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Moisture Affecting Your Measurements?The Answer Is DigitalA humid environment was severely affecting the reliability of pH

measurement during peptone production at a Solabia facility. An

Intelligent Sensor Management (ISM) solution not only solved the

problem, but also ensured precise measurements and dependable

performance.

Large bioindustrial group Solabia, based in Paris, design and manu-

facture compounds and active principles

for the cosmetic, pharmaceutical and

nutrition industries, peptones and protein

hydrolysates for bio-industry, and micro-

biological diagnostic reagents for food

processing, cosmetics, pharmaceutical

and environmental laboratories. The

group has several manufacturing and

research facilities abroad and in France,

including a 6000 m2 site at Beauvais near

Paris which specializes in fermentation,

enzymatic hydrolysis, purification extrac-

tion, grinding and compounding.

PeptonesAt the Beauvais site, peptones (hydrolysates

used in the manufacture of culture and

fermentation mediums) are produced by

enzymatic hydrolysis in 6,000 to 15,000 L

reactors. The solution in the reactors is

continuously stirred while being heated to

temperatures reaching 95 ° to 100 °C be-

fore being cooled. During the process,

which can last several hours, pH must be

strictly controlled in order to ensure opti-

mal process conditions. However, the

production team was not satisfied with the

performance of their pH measuring sys-

tem.

Challenging conditionsWith their previous pH installation Solabia

encountered problems when calibrating

electrodes due to the great deal of conden-

sation moisture produced during the

hot-cold process. In addition, the humid

conditions were testing for the cables and

couplings.

INGOLD Leading Process Analytics

Pharmaceutical Perspectives in Liquid Process Analytics

THORNTON Leading Pure Water Analytics

2 METTLER TOLEDO Pharmaceutical News 15

Publisher / Production Mettler-Toledo AG

Process Analytics

Im Hackacker 15

CH-8902 Urdorf

Switzerland

IllustrationsMettler-Toledo AG

Solabia S.A.S.

Boehringer Ingelheim GmbH

Noltelourens | Dreamstime.comSubject to technical changes.

© Mettler-Toledo AG 12/09

Printed in Switzerland.

RequirementsSolabia turned to METTLER TOLEDO for

a solution. The main requirements posed

by Mr Guemene, production engineer at

Solabia, included combating the moisture

problems and reducing the effects of in-

formation lost due to the extremely long

cables (> 20 m) that were being used.

METTLER TOLEDO installed a test system

comprising the following:

n InPro 3253 i electrode placed directly

at the bottom of the tank using an

Ingold coupling

n M400 transmitter

Benefits of the equipmentInPro 3253 i electrodeThe METTLER TOLEDO InPro 3253 i is a

low-maintenance, digital pH electrode

with pressurized liquid electrolyte. It has

been specifically designed to meet the

requirements of applications in biotech-

nological processes in the pharmaceutical

industry.

n Ready for use in an instant: The Plug

and Measure feature of METTLER

TOLEDO’s ISM technology means that

the electrode can begin measuring

within seconds of being connected.

n Long lifespan: Pressurization of the

liquid electrolyte prevents penetration

of the process medium into the refer-

ence system and also ensures constant

cleaning of the diaphragm thanks to

the outflow of a very low quantity of

electrolyte.

n Insensitive to contamination: A silver

ion barrier built into the reference

system prevents adulteration and

blockage of the diaphragm by silver

sulfate in media containing sulfates

and amino acids.

n Precise measurement: Compensation

measurements from the built-in tem-

perature sensor ensure the pH reading

is always accurate. Further, the mem-

brane glass, developed specifically for

biotechnology and pharmaceutical

processes, minimizes zeroing of the

electrode when sterilized.

Stay one step ahead of maintenance with ISM

Intelligent Sensor Management reduces the installation, main-tenance and calibration effort for METTLER TOLEDO’s digital sensors to a minimum. This considerably improves reliabili-ty, productivity and system availability.

