New medicines bring new concerns for product and personnel protection, and the cleanroom industry is evolving to cope with these challenges in two key areas: pharmaceutical manufacturing and the compounding of sterile preparations (CSP) within hospitals and pharmacies.

By John Williamson

The life sciences industry, from manufacturers to compounders to the various regulatory and standards agencies involved, is in the midst of extraordinary changes, the end of which may never be in sight. Underlying this is the fact that drugs are becoming more complex.

“New treatments call for more aseptic potent or aseptic cytotoxic drugs, which can have an extremely adverse affect on personnel should they become exposed,” says Bill Friedheim, technical sales representative for Skan US, Inc. (Broomfield, CO). “At the same time, these drugs must be protected from contamination, the largest source of which is people.”

Shrinking spaces

It is an environment where laminar flow air benches and cabinets are becoming less relevant and where constructing traditional ISO Class 100 cleanrooms also often proves financially impractical.

“Cleanrooms can be expensive places, ranging from $200 to $2,500 per square foot in the life sciences industry,” says Richard Matthews, chairman of Filtration Technology, Inc. (Greensboro, NC). “Such expense is driving industry to look for better ways to enclose critical process areas into smaller spaces. Instead of classifying an entire room as a cleanroom, concentrate on those spaces where a controlled environment is critical. Self-contained, controlled clean environment enclosures around a critical core process are an economical alternative.”

The changing paradigm is causing new thinking in containment technology and how cleanrooms and cleanroom processes are incorporated into manufacturing and compounding sterile preparations.

“While all agree that protection is paramount, there is disagreement on terminology used to describe equipment involved,” says James Agalloco, president of Agalloco & Associates (Belle Mead, NJ). “For example, definitions of an isolator or a barrier can differ within the life sciences industry, across national borders, within applications such as hospitals and labs and even within a single organization.”

Among the life sciences terms used for containment devices are enhanced clean devices, barriers, isolation systems and restrictive access barrier systems (RABS) as distinguished from “cleanrooms” as covered under ISO 14644 standards.

The IEST, which serves as the secretariat to ISO Technical Committee 209, Cleanrooms and associated controlled environments, went through several iterations in developing ISO 14644-7, Cleanrooms and associate controlled environments-Part 7, which is the standard relating to these devices. The working group wrestled with a number of terms to describe what the standard covers and how the products differ from conventional cleanrooms. It settled upon the term separative devices, defined in the standard title as clean air hoods, gloveboxes, isolators and minienvironments.

“The standard purposely stayed away from being industry-specific,” Agalloco explains. “It was left to the users and equipment providers to iron out the details of just what is needed-while hoping they speak the same language.

“For example,” he says, “there is a difference between a barrier and an isolation system, although the isolation system can have a barrier. Barriers can be breached, like jumping the line for playoff tickets. But isolation systems are like Fort Knox, which can, but should not be, breached without very strict procedures. The weakness of a true isolation system is generally the use of gloves, also known as access devices. Thus, we compare the use of RABS to the ‘perfect’ isolator that, via total automation, functions independently of human intervention.”

RABS and isolators: An ISPE definition

In August 2006, the International Society for Pharmaceutical Engineering (ISPE) issued a definition describing RABS. Jack Lysfjord, vice president of consulting for the Valicare Division of Bosch Packaging Technology (Brooklyn Park, MN), chaired the ISPE definition committee and provides commentary on the differences between RABS and isolators.

“Both RABS and isolators serve as barriers between operators and the ISO Class 5 critical zones where fill-finish operations take place,” he says. “Both use rigid walls, glove ports and transfer ports for components. RABS are typically open on the bottom and provide product protection by airflow. In contrast, isolators provide product protection by overpressure or perhaps negative pressure for containment applications. RABS operate in an ISO Class 7 surrounding room and isolators in an ISO Class 8 surrounding room.”

Lysfjord notes that before beginning batch manufacture in a RABS there must be thorough high-level manual disinfection procedures for all non-product contact surfaces using an appropriate sporicidal agent. Isolators typically use an automated vapor high-level disinfection.

“While the design intent for RABS is to operate as closed at all times, operator intervention is permitted with product protection provided through the use of HEPA or other filters, a controlled unidirectional airflow and an upgraded local surrounding classification to ISO 5,” he says. “The intent is to always maintain ISO 5 in the critical zone.

“Some firms are using RABS that are never opened during operations and are achieving very good results,” Lysfjord says. “Others have RABS that, while operating closed, may have rare exceptional events that require opening of the enclosure. Such interventions create product risk and are considered deviations that must be documented so that any risk to the exposed sterile product can be assessed.”

Operators must be properly attired. System design and process control are as much a matter of how you do it as how you defend your position to the FDA during an inspection.

“It is important to view RABS as a concept for enhancing conventional equipment and tightening up procedures instead of making excessive equipment investments,” Lysfjord explains. “Although they are not as robust as isolators, they can provide initial capital cost savings and are certainly more advanced than traditional conventional cleanroom operations.”

Isolator process equipment systems are experiencing a paradigm shift in cost perception, Lysfjord says. “The system does much more to protect the product while saving other capital and operational costs. With isolators, the facility footprint is smaller, and multiple-line operation results in reduced personnel, reduced HVAC and utility costs and reduced gowning and environmental monitoring costs.”

Smart pharma design

Julian Wilkins, vice president and senior consultant for PharmaConsultUS, Inc. (Bridgewater, NJ), says factors reshaping the life sciences industry include trends toward live vaccines, small molecules, larger molecule combination and small-volume, high-value, highly targeted drugs.

“This means high-throughput manufacturing churning out millions and millions of dosages is becoming impractical,” Wilkins believes. “Constructing cleanrooms under the old operating standard to meet new market realities would cost and waste billions. Instead, we’re moving to highly flexible facilities that meet stringent standards while being tailored to small product runs.”

Put another way, the trend in pharmaceutical manufacturing is toward continuous small-scale production in facilities that will minimize the need for conventional cleanrooms.

The mini-cleanroom is geared to produce small-volume, high-value drugs as opposed to mass-produced products. “This is lean manufacturing,” Wilkins says. “It uses continuously running, closed-production equipment that is easy to monitor from the outside.” Major added benefits are substantial cuts in labor, gowning and other costs.

According to Wilkins, smart pharma design includes several continuous-output, isolator-based production lines that allow a stepwise increase to suit demand and a stepwise decrease as demand falls. “Such a scenario allows downtime without significant impact on throughput,” he says. “The lines are adaptable, so that they can be reconfigured for other products. Product-contact parts can be used for other compounds where science-based risk assessment is made, or can be product dedicated. With multiple mini-lines available, maintenance can be scheduled. The plant gains production flexibility because it does not rely on a single process system.

“Pharmaceutical production equipment must go through a design revolution,” Wilkins says. “For instance, little has been done in the oral solid dosage (OSD) area. OSD design would move away from the unit operations that our grandfathers would recognize. Closed systems would be used to provide a product environment, while the operator would be in a separate environment tailored to meet human comfort. The result would be a cleanroom-in-a-box using a fraction of the energy currently used in conventional cleanrooms.”

Wilkins says that the biotech industry-the architects, engineers, safety, compliance, R&D, QC, production, packaging and other personnel-must get on board with this thinking.

What’s the holdup?

Despite the apparent benefits of new aseptic processing systems, the industry has been slow to respond, especially in the United States. Sterling Kline, R.A., senior director of project development for Integrated Project Systems (Lafayette Hill, PA), says one of the reasons is that pharma failed to take ownership of the challenge.

“There’s an obligation in the pharma industry to achieve aseptic processing, and the reason is patient protection,” he says. “That is the position of the Food and Drug Administration (FDA), and it’s up to the manufacturers and compounders to prove that their processes achieve that end. It’s not up to the FDA to tell them how to make it happen.

