vessel to optimize microbial growth and metabolism. This requires an accurate and reliable in-line DO measurement system with high repeatability.

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1 Anhui BBCA Biochemical Co. Ltd. is one of the leading processing enterprises in China for the production of biochemical products. Established in 1998 in Bengbu, Anhui province the company employs over 10,000 people over a number of facilities. For the production of amino acids amongst other products, the company has developed low-temperature liquefaction, filtrate fermentation technology. In aerobic fermentation during amino acid production control, dissolved oxygen level is one of the most important parameters for maximizing production yield. Facility engineers at Anhui BBCA Biochemical need to ensure adequate but not excess oxygen (which would mean unnecessary use of air compressors) is being fed to the vessel to optimize microbial growth and metabolism. This requires an accurate and reliable in-line DO measurement system with high repeatability. Bing Dixiang, a technical engineer at Anhui BBCA Biochemical, was interested in comparing the performance of an optical DO sensor with the polarographic sensor they had been using. During fermentation, the dissolved oxygen level is more meaningful when it is a relative value rather than an absolute value. But this requires setting the dissolved oxygen fermented by different batches at the same value, so as to conduct comparison and analysis on the fermentation data. However, when the fermentation in each

2 tank is completed, the dissolved oxygen sensor will, to some extent, drift and the reading may be too high in some cases. This means that calibration of the DO sensor is required prior to loading each tank, which increases maintenance work and reduces productivity. And if the sensor membrane or electrolyte has been replaced, polarization time is required. I wanted to find out what advantages could be gained from using optical DO sensors instead. Bing Dixiang ran a six-month trial of a METTLER TOLEDO InPro 6880 i sensor and M400 transmitter. The probe utilizes the phenomenon of fluorescence quenching to accurately determine DO. Lightsensitive molecules embedded in the replaceable sensing element, the OptoCap, absorb light from the sensor s internal LED. After a fraction of a second, the molecules emit this light which is then detected by the sensor. Oxygen in the measuring media changes the behavior of the light-sensitive molecules. Based on this change, the sensor is able to determine the oxygen content of the media. One of the main advantages of this sensor design for Anhui BBCA Biochemical is the almost zero drift. According to our experience, for every 20 fermentation batches calibration is only required once, said Bing Dixiang. And as no electrolyte is involved, no polarization is required, increasing system availability and reducing time spent on maintenance. For Bing Diaxing, the advantages of the InPro 6880 i do not stop there. For fermentation processes in the high viscosity mediums we measure in, damage to the dissolved oxygen membrane of the polarographic sensors we use is a significant problem. Due to the rapid stirring speed and the viscosity, the sensor membrane has to be replaced after 12 batches or so. Also, because the cathode at the tip of the sensor is easily coated, the sensor will become slow in response and need replacing after approximately 18 months use. As the InPro 6880 i has no membrane, such problems are eliminated. The i in the sensor s name indicates that it is equipped with Intelligent Sensor Management (ISM) technology. ISM reduces maintenance of the InPro 6880 i still further by supplying real-time diagnostics which are displayed on the transmitter. The diagnostics data informs operators if the sensor needs maintenance or replacement, crucially before measurement is affected. Therefore, scheduled but perhaps unnecessary maintenance is avoided. The Dynamic Lifetime Indicator provides clear indication of the remaining life of an InPro 6880 i, meaning the risk of sensor failure during a fermentation run is minimal. Bing Diaxing is more than satisfied with the InPro 6880 i. We tested the METTLER TOLEDO optical dissolved oxygen sensor continuously for six months without any sensor response problems, and the OptoCap, which is the only consumable of this sensor, has not yet been replaced. Given its fast, stable performance and strong reproducibility, the InPro 6880 i will definitely help to improve our fermentation process control and raise the fermentation level. If you want to benefit from optical oxygen measurement at your facility, go to: c c