Find out how ISM can help you, at:

Best Practice

www.mt.com/ISM

n Wide range of applications: Designed

for use in mixers, receiving vessels,

open tanks and fermentation installa-

tions in up to 4 bar overpressure.

n Simple maintenance: Totally autocla-

vable or sterilizable in situ

(sterilization possible up to 140 °C)

Transmitter M400pH electrode InPro 3253 i

METTLER TOLEDO Pharmaceutical News 15 3

O 2 M

easu

rem

ent

exists between sufficient performance and

reliability, and reasonable maintenance

effort and system availability. In order to

function correctly, paramagnetic systems

need to protect the measurement cell from

heat, moisture and/or corrosive gases.

However, the more instruments there are

between the process and the sensor, the

longer the response time will be and the

higher the probability of system failure.

Amperometric: simple and reliableLooking at the field of dissolved oxygen

measurement however, membrane-based

Measure Oxygen Where It Really MattersDirectly in Your ProcessPerformance of gaseous oxygen measurement is now redefined with

METTLER TOLEDO’s amperometric systems. They not only allow reliable

and stable measurement, they are inexpensive to maintain and, what’s

more, do not require any gas sampling system.

Unwanted oxygenOxygen levels in industrial processes are

heavily controlled to contain the risk of

explosion of flammable liquids and dusts,

as well as to protect products against oxi-

dation. Not only is oxygen monitoring a

critical issue in transport systems, storage

tanks or centrifuges, it can also nega-

tively affect the yield of a chemical

reaction in a vessel.

Many solutions – which is best?When selecting a vendor for a measure-

ment system, technologies and solutions

abound, but in many cases a trade-off

amperometric sensors using the Clark

principle have for decades demonstrated

optimum performance in a wide range of

applications ranging from fermentation

processes in breweries, in biopharmaceu-

tical industries or in chemical process

applications. This technology, with a

proven industrial track record due to its

simplicity and ruggedness, is ideally

suited for the in-situ measurement of

gaseous oxygen.

METTLER TOLEDO offers a comprehen-

sive range of amperometric systems with

sensors for wide application coverage, re-

M400 transmitterThis is a single-channel, multi-parameter

transmitter for measurement of pH / redox,

pH ISFET, oxygen, dissolved CO2 or con-

ductivity. ISM functionality provides

real-time sensor status information for

true predictive maintenance.

n Reliability: The Dynamic Lifetime

Indicator tells you when the sensor

needs to be replaced. Therefore, you

have assurance of sensor reliability

before a batch starts.

n Flexibility: The M400 accepts both

digital ISM and analog sensors.

n Low maintenance: The Adaptive

Calibration Timer monitors the time

to the next electrode calibration, so

you only calibrate when necessary.

Simplified commissioning minimizes

the risk of installation problems.

Digital signalThe high-impedance pH signal of analog

systems is very sensitive to interference

and moisture, and the longer the cable the

greater the chance there is of data loss. In

an ISM system a microchip in the head of

the sensor converts the analog measure-

ment signal to a digital one. As

low-impedance digital signals are unaf-

fected by moisture, and data loss from

sensor to transmitter is exceptionally low,

humidity and cable length are not a

problem.

Highly satisfied customerThe test phase lasted three weeks, during

which the InPro 3253 i and M400 were

used on seven batches. Moisture problems

were eliminated and cable lengths were

extended to 50 m without any deteriora-

tion of the signal. Such has been Solabia’s

satisfaction that they have since ordered

six additional pH measuring systems for

other applications.

To benefit from digital sensor technology

at your facility, go to:

www.mt.com/InPro3250 iwww.mt.com/M400


F O2

Paramagnetic system

N2 in

METTLER TOLEDO solution

process, minimizing the time necessary

for maintenance and without the need for

specialist know-how. Additionally, ISM

sensors have built-in self-diagnostic

abilities in order to detect early signs of

failure such as low electrolyte levels, and

to alert users before measurement quality

or process availability is impacted.

The benefits of ISM technology are fully

exploited with the use of iSense, METTLER

TOLEDO’s software suite for asset man-

agement. Using iSense, the sensor’s status

is analyzed in a lab environment, enabling

the user to make a better decision about

the fitness of a sensor prior to installing it

in the process.