“This was a hurdle,” Kline continues. “Although isolator technology was proven in Europe, the attitude of the FDA was ‘show me.’” This involved companies making financial and other resource commitments to prove the process. Today, however, there has been positive progress. For example, three pharma companies, the ‘LUM’ group (Lilly, Upjohn, Merck), stepped up to the challenge and made investments to prove the process, without a guarantee that the FDA would accept the findings. Today the FDA considers isolators, specialized barriers and robotic systems as among the advances in aseptic processing technology.

Another key aseptic operating issue was resolved with the reduction of vaporized hydrogen peroxide (VHP) cleaning cycles from eighteen hours to three. This provided a positive impact on system flexibility.

Internal struggles have also often impeded progress. “Decisions on achieving advanced aseptic processing can be hampered due to conflicting objectives within a company,” Kline says. “Management looks at financial performance and sees investment in a process it might not understand as a risk to that performance. This can lead to the position, ‘If conventional cleanrooms work, why change?’ Conversely, however, with the unit cost of some of today’s formulations reaching astronomic levels, the risk of losing a batch of drugs due to contamination can likewise be extreme.

“Summing up,” says Kline, “the challenge is to get people on board. The FDA accepts isolators as a means of achieving reproducible performance. Operating issues are being addressed. It comes down to the mindset of corporations and the people within; their attitudes, prejudices, being ‘risk averse’ and other notions of changing the way things are done.”

There’s no question that companies thinking about advanced aseptic processing face important decisions. Fortunately, more data is available to help them. Valicare’s Lysfjord says, “Looking at the big picture, designing and installing an advanced aseptic processing system must be well-thought-out, with the ultimate goal being validation by FDA and/or other agencies. We believe the best approach is a design of isolators and fillers where components work together while being fully integrated into the building power, HVAC and plumbing systems (see Fig. 1). System monitoring must be continuous. Similarly, personnel training is crucial in order to raise knowledge of cGMP aseptic processing to protect the product as well as containment of potent products to protect themselves.”

Compounding sterile preparations

IEST 146447-7 addresses “separative devices” from the perspective of pharmaceutical manufacturing. Compounding sterile preparations at the corner pharmacy, in the hospital, in physicians’ practice facilities and similar locations is addressed by United States Pharmacopeia Chapter 797 (USP <797>). It covers low, medium and high risk levels.

“Pharmacy compounders work in an environment substantially different from that of pharmaceutical manufacturers,” says Henry D. (Hank) Rahe, technical advisor for Containment Technologies Group, Inc. (Indianapolis, IN). “That’s because they take components from several sources and then manually sanitize them before compounding. Although the insides of the container are considered sterile, the outside of the container is not, due to touch contamination.

“Within this segment of the industry there are also a number of terms used to identify equipment,” Rahe explains. “Examples include isolators, barrier isolators, biological safety cabinets and aseptic compounding isolators. Whatever the name used, however, the objectives are similar to those on the manufacturing side-product and personnel protection.”

One firm, The Baker Company (Sanford, ME), uses the term isolators. “These replace open-fronted laminar flow cabinets in the aseptic preparation of drugs-mostly intravenous or parenteral-which are immediately given to patients,” explains David Eagleson, vice president of business development. “Positive pressure isolators are used for sterility assurance in instances where drugs do not pose a hazard to the pharmacy worker, whereas negative pressure systems are used where such exposure is hazardous.” The most common class of the latter are drugs used in chemotherapy.

Figure 1. An isolator system showing (from left to right) a rotary washer, a sterilization tunnel, an isolator with an accumulation area, filler and stopper insertion station, and a RABS hood with a capping station. Photo courtesy of Bosch Packaging Technology.Click here to enlarge image

“USP <797> provides guidelines for these activities, but changes are in the making,” Rahe says. “Since 2006, more stringent proposals have been under review by the industry, attracting hundreds of comments, many of which are not favorable. For example,” he points out, “there is a high level of questioning on the validity and science of proposed revisions. But what is consistent between the original 2004 guidelines and the proposed 2006 revisions is that isolators are not required to be in a cleanroom and that they are recognized as superior tools for compounding because they provide high sterility assurance levels. In short, they are proven in practice because they eliminate touch contamination.”

Although the debate on the proposed revisions is having an impact on investment decisions within organizations impacted by <797>, until such time as the 2006 revisions are adopted, the 2004 recommendations remain in effect. Rahe says, “Organizations expecting a ‘final product’ won’t see it happen. That’s because the final product is the USP process itself, which allows for annual changes.”

Biological safety cabinets

Biological safety cabinets are another member of the barrier and containment system family, sharing many attributes and similarly charged with protecting people, product and the environment from biohazards and cross contamination during routine procedures (see Fig. 2).

Figure 2. SterilchemGARD® III Advance° Class II, Type B2 total exhaust cabinet. Typical applications include toxicology laboratories and similar facilities where microbiology, cell culture and pharmaceutical procedures are common. Photo courtesy of The Baker Company.Click here to enlarge image

“This is becoming increasingly important,” says Baker’s Eagleson. “Protection is provided in Biosafety Levels (BSL) 1, 2, 3 and 4 corresponding to Class I, II and III cabinets, with the latter specified for high-risk (BSL 3 and 4) biological agents. Standards are set and periodic testing is administered by NSF International through NSF/American National Standards Institute (ANSI) Standard 49.

“The highest BSL levels of agents must be handled in a Class III cabinet operating under negative pressure and with gas-tight construction,” Eagleson says. “Supply and exhaust air must also be suitably treated to protect the environment.” Cabinets are fitted with rubber gloves to provide the highest containment reliability consistent with high-risk agents. Some Class III cabinets used in containment laboratories (BSL 3 or 4) provide aseptic conditions within the work area.

Design features

There are many sources for equipment used in advanced aseptic processing and the selection procedure can be extremely complex. Decisions, made with the help of experts, should focus on the processing to be accomplished, maximizing efficiency and flexibility, and complying with applicable standards. Several features can contribute to achieving these goals.

Equipment should be easy to clean and sanitize inside and out. Stainless steel, glass, high-performance scratch-resistant plastic and rounded corners contribute to this. Accessibility, spray guns, vacuum wands, well-placed drains and quick-drying capability are also pluses.

Conclusion

Choosing between conventional cleanrooms, RABS, isolators and their various configurations is not an easy task. As Kline notes, “Think of what you need to do, then design the process to make it happen.” Kline suggests setting up procedures in advance, focusing less on the building and more on the fact that you are making products. Isolator-based manufacturing can work in a variety of configurations, he says. “It works for vials and pre-filled syringes. Properly designed, it can work for mass production, and because it is easy to validate cleaning between batches, it works for generics and contract manufacturing.”

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Industry experience

Bristol-Myers Squibb’s Manatí Sterile Expansion Project in Puerto Rico provides an example of the thinking that goes into investing in a new aseptic processing system for parenteral manufacturing.

Robert Roy, associate director of global engineering, says design considerations called for incorporating new technologies in a multi-purpose facility producing both liquid and lyophilized products.

“We wanted four production cells, each capable of independent manufacturing capacity, and each capable of being taken off- line without impacting other cells,” he says.

Cell capabilities include formulation, primary packaging and ancillary support services such as autoclaves and parts washers. Although current cells are non-potent, future cells can accommodate potent products.

ISO Class 5 biological safety cabinets in a high-risk blood labeling operation. Photo courtesy of Radiology Services of Hampton Roads.Click here to enlarge image

After looking at cleanrooms vs. isolation technology, Mr. Roy said his team determined that the latter had matured to the point where it could be reliably deployed. “The next decision process was RABS vs. isolators,” he says.

There were three key considerations. “First,” Mr. Roy says, “the VHP decontamination schedule is validatable, reproducible and short-four hours in our case. In terms of facility layout, isolators eliminate the Grade A (ISO Class 5) space required around the RABS and the attendant gowning rooms. And third, in terms of operating factors, isolators eliminate manual sanitization and reduce the need for environmental monitoring.”

