Not included in Averages.
Table III: Pressure Sensor, NaOH Exposure Test
Test Conditions: 100 hour exposure of SciPre to 1.0N Sodium Hydroxide at 22 °C, 10 psi Pressure
Sensor Sensor
Average SD*
SciPres®
Luer
Sensor ID
psi
0.00
psi
30.00
psi
0.00
psi
30.00
psi
0.00
psi
30.00
psi
0.00
psi
30.00
psi
0.00
psi
30.00
S1-240058-1007
0.00
30.05
0.00
30.07
0.00
30.06
0.00
30.08
0.00
30.00
30.05
0.03
S1-240057-1007
0.01
30.19
0.00
30.20
0.02
30.18
0.02
30.22
0.00
30.21
30.20
0.02
S1-230238-1007
0.02
30.02
0.01
30.03
0.00
30.03
0.00
30.02
0.00
30.03
30.03
0.01
S1-240061-1007
0.00
30.03
0.01
30.07
0.00
30.06
0.00
30.06
0.00
30.05
30.05
0.02
S1-230107-1007
0.01
30.05
0.00
30.08
0.00
30.06
0.00
30.05
0.00
30.06
30.06
0.01
S1-230110-1007
0.00
30.05
0.00
30.04
0.01
30.03
0.00
30.03
0.00
30.02
30.03
0.01
Group Average
Group SD*
0.01
0.01
30.07
0.06
0.00
0.00
30.08
0.06
0.01
0.01
30.07
0.05
0.00
0.01
30.08
0.07
0.00
0.00
30.06
0.07
Start
25 hr Test
50 hr Test
75 hr Test
100 hr Test
30.00 psi 30.00 psi
SD = Standard Deviation
www.parker.com/dhsingleuse
63
S
case study
ingle-use processing
equipment & technologies
reduce capital costs,
increase flexibility and
minimize the risk of product cross
contaminations. Disposable
solutions are available for nearly
every stage in the production
process including bioreactors,
filtration and chromatography
systems.
Customized manifolds consisting
of tubing, BPCs, filters and other
components can be assembled to
meet the needs of any application
and supplied pre-sterilized by
gamma irradiation, ready to use in
sterile operations.
air, gas
& vent filtration
Bioprocess container bags (BPCs)
are an excellent and safe way to
store and transport solutions such
as the buffers used in molecular
purifications and are suitable for
a wide range of volumes from litre
quantities to tens and even
hundreds of litres if required.
Tubing sets are the ideal way to
transfer liquids into BPCs using
peristaltic pumps and single-use
filter capsules can be added to
either sterilize or remove
particulates from solutions.
Platinum-cured silicone tubing
can be readily incorporated into
manifolds with molds that prevent
leakages that typically occur with
tie-wraps.
Custom-Designed
TOP: DuraPure™ BPCs are available in sizes from 250mL to 1000L in 2D pillow bag or 3D formats.
Bottom: klave-it™ autoclavable BPCs are ideal for applications where the container and its contents must be sterilized.
Left to Right
Y, T, cross and
reducer over-molded
junctions are
available to
maximize design
flexibility.
64www.parker.com/dhsingleuse
Over-molding technology allows
more complex assemblies of
tubing and containers to be
integrated saving time that would
otherwise be spent creating
these assemblies. Customized,
over-molded designs can be
supplied pre-sterilized by gamma
irradiation to ensure sterile
processing within closed
processing systems.
Eliminating
contamination risks
Parker domnick hunter understands that every
bioprocess is different. We custom-design our single-use
molded manifolds to meet the individual processing needs
of each customer.
Many biopharmaceutical
processes use single-use
perfusion bioreactor systems
which incorporate numerous
disposable media bags
simultaneously connected
to a single bioreactor.
To accommodate their unique
process, customers are often
forced to assemble their own
systems.
Parker domnick hunter’s custom
molded manifold and bioprocess
container systems prevent
product losses and contamination
associated with hosebarb failures
and increase productivity through
reduced system set up time.
www.parker.com/dhsingleuse
65
bpsa means business:
access the power
of partnership
Improvements in
Single-Use
Bioprocess
Product Testing
By GREGG A LARSON - PRODUCT Manager, SINGLE-USE
T
esting of single-use bioprocessing products is
performed to mitigate risk for customers by validating
products will perform as intended and reducing the
possibility they will damage or contaminate the biological
materials processed through them. The manufacturers’
organization, Bio-Process Systems Alliance (BPSA), has
been a leader in providing guidance to manufacturers on
recommended testing that is aligned with the needs of the
BioPharma customer. The biopharmaceutical organization,
BioPhorum Operations Group (BPOG), is also working to
standardize the testing protocols performed by manufacturers.