If you want to save costs on O2 measure-

ment at your facility, go to:

tractable housings for sensor extraction

without process interruption, and trans-

mitters for signal conversion and

connection to process control systems

using HART, FOUNDATION fieldbus or

PROFIBUS. Naturally, the complete mea-

surement system is available with ATEX

Zone 1 / FM Class 1 Div 1 approval if re-

quired.

Amperometric sensors can be maintained

in two minutes, with minimum impact on

your running process. All that is required

is to replace the membrane body and fill

it with fresh electrolyte solution.

Subsequent calibration can be performed

on site using air as a calibration gas.

Intelligent sensors for smart processesAll amperometric sensors from METTLER

TOLEDO are available in digital versions

equipped with the Intelligent Sensor

Management (ISM) technology. With the

Plug and Measure feature, pre-calibrated

sensors can be immediately used in the

Reduce expenditure, reduce risk

Most installed gaseous O2 mea-surement systems are based on expensive paramagnetic or zirco-nium dioxide measurement principles. Such systems have the additional expense of requiring gas conditioning equipment. The purchasing and maintenance costs for such systems can be substantial. Further, the chance of process interruption due to system failure is high.

METTLER TOLEDO gaseous O2 systems are based on inexpensive amperometric technology and re-quire only a sensor and transmitter. As the sensor is placed directly in the process vessel, the measuring point provides you with real-time, continuous and reliable data.

Discover more at:

Best Practice

www.mt.com/o2-gas

www.mt.com/o2-gaswww.mt.com/ISM

The sample path through a The METTLER TOLEDO solution paramagentic system is long and slow. measures directly in the vessel – immediately.


Mor

e Pr

oduc

t, Le

ss W

ater

Los

s

ISM technology for conductivity With the new “i” suffix conductivity sen-

sors we extend METTLER TOLEDO’s wide

range of instruments featuring our pro-

prietary Intelligent Sensor Management

(ISM) technology. ISM is a smart approach

for storing all data in the head of the

sensor, including the cell constant, serial

number and calibration data. In combi-

nation with Plug and Measure

functionality this means that as soon

as the sensor is connected, fast start up is

guaranteed because the relevant data

stored in the sensor head is sent to the

transmitter.

ISM conveys the measured conductivity

value to the transmitter using a digital

signal. This guarantees interference-free

transmission that is unaffected by humid-

ity or cable length.

Discover more at:

Precise Phase Separation Identificationwith New Intelligent Conductivity SensorsWithout fast and accurate detection of phase separation, you will be

losing product and wasting water. With METTLER TOLEDO’s new, high

performance conductivity sensors, that is something you will not need to

worry about.

Quick and reliableTo help ensure you are maximizing yield

and optimizing water consumption in

your processes, you need accurate phase

separation detection equipment. New in-

telligent conductivity sensors from

METTLER TOLEDO – the InPro 7100 i

series – ensure fast, accurate phase sepa-

ration identification. Hygienic design

supports high process safety in pharma-

ceutical applications, with the PEEK shaft

material offering superior resistance

against CIP cycles.

Easy process integrationDue to the broad range of METTLER

TOLEDO static and retractable housings

and the compact 12 mm design of the

sensor, installing the InPro 7100 i is fast

and straightforward. The ample choice of

housings allows integration into an ex-

tensive range of process applications and

makes installation into existing processes

simple and cost effective.

Benefits of the InPro 7100 iSuitable for a wide variety of applica-

tions:

n Extensive measuring range

Helps maximize uptime and yield:

n Fast, precise response

n Retractable housings mean no process

interruptions

Easy installation:

n Compact design

n Wide range of housings available

Fast commissioning:

n Fast interface detection

n Calibration data stored in the sensor

n Automatic transmitter configuration

www.mt.com/InPro7100i


DO

Mea

sure

men

t in

O 2-s

ensi

tive

Reac

tions

Dissolved oxygen sensors and the solubility factorTraditionally, dissolved oxygen sensors

have not been widely used in non-aqueous

systems because many solvents, such as

tetrahydrofuran (THF) or toluene, have a

tendency to degrade the silicone in sensor

membranes and O-rings. In addition, the

solubility factor used in calculations that

all dissolved oxygen measurements are

based on, is for water. For non-aqueous

systems the solubility factor ’a’ in Henry’s

Law (CL = pO2 3 a) can be very different

to water, so the readings displayed on

the transmitter have to either be con-

verted using known literature values for a

particular solvent, or just taken as a di-

mensionless number and used relatively.

