Over the next five years, there will be a 65 percent increase in air filtration product sales into the electronic fabrication industry, according to industry analyst firm The McIlvaine Co. For bioclean applications in the pharmaceutical and biotech industries, McIlvaine is forecasting sales growth of approximately 38 percent over the same time period.

In its online report, “Air Filtration and Purification World Markets,” The McIlvaine Co. forecasts the world market for H10-U17 filters for HEPA and ULPA applications to reach $1.3 billion by 2012, compared to $930 million in 2007. The report cites Asia as the biggest growth market for HEPA and ULPA filters, with 2012 expected to reach $533 million or 42 percent of sales (in terms of dollars).

“By tracking trends in the electronics, pharmaceutical, and biotech industries we are able to forecast sales of HEPA and ULPA filtration products. Right now, we see Asia as the strongest growth market for electronics applications,” states McIlvaine Co. president Robert McIlvaine.

The McIlvaine “Air Filtration and Purification World Markets” forecasts allow subscribers to breakdown forecast data by product class, industry, country, continent, and world region.

2012 sales forecasts for HEPA and ULPA filters sales in the electronics industry for the “top 10” countries are (all US$) South Korea, $76.3 million; Taiwan, $76.3 million; Japan, $75.4 million; United States, $66.4 million; China, $25.7 million; United Kingdom, $17.0 million; Germany, $10.6 million; France, $7.1 million; Russia, $5.7 million; and Singapore, $5.5 million.

Allied Minds, a Boston-based pre-seed investment firm specializing in early stage university business ventures, has established RF Biocidics, Inc., to develop and commercialize a novel disinfectant and disinfestant technology invented at the University of California

By Bruce Flickinger

End users need to juggle product and worker protection, comfort, utility, and cost-effectiveness in making the right choices about specialist laundries and cleanroom garmenting programs.

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Any tailor will tell you that the signs of quality clothing can be found in the details, and the same can be said of cleanroom garments. In this analogy, companies such as Nitritex Ltd. (Newmarket, UK) are the high-tech haberdasheries, manufacturing cleanroom garments and apparel items to very high technical standards for customers operating a variety of demanding research and manufacturing environments.

“The construction of the garment is extremely important to ensure its effectiveness when worn in the cleanroom,” says Richard Bryant, Nitritex group sales director. “The fabric needs to be chosen carefully and be thoroughly technically specified to ensure it does not cause contamination in the finished garment. Each component–studs, thread, fabric, zippers–should be non-linting and made of non-plated stainless steel. Seams should be enclosed using continuous polyester thread at no less than 12 stitches per inch.” Garment edges usually are serged; that is, chain-stitched using two or more threads that form an overcast edge on a fabric.

Despite many advances in construction and fabric technology, the primary objective for cleanroom garment systems remains unchanged: to capture and entrain particles to prevent them from being dispersed externally and making contact with equipment or product. These contaminants largely are generated by the human body, including bacteria and yeasts, hair, dead skin cells, dandruff, and even elements such as sodium, potassium, chloride, and magnesium. It bears repeating here that people are the most significant source of contamination in cleanrooms and ancillary facilities.

But people also need to be protected, and a second but equally important function of cleanroom apparel is protecting workers from hazardous materials.

Risk assessments are used to ascertain the types and degree of worker protection required in a particular environment. Chemical splash protection is often needed, and difficult-to-control chemical flow or vapor eruption might warrant additional protection in some environments. Additionally, fire resistance is a concern for some applications, and awareness is heightened about OSHA/NFPA 70E requirements for protecting workers against potential arc flash events.

“The correct garment type is determined by the applicable technical standard, the type of cleanroom being operated, and the kind of work being carried out,” Bryant says. “We often provide on-site surveys to establish the correct garment type, along with training to assist wearers with the correct donning procedures to ensure that they adhere strictly to GMPs [Good Manufacturing Practices].”

Fabric options and tradeoffs

Garment considerations vary somewhat between industrial and life science cleanrooms. The former generally do not have a defined standard to work toward when choosing garments and must make the selection based upon the grade of cleanroom required or level of air cleanliness as defined by international standard. The life science or biopharmaceutical cleanroom, however, will have a more rigidly defined requirement for cleanroom clothing and its use as stipulated by GMP.

“Garments used in controlled environments share many common characteristics, such as compatibility with industrial laundering processes and low-particulation fabrics,” says Greg Winn, general manager, Controlled Environments Division, at White Knight Engineered Products (Charlotte, NC). “Carbon-grid fabrics are more commonly used in microelectronics applications because these customers will go to great lengths to control static buildup and/or discharge events. Pharma/life science customers must often maintain aseptic manufacturing conditions, so garments and materials undergo additional gamma sterilization or autoclaving procedures, which can significantly reduce material lifetime.”

Across all applications, key garment performance properties include air permeability, particle barrier efficiency, antistatic behavior, and moisture vapor transmission rate (MVTR). These speak broadly to a garment’s ability to both contain particles and keep the wearer comfortable. While all cleanroom garments need to meet technical specifications with regard to these properties, performance levels will vary and users need to assess carefully what criteria need to be emphasized while potentially compromising others.