In 2007, the BPSA published consensus quality test
matrices(1) to ‘serve as a guide to maintain suitable
component quality for operation of single-use systems in
pharmaceutical GMP environments.’ These matrices list
specific recommended tests manufacturers should perform
on several categories of single-use products, including films
and containers, connectors, filters, and tubing. Notably
absent from this list was single-use sensors. The types of
testing suggested in the 2007 BPSA matrices included
tests categorized as mechanical, permeability, chemical,
biological, functional, and sterilization validation. The
compilation of these matrices by competitors working
together is commendable but, because the matrices were
produced by consensus, these matrices can be thought of as
the minimum threshold of testing that should be performed
by the manufacturer.
www.bpsalliance.org
66www.parker.com/dhsingleuse
Currently, each biopharmaceutical company has its own list
of quality testing required before adoption of a single-use
product. These lists generally follow the suggestions of the
BPSA; however some companies break the matrices down
to must-haves and nice-to-haves, and some companies
are more discriminating with additional requirements.
The testing bar is moving ever higher as new issues of
concern are raised by unfortunate events such as the
discovery of specific polymer constituents that inhibit
the growth of cells in a single-use bioreactor(2). For this
reason, an exhaustive list of extractables and leachables
testing will be necessary to ensure none of the offending
chemicals are present at critical levels, especially as
bioreactors are run for weeks during perfusion protocols.
The BPSA is working to update the 2007 matrices, and the list
of recommended tests is getting more expansive. Single-use
sensors have been added to the list of products for which
recommended testing requirements will be listed. While
sensors must undergo testing similar to the other single-use
products, they also have unique testing requirements.
Sensors are electronic measurement devices and must be
pre-calibrated. They must also maintain their calibration
during irradiation or sterilization by other means, and later
during use. To accommodate GMP, each device must also be
fully traceable.
The prudent manufacturer should perform testing that is
currently in the “nice-to-have” section of the customer’s
testing checklist as these present-day nice-to-haves will soon
become must-haves. In the not too distant future, as the
recommended testing protocols become standardized
through the work of BPOG and the BPSA, adherence to these
protocols by manufacturers will allow customers to make
apples to apples product comparisons. These efforts will lead
to improved quality of product, resulting in reduced risk for
the customer and ultimately the patient.
References:
1. BioProcess International 5(4-5) (April-May 2007), Jerold Martin
2. PDA J Pharm Sci and Tech 2013, 67 123-134, Matthew Hammond,
Heather Nunn, Gary Rogers, et al.
www.parker.com/dhsingleuse
67
case study
Clockwise from top left.
Filter bag, Standard
reducer mold, Filter bag,
T-mold, Large filter bag
Cross-mold, Large filter bag
& tubing, Y-mold.
air, gas
& vent filtration
Bioprocess Bag Systems
Solutions to
streamline
your process
The sterile transfer of microcarrier beads into the bioreactor
can significantly delay biopharmaceutical processes.
Parker domnick hunter's tailored bioprocess bag systems
facilitate microcarrier transfer.
Biopharmaceutical customers using
microcarrier beads to grow cells in
attachment cell culture can find
sterilization of the microcarriers
is a long and difficult task. The
microcarriers are often autoclaved
in small batches prior to addition to
the bioreactor and, as the process is
scaled up, this brings even greater
challenges.
Parker domnick hunter developed
a solution by which microcarriers
were sterilized by irradiation within
a customized bioprocess bag
allowing subsequent quick and easy
sterile transfer of microcarrier
beads streamlining the process
and reducing downtime.
68www.parker.com/dhsingleuse
www.parker.com/dhsingleuse
69
From top left
WeighPro™
Together, we can increase your process
precision and system flexibility.
Reliable gravimetric fluid handling with an assortment of portable and compact
bioprocess container (BPC) holders that can add functionality without the need
for process reconfiguration.
The Parker domnick hunter WeighStation™ family of products can be used as an
alternative to any floor or bench top balance that is used throughout a biopharmaceutical
facility with the unique advantage of being specially designed to be used with bioprocess
containers. Common applications include media / buffer filling, mixing, preparation and
storage, retentate / permeate quantification for TFF, transfer of bioreactor contents and
final fill and finish.
