pH Sensor Improves Product, Process, and Profits
Inconsistencies had to stop. Not to mention the need to replace three failed $600 sensors per batch and adding anywhere from 20 to 40 trips to the lab with samples. Gilead Sciences Inc., is an international biopharmaceutical company that discovers, develops and commercializes innovative therapeutics to fill areas of unmet medical need.
Inconsistencies had to stop. Not to mention the need to replace three failed $600 sensors per batch and adding anywhere from 20 to 40 trips to the lab with samples. Gilead Sciences Inc., is an international biopharmaceutical company that discovers, develops and commercializes innovative therapeutics to fill areas of unmet medical need. Headquartered in Foster City, CA, the company is faced with developing and scaling a wide range of chemistries and products, and ultimately delivering these on a commercial basis. “The compounds we produce are used in various human applications from cancer treatments to anti-virals,” says Rob Pastushak, senior manufacturing specialist, technical operations, at its facility in Alberta, Canada. “Processes have to be controlled tightly to ensure quality and consistent high yields. While our products are generally high value, it is a competitive industry so delivering high yield to the customer is a must.”
“Batches typically range from 300 to 900 kg. (660 to 1980 lb), and 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.
Another critical and ongoing challenge facing Gilead is demonstrating to the U.S. FDA (Food and Drug Administration), that it has complete control over its production process. The Gilead, Alberta, facility is CGMP (current good manufacturing practices) certified, which builds quality and repeatability into a production process. All of the company's production equipment must be tested and certified, which involves a strict qualification process for regulatory compliance and ongoing regular audits by the FDA. Gilead must document its processes to verify it can deliver quality ingredients consistently and in the high volumes required. “The majority of our business involves exports to the United States. If we don't receive FDA approval, we will go out of business,” says Pastushak.
Problems with pH measurement
To assure consistent product quality and maximize batch yields, Gilead launched an effort in 2003 to improve efficiency of its manufacturing process. One critical area Pastushak focused on was pH measurement.
“Measuring pH was a problem because of the unreliability of our pH sensors. They simply could not hold up to aggressive chemicals, such as hydrobromic acid. The organic solvent constituent caused the probe's O-rings to degrade during the most critical stage of the process. In many cases, three probes, at approximately $600 per probe, would fail while processing just one batch,” he says.
Because of the pH probes' unreliability, Gilead was forced to confirm measurements on a benchtop meter in its lab. “When you process 3,000 to 5,000 liters (790-1,320 gal.) and add 5 to 10 kilos of caustic solution at a time, it might take 20 to 40 lab tests to ensure the pH is right during adjustment,” says Pastushak. “Going to the lab so often just killed production efficiency.”
Pastushak points out that given the competitive nature of the biopharmaceutical manufacturing business and the tight margins that exist in the industry, even a small variance in yield can have a huge impact on the bottom line. “A 1% or 2% increase in the target commercial yield translates to 100% profit gain. Likewise, a consistent loss of 1% or 2% of the commercial target yield translates as lost profit. You don't stay in business long with that type of performance,” he says.
To resolve the pH measurement issue, Pastushak researched several probes and decided to test the Foxboro 871PH Series sensor, from Invensys Process Systems. The 871 is a rebuildable pH probe that incorporates patented technology from the Foxboro DolpHin sensor line.
“We found many vendors that offered quality sensors, but Foxboro was the only one that could provide a design that stands up to all the reagents and solvents in our solutions,” says Pastushak. “Foxboro offered the technical expertise and production capabilities to modify the 871 sensors to include O-rings made out of Kalrez. The other units we considered were only available as is, off-the-shelf.”
Being rebuildable, the sensor includes a robust and continuously reusable sensor body with a field replaceable measuring electrode, reference junction and electrolyte. The measuring electrode is the “business” area of the sensor and includes glass that comes in contact with the media being measured. The sensor features a patented glass formulation that improves measurement stability, accuracy, and service life in high temperature applications, up to 120 °C (250 °F). The glass also increases response speed up to five times compared with conventional sensors and allows longer duty cycles. Pastushak put the new sensor through extensive testing before integrating the unit into the manufacturing process. In the application Gilead uses the Foxboro 871PH probe in conjunction with two 7,600-liter reactor vessels stationed side-by-side with a shared condenser.
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 871sensor measures pH in a slurry loop. The probe 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, as a matter of quality assurance protocol. Previously, every time we grabbed a lab sample, we had to put the process on hold until we got the results back. This is significant when you consider not only the yield impact but the cost of a process hour,” says Pastushak.
This reduction in the number of confirmation measurements also improved personnel safety. With fewer the confirmation measurements, the technicians do not need to open the line as often to obtain samples manually. This fits in line with Gilead's strong commitment to implementing the highest precautions with all of its safety controls.
During an initial one-month test, Gilead discovered that the system allowed them to control pH faster by adjusting to solution changes over a shorter 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
The sensor's fast response, coupled with its long duty cycle and elimination of 40 grab samples also allows Gilead to produce more batches in the same period of time, reducing manufacturing cycle time by up to 20%, which increases capacity and competitiveness.
Durability is critical in a chemical plant, where one delay can cause cascading schedule impacts. “When a day is lost in manufacturing, you lose it forever. A one-day delay can cause a backlog that snowballs from days to weeks to months for future batches,” says Pastushak. “The bottom-line is that the 871PH has had a huge impact on the success of our business. The role it plays is critical since pH failures can ruin an entire batch.”
But the benefits go far beyond improving Gilead's bottom-line. “By enabling us to increase product quality and yield, the 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.
John P. Connelly is sensor product manager, Foxboro Measurements and Instruments, Invensys Process Systems.