Concurrent need for speed, resolution, cost-effectiveness and other factors shape new products
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By Sarah Fister Gale
In the ever-changing world of cleanroom tools and technologies, size is everything. As chips shrink, and nanoscale devices invade every high-tech and biotech product category, even nanosized contaminants can have devastating effects on some products if they aren’t kept under control. As technologies shrink and contamination-control standards tighten, cleanroom operators are required to monitor and eliminate ever smaller particles from the atmosphere, and particle counter manufacturers continue to make strides in collecting and counting these tiny contaminants.
But, for certain cleanroom professionals, size isn’t the only issue-they’re just as concerned about the speed of performance.
The speed at which a particle counter can sample the air is determined by the flow rate of the device. Current particle counters on the market range in flow rate from less than 25 liters per minute to 50 liters per minute (LPM). “When considering the purchase of a particle counter, cleanroom operators evaluate factors such as price, quality, laser lifetime, warranty and service,” says Bill Belew, product manager for aerosols at Particle Measuring Systems (Boulder, Colorado). “However if it will be used to certify a cleanroom to ISO 14644-1, sensitivity and flow rate are the most important parameters, both of which impact the collection efficiency, which in turn determines the required sampling time.”
The higher the flow rate, the more data the counter collects per time period-or the faster it can collect a specified volume. The collection efficiency of a particle counter defines the combined effects of sensitivity and flow rate with regard to the counter’s ability to collect data.
Historically, the flow rates of most particle counters used in cleanroom certification were 0.1 cubic foot per minute (CFM) and 1.0 CFM. However, recent particle counting and regulatory trends have increased the utility of 1.78 CFM (50 LPM) and 1.0 CFM counters, while reducing the value of 0.1 CFM particle counters.
The real value to manufacturers of these advances in particle counter technology is the decrease in time needed to complete a sample. “It takes 35 minutes for a particle counter with a 25 liter flow rate (0.1 CFM) to test one cubic meter of air, but only 20 minutes for a particle counter with a 50 LPM flow rate,” Belew says. Although for some industries, higher flow rates aren’t yet critical because they can test smaller amounts of air to verify and certify their cleanroom conditions, but that is changing rapidly.
EU GMP Annex 1 spurs trend
The transition began in the pharmaceutical industry three years ago. In the United States, all drugs must be manufactured in accordance with current Good Manufacturing Practice (cGMP) regulations, which state that cleanroom validation must be performed, and which impose limitations for production environments. These regulations are governed by FDA’s 21st Code of the Federal Register (21CFR). Likewise, in Europe, EC guidelines must be met, which require pharmaceutical companies manufacturing the product to prove that they have been in compliance with the European Union Good Manufacturing Practice (EU GMP) Annex 1 regulations at every stage before a drug can be released to market and ultimately to the end user.
In September 2003, a revision to the EU GMP Annex 1 regulation changed the requirements for nonviable particle counting in pharmaceutical Grade A and B areas, requiring one cubic meter of air as the minimum sample size for particle monitoring and stipulating that the measurements must be done using a laser-based light-scattering optical particle counter to be valid for monitoring. That adds significant time and cost to testing, Belew points out. “In a large facility with multiple testing points, particle counters with slower flow rates can tie up a team of technicians all day.”
In September 2004, the FDA released its Guideline on Aseptic Manufacture. In both of these documents, the focus on proving control over the manufacturing environment has been increased.
Even though there is currently no volume requirement from FDA for routine sampling of pharmaceutical drug manufacturing in Class 5 to 7 rooms, which are comparable to EU Class A and B, if US companies want to sell their products globally they must adhere to the standards for those countries. As a result, many pharmaceutical manufacturers are adhering to the strictest monitoring regulations of each set of standards to ensure their products are acceptable worldwide, says Morgan Polen, vice president of application technologies for Lighthouse Worldwide Solutions (Milpitas, Calif.). “The standards are somewhat ambiguous, but it means a lot of people are trying to sample more air.”
Because the sample size is so much larger, it has added considerable time to the testing process and that costs money and impacts productivity, Belew explains. “It has resulted in a lot more particle counting in this industry, and it has created a huge drive for mobile particle counters with high flow rates.”
In pushing for high-flow-rate handheld counters, Polen says, some customers are sacrificing other benefits of portable particle counters, which he feels is shortsighted. “They want small lightweight models but it limits the effectiveness of the tool,” he states. For example, smaller tools that use blowers instead of pumps and have shorter lengths of tubing to draw air can’t be used for filter scanning or aerosol challenge tests. “It’s important to look at performance as well as size to get the best value.”
New Biotest model samples 100 liters per minute
The need for speed has driven many in the industry to explore alternate technologies to create particle counters that have faster flow rates with the same level of accuracy.