An example is giving proper attention to worker comfort and mobility, which not only allows workers to carry out their duties throughout the day but also encourages compliance to the garment program. Cleanroom garments must permit the body to breathe, but the fabric’s breathability walks a fine line between comfort and contamination prevention: The body’s normal cooling process must be accommodated, but the airflow generated contains contaminants that can be transferred to the process or product. Lower MVTR and air permeability measurements mean lower potential for contamination but also reduced comfort for the wearer.

The fabrics used in making cleanroom apparel are largely polyester-based or 100 percent polyester weaves. Carbon matrices are used in some fabrics, and nylon and non-woven polyethylene materials are used in some special-purpose garment systems. The polyester weaves used in cleanroom garments are both hydrophobic and oligophilic and are constructed of very fine, tightly woven fibers. This creates small pore sizes for entraining skin flakes and other particles.

Sterilization, particularly gamma processing, will break down any fabric fiber to some extent. Polyester fabrics also are easily abraded by rough surfaces and are sensitive to extreme levels of acid or alkali and temperatures above 160

An exposure control plan is only as effective as the understanding and compliance of the personnel who implement it, so biosafety reviews are crucial

By Ted A. Myatt, Sc.D., Environmental Health & Engineering

In the past year, there have been a number of high-profile incidents at high-containment biological laboratories (biolabs). At Texas A&M University, a laboratory worker was exposed and infected with Brucella during an aerosolization experiment. This incident was not reported to the Centers for Disease Control and Prevention (CDC) as required by federal regulations. Research with “select agents” at the university was terminated and the university was levied a $1 million fine as result of not properly reporting the incident. At the CDC, a power outage in the Biosafety Level 4 (BSL-4) laboratories made headlines. In the United Kingdom, a faulty wastewater drain at a laboratory facility resulted in an outbreak of foot-and-mouth disease. Ongoing controversy surrounding the planned construction of a new, federally funded BSL-4 laboratory in Boston, MA, has increased the media coverage of these (and other) events. This increased media focus has fueled concern among the public about the potential for a release of infectious microorganisms from biolabs regardless of their containment level.

Primarily due to these publicized events, the U.S. Government Accountability Office (GAO) was asked to investigate oversight at BSL-3 and -4 laboratories in the U.S.¹ The GAO investigators identified six lessons from the incidents that are relevant not only for work in high-containment laboratories but all biolabs:

1. Identifying and overcoming barriers to reporting in order to enhance biosafety through shared learning from mistakes and to assure the public that accidents are examined and contained.
2. Training lab staff in general biosafety, as well as in specific agents being used in the labs to ensure maximum protection.
3. Developing mechanisms for informing medical providers about all the agents that lab staff work with to ensure quick diagnosis and effective treatment.
4. Addressing confusion over the definition of exposure to aid in the consistency of reporting.
5. Ensuring that laboratory safety and security measures are commensurate with the level of risk these labs present.
6. Maintenance of laboratories to ensure integrity of physical infrastructure over time.

Figure 1. When working in a biosafety cabinet in a Biosafety Level 2+ (BSL-3 practices in BSL-2 containment) area, the proper personal protective equipment includes a front closing gown, double gloves, and safety glasses. Photo courtesy of Environmental Health & Engineering (EH&E).Click here to enlarge image

All of these lessons can be applied to any biolab, including biotechnology and pharmaceutical laboratories. Development of new products from cells and tissues for therapeutic use, isolation and identification of genes, and introduction of genes into microorganisms, plants, animals, and human cells are all current and expanding biotechnologies. However, these procedures can present health risks for infections in laboratory workers during the handling of bacteria, fungi, viruses, viral vectors, recombinant DNA (rDNA), and organisms containing rDNA. Careful consideration of safety guidelines and regulations is warranted.

Relevant guidelines

The CDC and the National Institutes of Health (NIH) have developed guidelines for the four levels of biosafety. These guidelines, which are designed to protect not only laboratory personnel but also individuals in the surrounding community, are described in two publications: Biosafety in Microbiological and Biomedical Laboratories (BMBL) and the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines). In addition, the Occupational Safety and Health Administration (OSHA) Bloodborne Pathogens Standard (Title 29 Code of Federal Regulations Part 1910.1030) applies to laboratory workers who come in contact with the human blood, bodily fluids, and tissues frequently used in research laboratories.

Companies and institutions with biolabs understand that complying with biosafety guidelines and regulations is critical to maintaining the safety of their workforce and to sustaining a solid relationship with the community in which they conduct business. Yet remaining in compliance can be demanding and complex as research and development efforts continue to expand into new areas. As a proactive approach, these companies and institutions are recognizing the value of investing in a laboratory review to ensure compliance with the existing guidelines and standards.

Review process is key to control plan

For many years, we have seen how a laboratory review process can be successful in mitigating potential gaps in biosafety, whether in biotechnology, pharmaceutical, or research laboratory environments. The review process typically begins with a meeting with lab representatives to understand overall activities in the laboratory. This is followed by a walkthrough to evaluate compliance with applicable biosafety guidelines and the OSHA standard, as well as a review of laboratory equipment and relevant documents, such as a biosafety manual.