Ultimately, the Manatí team recommended isolators for the project. “Benefits include an improved compliance profile, product and personnel protection, expectations of reduced operating costs, and a validated VHP decontamination schedule-more effective and reproducible than manual sanitization,” explains Mr. Roy.

Another example can be seen in Amgen’s selection of fill/finish equipment at its facilities in Puerto Rico and Ireland. Stanley Cooper, executive director of corporate quality, describes the assignment as involving several aspects. “We wanted to conform to anticipated preferred technologies-including regulatory requirements-in effect in 2010 for aseptic filling of parenteral products,” he says. “We wanted a cost-effective solution leveraging the capabilities of modern technologies, and we needed to mitigate or eliminate the risks inherent in our current capability at least for three years post-startup.”

Cooper collected information needed to educate the company on several new aseptic fill/finish technologies. “These included isolators, RABS, cleanrooms, cleaning and sanitizing processes, operational requirements and startup/validation requirements. We found we had to overcome preconceived notions concerning these technologies,” he explains.

The Amgen team met with the FDA, manufacturers, industry experts, and pharmaceutical firms in the U.S. and Europe, created white papers, attended industry conferences, held group discussions and prepared a cost analysis of candidate technologies. Conventional cleanrooms, RABS and isolators were the areas of focus.

“Our team achieved consensus on a recommendation for isolator technology over RABS,” Cooper says. “The margin was small, and the fact that the industry is divided on the same issue was consistent with this finding. We also recommended an E-beam sterilization interface for decontaminating syringe tub overwrapping.”

Radiology Services of Hampton Roads in Chesapeake, VA, is a large, central nuclear pharmacy serving southeast Virginia and northeastern North Carolina. It supplies time-critical, sterile radiopharmaceuticals to healthcare facilities for use in disease diagnosis and treatment.

“Our intent, more than a year ago, was to evaluate our operation and make any engineering upgrades necessary to be in full compliance with USP <797>,” says manager and radiation safety officer John M. Tabb, Jr., RPh, BCNP.

Most of the firm’s radiopharmaceuticals are compounded with Tc-99m as the radioactive portion of the molecule. Tabb says, “These products are considered low-risk using USP <797> criteria: They are compounded from sterile components, prepared using closed system transfer and must be used within several hours.

At the other end of the risk spectrum, one of the specialty products they provide is radiolabeling of white blood cells (leukocytes). “This is a labor-intensive operation in which a patient’s blood is transported from the hospital to the pharmacy,” Tabb explains. “The leukocytes are separated from the platelets and plasma and radiolabeled with either Tc-99 HMPAO or In-111 Oxine, then returned to the patient’s hospital and injected back into the patient.” Radiolabeled leukocytes allow clinicians to identify an infective process. Says Tabb, “We perform a large number of these procedures and consider this to be among the highest risk operations that one could perform within the scope of our practice. We wanted to provide the best possible environment.”

Renovations called for enclosing the low-risk operations by using ceiling-to-floor vinyl flap curtains. As Tabb explains, this is because a requirement specific to nuclear pharmacy is the need for operators to move frequently in and out of the work area to elute medical generators supplying fresh Tc-99m sodium pertechnetate used in compounding. “Four banks of HEPA filters provide laminar flow to this ISO Class 7 work area,” he says. “Actual product preparation takes place within one of three ISO Class 5 biological safety cabinets.”

There were two design requirements for the high-risk blood-labeling operations. One was the ability to disinfect incoming blood shipping containers prior to their being introduced into the blood-labeling lab. This is performed before the container is introduced into the airlock, where the blood-containing syringe and documentation are removed from the outer packaging. The second requirement was to accommodate operator mobility within the blood lab, as blood components and radiopharmaceuticals must be transferred many times during the labeling process.

As Tabb reports, the new ISO Class 5 blood-labeling facility comprises eight banks of HEPA filters, an airlock, an anteroom, a new ceiling, new walls and floor covering, and stainless-steel cabinetry. The four existing ISO Class 5 biological safety cabinets were reinstalled and recertified.

Commenting on the design decision, Tabb explains, “One of the major considerations in safely handling radioactive materials is the detection of radioactive contamination and its containment, shielding, and clean-up. I believe that the unrestricted access to work space provided by a BSC makes it better suited to this function than a barrier isolator.”

We’ve all become accustomed to seeing the new Direct to Consumer (DTC) product advertising from pharmaceutical companies. I won’t give my opinion on the pros and cons of these. But there’s also a growing number of general image ads calling attention to the industry’s charitable assistance programs, the amount of new research being conducted and the many breakthroughs in treatments and even cures that have resulted. All good and all true, and also all clearly directed at improving the industry’s public image against a negative backdrop of continually escalating drug prices. As noted by Billy Tauzin, president and CEO of the Pharmaceutical Research and Manufacturers of America (PhrMA) organization, “The key is our ability to communicate, advocate and educate patients, physicians, health policy makers and the general public about this industry and how it works and the work it does.” And I agree with that also.

But beyond laboratory research and clinical trials, what does the general public, or healthcare practitioner for that matter, really know about what is involved in bringing consistently efficacious and safe drug products to market? Are they aware of how much more difficult this has become with the exponentially growing number of aseptically processed and packaged therapies? Do they have an appreciation of how hard the FDA and the industry work every day to make sure this is the case? Were I not myself professionally involved in studying the process, I’m quite certain I would not.

What we are all very knowledgeable about, however, are the consequences of inadequate attention to product-safety practices, regulation and enforcement activities-because we see it repeatedly casting an unwanted light on the food industry. Truly, here is an exception to the old adage that “there’s no such thing as bad publicity.”

In sharp contrast, however, rather than needing to hide from bad publicity, the pharma industry can instead showcase its ongoing commitment to product and patient safety by touting its investment in contamination control-in facilities, process equipment, monitoring tools, employee training, product testing, documentation and everything else that has been necessary to ensure the production and delivery of safe pharmaceutical products-and along with it, educate the public that there are very real costs associated with accomplishing this.

If the bio/pharma industry is actively looking for ways to improve its image, this would seem to be one obvious success story that could-and should-be told.

John Haystead,
Editor-in-Chief

First adopted by the semiconductor industry, fluoropolymer-coated stainless-steel exhaust duct has spread to many industries where corrosive vapors are generated

By Vincent Rocca, Fab-Tech, Inc.

The EPA’s Ruling 40 CFR1 and the National Fire Protection Association’s (NFPA) Standard 318 for Cleanrooms are affecting the way plant operators specify process ventilation systems. Manufacturers of one of the key components of these systems, the duct itself, are touting new materials of construction and innovations, which have been developed over the past fifteen years.

The evolution of one such specialized product, fluoropolymer-coated stainless-steel (FCSS) duct, began in the semiconductor industry in the early 1990s. Fires spreading through manufacturing buildings via ventilation systems made of combustible materials resulted in a string of catastrophic losses. Much of the work done at these sites was conducted in cleanrooms where corrosive chemicals were used and hazardous vapors were generated.

The role of the exhaust system is to safely transport these harmful vapors to devices where they can be rendered harmless and safe for discharge into the environment. The use of FCSS duct has now become the material of choice for this industry as it meets the extreme demands of both safety and corrosion resistance. And it is being discovered by other industrial sectors as well.

A material for broad applications

The choice of materials for a vent exhaust system is a function of the corrosive processes employed within the building. It is the role of the design engineering firm, working in conjunction with the architect and client, to choose the highest-performing, safest, yet most cost-effective materials.

Based on published data, ethylene-tetrafluoroethylene (ETFE) and ethylene-chlorotrifluoroethylene (ECTFE) coatings far surpass other materials in chemical resistance. And the stainless-steel tubing will not burn, collapse or leak. FCSS duct is 300 series stainless steel coated with a two-part (primer and top coat) fluoropolymer system then heated and “baked” to form a chemical and mechanical bond with the stainless substrate (see Fig. 1). Some manufacturers utilizing ETFE have developed proprietary primer technology that assures superior adhesion to the stainless steel, resulting in a coating that will not delaminate.