Biotest Diagnostics (Denville, New Jersey) is one such company. Using technology from a previous development project, Biotest has been able to build a new particle counter with a flow rate of 100 liters per minute, allowing technicians to sample a cubic meter of air in less than 10 minutes, says Ken Troia, Biotest’s director of marketing and sales in North America. The new counter, which will be part of Biotest’s APC product family, will be released this summer.
“If you can take more samples in less time you lower your cost per sample,” Troia says. “You can go from taking 14 samples in a day to 23 samples in the same amount of time.”
The new Biotest counter is portable and battery-operated. It uses an advanced optical design with high-speed signal detection that allows for accurate counting at the higher flow rates, and will be able to detect particles down to 0.3 micron. Says Troia, “If fast is good, faster is better.”
Experts in the particle-counting industry predict that the trend toward faster flow rates won’t stop at pharmaceuticals. Other industries, including semiconductor, are embracing the more rigorous sampling protocol as a matter of quality assurance. “More people are adhering to these standards in the spirit of continuous improvement,” Belew says. It also just makes good business sense for industries in which particle contamination has such a direct impact on products. “As we learn more about how cleanliness impacts yield, we get tougher about monitoring.”
Continuous monitoring
The move to embrace stricter standards for particle contamination has also led many companies to transition to daily continuous monitoring systems that constantly track the particle count of the environment. Continuous monitoring systems with dedicated systems placed in strategic positions throughout the cleanroom verify that constant conditions are being maintained. The collected particle counter measurements are stored in a centralized database. The systems also detect small problems or shifts in the particle density of a room early enough to give the cleanroom staff a chance to respond and fix the problem before it impacts yield or safety.
More and more facility managers are implementing particle monitoring as part of their daily routine. “The regulation requires you to certify your space every six months or so, but if you have to certify that room to those levels twice a year, you might as well monitor to that standard on a daily basis,” Belew says.
Polen agrees. “If you’re operating a cleanroom, you should be doing particle counting,” he says. “If you rely on someone else to verify your cleanroom every six months, that doesn’t tell you anything about what’s happening in the space, what people are doing or what contamination events have occurred.”
Polen acknowledges that for some smaller facilities a particle counter is a significant investment. A portable particle counter can cost roughly $3,500 to $8,000, while each sensor in a continuous monitoring system costs $2,500, with dozens of sensors placed in a single facility.
But, he says, compared to the impact on yield if contamination goes undetected, it’s worth it. “The cost of product loss or a recall is far greater than the cost of the instrument and the time to test.”
The true cost of equipment
Though every cleanroom operator would clearly like the best system available, cost is also always an issue, and cleanroom managers are getting more savvy about assessing the overall value of the tools they buy, says Todd Blonshine, senior scientist and global marketing manager for Hach Ultra Group (Cary, North Carolina). “When a customer purchases a particle counter, he is just as concerned about the true overall cost of the tool as the purchase price, and he expects greater proof of validation of those numbers than had been available in the past.”
“It is no longer true that the least expensive model gets all the business,” Blonshine says. “Now, the trend for customers is to demand lifecycle reports with great detail.”
Buyers want to know how long the tool will last, the cost to operate, and how soon they will have to replace each laser, he explains. “If you have a continuous monitoring system with hundreds or thousands of sensors, those can be a real chore to replace.”
Blonshine regularly has clients that expect validation studies demonstrating the total cost per year of a tool, including the cost to calibrate and tweak settings, and the predicted expense of additional parts and replacement costs over a five-year period before they make purchasing decisions. “They find out that the cheapest model isn’t always the best in the long run, and neither is the most expensive,” he says. “They’ve learned the lesson that you get what you pay for.”
Blonshine has also seen increased demand for faster execution times in getting equipment up and running. “It used to be that installation of a particle counter system could take a year,” he says. “Now companies want the proposal in 30 days and execution with validation in 90 days.”
Hach’s customer surveys show that speed to operation is more important than customization and that the number two objection to upgrading the cleanroom is that it takes the room out of operation too long. “The faster they can get back up and running, the more appealing the upgrade becomes,” he says.
When ramp-up time is critical, cleanroom operators are forced to give up some of the customization they would have expected in the past and opt instead for an off-the-shelf system that can be installed and operational in less than six months.
“In the past, every system was unique. The cost and time to validate these systems was high and they each required their own documentation,” states Blonshine. “With a stock system, there is one set of documents for every installation. It’s faster and cheaper.”
Blonshine says that cleanroom operators are willing to give up the customized database systems and special formats for reports in order to get the cleanroom monitoring process operational in as short a time as possible. The generic systems also cost significantly less, cutting the final price in half in some cases.
Particle counter sales in recent years reflect this data. Blonshine estimates that 70 percent of his continuous monitoring particle counter system sales last year were for off-the-shelf stock packages with 10 remote sensors or less; while five years ago 70 percent of sales were for custom systems. “Companies are looking for ways to be more efficient in their manufacturing processes, and this is one of them.”