A fundamental element of the laboratory review process is recognition that working safely in laboratories requires integration of safe laboratory practices and the design and operation of laboratory buildings. This integration of approaches, termed containment in the BMBL, includes primary containment provided by the use of good microbiological techniques and safety equipment as well as secondary containment provided by the design and operational procedures used by the laboratory facility.

Fgure 2. The pipetting work seen here requires a worker to be garbed with a lab coat, protective gloves, and safety glasses. Photo courtesy of EH&E.Click here to enlarge image

The biosafety guidelines summarized in the BMBL can be simply defined as a group of practices and procedures designed to provide safe environments for individuals who work in laboratories with potentially hazardous biological agents. Work with biological agents is classified into four distinct biosafety levels, BSL-1 to BSL-4, based on the potential health risks for both individuals who work in the laboratory environment and for members of the surrounding community. Each of these biosafety levels is matched with increasingly restrictive practices and facilities that are designed to reduce the risk of exposures to potentially hazardous biological agents.

Figure 3. Centrifuge work requires careful attention to load balance, proper cleaning of the equipment, and consistent use of personal protective equipment. Photo courtesy of EH&E.Click here to enlarge image

BSL-1 and BSL-2 practices and containment are applicable for the majority of work conducted in today’s biotechnology and pharmaceutical laboratories. BSL-1 is suitable for work with well-characterized biological agents that are not known to consistently cause disease in healthy adults; they pose minimal potential health hazards for laboratory personnel and the environment. BSL-2 is applicable for work with biological agents that present moderate potential health hazards to laboratory personnel and the environment. BSL-2 indicates that individuals working directly with the biological materials are at moderate risk for infection through skin and eye exposure, skin puncture, and ingestion.

Human cells, tissues, and body fluids may contain bloodborne pathogens (BBPs); therefore, work with any of these materials should be conducted at BSL-2. Although no specific federal regulations apply to the majority of cell and tissue culture activities in laboratories, the Bloodborne Pathogens Standard does apply to laboratory workers who come in contact with human blood, bodily fluids, or tissues. This standard was issued in 1991 based on health concerns related to increased risks for exposures to certain BBPs, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and other infectious agents that may be present in human materials. In addition to HIV and the hepatitis viruses, the standard covers a wide variety of bloodborne diseases. Sources of potential exposures to BBPs include a variety of potentially infectious materials, including all human blood, blood products, certain body fluids, any body fluids in which visible blood is present, and any unfixed tissue or organ from a human (living or dead).

Figure 4. When working with liquid nitrogen, the personal protective equipment includes a full face shield over goggles; cryogenic gloves; full-length trousers/pants, apron, or laboratory coat; and footwear that covers the entire foot. Photo courtesy of EH&E.Click here to enlarge image

The Bloodborne Pathogens Standard requires that an exposure control plan be written and implemented. The exposure control plan includes several required elements and policies and procedures to eliminate or minimize BBP exposures. These elements include identifying all individuals in a laboratory group who may be at risk for BBP exposures, annual training, and providing appropriate personal protective equipment. Unlike the biosafety guidelines, the OSHA BBP Standard has the force of law and non-compliance can result in serious financial penalties.

To minimize potential exposures to aerosols or splashes of infectious biological agents, designated procedures are conducted in biological safety cabinets (BSCs) or other physical containment equipment. As recognized by the GAO, workers should be trained to recognize potential exposure events and the proper procedures for conveying information regarding the agents they work with to medical staff in the event of an exposure. BSCs provide the primary means of containment for working safely with potentially hazardous biological materials. However, training on how BSCs operate, which should be included in general biosafety training, and good microbiological practices are necessary to protect laboratory personnel, the environment, and the sterility of the product.

While the risks of releasing infectious agents out of a BSL-1 or BSL-2 facility are not as great as a release from a high-containment laboratory, the GAO recommendation for proper maintenance of a biolab is important. For example, filtration mechanisms are an essential laboratory design feature for reducing levels of infectious agents in the air entering a laboratory and for removal of these agents from air exiting the laboratory. Filtration is critical for biotechnology and pharmaceutical companies to ensure product sterility. High-efficiency particulate air (HEPA) filters are also integral components for optimal operation of BSCs. To ensure optimal operation, it is very important that BSCs are tested and certified annually, preferably by someone accredited by the National Sanitary Foundation (NSF). BSCs should also be certified when they are first installed and whenever they are moved, even to a nearby laboratory.

In addition to complying with OSHA regulations and CDC-NIH guidelines, another challenge for companies using biological agents is the transfer or shipping of biological agents. To lawfully send samples, specimens, or other research-related materials via aircraft or by ground transportation, companies must comply with standards from the U.S. Department of Transportation (DOT), the International Civil Air Association (ICAO), or the International Air Transport Association (IATA). Before any “dangerous goods” packages are offered for transport, specific training must occur, and training is required for all employees involved in the shipping process. The phrase “dangerous goods” refers to a diverse list of materials that can include dry ice, cell lines, fixed tissue specimens, and pathogenic microorganisms.

Conclusion

In summary, compliance with the biosafety guidelines recommended by the CDC and NIH and with the BBP Standard requirements mandated by OSHA provides clear advantages for biotechnology and pharmaceutical companies. The laboratory review process can ensure compliance and address a company’s ethical responsibilities to its employees as well as reduce potential liability concerns related to exposures to infectious agents. This approach can support companies in meeting the CDC-NIH goal of providing safe environments for both laboratory personnel and the surrounding community.

