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Pharmaceutical &
Perspectives in Liquid Process Analytics
Leading Process Analytics
Optical DO Measurement
Simply Better
For a large European pharmaceutical group, accurate, low maintenance
dissolved oxygen sensors are central to efficiency in their research. The
predictive diagnostics, fast start up, and easy servicing of intelligent
optical measurement has made it their technology of choice.
Global pharma company
Our customer is a leading Italy-based
pharmaceutical group. Across 14 manufacturing sites spread throughout the
world, they annually produce over half a
billion packs of product. For thirty years,
the groupʼs biotech division has been a
leading center of excellence in biotechnology innovation.
through the control of dissolved oxygen
levels throughout fermentation.
The principal activities at the biotech
divisionʼs Italian facility are improving
cell line productivity, development and
validation of analytical methods, and drug
production for clinical trials and for the
Optical sensors are very low on
For many years, the biotech division had
been using DO sensors based on polarographic technology. However, the demands
of a long polarization time, high maintenance, and signal drift during extended
fermentations were impeding the divisionʼs
research. This prompted technicians at
the facility to contact METTLER
TOLEDO for an alternative solution. Our
engineers proposed optical technology as
a better option.
In the cultivation of mammalian cells,
scientists at the facility are currently conducting research into maximizing yield
DO sensors based on optical measurement
employ fluorescence quenching to provide
oxygen readings. Unlike polarographic
Leading Pure Water Analytics
probes, optical sensors do not contain a
membrane, inner body or electrolyte; elements which require regular replacement.
The InPro 6860 i optical DO sensor has
only one replaceable part, the oxygensensitive OptoCap. Exchange of the OptoCap can be done in a minute and on average is only required a few times a year.
Minimal drift and no polarization
Low drift is another major advantage of
optical DO sensors, and METTLER
TOLEDO has reduced drift further by employing Automatic Stability Control in the
InPro 6860 i. In addition, optical probes
require no polarization, so the InPro 6860 i
can be up and running very quickly.
Publisher / Production
Mettler-Toledo AG
Process Analytics
Im Hackacker 15
CH-8902 Urdorf
Subject to technical changes.
© Mettler-Toledo AG 01 / 15
Printed in Switzerland.
Predictive diagnostics for
measurement confidence
The facility installed three InPro 6860 i
sensors along with M400 transmitters
which would allow technicians to monitor
the sensorsʼ Intelligent Sensor Management (ISM®) predictive diagnostics. These
tools provide real-time status information
to provide assurance in sensor performance and hence confidence in the DO
High satisfaction
Technicians and biotechnologists at the
research facility are very satisfied with the
accuracy and low maintenance of the
METTLER TOLEDO solution and are considering switching all polarographic DO
measurements to optical.
The InPro 6860 i is now available with Ex
certification (see next page).
Optical O2 sensor InPro 6860 i
Mettler-Toledo AG
The combination of high measurement
accuracy, low and easy maintenance,
minimal drift, and rapid startup ideally
match the research facilityʼs requirements.
Pharmaceutical & Biotechnology News 24
Highlights of the InPro 6860 i Ex
•Improved optical technology
ensures high accuracy
•Automatic Stability Control for
superior measurement stability
• Pre-calibration in the lab with
iSense software
•Approved for hazardous area use
DO Measurement Solution
Accurate, Low Maintenance DO Measurement
in Hazardous Areas
Optical dissolved oxygen sensors are rapidly replacing amperometric probes. The easy
handling and exceptional performance of the InPro 6860 i has made it one of the most
successful optical DO sensors available. The addition of Ex certification means it can now
be used in hazardous areas.
Intrinsically-safe DO solution
Low drift, fast response, and less maintenance are the main reasons why optical
dissolved oxygen sensors are becoming
increasingly common in biopharma R & D
and production facilities. For applications
where there is a fire or explosion risk, a
sensor with Ex certification is required.
METTLER TOLEDO now offers a unique
intrinsically-safe DO measurement system
consisting of the M400 2-wire transmitter
and the new InPro 6860 i Ex sensor.
High stability, minimal
The InPro 6860 i Ex has all the features of
the non-Ex version including, digital and
analog outputs for compatibility with
benchtop bioreactors, high measurement
stability thanks to its Automatic Stability
Control feature, and a hygienically polished surface finish. Maintenance on the
sensor only amounts to periodic replacement of the one-piece OptoCap oxygensensing element.
The M400 2-wire transmitter is a singlechannel, multi-parameter unit for DO,
gaseous oxygen, ph / ORP and conductivity measurement. It is available with
HART®, FOUNDATION fieldbus™ and
PROFIBUS® PA communication protocols.
ISM® technology is a major
A key feature of the InPro 6860 i Ex / M400
system is the inclusion of Intelligent Sensor Management (ISM) technology which
provides Plug and Measure start up, calibration in any convenient location, and
intelligent diagnostics to provide confidence in sensor condition before and
during a batch.