Accurate DO Measurementin Aggressive SolventsA major API manufacturer trialed a more precise and more cost effective

method of monitoring the efficiency of nitrogen purging, using an

intelligent dissolved oxygen sensor. METTLER TOLEDO’s digital ISM DO

sensors proved robust against corrosive solvents.

Catalytic reactionsMonitoring dissolved oxygen levels in ox-

ygen-sensitive catalytic reactions is not

usually monitored in R & D or production

scale processes. Instead, a preventative

measure is routinely adopted whereby the

liquid medium is purged of air with nitro-

gen gas before the oxygen-sensitive (and

expensive) catalyst is added.

There are many assumptions attached to

this method, such as presuming that an

inert atmosphere is created during an

arbitrary length of time that is safe for the

introduction of the catalyst. Further, the

purge time stipulated is based on industry

experience and historical recommenda-

tion, but it is not often measured using

analytical techniques. Our customer, a

key chem-pharma company, wanted to

find a better method.

In-line measure-ment means optimized produc-tion and lower operating costs

The continuous stream of data that in-line measurement pro-vides lets you know that your processes are working as they should, and informs you the instant that they are not – helping you to maximize production and saving on lab costs.

Discover more at:

Best Practice

www.mt.com/PRO

Transmitter M400 DO sensor InPro 6850 i


Increased productivity – reduced wasteThis information has allowed production

staff to challenge how they currently deal

with oxygen-sensitive reactions, and they

have put procedures in place to purge

in accordance with readings from the

InPro 6850 i sensor. This has improved

efficiency in the plant as now they use the

exact amount of nitrogen required and

have eliminated the prospect of destroying

expensive catalyst due to residual oxygen

in the medium.

ConclusionDue to the success of the study our cus-

tomer purchased an Intelligent Sensor

Management (ISM) oxygen system

(InPro 6850 i and M400). The diagnostic

information that is one of the central

advantages of ISM technology, was con-

sidered a great benefit, especially as

working with non-aqueous solvents can be

unpredictable in terms of membrane

lifetime.

Our customer is pleased to have found a

solution to the long-term issue of measur-

ing the presence of oxygen in non-aqueous

solvents, and is considering further

METTLER TOLEDO systems for other

catalytic reaction vessels at their produc-

tion site.

Find the right DO sensor for your applica-

tion at:

Kalrez is registered trademarks of E. I. du Pont de Nemours and Company.

Considering that dissolved oxygen mem-

brane technology has improved over the

last decade with the introduction of T-96

coated membranes, coupled with the

option of using Kalrez O-rings, the chem-

pharma company in question decided to

carry out trials with a METTLER TOLEDO

InPro 6850 i DO sensor with T-96 mem-

brane and Kalrez O-rings, and an M400

transmitter.

Demonstrating T-96 membrane ability in solventsThe trials involved subjecting the sensor

to the various reaction conditions that

would be encountered during the produc-

tion process.

Firstly, the sensor and membrane were

exposed to a sample of THF solvent at

ambient temperature over a period of

days. No ill-effects were reported by this

exposure, so this was followed by testing

the sensor in THF at reaction temperature

(55 °C) for a further time period. As this

was also successful the customer finally

tested the system with a portion of catalyst

added to the THF solution.

It was found that over the course of the

testing that the membrane presented well

and maintained a satisfactory measure-

ment performance throughout.

In addition to this positive outcome, the

chemists were able to discover interesting

information about how long it actually

took to purge a solvent medium with

nitrogen (much longer than they antici-

pated). They also gained knowledge on

how oxygen-sensitive catalysts react to the

presence of oxygen and their capacity to

perform after exposure to the gas.

www.mt.com/DO


THORNTON Leading Pure Water Analytics

Wat

er V

alid

atio

n

and in economic terms. Measurement of

TOC and conductivity also makes it pos-

sible to assess the performance of a

purified or ultrapure water purification

and distribution system.