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Ted A. Myatt, Sc.D., is a senior scientist for Environmental Health & Engineering, Inc. (www.eheinc.com), a consulting and engineering services company based in Needham, MA. He also serves as the biological safety officer at Brigham and Women’s Hospital in Boston, MA, as well as a biosafety officer at several other high profile institutions. Myatt can be reached at [email protected] or 800-825-5343.

Reference

1. U.S. Governmental Accountability Office (GAO), Testimony before the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, House of Representatives, “High-Containment Biosafety Laboratories
   

Consider these recommendations for evaluating, validating, and implementing a USP <797>-compliant garment program

By Jan Eudy, Cintas

The latest revision to United States Pharmacopoeia (USP) General Chapter <797> Pharmaceutical Compounding–Sterile Preparations, was released in June 2008. The implementation of USP <797> in compounding pharmacies in the United States has been erratic at best. The information provided in this article is based on a case study of a company that operates compounding pharmacies in 23 metropolitan areas of the United States and its evaluation, validation, and implementation of a cleanroom garment program compliant to USP <797>.

The pharmaceutical cleanroom industry is acutely aware of the many possible sources of contamination that threaten production operations. The most significant threat is also the threat that is easiest to control–the people working in the cleanroom. These concepts of contamination control are the focus of USP <797> for compounding pharmacies.

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One of the most significant methods for reducing human contamination in the cleanroom is through a complete cleanroom uniform program. Cleanroom apparel is designed to capture and entrap particles and not allow contaminants to be dispersed into the critical environment. Apparel protects from numerous contaminants that are generated from the human body, including:

• Viable particles such as bacteria and yeasts
• Non-viable particles such as hair, dead skin cells, and dandruff
• Elements such as sodium, potassium, chloride, and magnesium

It is important to note that because the human body produces these contaminants in such large quantities the cleanroom apparel may be overwhelmed. Therefore, change frequencies and garment system configurations must be evaluated for the room cleanliness that each operation is expected to achieve.

USP <797> mandates that all compounding must be performed in an ISO Class 5 cleanroom environment or better. When the classification of the compounding pharmacy cleanroom has been determined and the decision made whether to use gloveboxes, unidirectional flow hoods, and barrier isolator systems to meet the cleanroom classification requirements of USP <797>, then cleanroom apparel can be selected. The compounding pharmacies in this case study chose to wear “tech suits” (also known as cleanroom undergarments) under the sterile coverall, hood, and boots as recommended in IEST-RP-CC003.3 for ISO Class 5 cleanroom applications.

The Institute of Environmental Sciences and Technology (IEST) published the recommended practice for garments, IEST-RP-CC003.3, “Garment Considerations for Cleanrooms and Other Controlled Environments,” in 2003. This document is a useful resource, providing guidance for the selection of fabric, garment construction, cleaning, and maintenance of cleanroom garments, and testing of cleanroom apparel and components for use in aseptic and non-aseptic clean-room environments.

Using ASTM and AATCC test methods

The contamination control industry has developed innovative fabrics and apparel to encapsulate workers in the cleanroom, thereby protecting the product and processes from possible deleterious contamination. There are several ASTM (American Society for Testing and Materials) and AATCC (American Association of Textile Colorists and Chemists) test methods used to evaluate new fabrics.

The weight of the fabric determines its strength and durability; however, a lighter fabric contributes to operator comfort. The grab tensile and tongue tear tests give an indication of the strength and durability of the fabric.

The pore size is an indicator of barrier efficiency. More particles will be entrained with a fabric that has a smaller pore size. Therefore, consideration of this characteristic is important to the evaluation of the fabric used in the cleanroom garment construction.

The moisture vapor transmission rate (MVTR) evaluates the ability to move moisture through the fabric and translates to more comfort for the operator. Moisture buildup causes the operator to feel hot due to the increase in humidity between the fabric and the body.

Air permeability is the ability of a fabric to allow air to pass through it, which is quantified by the volume-to-time ratio per area. Airflow in heating and cooling processes, such as the cooling process of the body, contains contaminants that can be transferred to the product. The lower the permeability or transfer of air from within the garment to the outside, the lower the contamination to the product.

There are several tests to determine the fabric’s splash resistance or ability for the fabric to resist absorption of liquids. These characteristics allow the operator to be better protected from spills in the cleanroom environment.

Static decay and surface resistivity testing is performed to document that the fabric is static dissipative. Fabrics outside of the static dissipative range of 105 to 1,011 Ω/square may cause an electrical discharge and subsequent product failure.

All testing of fabrics should be performed over time and exposure to gamma radiation. The results over time should not be significantly different from the original results, therefore demonstrating durability of the fabric characteristics over time.

These same tests may be used in the evaluation of the garment system (fabric and components of garments) to withstand chemicals used in the cleaning of the cleanrooms, the cleaning of the garments, the application of gamma radiation, and, in some cases, autoclaving.

Evaluation of seams and components via RP-CC003.3

Currently all reusable cleanroom garments are constructed of 99 percent polyester and 1 percent durable carbon yarns with cleanroom-compatible, gamma-compatible snaps, zippers, and binding. These garment systems are lightweight, non-linting, economical, and control both non-viable and viable particle contamination. The IEST document details recommended seam construction and components for cleanroom garments.

