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Paul Richards

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FDA Compliance

Ultra Low Pressure Calibrators Help Pharmaceutical Operation

A case study

Published: Monday, February 23, 2009 - 13:54

Lysosomal storage disorders may not sound as dire as diseases such as cancer or Alzheimer’s, but to the people that suffer from them, life can be a nightmare. In fact, three of the primary disorders in this categoryGaucher’s Disease, Fabry Disease, and Pompe Diseasearen’t only characterized by a variety of painful, lifelong symptoms, they can ultimately lead to lung and kidney problems, stroke, heart attacks, muscle weakness, and, in some cases, death.

It’s rare conditions like these that are at the heart of the mission undertaken every day by the therapeutics division of Genzyme, a global biotechnology company. At the company’s manufacturing facility located in Allston, Massachusetts, medicines for treating three distinct lysosomal storage disorders are produced:

  • Cerezyme (imiglucerase for injection), the only enzyme replacement treatment for Type 1 Gaucher’s disease for more than a decade.
  • Fabrazyme (agalsidase beta), an effective treatment against Fabry disease.
  • Myozyme (alglucosidase alfa), the first treatment ever approved for Pompe disease and the first for an inherited muscle disorder.

Few companies have the wherewithal to develop such sophisticated drugs. Certainly, the scientific and pharmacological expertise of Genzyme, dedicated to making a major positive effect on the lives of people with serious diseases since 1981, is a primary factor. In addition, with annual revenues exceeding $3 billion, Genzyme has the financial strength that enables it to pursue expensive research and development.

A less obvious, but equally critical element in this formula, is Genzyme’s overarching focus on adopting and maintaining superior production methods. Cerezyme, Fabrazyme, and Myozyme all require an almost fanatical obsession with quality, ensuring that every step of the manufacturing process is accurate and repeatable. As a subset of this approach, Genzyme spends ample time and effort to preserve the integrity of the plant itself, as well as all of the instruments that are used in the production process. The flawless functioning of its transducers, autoclaves, and pressure indicators, as well as the reliability of clean areas and other production areas, cannot be overstated.

The ramifications of instruments that aren’t properly calibrated can be dramatic. In fact, it's a scenario that Matthew Thompson, Genzyme’s metrology supervisor, would rather not imagine.

“Obviously, the absolute worst case would be a product recall,” says Thompson, who is responsible for calibrating everything from simple pressure gauges to the ultraviolet sensors on purification skids. “If somehow the room pressure is not being calibrated correctly, it would definitely impact the end product. I can’t even think of the cost to recall any of our drugs. We’d have to potentially halt one or more production runs; the possibilities are endless at a 24-hour manufacturing site. Any bit of a hiccup in the operation would just snowball. We’d also have to go back and recalibrate however many devices were calibrated with that particular faulty standard. We might have to go back to a hundred different calibrations over the course of a month.”

Ultimately, it all comes down to one issue: cleanliness. There’s a certain path that cleanliness takes in a manufacturing facility, and that path is measured by differential pressure from one room to the next. That’s where the accuracy of the instrument calibration is critical. In the end, if cleanliness during the manufacturing of Genzyme’s products can’t be ensured, it cannot be provided to the company’s customers.

To safeguard against the possibility of inaccuracy, Genzyme uses two new calibrators from Setra Systems to conduct quick, accurate calibrations of all instruments involved in the manufacturing process and the general maintenance of the facility.

The Micro-Cal Model 869, Ultralow Pressure Documenting Calibrator has been specifically designed for air-handling processes in environments that require portable, high-accuracy and low-pressure documenting calibration to certify pressure needs. The Model 869 provides this capability by performing calibration checks on sensors with accuracies as high as .00025 in. W.C.

Its accuracy is far higher than the results achievable in traditional laboratory bench-top calibration units, which are accurate only to .0004 in. W.C. and require at least one full hour to run calibration checks on one unit. To correctly perform on-site tests, many of these basic units need multiple components, such as pressure indicators and generators, voltage and current meters, and data loggers. 

The transition to using these units was simple. To begin with, the measurements and production processes remained intact; no modifications were necessary to incorporate the new instruments into the operation. And their ease of use required minimal training on the part of the operators.

The two new calibrators are subjected to a pretty exhausting workout on a daily basis. They are used to calibrate about 2,000 instruments per year on-site, including pressure gauges, thermometers, and differential pressure transmitters; some of the devices get calibrated three or four times a year. Thompson and his two reports perform about 4,000 to 5,000 calibrations per year—including 106 differential pressure indicators—which includes repair and emergency calibrations, along with the normal maintenance work.

“Last year we replaced a lot of our heavy filters in one particular area,” says Thompson. “So on top of the regularly scheduled six-month intervals, we did a prefilter change and a post-filter change on several of those instruments.”

While the calibrators are used for a widely varied scope of readings, their primary purpose is for measurement of room differential pressures. Even a few thousandths of an inch W.C. can jeopardize the integrity of the room.

“We have a number of clean rooms, many of them classified 10,000 and below, where we have to make sure that the dirty air stays out and the clean air stays in. We have to monitor the differential pressure between clean and dirty. The range can be from -0.5 inches of water to +0.5 inches of water.” explains Thompson. “It’s critical to be certain that the measurements are 100-percent accurate so that when the numbers are recorded to the facilities department, they’re getting accurate readings. That way, they can tell when maybe a handler needs to be more finely tuned to provide higher pressure to a room.”

Programming the Model 869 is simple; more important, it stays where's told. The operator punches in the number and it automatically corrects itself to stay on that number making the adjustments far more accurate.  The calibrator can also program multiple set points.

“If we have a differential pressure transmitter that’s goes -0.5 to +0.5 and the next one is -0.1 to +0.1, we can easily make that change,” says Thompson. “We tie it into the transmitter with the hoses on, punch in ‘go to 0.5 inches of water,’ the pump inside the Setra drives it to that point and holds it there. Then we check our computer maintenance system and compare it to what Setra is producing for us. If there’s something out of tolerance, we can use it to make that adjustment right there.”

This high degree of functionality, along with the calibrator’s inherent accuracy, translates to a significant time savings, especially considering the number or calibrations Thompson and his crew perform in a day.

“It used to take us two or three days to calibrate 50 differential pressure indicators. Now we do it in about half the time,” says Thompson. "And if necessary, the device is relatively easy for one person to use. It’s definitely easier with two, but one person alone can perform calibrations if we’re spread thin.”

While they comprise a small part of the Genzyme’s manufacturing process, the calibrators’ contribution to the company’s output cannot be ignored. Ultimately, their performance illustrates Genzyme’s commitment to ensuring that its medications are produced under the safest, cleanest, and most consistent conditions.


About The Author

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Paul Richards

Paul Richards is the sales manager for Setra Systems.