Lysosomal storage disorders may not sound as dire as diseases like 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 category - Gaucher's Disease, Fabry Disease and Pompe Disease - are not 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 is rare conditions like these that are at the heart of the mission undertaken every day by the therapeutics division of Genzyme, one of the world's foremost biotechnology companies. At the company's sophisticated, 24 hour/day manufacturing facility located in Allston, MA, 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 over 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, which since 1981 has been dedicated to making a major positive impact on the lives of people with serious diseases, is a primary factor. In addition, with annual revenues exceeding $3 billion, Genzyme has the financial strength that enables it to pursue the expensive research and development process. What's more, with 10,000 employees in worldwide, Genzyme possesses the human capital necessary to not only produce these medicines but bring them to market and ensure they get into the hands of those who need them.
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, is an area whose importance cannot be overstated.
The ramifications of instruments that are not properly calibrated can be dramatic. In fact, it is a scenario that Matthew Thompson, Genzyme's metrology supervisor, would rather not imagine. "Obviously, the absolute worst case would be a product recall," said 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," he added. "We might have to go back to a hundred different calibrations over the course of a month. It could start with just taking doing a reverse trace to find out what was calibrated with that instrument, or it could require much more effort."
Ultimately, it all comes down to one thing: cleanliness. There is a certain path that "cleanliness" takes in a manufacturing facility such as Genzyme's, and that path is measured by differential pressure from one room to the next. That is 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.
"Our manufacturing managers and supervisors trust us to make sure everything runs correctly," Thompson emphasized. "They've got enough on their plates to worry about during the manufacturing process. We are trying to lighten that load by providing accuracy in the instruments around them."
Fortunately, Thompson has taken an extremely effective safeguard against this possibility. Genzyme uses two new calibrators from Setra Systems, a leading designer and manufacturer of pressure measurement devices, 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, Ultra-Low 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.
The accuracy of the Model 869 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, according to Thompson. 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 for calibrating 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. According to Thompson, he and his two reports perform about 4,000-5,000 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," Thompson said. "So on top of the regularly scheduled six-month intervals, we did a pre-filter 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.
"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," Thompson explained. "Basically, we have to monitor the differential pressure between clean and dirty. And the range can be from -.5 inches of water to +.5 inches of water.
"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. Even a few thousandths of an inch of a water column can jeopardize the integrity of the room." Programming the Model 869 is simple; more importantly, it stays where it is told.
"The beauty of the calibrator is that you just punch in a number and it automatically corrects itself to stay on that number," Thompson said. "The fact that it's automated and that it holds it, makes our adjustments far more accurate.
"We can also program multiple set points," he added. "If we have a differential pressure transmitter that's goes -.5 to + .5 and the next one is -.1 to +.1, we can easily make that change. We tie it into the transmitter with the hoses on, punch in ‘go to .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 fifty differential pressure indicators. Now we do it in about half the time. 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."
Thompson found out about the Setra Model 869 through one of the company's other facilities; apparently, good news travels fast.
"Our Framingham, MA site had purchased one," Thompson said. "We took a look at it here, and we decided it was something we were interested in, based not only on the apparent accuracy of the readings but also the number of calibrations we could do with it. We had been using a different machine where you had to dial in the pressure. The problem is that at such a low pressure say .1 or .2 inches of water we were almost always having to adjust it. We just couldn't get it perfect."
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.
Ironically, Thompson, a man whose primary job responsibility is the pursuit of accurate measurement, said it best when he said, "The Model 869 provides a service that, frankly, is immeasurable."