Using body box testing

All cleanroom garment systems will deteriorate over time due to multiple wash/dry/wear and sterilization cycles. The ability of the garment system to act as a barrier to contamination and its filtration efficacy is evaluated in a “body box” test. The body box is a mini-cleanroom. The particle cleanliness of the area is determined by typical room particle measurement with a particle counter and probe. Wearing the garment system, the operator inside the body box performs a series of prescribed movements to the prescribed cadence of a metronome. The particle measurement during the prescribed movements determines the garment system’s efficacy.

A compilation of the test results and information including the validation of the selected fabrics and garments was evaluated by the quality department of the compounding pharmacies during this case study.

Evaluation of the cleaning of the garment system

The latest revision of IEST-RP-CC003.3 details recommended parameters for the cleaning of cleanroom garments and revised the performance of the Helmke Tumble test for particle cleanliness. This revised version has established test parameters that, when followed precisely, produce results that are more robust, repeatable, and reproducible over various test laboratory settings. The Helmke Tumble test is specifically designed to test the particle shedding of a garment over time. This test evaluates the integrity of the garment as well as the cleanroom garment laundry’s overall ability to render the garment item “particulately clean.” The Helmke Tumble test evaluates particle shed at 0.3 μm and larger. The ASTM F51 test evaluates the same characteristics but at a larger micrometer particle (>5 μm) and fibers. This test is less reproducible due to technician variability over various laboratory settings.

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Additionally, extraction testing can be performed to determine if residual elements and/or compounds are present in the cleanroom garments after cleanroom laundering.

Validating a cleanroom garment system supplier

There are numerous steps involved in validating a cleanroom garment system supplier:

• Complete an installation qualification that audits the garment system supplier and evaluates their qualifying tests and testing results.
• Perform an operation qualification that includes a trial at the customer site and evaluation of the customer-qualifying tests and results.
• Conduct a performance qualification that includes evaluation of the performance of the fabric and garment system over time within the customer’s cleanroom.

All of these steps are necessary to ensuring that a garment system meets the expectations and apparel needs of the individual operation. This information, reviewed during an on-site audit, comprised the validation of the regularly scheduled cleaning of the garments and the cleanroom garment system supplier for the compounding pharmacies in the case study.

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Jan Eudy is corporate quality assurance manager at Cintas (www.cintas.com) and President Emeritus of the Institute for Environmental Science and Technology (IEST). She is also a member of the editorial advisory board for CleanRooms magazine.

Reference

For more information on the revised USP Chapter <797>, visit http://www.usp.org.

Sometimes in the dog days of summer, with things slowing down a little bit, people on vacation, and the U.S. Congress getting ready to head out on a recess from its recess, I get to daydreaming. For example, do you ever think about what it would be like if you got to run your business like a government?

One benefit you’d get right away right away is the ability to hire at least four times the number of people actually required to produce something. Not only do you not have to worry about how much that’s going to cost, but you can then also have some possibility that something might actually get produced. I really like that idea.

But–even better–it doesn’t matter whether you really do produce anything. You can still bill the customers! Then, when they call to complain about not getting anything for their money, you can bill them again, for the phone time! It’s great!

Another particularly good thing, though, is the ability to jack your prices up every year. Government customers aren’t like regular customers; they’ll pretty much pay anything. And besides, since you’re taking it all up front, on the installment plan, half of them don’t even know how much they’re paying.

Let’s be realistic, though. Some services actually do need to be provided and some things actually do need to get produced. Otherwise, the customers can’t do their own jobs, and that means they can’t pay your bills. No one wants that, and you certainly can’t expect your own employees to deal with it. They just won’t hang around long in that kind of high-stress environment. It might have been a real problem if not for this new outsourcing craze. It started in the private sector, but it’s really taking hold in the government business. When something needs doing, you simply hire a real company to do it–and charge that cost back to the customer, too!

Of course, the government business does have that one unique drawback. The customers think they should have some say in who runs the company. It’s not a big deal, though; you can just offer them up a couple of choices once in a while. For example, you might just grab, I don’t know, a good-looking black guy off the street and, say, a tired old war hero. That’s a fun contrast, and one of them ought to keep the customers amused for a while.

Anyway, I guess that’s enough daydreaming. Have a great summer!

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John Haystead,
Publisher & Editor

The development of a comprehensive PHSS monograph will enhance the recognition of RABS as an alternative to isolators and provide a framework for regulatory compliance

By James Drinkwater, Bioquell UK

As aseptic processing and related activities follow risk-based approach initiatives, separation of the process from the most potentially contaminating source–operators and associated process personnel–becomes a key consideration. Conventional cleanroom “open” aseptic processing, including filling and related processes where “operator-to-process” separation relies on gowning and simple barriers, is starting to be challenged as current Good Manufacturing Practice (cGMP).¹

The basis of cGMPs requires that pharmaceutical facilities take reasonable advantage of available technology to improve quality assurance. With a clear need for separative barrier systems, the development of restricted access barrier systems (RABS) has provided an alternative to traditional isolators. Not every process is suited to isolation barrier technology; this is a step change from conventional cleanroom operations and can impose design challenges that restrict production operations.

