The pharmaceutical industry is not unlike other industries in its quest for better performing and more reliable instrumentation. And in the specific case of continuous level measurement, drugmakers increasingly are choosing fully solid-state, non-mechanical devices that deliver higher accuracy, need less frequent calibration and are installed in such a way that an instrument failure won't compromise process uptime or derail a batch that's in process.
At Genentech's South San Francisco, Calif., manufacturing site, hundreds of tanks and dozens of fermentation trains produce oncology drugs, vascular medicines and other specialty biotherapeutics. Metrologist Steve Ward has led the charge toward standardizing on two relatively recently developed technologies for measuring liquid level,magnetostrictive and guided-wave (probe-based) radar.
In both cases, high-accuracy, long-term stability and,perhaps most importantly,the ability to remove the probes from the top of the tank for calibration or replacement were deciding factors.
"Our processes run anywhere from 10 to 30 days," Ward says. "If we lose a batch in process, it's a lot of money down the drain."
An added bonus Ward has seen is in the area of calibration. Genentech devised an off-line calibration bench equipped with laser and target for verifying the accuracy of its radar and magnetostrictive probes.
"We can pull the probes and calibrate them, even while the process is running," Ward explains. In the past, the load cells used to measure tank contents had to be calibrated by filling the tanks with purified water run through a Coriolis mass flowmeter for reference.
"The procedure was time-consuming and purified water is very expensive. Plus, once it's been used, it has to be treated," Ward says. "Now we've eliminated routine water calibrations. We still go back to verify,but now it's every three or four years rather than every six to 12 months.
"We've tried almost everything," he concludes, "and we've settled on these two technologies because of increasing demands for higher accuracy and mounting pressure not to shut down."
At other pharmaceutical sites, however, level measurement is deemed so sufficiently problematic that pressure-based systems and load cells are relied on to infer rather than directly measure liquid level.
Abbott Bioresearch, Worcester, Mass., is ramping up production of the company's newly approved human anticlonal antibody Humira, prior to spinning out production to other manufacturing sites. Mark Edlinger, metrology manager, prefers a combination of load cells and pressure-based instrumentation to his other level instrumentation options. He has even used a top-mount, probe-style device with a pressure sensor mounted at the bottom of the probe to overcome the potential liabilities of bottom-mount pressure transmitters in some applications. Similar to other top-mount probes, it can be readily pulled and calibrated on a spool piece.
"I'm a strong proponent of pressure," he says, citing application-specific issues with capacitance probes and non-contact radar technologies. "Our biggest challenges are foaming and agitation."
Call it an axiom of applied instrumentation technology: The number of options available to measure a given process variable is directly proportional to the difficulty of that measurement. And while measuring liquid level in a tank is conceptually simple, the types of surfaces and interfaces encountered in industrial processes vary so widely that over the years more than 20 fundamentally different types of instruments have been developed and applied.
For the most part, when a continuous process level measurement is needed, the choice today falls to five major classes of level measurement devices: capacitance/radio frequency (RF) admittance, radar, ultrasonic, magnetostrictive and nuclear. Two approaches that don't strictly measure level at all,pressure transmitters and load cells,are also often used. If a point-level switch is needed rather than a continuous measurement, this opens the options up to another handful of alternative technologies. (See sidebar, "When a Level Switch Will Do.")
And while there are few absolute application rules, there are some basic "cost of entry" parameters that any level instrument used in a sanitary process must meet,excepting, of course, load cells and nuclear gauges that to their credit do not contact the process directly.
"They have to be made of process compatible materials. They have to be designed and manufactured such that there are no surface blemishes or crevices where bacteria can harbor. And they also need to be easy to clean, easy to sanitize, easy to inspect," explains Boyce Carsella, product manager, new technologies, for instrumentation supplier Magnetrol (Downers Grove, Ill.).
"In the end, though, sanitary is a user-defined parameter," Carsella adds. "It all comes down to what the user needs."
"The main difference between sanitary and general process instrumentation is the connection. It has to be suitable for clean-in-place (CIP) or easily taken apart," adds Jonathon Rowe, marketing manager, pressure and level, Invensys Foxboro (Foxboro, Mass.). In North America, Tri-Clamp connectors are used extensively with a variety of gasket materials, depending on the application. Fill fluid, in the case of remotely sealed pressure transmitters, must also be process compatible.