Highlights of the M400
•Wide parameter range
includes optical DO
and PROFIBUS PA protocols
• Compatible with ISM and
analog sensors
•Approved for hazardous area
Pharmaceutical & Biotechnology News 24
New Trends in Process Analytics
for the Pharmaceutical Industry
Kurt Hiltbrunner at METTLER TOLEDO is an expert in the deployment and use of process
analytical measuring systems in pharmaceutical production. He travels around the globe
advising pharma companies on how to improve their processes and increase profitability.
Pharmaceutical and Biotechnology News spoke to him about new trends in drug production.
Mr Hiltbrunner, what do you see
as being the current trends in biopharmaceutical manufacturing
and do they affect process
I think there are two major trends: the
increase in a move towards cell culturing
rather than microbial fermentation, and
the rise of biosimilars as more and more
drugs lose their patent protection.
The production of biosimilars doesnʼt
place any new demands on process measurement systems, but in respect of cell
culturing, batch duration is much longer
compared with most microbial fermentation processes. Also, ideal growth conditions are in a much narrower range. That
means analytical sensors must be very
high in accuracy and very low in drift.
start. Is the sensor at fault? Does it need
calibrating? Or is there something wrong
with the lab measurement? As changes to
the process are more likely to be based on
the in-line measurement rather than that
from the lab, technicians want to be as
sure as possible that the in-line sensor is
operating reliably. Accuracy leads to
batch-to-batch consistency.
What is the main pain point for
pharmaceutical companies
regarding cell culturing?
Obviously, they want to maintain optimal
growth conditions during a run as any
deviation slows production or lowers yield
or protein quality. Typically lab measurements of pH will be made periodically, and
if they differ from the measurement coming from the in-line sensor, the problems
Apart from pH, what other analytical parameters are important to
monitor during cell culturing?
Dissolved oxygen is important, as is dissolved CO2, which has sort of been overlooked. CO2 can easily pass the cell
membrane and enter the cytosol and the
mitochondrial compartment of a cultivated cell. If it does, intracellular pH will
change and important cellular processes
can be affected. So, keeping CO2 on track
can greatly reduce batch time and ensure
product quality is high.
You mentioned dissolved oxygen.
Optical DO measurement technology is growing in acceptance. Is
that likely to continue?
Absolutely. Compared with electrochemical sensors, optical sensors are much
easier to handle. I think over the next five
years the use of optical probes will overtake electrochemical. Validation is slowing conversion but the much lower
maintenance of optical will make it the
Pharmaceutical & Biotechnology News 24
Top sensor and instrumentation
companies today offer digital
measurement systems. Will digital sensors become the accepted
standard in the pharma industry?
Yes, Iʼm sure thatʼll happen. The situation
with digital systems is similar to that of
optical oxygen sensors: the advantages are
just too great, and digital sensors will
outnumber analog ones in the coming
years. Analog-to-digital conversion directly in the sensor provides a robust signal
which suffers no interference from humidity and allows longer cable lengths. This
is a big improvement in sensor signal
Beyond signal robustness, digital sensors
can offer sensor diagnostics and pre-calibration capabilities, so at the start of cell
culturing or fermentation you can be sure
the sensor will perform reliably
Do digital sensors mean transmitters will become obsolete?
Thatʼs a question I hear many times dur-
ing customer visits. I think the answerʼs
almost certainly ʼnoʼ, as itʼs normally a
requirement to have a measurement visible
at the process.
Also, digital sensor signals can be integrated into next level control systems, but
only if corresponding software for the
particular hardware is written. With a
transmitter, the full power of digital technology and diagnostics can be easily used.
And transmitters can provide outputs in
many different formats, from analog
4 – 20 mA to those designed for whatever
bus system is being used. Additionally,
they can display not just the measuring
value but also give relevant information
about the current status of the sensor,
which is a growing request from
process analytics that lower running costs
and also make operations easier in
pharma plants, and so reduce training
and maintenance: multi-parameter transmitters, and the optical and digital technologies weʼve been talking about are a
few examples. Indeed, our Intelligent Sensor Management digital technology can
save literally thousands of hours spent on
maintenance over the course of a year.
Cost pressures, which were not
such a great concern to the
pharma industry in the past, are
coming to the fore. How can process analytics help here?
There have been many developments in
Pharmaceutical & Biotechnology News 24
ISM Measurement Solutions
Highest Sensor Flexibility and Usability
at Leading Life Science Company
Pressures on the bioprocess industry are creating greater demands on process
equipment. In recognition, Eppendorf has incorporated Intelligent Sensor Management
(ISM®) technology into their latest bioprocess control station. The result is a unique
system that offers unequalled performance and ease of use.