The contamination control performance of isolators in meeting regulatory requirements is well established. To be a viable alternative, RABS must combine a number of contamination control measures using a system approach to achieve quality by design for risk-assessed operations.

Separation between operators and an aseptic process or related procedure is considered essential for reducing the risk of potential biocontamination. With a system approach this must be complemented by controls for the environment, operator access, and all aseptic and sterile process transfers.

RABS have been available for some time, but a clear definition, a framework of RABS types, and RABS operating methods have not been the subject of an international monograph or standard.

RABS definition and monograph development

The U.S. Food and Drug Administration (FDA) prompted initiatives for clearer definitions of RABS. The International Society of Pharmaceutical Engineers’ (ISPE) Joint USA and European working group formed to provide a definition document.² This was recognized as a key step toward establishing RABS technology as a significant contamination control measure for aseptic manufacturing.

Since publication of the ISPE definition, RABS development has continued in the areas of specification, application, and operating principles. The ISPE baseline definition includes key requirements of RABS situated in a minimum ISO Class 7 background environment and RABS barrier manual disinfection in association with sterilization of direct and indirect product-contacting parts. For example, direct product-contacting parts are the product delivery system and product closures/containers. Indirect product-contacting parts would be feeder bowls, trackways, stopper delivery chutes, and any gloves likely to make contact with contacting parts during processing or related activities.

Since the ISPE initiative, the European-based Pharmaceutical and Healthcare Sciences Society (PHSS) formed a RABS special interest group to develop a technical monograph³ that provides information regarding RABS developments and advances.

PHSS completed a comprehensive review of current industrial RABS that meet international regulatory authority requirements. During the review process it also became clear that there were some simple restrictive screen barriers that could not be considered RABS and did not offer adequate contamination control for more challenging aseptic processes. By more clearly specifying RABS, such inadequate contamination control measures would be unable to claim the control attributes and risk reduction provided by RABS.

The RABS concept

The RABS barrier concept differs from an isolator in that the contamination control attributes of RABS include a combination of a physical personnel access barrier (rigid screens) and aerodynamic barrier (HEPA-filtered) downflow air, typically with overspill air to the surrounding environment. This combination of physical and airflow barrier surrounding the ISO Class 5 critical process zone is one of the key specifications that differentiates RABS from isolators. Another discerning factor is that the minimum background environment for RABS is ISO Class 7 in variance to isolators that can be installed in a minimum ISO Class 8 environment.

ISPE set out the principle of “active” and “passive” RABS relating to associated air handling (HVAC) systems. Active RABS have dedicated, onboard, downflow air handling systems. Passive RABS share the downflow air handling system with the cleanroom. PHSS has continued to use this classification within the new technical monograph.

Considerations for RABS selection

Operational principles of barrier function, sterilization processes, barrier/equipment disinfection, and process operations/procedures all have to be integrated for RABS to be an effective contamination control measure. With the separation concept established⁴–operator-to-process separation–operator intervention under barrier-aseptic conditions becomes a significant event. Avoidance of such interventions should be the starting point for any defined aseptic process. Unavoidable interventions (open-door operator access to the ISO Class 5 process zone during aseptic operations) would need justification supported by risk assessments and adequate risk reduction measures. Such deviations are likely to be subject to more intense scrutiny.

The combination of contamination control methods becomes a key consideration in RABS selection. There are different processes, different levels of biocontamination risk, and varying operational requirements. The PHSS RABS monograph considers the operational challenges and variance in user requirements, together with providing a framework for RABS types and practices to meet current and future challenges.

How sterilization and disinfection technologies interact in the aseptic process are critical components in the RABS selection process.

There is a key separation in RABS operating principles based on the type of disinfection process (manual disinfection or automatic sporicidal gassing) and how the necessary sterilization processes are applied to product-contact parts.

With isolators, it has become an accepted practice that indirect product-contacting parts can be disinfected in place (without need for pre-sterilization), provided the high-level disinfection process can be validated with sporicidal challenge biological indicators and achieves robust and repeatable 6-log reduction. Such disinfection performance is typically only achieved by automated sporicidal gassing processes.

RABS may also be specified with sporicidal gassing, thus adopting the same technique used for disinfecting isolators.

Alternatively, with manual disinfection of the RABS, indirect product-contacting parts would be subject to a sterilization process.

Figure 1. Left: An “active” RABs has a dedicated, onboard downflow air handling system. Right: A “passive” RABS shares the downflow air handling system with the clean environment. Photos courtesy of Franz Ziel Germany and Boehringer Ingelheim Pharma, respectively.Click here to enlarge image

In all cases, sterilization is required for all direct product-contact parts (e.g., product delivery path, delivery pumps, associated filling needles, and product closures). This process can be completed via a validated clean-in-place and sterilize-in-place (CIP/SIP) process or sterilization out-of-place with subsequent aseptic transfer and assembly into place.

Manual vs. automated disinfection

It is recommended to base RABS disinfection validation on disinfectant standards published by the European Committee for Standardization (CEN).⁵

A manual “wet and wipe” disinfection process may be used for the RABS barrier and enclosed process equipment (non-critical surfaces) if the disinfection process is capable of validation with repeatable efficacy. There is an important distinction between validation of a disinfectant (under standard conditions) and a disinfection process (under operational conditions). The process of disinfection is completed with the RABS airflow systems fully operational, so it is subject to process variables including drying effects that reduce contact time.