In terms of materials, pharmaceutical manufacturers typically use the dairy industry's 3A parameters of 316 stainless steel, polished to a 20 Ra finish, as a starting point. Acid wash as part of a CIP procedure might necessitate an upgrade to Hastelloy C for the process-wetted parts, says John Schnake, pressure products business manager, Honeywell (Phoenix).
"For a pressure transmitter diaphragm, this typically represents a 15 percent premium over stainless steel," Invensys Foxboro's Rowe adds.
The instrument also must tolerate temperature extremes encountered as part of any sterlize-in-place (SIP) procedure. "That's typically a minimum of 121degrees Celsius for half an hour, but may go up to 140 degrees Celsius for an hour," says Bill Wilson, vice president marketing for Anderson Instrument (Fultonville, N.Y.).
Another parameter that relates to pressure transmitter performance is how fast the instrument responds to temperature changes, notes Scott Richardson, pressure product manager for Endress + Hauser (Greenwood, Ind.) "Most pressure transmitters are temperature-compensated, but if you have fast hot-cold cycles, the transmitter should respond quickly," he says.
Finally, the instrument enclosure itself will likely need to meet at minimum NEMA 4X or IP67 standards for washdown. "If there's a caustic wash, standard painted aluminum isn't appropriate," adds Wayne Shannon, level product manager for Magnetrol. "Then you're looking at epoxy finish, a plastic housing or even stainless steel."
One Size Doesn't Fit All
Of course, the cost-of-entry criteria are crucial elements in decision-making. However, the following application criteria should steer the instrument selection process and be accommodated as a particular application allows:
Beyond that, difficult applications are simply that: difficult.
"Sometimes, the only way to figure it out is to try it," says Anderson Instrument's Wilson. "Twenty percent of pharmaceutical applications don't have an ideal solution."
"Every fermentation is different," adds Ohmart/VEGA's Oeder. "There isn't a good, general solution out there. You have to take it application by application."
What's Hot, What's Not in Continuous Level Instrumentation
On The Rise
Top-mount and non-intrusive, open-beam approach now packaged in more affordable, loop-powered configurations.
Intrusiveness of probe-style, guided-wave devices offset by performance advantage relative to capacitance devices.
Intrusiveness of probe and single moving float offset by high accuracy in appropriate applications.
Top-mount and non-intrusive, ultrasonics are more economical than radar and have carved a niche where condensation isn't likely and headspace gas composition is consistent and predictable.
Holding Their Own
Non-intrusive but requires a tank-bottom penetration, with exception of some top-mount, probe-based devices.
The ultimate in non-intrusiveness, but large tanks with relatively large tare weights can reduce accuracy. Cannot be calibrated offline.
Remains the continuous level gauge of last resort,entirely non-intrusive but still relatively expensive with the added complexity and paperwork of a Nuclear Regulatory Commission-registered radiation source.
Susceptibility to changes in fluid composition is an asset in some applications, but liability in many. Price advantage of this economical choice eroding with falling prices of competitive technologies.
When a Level Switch Will Do
Sometimes a continuous level gauge is overkill. All you need to know is whether the liquid level is above or below a certain point--when fermenter foam has reached a certain point and a dose of defoamer should be added or when a feed-tank is getting low and a pump about to run dry should be turned off.
Enter the humble level switch, or detector, which over the years has proliferated in nearly as many variations as there are laws of physics to operate on. Buoyancy, thermal dispersion, electrical capacitance, electrical resistance, vibration and optical transmittance--all have been harnessed to tackle the point-level question for liquids, solids and interfaces.
For sanitary applications common to the pharmaceutical and biotech sectors, level switches that penetrate the vessel wall must meet the same criteria as continuous level gauges in terms of process compatibility of materials, harborless design and finishing, and ease of cleaning, sanitation and inspection.
But what if your point-level switch didn't need to penetrate the vessel wall? One fewer tank penetration is one fewer chance of contamination, one fewer headache for you and your staff. At least that's the thinking of Roger Saba, business development manager for Turck Inc. (Minneapolis).
The company, well known for its proximity sensor technology, has adapted that competency into a new level switch called the LevelProx, which uses high-frequency ultrasonic radiation, similar to that used in non-destructive test applications, to reach through tank walls and sense whether there's liquid on the other side.
"We ping the wall, and if there's fluid there, it attenuates the return signal," Saba explains.
The elegance of non-intrusive detection is complemented by the company's background in electrical connectivity, Saba continues. Once a welding ring is attached to the outside of the tank, wiring is done via Eurofast M12 washdown-rated connectors. "There's no need to run conduit," he says.