News. Pharmaceutical. Greater Process Availability in Lysine Production. Perspectives in Liquid Process Analytics INGOLD THORNTON

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1 Pharmaceutical Perspectives in Liquid Process Analytics Greater Process Availability in Lysine Production 16 News INGOLD Leading Process Analytics THORNTON Leading Pure Water Analytics Successful manufacture of lysine relies on strict control of dissolved oxygen (DO). For one of the world s largest lysine producers, switching to optical DO measurement has resulted in increased process availability and less maintenance. Lysine demand World production of lysine as an additive in animal feed has seen enormous growth since it was first introduced in the early 1960s. Estimates put current global production at 1.2 million tons with an annual increase of around 8 %. Lysine is manufactured today almost exclusively by fermentation processes, normally using Corynebacterium glutamicum bacteria or a related strain. Leading producer Our customer is one of the world leaders in the production of lysine and other amino acids as food additives for livestock. At their production facility in Brazil they employ METTLER TOLEDO measuring systems to monitor ph, redox, conductivity and DO throughout production. Application During fermentation the bacteria consume sugars and oxygen enabling them to produce the enzymes required for the fermentation process. The level of dissolved oxygen in the medium is crucial as too low a level results in anaerobic fermentation and hence the production of unwanted ethanol. It is not only a minimum concentration of dissolved oxygen that is important but also a maximum. If an optimum dissolved oxygen level is maintained, only the necessary amount of oxygen is injected into the reactor, with the advantage of lowering power consumption for air compressors.

2 The heart of the InPro 6880 i optical DO sensor Optical measurement technology Amperometric measurement technology in the Pharmaceutical industry is well established due to its broad application coverage. Nevertheless, over time there has been an increase in the demands on measurement systems to be more efficient, in need of less maintenance, to operate for longer periods between calibrations and be easier to use. This led METTLER TOLEDO to develop a sensor that utilizes the process of fluorescence quenching to measure DO the InPro 6880 i. At the tip of the sensor, marker molecules embedded in a matrix are able to modify their fluorescence behavior according to the concentration of dissolved oxygen present in the media. Using this principle, measuring DO is fast and precise, and the marker molecules are extremely resistant to the influence of the media of SIP cycles. A further advantage of the InPro 6880 i is that no electrolyte or membrane is required. Instead, it is the sensing element housing the matrix, the OptoCap, which takes over these roles. The absence of electrolyte means that liquid handling and the risks of wrong operation associated with it, can be forgotten. And because of its very simple design, the OptoCap can be exchanged in seconds. Built-in intelligence METTLER TOLEDO's extensive knowledge of the ever-changing requirements for increased performance and regulatory compliance in biotechnology led to the development of our Intelligent Sensor Management (ISM) concept. Measurement systems equipped with ISM monitor themselves for sensor wear and performance. This enables users to make a real-time assessment of sensor state based on diagnostic tools such as the Dynamic Lifetime Indicator. Pre-emptive corrective maintenance can be performed on a sensor before initiating a batch, eliminating the potential for sensor failure during the process. Easy sensor management Sensor status can also be easily monitored using our isense Asset Suite software and a PC or laptop. Connecting the InPro 6880 i to isense via USB provides access to not just analysis tools, the software also allows DO ISM sensors to be calibrated conveniently in the lab prior to installation to verify correct operation. After sterilization, sensors can be calibrated as usual at the measuring point. More process uptime Though our customer was very pleased with the performance of the non-ism InPro 6800 DO sensor that they had been using, the advantages of greater process availability due to diagnostic tools, lower maintenance and recording of calibration convinced them to upgrade to the InPro 6880 i for DO measurement in lysine fermentation. The facility is now considering switching to ISM systems for ph measurement. Publisher / Production Mettler-Toledo AG Process Analytics Im Hackacker 15 CH-8902 Urdorf Switzerland To benefit from optical DO measurement at your production plant, go to: Illustrations Mettler-Toledo AG Suncombe Ltd Siemens-Ionpure Sufi70 Dreamstime.com Subject to technical changes. Mettler-Toledo AG 07/10 Printed in Switzerland. InPro 6880 i DO sensor 2 METTLER TOLEDO Pharmaceutical News 16