In evaluating the level of corrosiveness of a given application, it’s vital to consider the entire range of chemicals to which the duct system will be exposed. Even more important is the potential impact of chemical combinations. “It is also important to evaluate complex systems with several different types of process streams (e.g., reactor, storage tank, relief stream) discharging into a common header. Where vents from several sources are combined, it’s necessary to carefully consider all possible interactions between the different streams in terms of both chemical reactivity and flammability.”1

Fluoropolymers have a wide corrosion-resistant envelope to handle most chemical situations. Additional reasons for considering FCSS duct include robust mechanical strength; light weight; ease and speed of installation using rotating van stone flanges or EZ-type clamps; the ability to be field-modified (e.g., it can be shortened; nozzles or drain ports can be added); and it doesn’t need painting. Unlike FRP and other “glued” plastic systems, there is no need for grinding, sanding, prep work or the use of malodorous epoxies and heating blankets.

FCSS duct is priced competitively compared to other materials such as FRP, composite materials and PTFE-lined pipe. It’s important not only to compare per-foot costs but also to evaluate the total installed cost of the system, including the mechanical contractor’s labor and any related piping and sprinkler costs.

Even among the manufacturers of FCSS duct, there’s debate regarding the selection of ETFE vs. ECTFE. Both polymers fall into the range of partially fluorinated polymers, but ECTFE has a chlorine atom substituted for fluorine-a difference in molecular composition that has an effect on performance. Some believe fluoropolymer ETFE has a performance edge over ECTFE. “ETFE has better chemical resistance and higher temperature resistance, as determined empirically and supported by a sound basis in chemical principles. These primary advantages not only provide an extra margin of performance in chemical service, but also impart more consistent quality in daily production as well as allowing greater production flexibility for better customer service.”2

Safety benefits: Fire and smoke ratings

As in the semiconductor industry, hazards in other manufacturing segments that also use chemicals include fire or explosion due to the use of solvents, flammable liquids or dust, and the resulting contamination of production, storage, and cleanroom areas by smoke or other substances released by the fire. Corrosive fumes that can attack and penetrate ductwork can allow fugitive emissions and corrosive liquid to enter clean areas, resulting in an unhealthy and hazardous work environment for employees.

Figure 1: FCSS duct is 300 series stainless steel coated with a two-part fluoropolymer system then heated and “baked” to form a chemical and mechanical bond with the stainless substrate.Click here to enlarge image

Many building codes and insurance companies require ducting made of stainless steel or other noncombustible materials. In some instances, fiberglass and other combustible duct materials may be used but require the use of internal sprinklers. As stated in the NFPA Standard 318, “Exhaust duct systems shall be constructed of non-combustible materials or protected with internal sprinklers in accordance with 2-1.2.6. Exception: Ducts approved for use without automatic sprinklers.”3

The NFPA standard continues with a hierarchy of material preferences: “Considering fire protection issues only, duct materials listed in descending order of preference are: (a) metallic, (b) approved coated metallic or nonmetallic not requiring fire sprinklers, (c) combustible with internal automatic sprinkler protection.” The standard notes that “although most NFPA standards are not laws, they are widely accepted industry standards with considerable legal standing. Failure to comply with them can potentially put manufacturers in serious liability.” Factory Mutual (FM) approved stainless-steel duct, coated internally with a fluoropolymer, satisfies this requirement without the use and costs of an internal sprinkler system. FM is an affiliate of the insurance company FM Global and conducts extensive research in loss prevention.

Manufacturers of FCSS duct use FM Research’s services to earn the FM Approval mark, certifying the reliability of their products. FCSS duct is regulated and approved by FM Research Standard Numbers 4922 and 4910. With FCSS duct, structural integrity is maintained in the event of a fire. With extremely low flame and smoke characteristics (flame spread under 10, smoke generation under 15), these systems will not burn, melt or generate large quantities of smoke, an extremely important consideration in cleanroom and laboratory environments.

Chemical and life sciences

In 1998, EPA Ruling 40 CFR imposed strict new standards to reduce the quantity of air toxins released from chemical and pharmaceutical manufacturing sites. “The agencies rule was intended to reduce emissions of a number of air toxins and hazardous air pollutants (HAPs), including methylene chloride, methanol, toluene, and HCl. It was estimated at the time that the ruling would reduce air toxins by approximately 24,000 tons or 65% from contemporaneous levels.”4

Various technologies to comply with this ruling are available, but the two leading methods for reducing air pollutants are the use of either a regenerative thermal oxidizer (RTO) or a caustic scrubber system. In some instances, both technologies are used in tandem: a thermal oxidizer capable of incinerating a variety of emissions, including methylene chloride, acetone, ethanol, isopropyl alcohol, methanol and mineral spirits, and then a scrubber that can remove the resulting hydrochloric acid emissions from the thermal oxidizer’s outlet. FCSS duct is increasingly being used to safely carry these hazardous pollutants.

In chemical synthesis and formulation processes, the materials of construction for reactor vessels, process equipment and process piping include borosilicate glass, glass-lined steel, exotic alloys, and fluoropolymer. The equipment is usually an ASME pressure-rated type, capable of containing process liquids and vapors up to 150 PSIG, that incorporates a vent nozzle or relief device connection.

The manufacturing suite may have a general exhaust (or snorkel vent at individual equipment stations) for the area, but increasingly, pharmaceutical and biopharm facilities also incorporate large walk-in reactor enclosures and fume hoods that are tied into the process vent system. In applications where higher pressures and full vacuum are customary, fluoropolymer-coated, schedule 10, stainless-steel pipe (150 PSIG-rated) would be the choice for corrosive vent lines.

Where pressures involved are lower (to negative 18 inches of water gauge) for use with cleanroom exhausts, fume hoods, snorkels, walk-in reactor enclosures or biological safety cabinets (BSC) where corrosive fumes are present, less expensive FCSS duct, rather than pipe, would be the appropriate product choice. These low-pressure, low-vacuum duct systems are governed by SMACNA HVAC guidelines (see Fig. 2).

Figure 2: FCSS duct, rather than pipe, would be a good choice for applications requiring low-pressure ductwork. Shown here: ETFE-coated duct bringing corrosive fumes to a HastelloyTM scrubber.Click here to enlarge image

Additional areas for use of FCSS duct in pharma/biopharm applications include “clean air” supply duct systems feeding the cleanroom. Hot, corrosive, ultrapure water for injection (WFI) is used to set incoming air humidity levels. Some manufacturing facilities have experienced corrosion in their galvanized and even stainless-steel supply-air ducting from these hot WFI vapors. Coated duct is also impervious to harsh chemicals used to disinfect and sterilize cleanrooms and ducting. Chemicals used can range from sodium hypochlorite (bleach) to quaternary ammonia to phenols to formaldehyde-based products. Steam temperatures for sterilization can often exceed 120°C (248°F).

Medical devices

Another industry that has benefited from the use of FCSS duct is the medical device industry, specifically, manufacturers of drug-eluting stents. Stent manufacturing employs many of the same chemistries and protocols used in semiconductor production. For example, the etchants and rinsing agents used to fabricate semiconductor devices are very similar to those used to fabricate stainless-steel coronary stents. These hazardous materials must be monitored and safely controlled to prevent accidental release.

Stent manufacturer Boston Scientific’s newest facility, Weaver Lake 3, in Maple Grove, MN, is a two-story building incorporating a “mid-story” interstitial level for handling utilities. Long used in semiconductor facilities, interstitial floors are now also gaining acceptance in pharmaceutical, biotech and medical device manufacturing.

Figure 3: Coated duct was chosen for use as main exhaust lines, manufacturing area and lab hood exhausts in Boston Scientific’s Weaver Lake 3 facility.Click here to enlarge image

In the Maple Grove project, the interstitial space was equipped with an exhaust system with variable speed fans. FCSS duct was selected for the safe handling of corrosive exhaust. Approximately 2,000 feet of coated duct was installed in sizes ranging from 12- to 40-inch diameters for use as main exhaust lines, manufacturing area and lab hood exhausts (see Fig. 3).