WeighStation™
Triple
WeighStation™
WeighSmart™
WeighCart™
The WeighStation™ is configured for hanging BPCs with Dual or Triple options that
accommodate 2 and 3 BPCs respectively without increasing the footprint.
WeighPro™ is a vertical mobile workstation that holds a single hanging BPC and also
incorporates a worktop, local weight display and configurable supports for a
customized solution.
WeighCart™ accommodates BPCs of 100 L or 200 L while incorporating a worktop
and supports to mount a SciLog laboratory automated liquid handling system.
filtration sensors
automated systems
www.parker.com/dhsingleuse
Europe: phone +44 (0)191 4105121 - email: dhprocess@parker.com
North America: toll free 877 784 2234
- email: dhpsales.na@parker.com
phone +1 805 604 3400
www.parker.com/dhsingleuse
71
events
CALENDAR
3-6 November 2013
Washington, USA
24-25 Feb 2014
California, USA
27 March 2014
San Francisco, USA
3-4 June 2014
Lyon, France
ISPE Annual Meeting
IBC Life Sciences 2nd Annual
Flexible Facilities Conference
ISPE San Francisco / Bay
Area Chapter Event 2014
A3P Bioproduction
Organizer’s description:
ISPE’s premier annual event
addresses current and future
industry challenges and
opportunities. This gathering of
experts from around the world
promises to provide you with
unparalleled education and fresh
perspectives, reliable methods and
innovative solutions that are unique
for our industry.
19-20 February 2014
Germany
The Disposable Solutions for
Biomanufacturing Summit
Organizer’s description:
The Disposable Solutions for
Biomanufacturing Summit is Europe’s
only event which focuses entirely
on the application of single-use
technology within manufacturing
– with studies on extractables and
leachables, supply chain reliability,
objective cost analysis and
innovative case studies; everything
that a normal biomanufacturing
meeting just doesn’t deem
important enough to dig into.
Organizer’s description:
This annual event has grown to be
one the most attended programs
for the chapter. It focuses on local
CEO’s and provides them the forum
to focus their vision of our industry
and address the future in terms of
the challenges, latest technologies,
local economic issues, mergers/
acquisitions and strategic
relationships, finance and resources.
24-27 March 2014
San Diego, USA
2-3 April 2014
Prague, Czech Republic
9-10 June 2014
Boston, USA
Biopharmaceutical
Development & Product
Week
BioProcess International
European Conference
and Exhibition 2014
IBC’s 11th Annual
Single-Use Applications for
Biopharmaceutical
Manufacturing
Organizer’s description:
The most in-depth coverage of
bioprocessing methods to help you
navigate the development,
production and regulatory
challenges of an emerging wave
of mAbs and novel molecules.
Organizer’s description:
BPI Europe is THE meeting place
for bringing together the latest
processes, technologies and
strategies driving every stage of
biomanufacturing.
18-20 March 2014
New York, USA
8 April 2014
North Carolina, USA
INTERPHEX 2013
ISPE CASA 2014
Organizer’s description:
INTERPHEX is the leading annual
pharmaceutical and biopharmaceutical trade show. Key decision
makers find the networking
opportunities, products, services
and information they need to
ensure quality and maximize
efficiency, agility, and flexibility that
solve manufacturing and supply
chain problems. INTERPHEX is where
intelligence and passion intersect
with the full spectrum of industry
products and services to create
new insights and innovation.
72www.parker.com/dhsingleuse
Organizer’s description:
A3P was founded in 1986 to meet
the needs of the pharmaceutical,
biotechnology and biomedical
industries in the face of rapidly
changing technologies and
processes production and control.
Organizer’s description:
IBC’s 2nd Annual Flexible Facilities
conference brings together senior
level executives and scientists from
biopharmas, CMO’s, technology
providers, engineering firms and
regulatory groups to explore the
changing landscape of biologics
manufacturing and to share case
studies of the latest flexible facility
implementations, lessons learned
and practical experiences.
Organizer’s description:
ISPE Carolina-South Atlantic Chapter
is a not-for-profit volunteer society
of technical professionals who
apply their practical knowledge
in the regulated pharmaceutical
and medical device manufacturing
industries. The Chapter is committed
to the advancement of the
educational and technical
efficiency of its nearly 1300 members
through forums for the exchange of
ideas and practical experience.
It is through events (congresses,
scientific meetings, forums) that
A3P is assured leadership in its field.
Our Lyon, France event focus will be
on biopharmaceuticals.