3 InPro 4800 ph Electrode Portable ph System Solves Measurement Issue in API Pilot Plant Using a mobile in-line ph system to control reactions in an API pilot plant demands a robust ph electrode with the flexibility for use on a variety of vessels. METTLER TOLEDO provided a leading pharmaceutical company with the ideal solution. API developer Our customer, one of the world s largest pharmaceutical companies, has a regional research and development base in the UK. This includes a pilot plant facility that concentrates on developing active pharmaceutical ingredients (APIs) via chemical synthesis. Work carried out on the site involves leading an API from development work, through clinical trials to the ultimate goal of taking the product to market. Delay in measurement The customer has more than 20 vessels of varying capacity that are used for development chemistry projects. Depending on the composition and synthesis steps involved, measurement of ph is an important consideration for many of the reactions. In the past, ph measurement had been achieved by taking grab samples from the process and measuring them using a laboratory ph meter. This practice was inefficient as the time taken to obtain ph readings led to delays in making additions to achieve the target ph. This ultimately led to longer batch times and created delays in the tight schedule of project throughput of the plant. Importance of flexibility In order to improve ph measurement during pilot plant projects, our customer discussed with METTLER TOLEDO technicians the possibility of measuring ph in-line with a mobile unit. Our customer was looking to achieve a reliable ph measurement in a potentially wide range of chemistry projects. The ultimate goal was to use ph to control dosing pumps to achieve a specific setpoint. Flexibility was another key to the success of the installation as the unit would only be utilized effectively if it could operate on the majority of the vessels in the pilot plant. Flexible and robust solution METTLER TOLEDO suggested using an InPro 4800 ph electrode in combination with an InFit 763 e housing and M700 transmitter. The housing allows the ph sensor to access the majority of the vessels using a flange connection. The InPro 4800 electrode s record as a top of the line combination ph and temperature sensor means that it has been designed to handle high pressure and temperature applications and has a strong resistance to oxidizing media, solvents and acid / alkali solutions. METTLER TOLEDO Pharmaceutical News 16 3

4 The M700 transmitter, which completes the measurement system, was installed with a PID module that controls two dosing pumps to facilitate neutralization reactions. The ph equipment including dosing pumps was located on a mobile skid that can be moved to any part of the plant when required. As all of the components of the system are ATEX rated we achieved the customer s expectation of a fully flexible ph measurement system. There has been such a high demand for use of the mobile ph system among chemists working on a variety of projects, that an order has been placed for a second system to work alongside the existing unit. Find the right ph measurement system for your facility, at: InPro 4800 ph electrode Enhanced Reliability with Digital Sensors ph and DO The risk of human error for pharmaceutical manufacturers does not just apply to production. Inadequate measurement system documentation can be a significant headache. For a Chinese API producer, the advantages of digital sensors and asset management software were obvious time saved, simpler maintenance and documentation at the touch of a button. Chinese API producer Zhejiang Hisun Pharmaceutical Co. Ltd. was established in It is located in Taizhou, an emerging port city in the middle of China s south-eastern coast. Hisun produces a diverse range of products including anti-tumor, cardiovascular, anti-infection and immunosuppressant treatments. The company actively explores overseas markets and has established strategic cooperative relationships with Lily, Pfizer, Merck and Bayer amongst others. ph and DO measurement During the fermentation stages of pilot testing and production, Hisun pay particular attention to maintaining the correct ph and DO levels due to the considerable influence these parameters have on fermentation yield. For ph and DO measurement, Hisun have used in-line measurement systems from METTLER TOLEDO for many years. Over this period, Hisun purchased InPro 3253 ph electrodes, InPro 6800 DO sensors and the corresponding transmitters, and they were very satisfied with the performance of the systems. However, asset management of the sensors was problematic and calibration records were kept in notebooks which could easily be misplaced. Due to there being too many human factors it was impossible to understand in detail the use of each electrode and sensor. As a result, there was often no time to purchase spare parts when it came to replacement and the facility had no contingency in this regard. 4 METTLER TOLEDO Pharmaceutical News 16