Photovoltaics

Several photovoltaic (PV), or solar cell, manufacturers have also installed FCSS exhaust duct in their facilities to handle their corrosive exhaust requirements. One company has unveiled a new type of solar cell technology using thousands of tiny silicon spheres. Spheral Solar (Cambridge, Ontario) debuted its new manufacturing plant in June 2004. It is Canada’s first full-scale solar cell manufacturing facility.

Solar cell manufacturing also employs many of the same materials and protocols used in semiconductor production. For example, the etchants and rinsing agents used to fabricate semiconductor devices are very similar to those used to fabricate PV cells. Since PV manufacturing processes involve the use of highly corrosive, combustible and toxic chemicals and gases, double-contained chemical areas, hazardous-vapor sniffers and many cutting-edge safety devices were incorporated into the design of the new facility. For the safe handling of corrosive exhaust, FCSS duct was selected.

University nanotech and science centers

On university campuses, from Albany, NY, to Berkeley, CA, billions of dollars are being spent on construction of new nano-facilities. And it is also at these new and expanding nano-sites where manufacturers of FCSS duct have seen a significant increase in the demand for corrosion-resistant product.

Major corporations such as IBM, Fujitsu and Intel are also pouring vast sums of money into nanotechnology research, and the U.S. government, which lagged behind other nations, is now spending billions to catch up on the nanotechnology racetrack. Spurred on and financed in great part by the National Nanotechnology Initiative’s (NNI) $2 billion 2006 budget,5 more than 50 universities are either building or expanding facilities, or conducting research into nanotechnology.

Figure 4: CNSE has installed several thousand feet of FCSS duct on three nanotech cleanroom projects.Click here to enlarge image

One of the nation’s top nanotechnology sites is the College of Nanoscale Science and Engineering (CNSE) at the University at Albany. CNSE is the first college in the world devoted exclusively to the research, development and deployment of innovative nanoscience, nanoengineering, nanobioscience and nanoeconomic concepts. Its Albany NanoTech complex-a $3.5 billion, 450,000-square-foot facility-is the most advanced research complex of its kind at any university in the world.

Figure 5: CNSE has installed several thousand feet of FCSS duct on three nanotech cleanroom projects.Click here to enlarge image

Nanotechnology research employs many of the same manufacturing protocols as microprocessor manufacturing. For example, it requires that research and manufacturing be conducted in a cleanroom, and as in semiconductor manufacturing, nano-facilities use chemicals to harden an unexposed photoresist and then chemically etch it to selectively strip off an oxide layer where no photoresist protects it. Through the end of 2006, CNSE had installed several thousand feet of FCSS duct on three nanotech cleanroom projects (see Figs. 4 and 5).

Conclusion

Although FCSS duct is new to many industries, it has been successfully used in manufacturing for more than 17 years. It meets all the required design and operating criteria for extreme service when applied and installed according to the parameters for its intended use. If corrosive vapors and fire safety are a concern, FCSS could be the ideal solution. Professionals who design, build or manage laboratory and manufacturing sites that contend with corrosive and hazardous vapors can benefit by doing additional research into this new type of product.

Vincent Rocca is industrial sales manager for Fab-Tech Inc. (Colchester, VT). Previously, he held management positions with DeDietrich, Pfaudler and Resistoflex. He is a graduate of Seton Hall University in South Orange, NJ.

References

1. Ennis, Tony, “Collect and Destroy Emissions Safely,” Chemical Engineering Progress, May 2004.
2. Obals, W. Douglas, “Teflon Finishes in the Semiconductor Industry,” Cleanroom Technology, July 1999.
3. National Fire Protection Agency (NFPA) 318 Standard for the Protection of Cleanrooms.
4. Kudronowicz, Jeff, “RTOs Leave Nothing to HAP-penstance,” Pollution Engineering, April 1, 2005.
5. For more information, see http://www.nano.gov/.

Cleanroom packaging decisions should never be an afterthought

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Michael Fisher, president of Fisher Container Corp. (Buffalo Grove, IL), says it’s very easy for him to describe the market of his company’s “Precision Clean Products” division. “Wherever there’s a product manufactured in a cleanroom or some other contamination-controlled environment, and that product has to be shipped somewhere, even if it’s just across a hallway, we have a potential customer.” And that pretty much also explains the size and critical importance of the cleanroom packaging industry.

Figure 1. Precision Clean manufactures cleanroom bags, pouches, and materials used to package a wide array of cleanroom products.Click here to enlarge image

Precision Clean manufactures cleanroom bags, pouches and materials used to package a wide array of cleanroom products ranging from wipers and swabs to cleanroom garments, as well as products produced by a host of other contamination-sensitive industries including microelectronics and aerospace, medical devices, food and bio/pharmaceuticals (see Fig. 1). The total size of this worldwide market would be nearly impossible to estimate, but just looking at the world market for cleanroom consumable products, which is estimated around $5.7 billion, and culling out a conservative 3 percent for packaging, results in $175 million for just this segment.

Fisher observes the cleanroom packaging industry has come a long way since he first got into this segment of the business some 23 years ago. “In general, customers have become much more serious and concerned about doing things the right way relative to their cleanroom packaging. They’ve also become much better educated to their particular industry’s cleanliness requirements.”

The reasons behind this evolution have more to do with the amount of information available to customers than changes in the products being packaged, says Fisher. “Today, specifications are well defined and technical data is easier to obtain. Unlike the situation years ago, when users had to rely on a lot of vague and unsubstantiated claims, today they can really evaluate and compare products (be it a swab, wiper, garment, etc.) and know that what they’re getting is a true example of what a provider is consistently producing.”

This change has clearly had a parallel impact on the cleanroom packaging industry as well. “Packaging manufacturers can’t just send out product anymore with false claims and sketchy descriptions that don’t really meet the specifications required by the user industry,” says Fisher. To make his point, he points out that today Precision Clean manufactures its cleanroom bags and packaging materials in an ISO Class 4 (Fed. Std. 209E Class 10) cleanroom and certifies its products to specific surface cleanliness levels (see Fig. 2). Precision Clean was also the first cleanroom packaging company to be ISO-certified (ISO-9001-2000).

Prescribing the right package

Another significant change in the cleanroom packaging industry is the number of different packaging options that are now available, and with them more choices and decisions for the user. Choices include multiple packaging types and film materials, various thicknesses (gauges) of films, different types of seals or closures, printed or unprinted, testing parameters and protocols, and of course, price points.

Making the best choices for a particular product can be a daunting task, particularly for those new to the technology. To help them through the process, Fisher says they basically assume the role of a no-fee industry consultant. “We do a full evaluation of each customer’s specific requirements and desires starting with basic questions like, ‘What’s it used for and where’s it going? Is it fragile and does it have sharp edges?’ Then, we look at specific requirements such as cleanliness level, package clarity, printed or plain, desired seal type, sterilization method, etc. From this information, our policy is to prescribe exactly what is needed-not less, but also not more.”

As a routine part of any new package-development process, customers are asked to provide samples of the product to be packaged. “Usually, as a minimum we request two sets of the items that will go into the package,” says Fisher. “Using these, we go ahead and mock up a package to demonstrate and discuss with them.”

This is not always possible, however, as it’s not uncommon for customers who are just ramping up a new product to be unable, or unwilling, to submit a finished piece. In these cases, the package design and specification job becomes much more difficult. “Working only with drawings, it’s difficult to confidently prescribe material and gauge, and also cleanliness levels. We can guess, and will do the best we can with the information provided, but always with the caveat that it is an educated guess until we see the actual product.”