Bioprocess equipment has to
As the landscape within the bioprocess
industry continues to evolve at record
pace, advances in sensor technology remain at the forefront. Process demands for
fermentation and cell culture have drastically increased in complexity, driving the
need for more sophisticated R & D and
production equipment. Increased precision and accuracy of measurements,
flexibility between sensor platforms, and
advanced quality control will continue to
be the most sought after improvements in
new product offerings.
Global life science equipment
Eppendorf is a leading life science company. Through their ever-expanding bioprocess product portfolios and by exploiting the strong synergies in bioreactor
technology and polymer manufacturing,
Eppendorf has emerged as a global player
and valuable resource to its customers in
the bioprocess marketplace.
A universal control station
Developments in the world of sensor technology have not always coincided with
developments in the equipment needed for
process control. This has left many laboratories struggling to retrofit modern
sensors into existing control platforms.
Recognizing this challenge, Eppendorf
has launched the BioFlo® 320, their newly
introduced bioprocess control station. The
BioFlo 320 was designed with one goal in
mind: to bring the first truly universal
control station to the scientists who need
it. Central to the performance of the unit
is the inclusion of METTLER TOLEDO
sensors with Intelligent Sensor Management (ISM®) technology.
ISM is a process analyzer platform that
increases measurement system reliability,
improves process safety, and significantly
reduces sensor handling and maintenance. Eppendorf realized how the advantages of ISM would benefit its customers
and were eager to integrate it into their
Simplicity and high performance
The addition of ISM in the BioFlo 320
means the need for cumbersome sensor
retrofitting has been removed; plus, flexibility has been significantly increased.
Users can choose to control their process
using any ISM sensor (pH, amperometric
or optical DO, dissolved CO2, or redox)
without having to think twice about what
else is needed. The control station is set up
to recognize which sensor is connected
and automatically configures the software
for use, leaving no work for the operator.
The ability to view sensor diagnostics
Pharmaceutical & Biotechnology News 24
means any required sensor maintenance
can be conducted before a batch, providing
high confidence in sensor performance
throughout the run.
The universal concept of the BioFlo 320
does not end with the sensors. Incorporating interchangeable autoclavable and
single-use vessels, field-upgradeable
TMFC modules, bi-directional agitation
and peristaltic pump motors, and universal software designed for both microbial
and cell culture applications are some of
the features that emphasize ʼuniversal
Flexibility reaches new heights
The combination of ISM with Eppendorf
bioprocess control stations offers a new
level of flexibility, as Kevin Voll, Product
Manager for Benchtop Bioprocess at Eppendorf explains: “Bioprocess is a tremendously complex and diverse field. The
ability to meet the current and future
process needs of our customers is a top
priority at Eppendorf. Sensor flexibility is
paramount to the concept of universal
equipment design and the integration of
the METTLER TOLEDO ISM platform into
our bioprocess equipment is a new and
exciting step for us. The advent of digital
sensors has made it possible to offer inprocess flexibility for a range of sensors on
a single device.”
The range of ISM sensors includes pH, ORP,
dissolved oxygen, and dissolved CO2
Pharmaceutical & Biotechnology News 24
UniCond Sensors
Ensure Pharmacopeia Compliance
with Digital Conductivity Sensors
The conductivity limits of pharmaceutical bulk waters must meet the requirements of the
applicable global pharmacopeia. Further, the conductivity instrument itself must comply
with calibration requirements to meet all global pharmacopeias. UniCond® sensors not only
confirm compliance, they also provide the highest degree of accuracy.
The need for better performance
As requirements for pharma waters become ever stricter, so the need for increased
analytical measurement accuracy and
repeatability has become greater.
The advent of the digital sensor has opened
up new horizons for the performance of
in-line analytical equipment, and provides benefits in ease of use that nondigital sensors cannot match.
Digital signal is extremely robust
Traditional analog conductivity measurement systems can be prone to signal loss
between sensor and transmitter due to
interference to the AC signal.
UniCond sensors operate differently. Signal processing takes place within the
probe head itself. Measurements are then
sent digitally to the transmitter. Digitizing
the analog signal in proximity to the sensing element is a significant improvement,
as the robust signal is immune to interference or degradation. High confidence in
the reliability of the measurements received at the readout instrument is therefore always assured.
Pharmaceutical & Biotechnology News 24
Major improvement in accuracy
Signal degradation and variance is eliminated with UniCond sensors because of the
integrated measurement circuit. Impedance and capacitance problems associated
with analog sensors and cable length are
eradicated. Further, integrating the sensor
and the measuring circuit provides far
greater measurement accuracy compared
with analog probes.