If a manual disinfection process is used for the RABS barrier and non-critical surfaces of the enclosed process equipment, then it will be necessary to use sterilization processes for all indirect product-contact parts. Sterilization would normally be out-of-place–with aseptic transfer and assembly of all indirect product-contacting parts, including feeder bowls, trackways, chutes, and glovesleeves that are specified as potentially making contact with sterilized surfaces during aseptic processing or related procedures.

RABS may also be integrated with an automated sporicidal vapor disinfection system for high-level disinfection achieving 6-log sporicidal reduction on specified RABS barrier and associated process equipment surfaces.

The most widely used sporicidal vapor gassing process for isolators–which may also be applied to RABS–is hydrogen peroxide vapor.⁶

The sporicidal gassing process for RABS should be low temperature (guidance figure: within ~10

By Hank Hogan

After the shaking stopped in China on May 12, officials at Intel (Santa Clara, CA) began a familiar drill. The company has a microprocessor test facility in Chengdu, some 50 miles from the epicenter of the powerful quake. According to spokesperson Agnes Kwan, company officials first checked on employees, making sure everyone was all right. They then turned their attention to the buildings and the equipment inside them.

As part of this effort, Intel took immediate action. “As a precaution, we removed the facility from local power and water service until we could do a full assessment,” says Kwan.

In the end, the manufacturing areas at the site turned out not to have sustained damage. The facility was back on line in less than 10 days, notes Kwan.

Sanyo (Osaka, Japan) wasn’t so lucky back in 2004. During that year’s Chuetsu earthquake, the company’s Niigata semiconductor fabrication cleanroom facility suffered extensive damage. Of the five manufacturing lines, one was rendered inoperable and it was months before the buildings were inspected and utilities restored. In the end, says company spokesperson Aaron Fowles, the five lines that had existed at the site prior to the quake were reorganized into two and manufacturing resumed. “In a period of five months, the production levels were back at 70 percent of their original capacity,” he says.

Because of its experience, Sanyo has implemented changes that should help diminish the impact of future earthquakes. These innovations were tested in a 2007 quake in the same region. Fowles says these improvements fall into two categories: one equipment/facilities related and the other involving procedures.

With regard to hardware, changes included fitting gas and chemical dispensing systems to withstand all but the most severe earthquakes. That reduces the chance of hazardous leaks and cuts the time needed to assess damage, since personnel likely won’t have to wait for containment efforts to be complete. Other changes fortified wiring to absorb serious shaking without damage. A third modification added wheels to line machines, mobile shelves, and desks. This allowed them to slide back and forth across the floor without tipping over.

Procedural changes involved reviewing and updating manuals, along with the associated employee training. One result was that the handling of the 2007 earthquake was much smoother than had been the case in 2004. “This aided us in confirming the whereabouts and conditions of all employees within one day, when last time it took up to three days to confirm,” says Fowles.

In some ways what Sanyo did is representative of the industry as a whole. Pat McCluskey, a senior structural engineer with engineering and construction firm CH2M HILL (Denver, CO), notes that the semiconductor industry came of age in earthquake-prone California and is now located in Japan, Taiwan, and China, all of which have their own quake issues. As a result, the industry has had to contend with shaky situations many times and a bit more is learned with each event.

McCluskey notes, for example, that decades ago there was little interest in anchoring things within a building. Today it is standard practice. Also, other improvements are being implemented, ones that avoid the rigidity that can allow more damage to take place. “We’re starting to see the application of systems that don’t just rely on strength. They rely on displacement. They rely on damping. We’ve gone from building a concrete box to trying to build a willow tree,” he says, referring to the flexibility that can save a facility and its internal components and structures.

The reason for this shift is a recognition that movement can’t be stopped and the more rigid something is the stronger it has to be. One idea is to convert movement into heat by, for example, bronze slide plates. These let some slip occur but also transform kinetic energy from movement into heat that is dissipated. Active damping that counteracts incoming disturbances is also becoming more prevalent in vibration-sensitive tools, reports McCluskey.

However, all such efforts fly somewhat in the face of good business continuity planning. What some companies do is have an alternate location they can operate from, explains Gartner research vice president Roberta J. Witty. But fabs are very expensive, so it’s not really feasible to have a spare sitting around ready to take over in the case of a disaster.

“If you’re not going to build out a second site, you really have to pay attention to mitigating as much risk in the existing site as you possibly can,” says Witty.

One way to do so is to have multiple utility feeds and access routes. But the best solution may be the most obvious one, she notes: to avoid the problem entirely by not building in an earthquake zone at all.

Choosing the wrong vacuum can put your facility, processes, and personnel at risk

By Paul Miller, Nilfisk CFM

In the past several years, plants across the United States have seen an increase in dust-related explosions. From sugar dust to phenolic resin, blasts in the workplace are becoming all too common. Although critically controlled environments–like those found in food, pharmaceutical, and electronics manufacturing–may not contain an explosive concentration of combustible dust as seen in the plants that did fall victim to dust-related catastrophes, these facilities are not immune from similar disasters that can destroy more than just infrastructure, especially those that handle hazardous materials.

