June 17, 2014

The Importance of pH Control Throughout Drug Manufacturing

By Jill Jermaine, Sr. Product Manager, pH Measurement

Reducing the risk of product failure during drug manufacturing requires biopharmaceutical companies to implement robust risk mitigation strategies throughout their supply chain. Improving process control parameters will allow for greater lot-to-lot consistency thus decreasing the amount of scrapped batches and product reworks, which ultimately result in lost time and money. Below I will briefly discuss the significance of accurate in-process electrochemical measurements, specifically pH, that take place throughout bioproduction.

FermentersFermentation
A common challenge experienced in upstream manufacturing is to accurately monitor and control pH during the fermentation process. A natural shift in pH occurs due to the metabolic activity of the cells as they grow and consume nutrients in the surrounding medium. This pH change threatens to deliver a reduced product yield since growth conditions are greatly dependent on pH. It’s crucial for process engineers to use precise & reliable pH sensors to ensure process optimization in order to achieve high levels of product yield. A poor in-process pH sensor may report erroneous information and jeopardize the health of the batch which can lead to batch loss.

Purification
After the fermentation process has concluded, the protein of interest needs to be recovered and purified. The goal of the purification process is to isolate the therapeutic protein from other impurities, by-products, and potential viruses that were produced during the fermentation phase. Liquid chromatography is a widely utilized method for purification due to its high resolution. Chromatography separation technologies include gel filtration, ion exchange, hydrophobic interaction, and affinity. High resolution during chromatography is contingent upon buffer accuracy since buffers maintain the pH and ionic strength for reproducible purification. For example, faulty pH sensor readings during buffer prep may consequently lead to protein denaturation during ion exchange chromatography. The protein may become unstable at the incorrect pH reading and begin to unfold, therefore resulting in reduced product yield or disposal of the batch.

Cleaning
Lastly, stringent sterilization practices are implemented to safeguard against cross-contamination between product batches. The Steam-in-Place (SIP) method applies pressurized steam in areas where product contact occurs in bioreactors, vessels, ports, etc. during the production run. In-process 338pH sensors experience a reduction in sensitivity and lifespan due to the multiple rounds of thermal shock during the SIP process. The Clean-in-Place (CIP) method typically uses vast amounts of WFI (Water-for-Injection) to rinse and re-rinse between an alkaline-based detergent wash, such as NaOH. Overtime the NaOH tends to leach the pH glass electrode causing a reduced reading response time and inaccurate measurement. Therefore, it’s critical to select pH probes that can withstand high temperatures and chemical attack.

For superior pH measurement and control during bioprocessing, the Rosemount Analytical Hx Series sensors are ideal. Our Hx Series pH sensors feature the latest innovations in reference and electrolyte technology by providing bioprocesses with the unique Tri-Triple reference technology. Tri-Triple reference is comprised of three overall reference junctions working together to help maintain a drift-free pH signal with the use of a special electrolyte solution to withstand high protein and salt concentrations, even after numerous sterilization cycles. The specialized design of the Hx Series sensors meet the critical needs of the life science industry. For more information on pH measurement in biopharmaceutical manufacturing, click HERE.

June 4, 2014

Conquering the Leak Detection Challenge in Air-Driven Heat Exchangers with Ultrasonic Detectors

Hello. I’m Eliot Sizeland and I’m your Analytic Expert for today. Maybe I should say detection expert because I’d like to talk about air cooled heat exchangers, which are a classic example of an application environment where traditional means of leak detection are generally inappropriate. These heat exchangers have hundreds of potential leak points and are normally located in elevated positions far above the ground or deck where air movement is considerable. Since most traditional leak detectors, like point and open path IR, catalytic beads, and electrochemical sensors, are dependent on the formation of a large localized gas cloud for detection, these devices are unable to detect leaks in the high pressure, high temperature, and rapid air movement in such applications. Due to speedy gas dilution, point and line of sight detectors rarely detect gas in concentrations which are sufficient to trigger alarms. In addition, line of sight detectors may suffer from persistent issues with misalignment due to high vibrations caused by the fans used in the heat exchanger.

RAI.GDUIncusFortunately, ultrasonic gas leak detectors are ideally suited to monitor wide areas in high pressure gas process equipment. One such example occurred on an offshore platform in the North Sea in the United Kingdom. The operator’s heat exchangers used line of sight detectors to detect gas leaks, but the vibration from the fans themselves tended to make the detectors lose alignment and initiate unwanted alarms. A GDU-Incus from Emerson was employed to maximize coverage area with none of the problems of traditional detectors. Because they are triggered by ultrasonic sound versus a gas cloud, they are unaffected by the air movement and vibration from the fans.

Determining if ultrasonic gas leak detection (UGLD) is the best solution, however, requires a survey and ultrasound mapping. The survey makes recommendations to establish detector positioning, sensing range, minimum and maximum leak rates detectable, alarm levels, and recommended alarm delay settings. The single most important factor for detection is the difference between the sound level of a potential gas leak and the normal plant operation for UGLD to work.

Ultrasonic noise can be generated in a number of ways that may lead to inappropriate positioning or alarm condition such as mechanical noise, process generated ultrasound, or electrical equipment. The main reason for undertaking a survey is to measure the ultrasound in the operational plant. Where new build installations are considering the use of UGLD, assumptions of background sound levels are made based on a wealth of experience from live plant studies.

RAI_coolerUltrasound mapping is undertaken using a calibrated device that measures the operational plant sound level in the detector’s frequency range. A scaled plot of the target area is divided into a 5m grid, with lines running North-South, East-West. At each intersection the sound level is measured and a polar plot constructed, which then can be amalgamated into an overall background ultrasound plot for the target area (see Figure 1). The detection area is then matched to the plant process and can be verified on commissioning.

In most cases, UGLD is specified to detect a leak rate of 0.1 kg/s. That said, the main challenge with specifying a single leak rate is that not all 0.1 kg/s leak rates are detectable by UGLD. Rather than specifying a single leak rate, a refined technique is to find a suitable detection radius (meters) that ensures the desired leak rate is detected while maximizing the range of leak diameters (gas leaks) to be covered. The images below are presented for illustrative purposes.

RAI_charts

Figure 2 stretches the detection range to the maximum, but only a tiny window of gas leaks is detectable. By contrast, Figure 3 shows a significantly increased rate of detectable leaks, but sacrifices detection range. For many installations general area coverage (maximum range) is not appropriate, and it is important to tailor the range to the target risk.

With an ultrasound map in hand, plants with air cooled heat exchangers can detect leaks in extreme weather conditions with no loss of detection capability. Click HERE for more information on ultrasonic gas leak detection in this application and click HERE for more information on the GDU-Incus and its technology.

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