Small tools for small spaces
Particle counter manufacturers have also seen a dramatic rise in purchases of small handheld devices in response to U.S. Pharmacopoeia (USP) 797. USP 797 is a far-reaching regulation that governs a wide range of pharmacy policies and procedures. The regulation is designed to both cut down on infections transmitted to patients through pharmaceutical products, and to better protect staff working in pharmacies where they’re exposed to pharmaceuticals.
As a result of a recent revision, USP 797 now requires several new environmental controls and monitoring systems-that weren’t previously required-in pharmacies where compounded sterile preparations (CSP) are processed. These controls include particulate counting in all buffer and preparation areas for CSPs, which include injectable medications, biologics, inhalations, irrigations, and ophthalmic and otic preparations. Although typical convenience store pharmacies are exempt from this requirement because they outsource all of their CSP processing, many other pharmacies are not, especially those in large hospitals. However, few of them have the necessary environments to meet the requirements.
“Most of these pharmacies had no cleanroom spaces prior to this regulation change,” notes Troia. “It’s a huge issue and it has increased the market for smaller, handheld instruments.”
The solution for most of these pharmacies is to create minienvironments or to use barriers or isolators to create small-scale cleanroom conditions within the overall facility. Particle monitoring is an important part of that solution because it verifies that their clean spaces are up to code, Polen says. “The pharmacies know they need to have proven records of the tests they perform to meet these standards.”
“It is an onerous task,” Troia adds, “but we believe that more and more pharmacies will need to follow cleanroom regulations if they are going to manufacture products on-site.”
Moving beyond optical
Along with speed and performance, particulate size will continue to be a concern for many operators.
Controlling particulates in the cleanroom begins and ends with monitoring that tells operators whether conditions are ideal and when events happen that increase contaminants in the air.
Conventional particle counters deliver that service by counting airborne particles using optical lasers, either on a continuous basis or during daily sampling with portable devices. The counters draw air into the optical chamber where the particles in the air are sized and counted in real time, giving immediate information relating to contaminant levels.
Optical particle counters do not directly count particles. Instead, using lasers, they count flashes of light scattered by particles (or shadows cast by backlit particles) as they flow through the chamber.
Modern particle counters used for cleanroom certification typically have sensitivities of 0.1, 0.3, or 0.5 micron. Particle counters with greater sensitivity can count smaller particles, giving a more accurate reading of what exactly is in the clean-room air.
“Typically there are many more smaller particles than larger ones,” Belew says. For example, under ISO conditions a particle sensor with a sensitivity of 0.1 micron can count twenty-eight times more particles of that size than a 0.5-micron instrument can count of 0.5-micron particles.
But optical counters have their limits. When particles are smaller than 100 nanometers they do not reflect enough light from the laser to be measured by the optical particle counter.
As cleanroom industries set stricter limits on contaminants, the demand for monitoring of sub-100 nanometer particles will eventually overtax the abilities of the optical laser counters, notes Sam Balshe, sales support engineer for TSI (Shoreview, Minnesota). “Optical particle counters are very well accepted today, but semiconductor manufacturers have pushed the technology to its limits,” he says. “As they roll out new tools that utilize smaller line widths, they will need also to rely on condensation particle counters to monitor that environment.”
TSI manufactures condensation particle counters that use a completely different method to collect and count particulates. These counters can detect particles down to 10, 5 and even 2 nanometers. “We’re talking about particles that are 25 times the size of an atom,” says Paul Leslie, regional sales manager for TSI. “It’s graying the area between molecular gas and particles.”
Condensation particle counters absorb the air sample through a saturator where the particles are condensed using water or alcohol, making them two- to three-thousand-times larger so that they can be detected. “When you’re counting particles of this size, you want results to be very accurate. Not many other counters can do this,” Leslie says.
 The Handilaz Mini is an ergonomically designed, simple-to-use handheld that counts particles as small as 0.3 micron. Photo courtesy of Particle Measuring Systems. |
TSI has continuous monitoring systems using condensation particle counters that count particles down to 2 nanometers, as well as a handheld model that detects particles to 10 nanometers.
Currently, these devices are used primarily in climate research and biochemistry studies in which biological particles or viruses must be constantly monitored, however that could soon change. Pharmaceutical standards are setting stricter particle limits for safety, while semiconductor manufacturers continue to look for ways to remove even nanosized contaminants that can impact yield.
“There will be a trend toward condensation particle counters for semiconductor manufacturing. It’s the obvious next step,” predicts Leslie, who expects this particle counting technology to take hold in semiconductor fabs in the next two to three years.
“It won’t replace traditional particle counters, it will add to them,” Balshe adds. “It’s becoming part of the culture. As line spaces narrow, smaller contaminants need to be detected.”