3 In striving to achieve the goals of PAT and QbD, in-line monitoring and subsequent control of CO 2, ph and temperature during fermentation processes can be of great value. Furthermore, analytical measurements are of enormous benefit in yield optimization and product quality assurance. Real-time, in-situ monitoring of the dissolved CO 2 levels in the fermentation medium allows timely actions for maintaining ideal process conditions. CO 2 measurement with the same family of sensors permits faster scale-up during process development, and quicker time to market for new products. The new InPro 5000 i is a fully sterilizablein-place and autoclavable in-line CO 2 sensor. It features a class N5 surface and EHEDG certification for compliance with hygienic requirements. The sensor s membrane provides an excellent barrier against volatile organic acids, ensuring errorless measurement. For measurement accuracy where it matters most, the InPro 5000 i CO 2 sensor is designed for direct mounting into fermenters. Its modular design makes maintenance and spare part replacement fast and convenient. The ideal housing for the sensor is the retractable InTrac 797 as its integrated flushing chamber allows easy sensor calibration and cleaning, even during a running fermentation. The InPro 5000 i is the latest member of METTLER TOLEDO s Intelligent Sensor Management (ISM) family of sensors and transmitters. Benefits of ISM include: j Predictive diagnostics: Determine whether a sensor can be safely used for the next fermentation run. j Sensor de-activation: Prevents a failed sensor being used at the measurement point. j edocumentation: Provides full traceability of sensor calibration and maintenance. j Digital sensor to transmitter signal: Measurement data is unaffected by cable length, interference or moisture in the environment. Find out more about the InPro 5000 i, at: c c

4 Química Montpellier S.A. is a pharmaceutical laboratory with production facilities in Buenos Aires, Argentina. Both its facilities and equipment at its manufacturing plant have been extensively refurbished, positioning it among the most modern pharmaceutical laboratories in South America. The company produces betamethasone injections, a corticoidsteroid used in the treatment of allergic reaction symptoms. The vials of betamethasone for injection combine soluble and insoluble forms of the active drug. The concentration and uniformity of the insoluble form (acetate or dipropionate) is determined by measuring samples in the lab. This is a time-consuming operation and does not confirm uniformity throughout a batch. Química Montpellier technicians wanted a method of measuring the concentration of the insoluble form at the filling line in a continuous way to ensure dose uniformity, without any risk of product contamination. As the only insoluble component of the formulation is the insoluble form of the active principle, the optical density of the medium is proportional to the concentration of the API. The InPro 8100 OD sensor utilizes backscatter light technology to measure particle concentration, and is very accurate over a wide measuring range. Combined with the Trb 8300 transmitter, the system is highly suitable for OD measurement in pharmaceutical applications. However, to ensure sterility of the solution, Química Montpellier technicians decided that using a sensor in line was unacceptable. METTLER TOLEDO, through its representative in Argentina, HITEC S.R.L realized that the betamethasone solution could be measured through glass before entering the vials, therefore avoiding contact with the sensor. To achieve this would require the flow of insoluble betamethasone being redirected to a glass tube placed inside a specially developed housing. The success of this solution would depend on the sensor s ability to accurately measure OD through the glass. After some research at HITEC s facility, a housing was developed that would hold the InPro 8100 at the optimal angle and encase the glass tube to prevent unwanted light ingress that would affect measure-

5 ment results. The system was installed and a test phase initiated. Results showed a very precise correlation between measurements from the new system and those obtained by the off-line method. Benefits of this system are numerous: continuous real-time data, assurance of betamethasone uniformity in every finished vial, instant detection of out-of-spec bulk suspension (eliminating incorrectly filled vials, reducing product loss and increasing the overall yield per batch), PAT initiative compliance through enhance- ment of process understanding, and time and cost savings from reduced lab measurements. Química Montpellier is more than satisfied with the OD system s performance. As well as the above benefits, technicians note that system maintenance is very low; the sensor rarely requires cleaning since coating and fouling do not occur. If accurate, real-time OD measurement is important at your facility, visit: c c j j j

6 Intelligent Sensor Management (ISM) technology not only offers precise measurement data, it also provides sophisticated real-time sensor diagnostics that inform you of remaining sensor life, and time until the next calibration or maintenance will be required. ISM-equipped transmitters from METTLER TOLEDO display this diagnostic information in real-time, providing continuous data on sensor condition at the measuring point. The real-time diagnostics and measuring information can be easily integrated into process control systems for convenient monitoring in control rooms. This allows technicians and managers to improve process control and to keep track of the health of sensors across an entire facility at the same time. Sensor diagnostics means that measurement point maintenance can now be managed more efficiently. Unplanned shutdowns due to unforeseen sensor failure no longer occur, and the resulting increase in process availability and reduced maintenance leads to improved productivity and lower operating costs. In addition, ISM sensors can be pre-calibrated in a maintenance shop and stored for later use. Together with Plug and Measure functionality this means that at the first sign that a sensor might be failing, a replacement can be installed and be operating within minutes. Plug and Measure ensures fast, simple and errorfree sensor installation and replacement. ISM offers the unique opportunity to not only transmit measurement data, but also real-time diagnostics information as well as characteristic sensor data to a process control system. This enables new process safety features such as sensor recognition and traceability as well as enhanced process reliability through real-time diagnostics information in the process control system. As a result, ISM offers tailoring of analytical solutions for a wide range of process industries based on particular needs. METTLER TOLEDO s extensive transmitter portfolio offers advanced instruments with HART and fieldbus protocols such as FOUNDATION fieldbus and Profibus PA. The support of all major asset management tools such as AMS (Emerson), PDM (Siemens) and the open standard FDT/ DTM ensure maximum compatibility. Integration of ISM diagnostics into the process control system can be most easily achieved over the analog signal outputs or relay outputs of the M800, our latest multiparameter/multi-channel transmitter. The robust, state-of-the-art, 2-wire transmitter M420 allows the integration of measuring and diagnostics data through standardized HART interfaces including all relevant device descriptions. Our fieldbus transmitter, M700, offers full digital integration of sensor recognition and ISM sensor data into the process control system which allows easy and safe measuring point commissioning and maintenance management. Discover more about ISM at: c