5 Best Practice Stay one step ahead of maintenance with ISM From analog to digital In 2009, Hisun began making the switch from METTLER TOLEDO s analog sensors to our digital Intelligent Sensor Management (ISM) sensors. The features of ISM were exactly what Hisun required. A microprocessor in the head of each ISM probe stores all relevant sensor and calibration data as well as the measurement values recorded during the process. The data is transmitted digitally to an ISM compatible transmitter which displays diagnostic information on the condition of the sensor. This allows engineers to quickly determine if a probe requires cleaning, calibration or has to be replaced before the next batch starts; making maintenance planning and stock control significantly easier. pleased with the new system. In the past, operators conducted calibration using buffer solutions at site which was often polluted, and the calibration result was not particularly satisfactory. Now that calibration can be conducted using the isense software, we only need to bring the sensor to the workroom for calibration. The software is easy to operate and saves a great deal of time. As Hisun continue to make the switch from analog to digital in-line measurement sensors, they will benefit further from predictive maintenance and competent sensor asset management, and can put their calibration notebooks in the wastebasket. Intelligent Sensor Management (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. Find out how ISM can help you, at: Discover more about intelligent sensors and isense, at: isense Asset Suite Of even greater use to Hisun is the isense Asset Suite software for ISM sensors. With isense, a record of every sensor calibration as well as the entire history of each sensor used at the facility is stored in the software. With complete and reliable documentation for each sensor easily accessible, requirements of regulatory standards are simply met. Sensor documentation is not the only function of isense. The software performs accurate pre-calibration in the lab, which yields better sensor performance in the process and also means that pre-calibrated probes can be stored for quick exchange later. Li Hui, Technology Center Measurement Supervisor at Hisun is InPro 6850 i DO sensor InPro 3253 i ph electrode METTLER TOLEDO Pharmaceutical News 16 5

6 InTrac Housings Better Process Safety, More Uptime with Retractable Housings If you have processes that run over extended periods or where sensor contamination is a concern, retractable housings allow easy and safe sensor access without process interruption. That means process safety is ensured and uptime increased. Concept The idea behind InTrac retractable housings is to offer enhanced reliability and operational safety and increased process uptime, plus significantly reducing measuring point operating costs. InTrac housings have been designed for use in demanding applications in the Pharmaceutical industry where the use of ph/orp, DO, conductivity and turbidity sensors is necessary to control and monitor process conditions. High safety Central to the design of InTrac housings are the Tri-Lock safety features: sensor detector, safety immersion tube and positive position locks. All of which have been designed to avoid unintentional release of process fluids. The sensor detector prevents the housing from being inserted without a sensor being present. The patented immersion tube seals the housing from the process at all times during operation, and the positive position locks always keep the sensor in an optimal measuring position. Complete separation of the sealing and bearing functions improves operation and reliability even in highly contaminating applications. In combination with an EasyClean cleaning and calibration system, a fully automated measuring system is available, bringing about a substantial reduction in operating costs. For sterile conditions InTrac 797 e has been designed specifically for the highest demands of the Pharmaceutical industry. This housing features a double flushing chamber to allow sterilization of the upper and lower sections of a sensor and the insertion shaft. Thus allowing removal and replacement of the sensor in a completely sterile environment. If process safety and increased uptime is important to you, go to: InTrac 797 e retractable housing 6 METTLER TOLEDO Pharmaceutical News 16