Consequently, the American Pharma-

copoeia (USP < 643 >) and the European

Pharmacopoeia (EP 2.2.44) have defined

a test for measuring TOC that makes it

possible on the one hand to evaluate the

capacity of a system to measure TOC, and

on the other to determine the conformity

of a pharmaceutical water to their require-

ments.

USP < 643 > and EP 2.2.44 apply to puri-

fied water (PW), highly purified water

(HPW) and water for injection (WFI).

With regard to TOC measurement the ne-

cessities of these two pharmacopoeias

precisely define the requirements for cor-

rect measurement carried out on

pharmaceutical water.

Our customer was looking for a simple

installation enabling the simultaneous

measurement of conductivity and TOC to

replace the two systems they had been

using. In addition, TOC measurement

would have to be carried out virtually in

real time, as the previous system required

20 minutes before an accurate result

could be obtained, leading to a huge loss

of water and valuable technician’s time.

Effective solutionMETTLER TOLEDO proposed a conductiv-

ity and TOC solution comprising the

following Thornton components:

n Smart conductivity sensor

n 5000TOC TOC sensor

n 770MAX transmitter

The customer fitted the conductivity sen-

sor upstream of the TOC sensor and used

the multi-channel, multi-parameter

benefits of the 770MAX transmitter to

connect both sensors.

Validate CIP Final RinseWhile Saving on Water and MaintenanceThe validation of final rinse water quality in a CIP procedure is essential

and should be carried out very rapidly to avoid water loss. A Mettler-

Toledo Thornton system ensures fast, accurate determination of

conductivity and TOC, significantly reducing wasted water and time.

CIP procedureCIP cycles are critical procedures in the

pharmaceutical industry and involve the

cleaning of lines or formulation vats. The

equipment is cleaned using acid and base

solutions and then rinsed with purified

water.

The purpose of the CIP procedure is to

obtain a final rinse water of the quality of

purified water in terms of conductivity

and Total Organic Carbon (TOC). The fi-

nal rinse is validated only if the rinse

water attains limits of less than 1.3 μS / cm

at 25 °C for the conductivity measurement,

and 500 ppb of TOC. These are thresholds

defined in order to conform to the USP

< 645 > specifications for conductivity

and USP < 643 > for TOC with respect to

purified water.

Our customer is a pharmaceutical labora-

tory that wished to validate the quality of

its final rinse water downstream of an

in-line CIP process.

RequirementsThe water used in the pharmaceutical

industry should respond to very strict

quality requirements. Measurement of

TOC and conductivity are indispensable in

the detection of impurities that are capable

of contaminating batches of pharmaceu-

ticals or degrading water purification

systems. Both cases can involve significant

losses both in production quality levels Total Organic Carbon Sensor 5000TOC e


Compact, rapid system One single transmitter makes it possible to

measure two parameters simultaneously:

conductivity and TOC. The 770MAX also

manages the water supply valve of the TOC

sensor. Alarms can be programmed

thanks to the USP limits integrated in the

software.

TOC measurement is achieved in only one

minute, enabling time-savings in rinsing

and almost real-time validation of con-

ductivity and TOC.

Product updateThe 5000TOC has now been superseded by

the 5000TOC e. Physical and software

improvements mean that the new model

is even more reliable and robust than the

previous version.

Discover more at:

The water supply valve to the 5000TOC is

controlled based on the measurement

from the conductivity sensor. When the

conductivity of the rinse water decreases

below 100 μs / cm, the water supply valve

for the TOC sensor opens. Likewise it shuts

when conductivity exceeds the set limit.

Control of the electrovalve makes it pos-

sible to ensure that the TOC sensor will

never be degraded by excessively con-

taminated water (contaminated water can

reach a conductivity in excess of

1000 μs / cm). Once the supply valve to

the 5000TOC is open, evaluation of the

rinse water takes place in less than one

minute.

Now, contrary to the previous situation,

our customer has found that loss of

enormous quantities of water by waiting

for the TOC analyzer to deliver its mea-

surement, has been avoided.

One transmitter for multi-parameters

The 770MAX transmitter is a multi-parameter instrument de-signed for a broad range of measurement sensors.

A single transmitter for up to six inputs saves panel space and lowers the cost per mea-surement.