Although Precision Clean tests and verifies that its materials and products meet accepted industry specifications, ultimately, customers must take ownership of the agreed-to packaging solution and perform the necessary testing to ensure the materials and specifications fully meet their needs for the intended use, and that their usage procedures are also appropriate and adequate. For example, as Fisher points out, “A package is only as good as its shipping container. If the final packaging doesn’t complement ours, you take out all the beneficial engineering that we put into the package design.” Customers are asked to perform a stress shipping test to ensure this compatibility.

New packaging, new equipment

Cleanroom packaging requirements continue to evolve and, as Fisher points out, many of his company’s new development products have come from customer inquiries and requests for special capabilities or features. Making many of the new packaging options possible is the company’s new lamination and pouch machine equipment (see Fig. 3). “This new equipment allows us to address a wider range of requirements with more products for a greater variety of applications.” In particular, Fisher notes that outside the realm of conventional cleanroom products, cleanroom packaging requirements often demand not only cleanliness and/or sterility, but also protection from other external factors such as oxygen, moisture or UV light.

For example, Precision Clean now offers a line of autoclavable bags for cleanroom-suitable products that also require sterilization, such as stoppers, vials, ampules and other products. The line is composed of 100 percent breathable Tyvek® on two sides, offering significantly faster sterilization cycle times.

In contrast, the company’s “Barrier” bags are manufactured with a foil lamination specially designed to protect products from moisture and oxygen, or to retain moisture in the packaged product. The bags have a typical moisture vapor transition rate (MVTR) of 0.006 g/24 hr/100 in2. Also available are ESD, UV-inhibitor, and flame-retardant anti-stat films.

The new machinery gives Precision Clean the ability to combine different material types (nylon/poly, saran, foil/polypropylene, Tyvek/polyethelene, etc.) into an array of unique pouch types, as well as to offer different seal or construction options. “For example,” says Fisher, “if, instead of tearing open or cutting open a product, I want it to peel open as a sterile presentation, I can use different materials with different sealing temperature points. Instead of adhering like a weld, these pouches peel apart smoothly without generating large amounts of particulate matter.”

Figure 2. Precision Clean manufactures its cleanroom bags and packaging materials in an ISO Class 4 cleanroom.Click here to enlarge image

Looking ahead, Precision Clean plans to soon roll out the industry’s first zip-lock bag certified for ISO Class 5 (Fed. Std. 209E Class 100) applications. The company has already produced its first samples and is compiling test data to support the product launch. Fisher says the bags will be targeted at laboratory scale and other relatively small applications. “There are a number of applications where people want to be able to go into a package, take some product out, and securely seal it up again. Using our ‘Precision Zip Clean’ bags, people will be able to do this.”

Clean printing

Not so long ago, the notion of bringing the potential contamination problems associated with printed products into a cleanroom environment, let alone part of an actual printing process, seemed foolhardy. Today, however, it is commonplace to see print-branded products, from multiple vendors, in all levels of cleanrooms.

Fisher says Precision Clean was one of the first companies to print cleanroom packaging. “From our background in retail packaging, we recognized and pointed out to our cleanroom customers the value of being able to market their products not only on the basis of their cleanliness levels, packaging advantages, support, etc., but also the brand recognition benefit that would result from users being able to readily identify whose products were actually being used in cleanroom environments. The challenge was overcoming their fear of adding particle burden to the outside of the package.”

At Precision Clean, the solution involves printing the outside of clean materials in a non-clean-certified area, then running the finished product through a special cleaning process to clean it to a level acceptable to the cleanroom industry. As explained by Fisher, “You can always print a bag in a clean manufacturing environment, but it’s virtually impossible to do it with cleanroom results. You have to ensure that the inside of the package is, and remains, clean, and that the outside doesn’t carry any additional foreign particulate matter into the cleanroom.”

The cost factor

Cost, of course, is nearly always an important factor for customers. But this has to be carefully weighed against the risk of possible compromise to a product’s cleanliness requirements and other factors. As noted by Fisher, there is a cost associated with certified cleanliness levels, and “we can’t really make our cleanroom packaging line operate in a less clean mode so that someone’s particular product can be less expensive. It doesn’t work that way.” The parent company, Fisher Container Corp., however, does address lesser requirement levels with a range of other products. “We’ve developed product solutions for those industries or applications that don’t have such rigid requirements, but that still consistently meet the cleanliness requirements they do have at a satisfactory cost point.”

Figure 3. New lamination and pouch machine equipment enable Precision Clean to offer more packaging options.Click here to enlarge image

Even change itself can be problematic in an industry (or industries) where a simple change in package appearance, whether neutral or even beneficial, can raise questions and red flags among users. Fisher notes this is particularly true for highly regulated industries such as pharmaceuticals. “Something as simple as changing gauge will require everything to be re-evaluated and field-tested from beginning to end. You have to carefully weigh the cost of taking something out of spec against the cost of recertifying.”

As a final word of advice, Fisher notes that a common pitfall many customers fall victim to is waiting until the last minute to begin investigating their packaging needs, adding that this is ironic since “without the packaging, the product isn’t going anywhere.” To avoid a last-minute scramble, he recommends people budget enough time to learn about, evaluate and test packaging materials and options and still allow themselves enough leeway to meet their customers’ delivery schedules.

Considerations for selecting and operating a particle counter

By Ross Bryant and Roger Carlone, Particle Measuring Systems

High particle levels in process chemicals have been shown to directly affect product quality. The need for continued reductions in particle size and quantity in cleanroom environments is well established. The International Technology Roadmap for Semiconductors (ITRS), sponsored by the United States Semiconductor Industry Association (SIA), defines the need for persistent decreases in particle levels in process gases, water, chemicals, and air in order to meet future generation technology nodes. The ability to accurately measure these contaminants is the first step in developing a comprehensive particle control plan.

Principles of operation

Although numerous techniques are available to monitor and characterize particulates, most require significant off-line analysis and interpretation. This usually reduces the number of measured samples, resulting in fewer data points and time-delayed results. Liquid particle counters (LPCs) are widely used for continuous on-line monitoring of process chemicals. Proper selection and implementation of an LPC are important for ensuring data integrity.

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Although the design, performance and specifications of LPCs may differ, a few key principles remain the same. First, particle counters do not directly count particles. Particle counters, based on light scattering, are designed to measure the equivalent optical size of particles as referenced against a calibration standard. In most cases, that standard is a polystyrene latex sphere (PSL). These are readily available and National Institute of Standards and Technology (NIST) size traceable.

Laser light, with wavelengths usually between 600 and 800 nm, is used to illuminate the sample cell or capillary. As individual particles traverse the laser beam, light scattering occurs because of the index of refraction difference between the transport media and the particle. The amount of scatter depends on many factors, but is largely dependent on the particle size, shape and index of refraction. Scattered light is then collected and focused onto a photodetector, where the signal is converted into an electronic pulse (see Fig.1).

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The dashed lines (see Fig. 2) represent the voltage values or channels defined for each particle size during calibration with PSLs. Each pulse represents an individual particle, while the magnitude of the pulse determines its size by comparing the PSL equivalent amount of scatter.

Selecting the right instrument

There are a few key things to consider when selecting a particle counter for your application:

• sample volume
• resolution
• sensitivity

Sample volume: LPCs can be classified as either volumetric or non-volumetric. The terms refer to the sample percentage illuminated by the laser beam in the sampling region or capillary during operation.

In volumetric counters, the beam is shaped such that its intensity is mostly uniform across the capillary. Because the energy intensity profile of a laser is Gaussian-shaped, the beam span in volumetric counters is significantly wider than the capillary. This has the effect of producing a uniform beam so that the traversing particle is exposed to the same amount of light energy regardless of where the particle is located in the flow path, improving resolution. Since 100 percent of the capillary is uniformly illuminated, all particles larger than the sensitivity limit of the instrument are counted. State-of-the-art volumetric counters can detect particles as small as 0.1 μm. These are used to monitor process baths, for incoming quality control checks, as well as for some process chemicals.