7 O2 Measurement Adding Safety and Efficiency to Your Inertization Process When handling potentially explosive substances in your manufacturing process, limiting the level of oxygen is the method of choice for ensuring safety. For continuous and direct in-situ oxygen measurement, the InPro 6850 i G sensors offer an industry-proven and reliable solution. Primary concern: safety Having vapors of flammable liquids or dusts exposed to air in a tank or vessel can be a major safety hazard. This is why a limiting oxygen concentration (LOC) must be determined for each particular application. Keeping the vessel safely below the predefined LOC level often relies on injecting additional inert gas to reduce the oxygen to nitrogen ratio to an acceptable level, adding a safety factor of usually a few % oxygen. How much purging is really needed? The purging is usually done by letting nitrogen flush either continuously or when a specific, fixed overpressure level is reached. Both techniques however are indirect and rely on assumptions on what the effective oxygen to nitrogen ratio in the vessel is, and on maintaining this ratio throughout all the process states of filling and emptying the vessel. So, in order to keep the vessel safe at all stages, very often too much nitrogen is consumed. Measure oxygen where it really matters With a measurement system based on the InPro 6850 i G amperometric oxygen sensor, the true oxygen concentration in the vessel can be measured in-line, continuously. By controlling oxygen, nitrogen purging can be contained and inert gas consumption optimized. Amperometric oxygen sensors convince through their excellent price / performance ratio, and their minimized maintenance time of only two minutes. Intelligent sensors The InPro 6850 i G sensor features Intelligent Sensor Management (ISM) technology for better measurement reliability and predictive maintenance. Digital ISM sensors monitor their own status in real time for early signs of wear and preempt maintenance requirements. Oxygen sensor InPro 6850 i G Benefits True in-line oxygen measurement j Direct oxygen determination in the vessel improves process safety Efficient operation j Continuous oxygen measurement in the vessel helps to keep inert gas consumption to a minimum Easy maintenance j Two-minute membrane exchange can be done at the measurement point Fast, easy calibration j One-point calibration in air requires no specialist skills or expensive calibration gases Predictive maintenance j ISM technology for enhanced reliability and advanced maintenance Excellent value j Extremely attractive price / performance ratio Learn more at: METTLER TOLEDO Pharmaceutical News 16 7

8 Purified Water Greentech Biopharmaceutical Water System Pharmaceutical Grade Waters Purity Without Chemicals Siemens-Ionpure is leading the way in high purity water production by effectively using Continuous Electrodeionization (CEDI) technology to purify pharmaceutical grade waters, thereby eliminating the use of chemicals and reducing energy costs. For monitoring water purity and system efficiency, Siemens-Ionpure trust Thornton. CEDI technology Electrodeionization theory, design and operating conditions were first investigated in the 1950s as a method to improve deionization, the final stage of water purification. The technology was commercialized in 1987 by US company Ionpure, now part of the Siemens group, using electric potential to facilitate the transfer of ions from alternating purified (dilute) compartments into waste (concentrated) compartments. The collected stream from the dilute compartments produces highly purified water without the need for regenerant chemicals. Today, Ionpure CEDI module technology is leading the way in pharmaceutical water with instant hot water sanitization for maximum system uptime. Hot water, in place of previously required chemical sanitants, is used for the control of microbial growth that can develop during the water purification process. CEDI is an environmentally green solution allowing chemical-free regeneration and sanitization. Innovative system Siemens innovative PreVUE systems integrate a pretreatment filter, RO membrane and an Ionpure CEDI module into one unit. The complete system can be hot water sanitized without the need for chemicals in controlling microbial growth in a validated pharmaceutical system. The PreVUE system is a closed loop in design. There is no reason to open valves or a process pipe to inject chemicals or measure samples, which can introduce particles into the process and risk contamination. Thornton M300 series in-line measurements are installed directly in the process stream for real-time measurement and control. According to John Yen, Global Director of Product Marketing at Siemens Water Technologies, CEDI carbon footprinting is a fraction of the cost of other water purification technologies, and the resulting waste is neutral in the end. Now we can reclaim and reuse valuable chemicalfree water from the end of treatment train by recycling it back into the pretreatment cycle for purification. A Siemens-Ionpure LX-HI module Ionpure Products relies on Mettler-Toledo Thornton resistivity measurements on all CEDI module quality control stations to ensure module performance on startup. Yen continues, All of our CEDI control test stands from the lab flow range to the pharmaceutical LX-HI module incorporate Mettler-Toledo Thornton resistivity monitoring. Thornton instrumentation and sensors are simple enough to set and forget. We re very impressed with the accuracy and reliability of the Thornton instrumentation and consider Thornton a long term partner. To find out how Thornton instrumentation can validate your pure water production, go to: Ionpure and PreVUE are trademarks of Siemens its subsidiaries or affiliates. 8 METTLER TOLEDO Pharmaceutical News 16