Find out how the 770MAX can improve water analysis at your facility, at:

Best Practice

www.mt.com/770MAX

www.mt.com/5000TOC

Transmitter 770MAX


Plug and Measure

Inte

lligen

t Sen

sor M

anag

emen

t Intelligent Sensor Management Reduces Life Cycle Costs and Improves Process Safety

Intelligent Sensor Management (ISM)ISM reduces the installation, maintenance and calibration effort for METTLER TOLEDO’s digital sensors to a minimum. This considerably im-proves process reliability, productivity and system availability.

Reliable installationDigital communication between sensor and transmitter means signal is always reliable and unaffected by moisture.

Intelligence – starts in the headISM sensors are equipped with integrated elec-tronics in the sensor head that store all relevant sensor parameters and includes algorithms for enhanced sensor diagnostics.

Predictive maintenanceIntelligent diagnostics information is calculated and displayed on the sensor’s transmitter and tells you if the sensor needs maintenance or replacement – no more downtimes due to sen-sor failure!

System integrationKey ISM parameters can be fully integrated in a process control system via PROFIBUS® PA or FOUNDATION Fieldbus™.

■ Sensors are immediately recognized when connected to the transmitter – eliminating difficult configuration procedures.

■ Operational availability of measurement point within seconds.

■ Wireless module available for transmission from sen-sor to transmitter – no need for costly cable installation.

■ Sensors can be pre-calibrated in the lab and stored for later use, saving time and increasing operational avail-ability.

METTLER TOLEDO’s ISM product range includes…

… a wide range of sensors for … advanced single- and multi-channel transmitters … software applications ■ pH ■ 4-wire ■ iSense Asset Suite ■ dissolved and gaseous O2 ■ 2-wire ■ pH data logger ■ conductivity ■ wireless module ■ turbidity


Intelligent Sensor Management Reduces Life Cycle Costs and Improves Process Safety

Diagnostics Maximum Performance

■ Any sensor maintenance requirement is recognized at an early stage, reducing downtimes and minimizing plant operation costs.

■ Dynamic Lifetime Indicator estimates in real time the remaining lifetime of the sensor.

■ CIP / SIP cycles counted automatically.

■ Sensor spider diagram for fast troubleshooting.

■ iSense Asset Suite software offers you a unique means of optimizing the performance of ISM sensors for en-hanced reliability and process safety.

■ Key Performance Table enables you to evaluate the condition of an ISM sensor at a glance, without the need of a transmitter.

■ Documentation of every calibration as well as the entire sensor history – documentation requirements to regu-latory standards are easily met.

METTLER TOLEDO’s ISM product range includes…

… a wide range of sensors for … advanced single- and multi-channel transmitters … software applications ■ pH ■ 4-wire ■ iSense Asset Suite ■ dissolved and gaseous O2 ■ 2-wire ■ pH data logger ■ conductivity ■ wireless module ■ turbidity

Intelligence starts in the head

www.mt.com / ISM

Visit for more informationwww.mt.com/pro

Complete Traceabilityfor pH and DO Sensors Effective sensor and calibration documentation is critical but very time consuming, especially for GMP processes. METTLER TOLEDO Intelligent Sensor Management (ISM) technology, together with our iSense software, can greatly improve the traceability and simplify the documentation for pH and oxygen measurement points. With iSense, only sensors that have been fully tested and documented can be released for your next batch. Complete information for all sensors e.g. calibration values, number of CIP / SIP cycles and serial number, are available for your validation guidelines. ISM sensors monitor themselves during the batch for abnormal sensor conditions and speed corrective action.

www.mt.com/ISM

Get in-line with METTLER TOLEDO

Mettler-Toledo Ingold, Inc. 36 Middlesex TurnpikeBedford, MA 01730, USATel: +1 781 301 8800Fax: +1 781 271 0681Toll Free: 1 800 352 8763Email: [email protected]

Mettler-Toledo Thornton, Inc. 36 Middlesex TurnpikeBedford, MA 01730, USATel: +1 781 301 8600Fax: +1 781 271 0214Toll Free (USA): 1 800 510 PUREEmail: [email protected]

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