Figure 3. The Liquistat is an example of a volumetric particle counter.Click here to enlarge image

In order to increase the sensitivity of an LPC, the background light scatter from the capillary must be eliminated. By removing the capillary, the laser beam is then focused and shaped in such a way that only a very intense portion of the beam illuminates a very small portion of the total flow, greatly improving the signal-to-noise ratio. The result is a significant improvement in instrument sensitivity. State-of-the-art non-volumetric counters can detect particles as small as 0.05 μm; however, the decrease in sample volume greatly reduces resolution. Non-volumetric counters are typically only used to monitor DI water and some extremely clean process chemicals. These counters tend to produce poorer instrument-to-instrument matching and should only be compared using total cumulative counts.

Resolution: Resolution is defined as the ability to distinguish particles of various sizes. For example, an instrument with very good resolution, a spectrometer, would be able to resolve the difference between a 0.8 μm and 0.9 μm particle. Instruments with average resolution would consider the particles to be of similar size. Volumetric counters provide great resolution and, hence, offer a large number of user-selectable size channels. In contrast, many non-volumetric counters offer a few very broad size channels that are manufacturer-defined.

Sensitivity: Sensitivity is defined as the smallest detectable particle size for a given instrument. End users often request the instrument with the highest sensitivity. This is usually impractical for two reasons. First, only a handful of process chemicals are truly clean enough to justify the highest level of detection. Second, incremental improvements in sensitivity require a significant improvement in signal-to-noise ratio, increasing instrument costs.

Data quality assurance

After carefully considering the factors influencing the proper choice of a particle counter, the next step is the implementation process. Experience has shown that this process is often overlooked. Follow the steps outlined below to be sure that the results from an LPC are stable, accurate and repeatable. These recommendations should be viewed in their entirety. Unless all aspects are considered, the data may be suspect.

1. Sample point
2. Filtration
3. Particle size distribution
4. Flow rate control
5. Coincidence loss and saturation
6. Background scattering
7. Zero counting
8. Bubbles
9. Molecules and colors

Sample point: Thought should be given to the particle monitoring location in the process flow. All components that contact the process chemical, such as valves, tubing, filters and pumps, will contribute particles, sometimes significantly. Only high-quality fluid components should be used where particle levels are monitored. Numerous methods exist for monitoring process chemicals in a manufacturing environment.

For continuous online monitoring, LPCs are typically located downstream of most filtration processes and tend to provide the most stable and repeatable results. Whenever upstream components are changed, the system should be given ample time to clean up before particle monitoring is continued.

Off-line batch sampling requires special attention, as sample containers and handling can cause poor data repeatability and reproducibility. It is important to be able to demonstrate clean and repeatable background counts with DI water before the chemical of interest is sampled.

Filtration: It is always recommended that process chemicals be filtered below the sensitivity limit of the particle counter whenever possible. Because particles slightly smaller than the sensitivity limit can affect background scattering, and potentially coincidence, a good manufacturing practice should include filtration well below the sensitivity limit.

Particle size distribution (PSD): Years of particle counting and customer data analyses show that most ambient particle distributions in continuously filtered liquid systems follow a D-3 size distribution (where D = particle diameter) on total cumulative counts. Figure 4 shows a typical particle distribution in liquid systems. In extremely clean DI water systems, the distribution can be steeper (D-4), and in dirty systems, the distribution can be flatter (D-2). It is equally important that the distribution remain consistent from sample to sample.

When analyzing particle data, it is essential to ensure that this type of particle distribution is present. Deviations from this type of ratio should immediately alert the user to a potential problem.

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Flow rate control: All LPCs have a flow rate specification and are calibrated at a precise flow. This means that real-world particles are intended to pass through the particle counter at the calibrated flow rate. If the proper flow rate is not maintained, both sizing and counting accuracy are compromised. The resident time of a particle, as it traverses the laser beam, has an appreciable effect on the amount of light scattered. If the flow rate is set too high, the electronics do not have sufficient time to fully integrate the signal, compromising sizing accuracy. Counting accuracy is also compromised because the resulting signal is now too small to exceed the particle size threshold. Further complicating the issue, the accompanying software is normalizing the data to the calibrated flow rate. Conversely, if the flow rate is too slow, the transit time is increased, and the particle appears to be larger than its actual size. It is critical that each LPC is controlled to the calibrated flow rate.

Figure 5. Particle Measuring Systems’ “CLS-700T” is an example of a bubble compression system.Click here to enlarge image

Coincidence loss and saturation: Because they are designed specifically to detect and analyze a single particle at a time, LPCs are often referred to as single particle optical sensors (SPOS). Situations in which more than one particle traverses the laser beam are possible in process chemicals with high levels of particles. In these cases, multiple traversing particles could be counted as a single large particle, or undercounting could occur if these particles are aligned in the beam pathway. This is defined as coincidence loss and varies by instrument type and manufacturer. For example, the specification may be 10 percent coincidence loss at greater than 10,000 particles/mL. This means that 10 percent of the particles are being lost at this concentration. Also, this phenomenon is not linear or predictable enough to make conclusions about the actual total number of counts once the manufacturer’s maximum concentration is reached. This can be seen in the data by looking at differential counts and observing a flattening of the distribution at the smaller size channels. If the concentration becomes too great, the instrument electronics themselves become saturated and can no longer integrate each pulse independently, leading to numerous errors.

Background scattering: Contamination of the capillary walls is the leading cause of excess scattering in LPCs. If the capillary is severely contaminated or scratched, the amount of scatter coming from it can equal the amount of scatter from the smallest detectable particle size. There are typically two ways to recognize whether this is occurring. First, the accompanying software reports the amount of background scatter, and each LPC has a specification for this value. Once the value has been exceeded, the collected data should be considered suspect.

Additionally, this can often be seen in the data. If the amount of scatter from contamination equals the amount of scatter from the smallest detectable particle size, there will be an excessive number of counts in the first size channel. This will shift the PSD further to the left, resulting in a significant departure from the typical D-3 relationship.

Zero counting: A technique known as zero counting is a good troubleshooting tool for process chemical monitoring. DI water is typically much cleaner than process chemicals and can therefore be used to baseline your instrument. Once you have an established baseline, at any point you suspect a problem, you can rerun the zero count test for instrument verification.

Bubbles: Bubbles in liquid systems will scatter light due to the index of refraction contrast between the liquid media and air. Usually, the amount of scatter is significant enough to be recorded as a particle, especially in the larger size channels. Bubbles can come in two forms: naturally occurring bubbles due to dissolved gases and process chemistry, and artificially created bubbles due to poor handling techniques. Issues with naturally occurring bubbles can be exasperated by the action of creating vacuum during syringe sampling. On-line or compression LPCs should be used in these circumstances. Poor handling of viscous chemistries, or chemicals with high levels of surfactants, can generate bubbles. The best method of dealing with this is preventing bubbles from forming in the first place by improving handling practices.

Molecules and colors: Other concerns with chemicals can include very large molecules, fluid color, or miscibility. These phenomena can scatter light, which may further complicate obtaining reasonable results with an LPC, making it that much more important that the appropriate particle counter be used and that the user fully understand the results being generated.

Conclusion

Selecting the appropriate LPC, and generating quality data, is critical for process control. It is also important to match the appropriate LPC sensitivity, type and sampling technique to the chemical of interest. Additionally, users must understand the fundamentals of optical particle counters and the properties of their process chemicals to ensure a valid measurement.

Ross Bryant is the application engineering manager at Particle Measuring Systems. He has more than 10 years of experience in the semiconductor industry related to metrology and materials research. He has a BS in chemical engineering, an MS in materials engineering, and an MBA. He can be contacted at (303) 419-2128 or via e-mail at [email protected].

Roger Carlone is an application engineer at Particle Measuring Systems. He has worked at PMS for more than six years specializing in liquid, part cleanliness testing and slurry applications. He has a BS in chemical engineering from the University of Texas at Austin. He can be contacted at (303) 944-9130 or via e-mail at [email protected].

