Foxboro pH Sensor Gilead Sciences pH Sensor has Improved Performance at a Pharmaceutical Plant

Editor: Dr. Jörg Kempf

At north American pharmaceutical manufacturer Gilead Sciences, accurate control of pH is critical to good crystallization and high yield. But aggressive chemicals used in the company’s processes, including hydrobromic acid, quickly wrecked on-line pH sensors – sometimes as often as several times per batch.

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Gilead Sciences is a biopharmaceutical company that discovers and commercializes innovative therapeutics. “Processes have to be controlled tightly to ensure quality and consistent high yields,” says Rob Pastushak, Senior Technical Supervisor of Pharmaceutical Manufacturing at the company’s manufacturing plant in Alberta, Canada. “While our products are generally high value, it is a competitive industry, so delivering high yield to the customer is a must.”

“Even the slightest variation in our process has a significant impact on costs. Over time, this could add up to substantial losses in production and profitability,” says Pastushak. A two percent drop in yield can wipe out the profitability of a process, he says. Of course, he adds, continuing FDA and cGMP approvals also depend on close control of process variability.

In 2003 the Alberta facility launched a project to improve manufacturing efficiency, with a particular focus on pH measurement. “At that time, the pH sensors we used simply could not hold up under aggressive chemicals that we use, such as hydrobromic acid,” says Pastushak. “HBr and organic solvents caused the probes’ O-rings to degrade during the most critical point of the process. In many cases, three probes, at approximately $600 per probe, would fail during processing just one batch.”

Once the O-ring degraded the pH probes no longer provided accurate readings, which presented another problem for Gilead. The process calls for two phases of crystallization, each of which requires pH to be controlled to ±1 pH unit. “Crystallization is critical, and pH is king. When the chemical composition of a drug falls outside of the correct pH range, quality and yield suffer because maximum crystallization fails to occur,” says Pastushak.

Because of the unreliability of these devices, Gilead was forced to confirm pH measurements on a bench-top meter in the lab. “When you process 3,000 to 5,000 l and add 5–10 kg of caustic solution at a time, it might take 20 to 40 lab tests to ensure the pH is right during pH adjustment,” says Pastushak. “Going to the lab so often to confirm pH just killed production efficiency, but it was a necessary evil to comply with our strict quality control standards.”

Foxboro solution

To resolve the pH measurement issue, Pastushak researched several probes and decided to test the Foxboro 871PH Series sensor from the Measurements & Instruments Division of Invensys Process Systems. The 871 is a rebuildable pH probe that incorporates patented technology from the award-winning Foxboro DolpHin pH sensor line.

“We found many vendors that offered quality sensors, but Foxboro was the only one that could provide a robust design that could stand up to all the reagents and solvents in our solutions. The 871’s Ryton polymer plastic construction is compatible with all the materials in our process and is just what the doctor ordered for our demanding application,” says Pastushak.

Foxboro worked closely with Pastushak to understand the requirements of the application and provide a solution tailored for Gilead’s process requirements. “Foxboro offered the technical expertise and production capabilities to modify the 871 sensors to include O-rings made out of Kalrez, which was a big factor in us choosing them over their competitors,” says Pastushak. “The other units we considered were only available ‘as is’. We needed a durable pH sensor with Kalrez O-rings, and Foxboro was able to deliver.”

The 871PH rebuildable sensor includes a robust and reusable sensor body with a field-replaceable measuring electrode, reference junction and electrolyte. It features a patented glass formulation that improves measurement stability, accuracy, and service life at temperatures up to 120 °C. The glass also increases response speed up to five times compared with conventional sensors, and allows longer duty cycles.

Proven in process

To ensure that the sensor met quality standards, Pastushak put the Foxboro 871PH through extensive testing before integrating the unit into the manufacturing process.

The Alberta plant uses the Foxboro 871PH probe in conjunction with two 7,600-l vessels stationed side-by-side with a shared condenser. One vessel serves as a reactor and the other as a receiver, quench reactor or work-up reactor. When mixing organic reagents, acidic or basic by-products are often generated with potential impact to the product because of the changing pH.

To ensure that the product comes out of solution with the proper pH, Gilead typically dilutes the organic mixture with water. This mixture must then be measured for pH and adjusted until the right balance is achieved. To adjust the pH, Gilead pump-circulates the solution through the bottom of each vessel to the top where the 871 sensor measures pH in a slurry loop. Based on the measured pH, a caustic or acid solution is added until the right level is achieved. If the pH remains stable for two minutes, the pH test for any secondary crystallization level ensues. The 871 provides reactive, real-time pH measurements, which are key to reducing cycle time.

“We can now complete a pH adjustment in three hours rather than the 18 to 24 hours it previously took,” says Pastushak. “And we no longer have to take 40 samples to the lab to confirm measurement accuracy — we only take one, for quality assurance.” Reducing the number of confirmation measurements has also improved personnel safety, because it has cut the number of times a process line has to be opened for sampling.

During an initial one-month test, Gilead, Alberta discovered that the 871PH allowed them to control pH faster by adjusting to solution changes over a shorter period of time. “The results have been consistent from batch to batch,” says Pastushak. “As soon as we add a solution to adjust pH, the probe responds immediately and provides the new pH reading. We’ve found it to be accurate to ±0.03 pH units, which is well within our target limits.”

The Foxboro 871PH sensor’s fast response, and long reliable duty cycle, coupled with the ability to all but eliminate manual sampling, have cut batch times by up to 20 percent and increased yield per batch. “When you add in the increase in quality, the improved pH readings from one sensor can be worth hundreds of thousands of dollars per year,” Pastushak says.

According to Pastushak, the 871 PH sensor is also very durable. “The one we deployed two years ago looks like it did the day we bought it. All we do is clean it after each use. The Ryton bodies are holding up extremely well. They display no degradation, pitting or corrosion, even though we run the gamut of pH ranges, solvents, and aggressive conditions,” says Pastushak.

During the past two years, Gilead, Alberta has replaced three legacy probes within its manufacturing process and plans to replace three more. Gilead also has a second manufacturing facility with 15 probes that will eventually be swapped out as well. “The bottom line is that the 871PH has had a huge impact on the success of our business,” Pastushak says. “The role it plays is critical, since pH failures can ruin an entire batch.” But the benefits of Foxboro 871PH go further than this. “By enabling us to increase product quality and yield, the Foxboro 871PH sensor has allowed us to do our job better, so we can contribute to improving the quality of life for countless people — and that’s what we’re in business for,” says Pastushak.

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