Moisture Affecting Your Measurements? The Answer Is Digital

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1 Pharmaceutical Perspectives in Liquid Process Analytics Moisture Affecting Your Measurements? The Answer Is Digital 15 News INGOLD Leading Process Analytics THORNTON Leading Pure Water Analytics A 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 manufacture compounds and active principles for the cosmetic, pharmaceutical and nutrition industries, peptones and protein hydrolysates for bio-industry, and microbiological 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 m 2 site at Beauvais near Paris which specializes in fermentation, enzymatic hydrolysis, purification extraction, grinding and compounding. Peptones At 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 before being cooled. During the process, which can last several hours, ph must be strictly controlled in order to ensure optimal process conditions. However, the production team was not satisfied with the performance of their ph measuring system. Challenging conditions With their previous ph installation Solabia encountered problems when calibrating electrodes due to the great deal of condensation moisture produced during the hot-cold process. In addition, the humid conditions were testing for the cables and couplings.

2 Best Practice Requirements Solabia 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 information 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 equipment InPro 3253 i electrode The 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 biotechnological 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 reference 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 temperature sensor ensure the ph reading is always accurate. Further, the membrane 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, maintenance and calibration effort for METTLER TOLEDO s digital sensors to a minimum. This considerably improves reliability, productivity and system availability. Find out how ISM can help you, at: n Wide range of applications: Designed for use in mixers, receiving vessels, open tanks and fermentation installations in up to 4 bar overpressure. n Simple maintenance: Totally autoclavable or sterilizable in situ (sterilization possible up to 140 C) Publisher / Production Mettler-Toledo AG Process Analytics Im Hackacker 15 CH-8902 Urdorf Switzerland Illustrations Mettler-Toledo AG Solabia S.A.S. Boehringer Ingelheim GmbH Noltelourens Dreamstime.com Subject to technical changes. Mettler-Toledo AG 12/09 Printed in Switzerland. ph electrode InPro 3253 i Transmitter M400 2 METTLER TOLEDO Pharmaceutical News 15

3 M400 transmitter This is a single-channel, multi-parameter transmitter for measurement of ph / redox, ph ISFET, oxygen, dissolved CO 2 or conductivity. 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 signal The 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 measurement signal to a digital one. As low-impedance digital signals are unaffected by moisture, and data loss from sensor to transmitter is exceptionally low, humidity and cable length are not a problem. Highly satisfied customer The 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 deterioration 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: i Measure Oxygen Where It Really Matters Directly in Your Process Performance 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. O2 Measurement Unwanted oxygen Oxygen 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 oxidation. Not only is oxygen monitoring a critical issue in transport systems, storage tanks or centrifuges, it can also negatively affect the yield of a chemical reaction in a vessel. Many solutions which is best? When selecting a vendor for a measurement system, technologies and solutions abound, but in many cases a trade-off 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 reliable Looking at the field of dissolved oxygen measurement however, membrane-based 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 biopharmaceutical 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 comprehensive range of amperometric systems with sensors for wide application coverage, re- METTLER TOLEDO Pharmaceutical News 15 3

4 F Best Practice tractable housings for sensor extraction without process interruption, and transmitters for signal conversion and connection to process control systems using HART, FOUNDATION fieldbus or PROFIBUS. Naturally, the complete measurement system is available with ATEX Zone 1 / FM Class 1 Div 1 approval if required. 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 processes All 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 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 management. 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 O 2 measurement at your facility, go to: Reduce expenditure, reduce risk Most installed gaseous O 2 measurement systems are based on expensive paramagnetic or zirconium 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 O 2 systems are based on inexpensive amperometric technology and require 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: N 2 in O 2 Paramagnetic system METTLER TOLEDO solution The sample path through a paramagentic system is long and slow. The METTLER TOLEDO solution measures directly in the vessel immediately. 4 METTLER TOLEDO Pharmaceutical News 15

5 More Product, Less Water Loss Precise Phase Separation Identification with New Intelligent Conductivity Sensors Without 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 reliable To help ensure you are maximizing yield and optimizing water consumption in your processes, you need accurate phase separation detection equipment. New intelligent conductivity sensors from METTLER TOLEDO the InPro 7100 i series ensure fast, accurate phase separation identification. Hygienic design supports high process safety in pharmaceutical applications, with the PEEK shaft material offering superior resistance against CIP cycles. Easy process integration Due 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 extensive range of process applications and makes installation into existing processes simple and cost effective. ISM technology for conductivity With the new i suffix conductivity sensors we extend METTLER TOLEDO s wide range of instruments featuring our proprietary 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 combination 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 humidity or cable length. Discover more at: Benefits of the InPro 7100 i Suitable for a wide variety of applications: 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 METTLER TOLEDO Pharmaceutical News 15 5