Organizer’s description:
IBC’s 11th Annual Single-Use
Applications is coming to Boston,
MA on June 9-10, 2014. Join the
priority contact list today for
exclusive savings and program
updates on the #1 forum for
biomanufacturing processionals
to obtain the latest developments
and applications of single-use
technology.
8-9 October 2014
Barcelona, Spain
BioProduction 2014
Organizer’s description:
Exchanging Knowledge and Data
to Drive Scientific Excellence.
Optimise, streamline and reduce
timelines whilst ensuring product
quality and regulatory success
for antibodies and novel
biopharmaceuticals.
Visit us at one of these shows
and discover how our latest
biopharmaceutical technologies
can improve your process
Would you like further information?
e-mail: jennifer.johnson@parker.com
www.parker.com/dhsingleuse
73
PRODUCT overview
Final Formulation
& Filtration
Intermediate Product
& Virus Filtration
Virus Inactivation
Tangential Flow
Filtration
Chromatography
Buffer Preparation
Downstream
Processing
Bioreactor Harvesting
Gravimetric Bioreactor
Maintenance
Cell Culture
Media Preparation
Upstream
Processing
PROCLEAR GF
•
•
•
PROCLEAR PP
PROPOR SG
PROPOR HC
PROPOR MR
PROPOR BR
•
•
•
•
•
Fluid Transfer & Storage
Mitos-P
Mitos-R
Mitos-C
DuraPure™ Bioprocessing Bags
Klave-it™ Bioprocessing Bags
Overmolding & Connectors
Automated Systems
SciFlex®
WeighStation™ Family
SciPure®
LabTec®
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ChemTec™
PureTec®
•
Condition Sensing
SciCon®
SciPres
®
SciTemp®
74www.parker.com/dhsingleuse
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MabTec®
SE – Sweden, Spånga
Tel: +46 (0)8 59 79 50 00
parker.sweden@parker.com
AE – United Arab Emirates, Dubai
Tel: +971 4 8127100
parker.me@parker.com
SK – Slovakia, Banská Bystrica
Tel: +421 484 162 252
parker.slovakia@parker.com
AT – Austria, Wiener Neustadt
Tel: +43 (0)2622 23501-0
parker.austria@parker.com
SL – Slovenia, Novo Mesto
Tel: +386 7 337 6650
parker.slovenia@parker.com
AT – Eastern Europe, Wiener
Neustadt
Tel: +43 (0)2622 23501 900
parker.easteurope@parker.com
TR – Turkey, Istanbul
Tel: +90 216 4997081
parker.turkey@parker.com
AZ – Azerbaijan, Baku
Tel: +994 50 2233 458
parker.azerbaijan@parker.com
BE/LU – Belgium, Nivelles
Tel: +32 (0)67 280 900
parker.belgium@parker.com
BG – Bulgaria, Sofia
Tel: +359 2 980 1344
parker.bulgaria@parker.com
CH – Switzerland, Etoy
Tel: +41 (0)21 821 87 00
parker.switzerland@parker.com
•
HarvestClear™
FilterTec™ / FilterTec™ Plus
•
•
•
•
•
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•
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Europe, Middle East,
Africa
BY – Belarus, Minsk
Tel: +375 17 209 9399
parker.belarus@parker.com
Filtration
PROCLEAR GP
worldwide support
•
•
CZ – Czech Republic, Klecany
Tel: +420 284 083 111
parker.czechrepublic@parker.