References

1. Nishi, Y., and R. Doering, Handbook of Semiconductor Manufacturing Technology, Marcek Dekker, 2000.
2. International Technology Roadmap for Semiconductors, www.itrs.net (ITRS 2006).
3. Carlone, R., “Troubleshooting for Liquid Particle Counting,” Application Note 72, 2006.
4. Terrell, E., J. Gromala, and D. Beal, “Understanding Liquid Particle Counters,” Particle Measuring Systems, Boulder, CO, 2005.

IEST-RP-CC013.2, Calibration Procedures and Guidelines for Select Equipment Used in Testing Cleanroom and Other Controlled Environments, addresses aerosol photometers and Laskin nozzle aerosol generators in detail

By David W. Crosby, Air Techniques International, and Chair, IEST Working Group CC013; and Keith Flyzik, Micro-Clean, Inc., and Secretary, IEST Working Group CC013

The Institute of Environmental Sciences and Technology (IEST) has released its revised IEST-RP-CC013.2, Calibration Procedures and Guidelines for Select Equipment Used in Testing Cleanroom and Other Controlled Environments. This document provides detailed procedures for calibrating aerosol photometers and verification of Laskin nozzle1 aerosol generators, as well as “common sense” care and use guidance for general test equipment used in controlled environment testing.

Introduction

The original recommended practice (RP) was released as a tentative publication in 1986. In 2005, David W. Crosby was elected as the new chair of the WG, succeeding previous chairs Robert I. Gross and Dr. Charles Montague. With help from the WG secretary Keith Flyzik, as well as the highly motivated membership of the WG, all the necessary components of the newly revised document were completed and subsequently published in October 2006 as IEST-RP-CC013.2.

The Document

IEST-RP-CC013.2 begins with general guidelines for calibrating instruments and provides a list of instruments commonly used in cleanroom certification, including recommended calibration intervals. The document also provides guidance for transporting and packaging instruments and also includes a procedure for anemometers. It addresses both Laskin nozzle and thermal aerosol generators, as well as both linear and logarithmic photometers. Generic calibration procedures are also provided along with a sketch of a 100 μg/L aerosol source, which is important in calibrating a photometer’s internal aerosol reference feature. The appendix lists most other instruments currently used in cleanroom certification and, where available, relevant instrument calibration references to appropriate national standards (ASTM, ISO, etc.).

Calibration guidance for the aerosol photometer consumes a majority of the newly published document. In a world of lasers, solid-state microprocessors, and emerging technologies, it is still amazing that the basic principles of operation of the aerosol photometer and Laskin nozzle aerosol generator have not changed significantly over the decades. Although many current production aerosol photometers now have microprocessors, digital displays and monitoring circuitry, most still rely on a photomultiplier tube-a vacuum electron tube-as the light detector.

Although the document provides the basic calibration procedures used by a variety of photometer manufacturers and calibration groups, it does not contain “how-to” guidance for specific model adjustments, alignments or diagnosing problems. That information is available by consulting individual manufacturers, attending specialized training and, in cases of problem diagnosis, from years of experience.

While IEST-RP-CC013.2 is important to the cleanroom and HEPA-filter testing industries, it is crucial to those involved with testing and certification of Class II biological safety cabinets (BSCs). The aerosol photometer is the only approved instrument listed in NSF/ANSI 49-20042 for performing the HEPA Filter Leak Test. This is mainly due to the fact that most photometers are equipped with an internal reference function to simulate a known aerosol challenge. This allows the certifier or tester to leak-test the HEPA filter without taking an upstream concentration, thereby preventing exposure of personnel, equipment and environment to potential contaminants trapped in the upstream plenum of the filter.

Verification of the operation of the Laskin nozzle generator becomes increasingly important when testing HEPA-filtered devices where an upstream challenge is either impractical or impossible due to safety concerns. The new RP provides detailed guidance on this procedure.

Those individuals involved in the NSF Biosafety Cabinet Field Certifier Accreditation Program should become familiar with IEST-RP-CC013.2 since it has historically been a study reference for the written examination and will have applications in the practical examination.

Finally, there is a “common sense” appendix that discusses proper instrument care. Much of this experience and many of these practices are a collection of simple guides obtained from decades of test equipment use and repair knowledge. The intention of the WG was to present these guides or care rules to prevent lessons from being learned “the hard way.”

The future

The WG plans to continue to create informative calibration procedures for equipment lacking industry-acknowledged calibration methods. However, it has no wish to compete against other organizations with previously established and available calibration procedures. In such cases, published calibration procedures would be referenced in an informative appendix for each type of equipment used in testing cleanrooms and controlled environments. The intention is that the RP become a single-source reference document for calibration resources. Although the listings in the current version are by no means complete, the document makes an effort to provide current and available information to those needing it most (i.e., calibration organizations, regulatory authorities, quality assurance groups, and test equipment end users). With the December 2005 publication of ISO Standard 14644-33, WG-CC013 has its work cut out for itself: to investigate calibration methods for equipment referenced in the document, which will allow for global application of IEST-RP-CC013.2.

The RP has also become a “nursery” for new test methodology. Just recently, the IEST established WG-CC042, Liquid-borne Particle Counting, to address issues involving liquid-borne particle counters (LPCs). The idea had its origins during WG discussions and deliberations. Other new WGs may follow depending on interest, participation of qualified and experienced volunteers, and the needs of the contamination control industry.

Although we are beyond merely “scratching the surface” on calibration procedures for cleanroom and other controlled environment testing equipment, we are nowhere close to being finished with the job. We ask for comments or suggestions on this latest version of the RP but, most of all, we ask for your active participation in moving this document to the next level. We invite anyone with a real interest in developing calibration procedures to attend future IEST working group meetings.

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David W. Crosby has been active in the air filtration and respirator industry for more than 40 years. He started with Air Techniques International in 1962 and currently serves as vice president and manager of the ATI Test Laboratory. He has managed and been involved with design, engineering, quality control and government contract administration. He holds degrees in electronics, heating/air conditioning/refrigeration and business management. Crosby is an active member of the IEST, the International Society of Nuclear Air Treatment Technologies, the American Society of Mechanical Engineers and the Controlled Environment Testing Association. He currently serves on IEST working groups 001, 002, 006, 007, 019, 021, 034, and chairs 013.

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Keith Flyzik is technical liaison and training manager for Micro-Clean, Inc. where he is responsible for all training programs for technical personnel and customers as well as keeping personnel current on regulatory agency issues and guidelines, industry recommended practices and equipment manufacturer specifications. In his 16 years with Micro-Clean, he has also held positions of certification technician, calibration technician, technical services manager and quality assurance manager. As an active member of IEST, Flyzik serves as the secretary for WG-CC13 and holds voting-member status on numerous other contamination control work groups. He is also a member of the Controlled Environment Testing Association, serving on the Cleanroom, Isolator Guide and Isolator Testing committees.

About IEST

Founded in 1953, IEST is an international technical society of engineers, scientists and educators that serves its members and the industries they represent (simulating, testing, controlling and teaching the environments of earth and space) through education and the development of recommended practices and standards. IEST is an ANSI-accredited standards-developing organization; Secretariat of ISO/TC 209 Cleanrooms and associated controlled environments; Administrator of the ANSI-accredited US TAGs to ISO/TC 209 and ISO/TC 142 Cleaning equipment for air and other gases; and a founding member of the ANSI-accredited US TAG to ISO/TC 229 Nanotechnologies.

References

1. Echols, W. H. and J. A. Young, “Studies of Portable Air Operated Aerosol Generators,” U.S. Naval Research Laboratory (NRL) Report 5929, Washington, DC, 1963.
2. NSF/ANSI Standard 49: Class II (Laminar Flow) Biosafety Cabinetry, NSF International, Ann Arbor, MI, www.nsf.org.
3. Cleanrooms and associated controlled environments-Test methods, International Organization for Standardization, Geneva, Switzerland.