9 Conductivity in CIP Clean in Place Systems Manufacturer Relies on METTLER TOLEDO In-line conductivity measurement technology plays an essential role in the efficient operation of Clean in Place (CIP) systems, ensuring the highest possible levels of cleanliness as well as optimal control over the cleaning solutions. A leading manufacturer of CIP systems has selected Thornton conductivity instrumentation for their performance and reliability. Leading process engineers Suncombe Ltd is one of the UK s leading mobile Clean in Place systems manufacturers and hygienic process engineers. Established in 1961 they have a wealth of knowledge in designing and manufacturing cleaning and hygienic process technology for the BioPharma, Food and other hygiene critical industries. Suncombe s products are supplied to UK, European and international companies who demand high quality, reliable CIP systems. CIP application The CIP cleaning procedure is a multistep process. Wash solutions are prepared in storage tanks and used in specific recipes to carry out the cleaning of vessels or pipework, etc. A final rinse with pure water takes place at the end of the cycle. Control of various process stages such as start of dosing of alkaline or acid, or rinsing with water is carried out effectively using in-line conductivity measurement. The system detects the conductivity of the solutions and provides outputs to the local process control system to manage the CIP programme. New mobile CIP system When Suncombe launched its latest range of portable CIP systems, it required the highest standard of instrumentation. Dave Adams, director at Suncombe, said, Our CIP systems are designed to incorporate top quality equipment to ensure that they provide reliable results in every use. We selected Mettler-Toledo Thornton to provide conductivity instrumentation on our MobileCIP systems, as we use their products extensively with excellent results. We view METTLER TOLEDO as an excellent strategic partner for our systems as they provide excellent service and support. Conductivity equipment expectations The conductivity instrumentation in mobile CIP systems for pharmaceutical customers requires a number of conditions including: j Tri-Clamp sensor connections j Conductivity ranges from 0.01 us / cm to 500 ms / cm j Material certificates for wetted parts j Panel mount transmitters providing analog outputs for both temperature and conductivity j Sanitary designed sensors METTLER TOLEDO solution METTLER TOLEDO provided a conductivity system using the M300 dual-channel conductivity transmitter. This allows two conductivity sensors to be connected to the same transmitter. The M300 comes in two convenient sizes, ¼ DIN specifically for panel mount applications and ½ DIN for field, post or wall mount applications. The system uses a Thornton 2-pole conductivity sensor for final rinse control as well as a Thornton 4-electrode conductivity sensor for cleaning agent control. Both of the sensors are hygienically designed and have Tri-Clamp process connections as well as 3.1 B material certificates to satisfy the requirements of the Pharmaceutical industry. If you are looking for high-quality conductivity instrumentation, visit: MobileCIP is a trademark of Suncombe Ltd A Suncombe MobileCIP system METTLER TOLEDO Pharmaceutical News 16 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 j Sensors are immediately recognized when connected to the transmitter eliminating difficult configuration procedures. j 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. j Wireless module available for transmission from sensor to transmitter no need for costly cable installation. j 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 j ph j dissolved and gaseous O 2 j conductivity j turbidity 10 METTLER TOLEDO Pharmaceutical News 16

11 Intelligence starts in the head / ISM Diagnostics Maximum Performance j Any sensor maintenance requirement is recognized at an early stage, reducing downtimes and minimizing plant operation costs. j Dynamic Lifetime Indicator estimates in real time the remaining lifetime of the sensor. j CIP / SIP cycles counted automatically. j Sensor spider diagram for fast troubleshooting. j isense Asset Suite software offers you a unique means of optimizing the performance of ISM sensors for enhanced reliability and process safety. j Key Performance Table enables you to evaluate the condition of an ISM sensor at a glance, without the need of a transmitter. j 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 j 4-wire j 2-wire j wireless module software applications j isense Asset Suite j ph data logger METTLER TOLEDO Pharmaceutical News 16 11

12 Get in-line with METTLER TOLEDO Oxygen Gas Monitoring for Higher Quality, Greater Safety To ensure high product quality and safe production in processes requiring a permanent gas purge or head space blanketing, you need accurate and consistent oxygen gas measurement. METTLER TOLEDO s InPro 6850 i oxygen gas sensors are designed to help you develop processes that consistently ensure high quality products, manufactured safely. Unlike conventional gas analyzers, METTLER TOLEDO solutions can be installed in-line and do not require a sampling and conditioning system giving you maximum uptime and minimal maintenance. Mettler-Toledo AG Process Analytics Im Hackacker 15 CH-8902 Urdorf Switzerland Visit for more information