com
DE – Germany, Kaarst
Tel: +49 (0)2131 4016 0
parker.germany@parker.com
DK – Denmark, Ballerup
Tel: +45 43 56 04 00
parker.denmark@parker.com
ES – Spain, Madrid
Tel: +34 902 330 001
parker.spain@parker.com
•
•
•
•
•
•
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FI – Finland, Vantaa
Tel: +358 (0)20 753 2500
parker.finland@parker.com
FR – France, Contamine s/Arve
Tel: +33 (0)4 50 25 80 25
parker.france@parker.com
GR – Greece, Athens
Tel: +30 210 933 6450
parker.greece@parker.com
HU – Hungary, Budaörs
Tel: +36 23 885 470
parker.hungary@parker.com
IE – Ireland, Dublin
Tel: +353 (0)1 466 6370
parker.ireland@parker.com
IT – Italy, Corsico (MI)
Tel: +39 02 45 19 21
parker.italy@parker.com
KZ – Kazakhstan, Almaty
Tel: +7 7273 561 000
parker.easteurope@parker.com
NL – The Netherlands, Oldenzaal
Tel: +31 (0)541 585 000
parker.nl@parker.com
NO – Norway, Asker
Tel: +47 66 75 34 00
parker.norway@parker.com
PL – Poland, Warsaw
Tel: +48 (0)22 573 24 00
parker.poland@parker.com
•
PT – Portugal, Leca da Palmeira
Tel: +351 22 999 7360
parker.portugal@parker.com
RO – Romania, Bucharest
Tel: +40 21 252 1382
parker.romania@parker.com
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RU – Russia, Moscow
Tel: +7 495 645-2156
parker.russia@parker.com
UA – Ukraine, Kiev
Tel +380 44 494 2731
parker.ukraine@parker.com
UK – United Kingdom, Warwick
Tel: +44 (0)1926 317 878
parker.uk@parker.com
Advertisers
Contacts
Life Science Connect
Andrew Lidums
LifeScienceConnect.com
Business Development Manager
North America
BioProcess International
www.bioprocessintl.com
andrew.lidums@parker.com
Stephen Sisman
Business Development Manager
Europe/Asia
stephen.sisman@parker.com
BPSA
Nick Hutchinson
www.bpsalliance.org
Market Development Manager
nick.hutchinson@parker.com
Informa
Todd Kapp
www.informa-ls.com
Market Development Manager
Single-Use
ZA – South Africa, Kempton Park
Tel: +27 (0)11 961 0700
parker.southafrica@parker.com
todd.kapp@parker.com
Gregg Larson
North America
Product Manager - Single-Use
CA – Canada, Milton, Ontario
Tel: +1 905 693 3000
gregg.larson@parker.com
Andrew Kelly
US – USA, Cleveland
Tel: +1 216 896 3000
Product Manager - Filtration
andrew.kelly@parker.com
Asia Pacific
Jennifer Johnson
AU – Australia, Castle Hill
Tel: +61 (0)2-9634 7777
Snr Marketing Specialist
jennifer.johnson@parker.com
CN – China, Shanghai
Tel: +86 21 2899 5000
Michelle Gray
HK – Hong Kong
Tel: +852 2428 8008
Snr Publications Designer
michelle.gray@parker.com
IN – India, Mumbai
Tel: +91 22 6513 7081-85
JP – Japan, Tokyo
Tel: +81 (0)3 6408 3901
KR – South Korea, Seoul
Tel: +82 2 559 0400
MY – Malaysia, Shah Alam
Tel: +60 3 7849 0800
NZ – New Zealand, Mt Wellington
Tel: +64 9 574 1744
SG – Singapore
Tel: +65 6887 6300
TH – Thailand, Bangkok
Tel: +662 186 7000-99
TW – Taiwan, Taipei
Tel: +886 2 2298 8987
South America
AR – Argentina, Buenos Aires
Tel: +54 3327 44 4129
BR – Brazil, Sao Jose dos Campos
Tel: +55 800 727 5374
filtration sensors
automated systems
Parker Hannifin Manufacturing Ltd
domnick hunter Process Filtration - Europe
Durham Road
Birtley, Co. Durham
DH3 2SF, England
phone +44 (0)191 4105121
fax +44 (0)191 4105312
email: dhprocess@parker.com
www.parker.com/dhsingleuse
CL – Chile, Santiago
Tel: +56 2 623 1216
MX – Mexico, Apodaca
Tel: +52 81 8156 6000
Parker Hannifin Corporation
domnick hunter Process Filtration - North America
Single-Use Technologies
2340 Eastman Avenue,
Oxnard, California, USA 93030
toll free: 877 784 2234
phone: +1 805 604 3400
fax: +1 805 604 3401
email: dhpsales.na@parker.com
www.parker.com/dhsingleuse
www.parker.com/dhsingleuse
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Together, we can provide cell culture
harvest. Straight out of the box.
HarvestClear™
Complete Cell Culture Harvest System
Pre-conditioned and ready straight from the box, our new integrated solution for cell
culture harvest provides automated, fast and cost-effective clarification of bioreactor
outputs up to 20 L.
The system can increase filter throughput by up to 30% by allowing walk-away operations
and increasing safety levels through automation.
The launch marks the first of our integrated, application-specific solutions combining
SciLog automation and sensor leadership with Parker domnick hunter filtration expertise.
www.parker.com/dhsingleuse
Europe: phone +44 (0)191 4105121 - email: dhprocess@parker.com
North America: toll free 877 784 2234 - email: dhpsales.na@parker.com
phone +1 805 604 3400