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8 All medicinal products use some Purified Water, Highly Purified Water or WFI component in their manufacturing process. This water is used either directly as an ingredient / solvent, diluent, vehicle for transmission, or reagent; or indirectly by cleaning contact. There are quality and compliance reasons for measuring conductivity and TOC for Purified Water and WFI. First, these are required measurements for release of water to production. These measurements can be performed on-line or off-line to assure product control. To meet USP requirements, non-temperature-compensated conductivity measurements are required. Second, while many measurements are used to control the water system, conductivity and TOC measurements are the most closely monitored attributes that indicate the water purification system is under control for ionic and organic impurities throughout the water system. The industry mandates the monitoring of TOC as specified in USP < 645 > Water Conductivity, < 643 > Total Organic Carbon and related tests in other international Pharmacopeia for global markets. The EP and ChP TOC test is identical to USP < 643 > in terms of limits and methods. TOC analysis in pharmaceutical-grade waters is used to detect organic contaminants. For a pharmaceutical water system, the most critical performance qualities in TOC instruments are fast response and high accuracy. The consequence of an excessive TOC level is that the production line must be stopped and the water system thoroughly inspected; a process that may require up to a week s lost production. Therefore, real-time determination of TOC can signal a rise in TOC that may be symptomatic of an impending failure in the pure water system. The Thornton 5000TOC sensor in combination with the multi-parameter, multi-channel 770MAX transmitter is a high-performance system for determination of TOC in pharmaceutical-grade waters. The system satisfies the international requirements of pharmaceutical standards. Thornton s 5000TOC provides an accurate TOC measurement, and responds to changes in TOC in less than a minute.

9 Established in 1973, Hanmi Pharmaceutical Co. Ltd. has become the second largest pharmaceutical company in South Korea, with 2009 gross sales of US$550 million. Through its Vision 2020 program, Hanmi is focusing on becoming the 20 th largest pharmaceutical company in global ranking by that year. Hanmi, dedicated to Quality of Life improvement, manufactures at three factory sites. Its products include Amlodipin (hypertension), Slimmer (obesity), and Guardix (anti-adhesion tissue bonding). Following the installation of a new Water for Injection (WFI) storage tank at one of Hanmi s main production sites, an off-line testing method indicated that TOC was above specifications. Another manufacturer s brand of analyzer had intermittently indicated TOC variations during sampling. However, the batch system measuring interval was long and the results were inconsistent, therefore, determining the cause of the TOC increase was problematic. water system, leading to the conclusion that TOC was directly related to system water level. Upon further investigation a hole no larger than a pin was discovered in the upper part of a WFI storage tank s insulating water jacket. This was allowing unprocessed water to leak into the pure water loop when the water jacket was close to full. Following repair of the leak, TOC measurement was restored to required levels. With the discovery of this pinhole in the tank jacket by continuous on-line monitoring of TOC, Hanmi Pharmaceutical was able to fix the problem while avoiding a costly and time-consuming plant shutdown. The customer expressed satisfaction with the accuracy, reliability, process stability and low maintenance of Thornton s on-line process monitoring instruments. In the coming year, the company is planning to build a new facility and will install three systems incorporating Thornton TOC analyzers. Find out how your facility can benefit from the 5000TOC and 770MAX, at: c At the production facility concerned, there are four conductivity systems installed in the water system. To this, Hanmi added the Thornton 5000TOC with the 770MAX transmitter. The Thornton TOC sensor indicated real-time TOC variations in the

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