6 DO Measurement in O2-sensitive Reactions Accurate DO Measurement in Aggressive Solvents A 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 reactions Monitoring dissolved oxygen levels in oxygen-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 nitrogen 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 recommendation, but it is not often measured using analytical techniques. Our customer, a key chem-pharma company, wanted to find a better method. Dissolved oxygen sensors and the solubility factor Traditionally, 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 (C L = po 2 3 a) can be very different to water, so the readings displayed on the transmitter have to either be converted using known literature values for a particular solvent, or just taken as a dimensionless number and used relatively. Best Practice In-line measurement means optimized production and lower operating costs The continuous stream of data that in-line measurement provides 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: Transmitter M400 DO sensor InPro 6850 i 6 METTLER TOLEDO Pharmaceutical News 15

7 Considering that dissolved oxygen membrane 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 chempharma company in question decided to carry out trials with a METTLER TOLEDO InPro 6850 i DO sensor with T-96 membrane and Kalrez O-rings, and an M400 transmitter. Demonstrating T-96 membrane ability in solvents The trials involved subjecting the sensor to the various reaction conditions that would be encountered during the production 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 measurement performance throughout. Increased productivity reduced waste This 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. Conclusion Due to the success of the study our customer 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 considered 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 measuring the presence of oxygen in non-aqueous solvents, and is considering further METTLER TOLEDO systems for other catalytic reaction vessels at their production site. 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 anticipated). 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. Find the right DO sensor for your application at: Kalrez is registered trademarks of E. I. du Pont de Nemours and Company. METTLER TOLEDO Pharmaceutical News 15 7

8 Water Validation Validate CIP Final Rinse While Saving on Water and Maintenance The 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. THORNTON Leading Pure Water Analytics CIP procedure CIP 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 final 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 laboratory that wished to validate the quality of its final rinse water downstream of an in-line CIP process. and in economic terms. Measurement of TOC and conductivity also makes it possible to assess the performance of a purified or ultrapure water purification and distribution system. Consequently, the American Pharmacopoeia (USP < 643 >) and the European Pharmacopoeia (EP ) 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 requirements. USP < 643 > and EP apply to purified water (PW), highly purified water (HPW) and water for injection (WFI). With regard to TOC measurement the necessities of these two pharmacopoeias precisely define the requirements for correct 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 solution METTLER TOLEDO proposed a conductivity and TOC solution comprising the following Thornton components: n Smart conductivity sensor n 5000TOC TOC sensor n 770MAX transmitter The customer fitted the conductivity sensor upstream of the TOC sensor and used the multi-channel, multi-parameter benefits of the 770MAX transmitter to connect both sensors. Requirements The 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 pharmaceuticals or degrading water purification systems. Both cases can involve significant losses both in production quality levels Total Organic Carbon Sensor 5000TOC e 8 METTLER TOLEDO Pharmaceutical News 15

9 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 possible to ensure that the TOC sensor will never be degraded by excessively contaminated 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 measurement, has been avoided. 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 conductivity and TOC. Product update The 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: Best Practice One transmitter for multi-parameters The 770MAX transmitter is a multi-parameter instrument designed for a broad range of measurement sensors. A single transmitter for up to six inputs saves panel space and lowers the cost per measurement. Find out how the 770MAX can improve water analysis at your facility, at: Transmitter 770MAX METTLER TOLEDO Pharmaceutical News 15 9

10 Intelligent Sensor Management 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 improves process reliability, productivity and system availability. Reliable installation Digital communication between sensor and transmitter means signal is always reliable and unaffected by moisture. Plug and Measure Sensors are immediately recognized when connected to the transmitter eliminating difficult configuration procedures. Operational availability of measurement point within seconds. Intelligence starts in the head ISM sensors are equipped with integrated electronics in the sensor head that store all relevant sensor parameters and includes algorithms for enhanced sensor diagnostics. Predictive maintenance Intelligent 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 sensor failure! System integration Key ISM parameters can be fully integrated in a process control system via PROFIBUS PA or FOUNDATION Fieldbus. Wireless module available for transmission from sensor 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 availability. METTLER TOLEDO s ISM product range includes a wide range of sensors for ph dissolved and gaseous O 2 conductivity turbidity 10 METTLER TOLEDO Pharmaceutical News 15

11 Intelligence starts in the head / ISM 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 enhanced 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 regulatory standards are easily met. advanced single- and multi-channel transmitters 4-wire 2-wire wireless module software applications isense Asset Suite ph data logger METTLER TOLEDO Pharmaceutical News 15 11

12 Get in-line with METTLER TOLEDO Complete Traceability for 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. Mettler-Toledo Ingold, Inc. 36 Middlesex Turnpike Bedford, MA 01730, USA Tel: Fax: Toll Free: mtprous@mt.com Mettler-Toledo Thornton, Inc. 36 Middlesex Turnpike Bedford, MA 01730, USA Tel: Fax: Toll Free (USA): PURE mtprous@mt.com Visit for more information