Error-free start up
A reliable and accurate digital signal is not
the only benefit of UniCond sensors. Intelligent Sensor Management (ISM®) technology means on-board memory stores
and communicates complete sensor identification and calibration data to the
readout instrument for simplified startup
and calibration. The result is convenient
Plug and Measure functionality, and
greatly reduced chances of operator error.
eliminates questions about which cell
constant to use, calibration data to enter,
spare parts to maintain and other decisions where multiple sensor types would
normally be required. This significantly
improves system simplicity and reliability.
UniCond for USP compliance
Compliance with USP < 645 >, EP 2.2.44
and all other global pharmacopeias requires calibration of the sensor cell constant, the measurement circuit, and the
transmitter. The measurement circuit in
UniCond sensors is traceable to NIST and
is calibrated prior to assembly. The cell
constant is traceable to ASTM. In addition,
UniCond sensors can be calibrated in-line,
as recommended by the USP and EP. Also,
ISM simplifies regulatory compliance by
storing sensor calibration data internally
and reducing written record keeping.
With conventional sensors, the user must
remember to manually enter the precise
cell constant and temperature calibration
data for each individual probe into the
transmitterʼs memory to achieve rated
accuracy. The UniCondʼs integral sensor
UniCond conductivity sensor
Main benefits:
•33 % improved accuracy over
analog sensors
•Digital signal ensures high process reliability
•No signal degradation over long
cable lengths
•Can be calibrated in-line as
recommended by USP and EP
Pharmaceutical & Biotechnology News 24
Karl Fischer Titration
Flexible Karl Fischer Titration
of Lyophilized Drugs
Also known as freeze drying, lyophilization offers a rapid and thorough technique for preserving
vaccines and other injectables during storage. The water content determination of lyophilized
materials is crucial and not always an easy process as the weight of the lyophilized material
may not be known initially. Combining LabX® balance software with a Compact Karl Fischer
Titrator, makes this analysis simple and foolproof.
A Karl Fischer determination of lyophilized materials can be carried out using
one of two techniques, i.e. either the entire
content of the vial is transferred to an oven
attached to a Karl Fischer Titrator or an
external extraction is performed. An extraction is preferred, as the vial remains
sealed while a solvent is injected into the
The METTLER TOLEDO C30 Coulometric
Karl Fischer Titrator is an ideal solution
for external extraction with the built-in
External Extraction method. The process
starts running blank solvent titrations in
order to determine the water content in the
solvent. To dissolve the sample, the solvent
is injected into the vial and then sonicated. A defined volume of sample dis-
Pharmaceutical & Biotechnology News 24
solved in solvent is drawn from the vial
and titrated. Prior to the titration, the
weight of solvent, sample and injected
solution are entered in the C30 for subsequent error-free result calculations.
The ideal vs. Day-to-day reality
The operator must know the initial weight
of the vial and sample for the aforementioned method. Ideally, testing labs should
know the weight of the lyophilized sample
and the empty vial when they receive it. In
this case, the C30 is able to calculate the
water content of the lyophilized material
However, testing labs often do not know
the weight of the sample either because
their customers do not provide the empty
vial weight or because of weight changes
in the material (as it is dried) during the
lyophilization process. This renders the
C30 built in method obsolete and forces
the operator to carry out the calculations
manually after the titration analysis, introducing extra time-consuming steps,
such as cleaning, drying and weighing the
empty vial. This manual procedure is also
prone to error.
Simplified and error free workflow
However, calculating the water content of
the lyophilized sample without knowing
its initial weight is no longer a manual
and tedious operation thanks to a new
method in LabX balance laboratory software. By connecting the C30 and an analytical balance to LabX software, the cal-
C30 Karl Fischer titrators
and LabX software for
automated and error-free
culation is performed automatically after
the analysis.
The solution is the tailored LabX balance
method that ensures a simple and instructed workflow with error-free calculations. From the first weighing on, the vial,
including sample and all subsequent
weighing (dried and empty vial) is automatically associated with the initial ID
that has been entered or scanned by a
barcode reader. LabX automatically calculates the final sample weight and the
water content of the sample using the C30
Titrator results. This early identification
ensures secure operation during further
stages to boost operator confidence and
reduce the margin of error.
The LabX balance workflow simplifies the
weighing and identification process for
the secure and simple water content determination of lyophilized substances where
the weight of the sample is not initially
Text: Matthew Eby
Product Manager Titration
Pharmaceutical & Biotechnology News 24
Get in-line with METTLER TOLEDO
New! DIN Rail Transmitter
High Performance in a Minimum of Space
The M100 DR is a compact, versatile and easy to commission
transmitter for DIN rail mounting. It is a single-channel, multiparameter unit compatible with 1-wire Intelligent Sensor Management (ISM®) sensors for measuring pH, oxygen and conductivity.
Ideal for process development environments, the M100 DR
provides an easy way of integrating ISM sensors via the HART
Mettler-Toledo AG
Process Analytics
Im Hackacker 15
CH-8902 Urdorf
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