In response to the recent blasts, the Occupational Safety and Health Administration (OSHA) is embarking on a journey to develop industry standards of prevention. The agency’s preliminary research includes random audits of any facility that handles powder and bulk solids. And in the meantime, officials have made suggestions that include incorporating an industrial HEPA-filtered vacuum into maintenance plans, but for facilities that are handling materials classified hazardous by the National Fire Protection Agency (NFPA), incorporating the wrong vacuum can actually add to the risk. For this reason, cleaning with a certified explosion-proof vacuum (EXP) that surpasses industry standards is critical.

Certifiable explosion-proof: Beware of ‘dress up’

Operators and managers cannot afford to take chances when it comes to protecting the facility. Look for EXPs that are explosion-proof to the core. This means that everything from the outer shell to the internal mechanics including the motor, switches, filters, and inner chambers should be grounded and constructed of non-sparking materials such as stainless steel. Some companies offer basic models dressed up with a few anti-static accessories and describe them as suitable for explosive material. These imposters may still create arcs, sparks, or heat that can cause ignition of the exterior atmosphere and overheating that can ignite dust blanketing the vacuum.

Figure 1. An explosion-proof vacuum should be certified by a nationally or internationally recognized testing agency. Shown here: Nilfisk CFM’s 118EXP. Photo courtesy of Nilfisk CFM.Click here to enlarge image

Approval by a nationally or internationally recognized testing agency such as CSA is imperative and will protect the buyer from purchasing a “poser.” Users should look for models that state they are certified for use in their specific NFPA classified environments. This provides legal certification and ensures that every component in the vacuum from the ground up meets strict standards for preventing shock and fire hazards.

Explosion-proof vs. intrinsically safe

In environments where electricity is unavailable or undesirable, pneumatic vacuums for hazardous locations are excellent alternatives. It is important to note that only electric vacuums can be certified and deemed “explosion-proof,” but properly outfitted pneumatic vacuums, referred to as “intrinsically safe,” often pack the same punch as their electric counterparts while still meeting the requirements for use in an NFPA classified environment. Again, beware of companies that refer to their pneumatic models as certified explosion-proof. Testing agencies for air-operated machines simply do not exist.

Filtration

As with any critical environment vacuum, superior filtration should not be sacrificed on an explosion-proof model. For peak operating efficiency, the vacuum should have a multi-stage, graduated filtration system, which uses a series of progressively finer anti-static filters to trap and retain particles as they move through the vacuum. For companies of all shapes and sizes, the use of HEPA filters is not just critical but mandatory. Quality HEPA filters offer an efficient, effective way to trap and retain the smallest dust particles, down to and including 0.3 μm, helping to preserve air quality and protect workers. Manufacturers also have the option for an ULPA filter, which captures particles down to and including 0.12 μm. In order to prevent combustible dust from being exhausted back into the ambient air, the HEPA or ULPA filter should be positioned after the motor to properly filter the exhaust stream. The motor’s commutator and carbon brushes generate dust, and if the exhaust stream is not filtered that dust will simply be released back into the environment.

Spill response

Spill response should also be taken into account when purchasing an EXP. Although OSHA’s current audits are specifically looking at companies that handle dry solids, manufacturers’ maintenance plans are also under the microscope. If the user plans to collect flammable or explosive chemicals, a wet-model EXP is a viable option; these are also available in both electric and pneumatic versions.

Figure 2. Facilities should develop and implement hazardous dust inspection, testing, housekeeping, and control procedures in order to prevent dust-related explosions. Photo courtesy of Nilfisk CFM.Click here to enlarge image

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Conclusion

Picking the right vacuum often raises a lot of questions, especially when it comes to disaster prevention. Ask the vacuum manufacturer to do an on-site analysis of each operation’s vacuum needs in order to recommend the appropriate types of vacuum, hose, and accessories.

As displayed in one too many plants all across the U.S., the term “maintenance” oversimplifies the role an industrial vacuum system plays in today’s manufacturing processes. The right vacuum can save money, protect the integrity of the product, increase productivity, and most importantly, protect your most valuable asset, your employees.

Paul Miller is vice president and general manager at Nilfisk CFM in Malvern, PA (www.nilfiskcfm.com).

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Guidance on dust explosion prevention

An ignitable material, an ignition source, and oxygen are all it takes for a potential explosion at a facility. Most manufacturing plants have all three. In 2006, fatalities involving explosions and fires increased by 26 percent in the manufacturing sector, according to the Bureau of Labor Statistics Census of Fatal Occupational Injuries. In addition to injuries, explosions cost companies millions of dollars. Between 1992 and 2002, FM Global’s pharmaceutical and chemical clients experienced dust explosions resulting in $32 million in losses. And OSHA has estimated that there are approximately 30,000 U.S. facilities at risk for combustible dust explosions. Simply put, there’s a lot at stake.

NFPA 654, Standard for the Prevention of Fire and Dust Explosions from the Manufacturing, Processing, and Handling of Combustible Particulate Solids, contains comprehensive guidance on the control of dusts to prevent explosions. The following are some of its recommendations:

• Minimize the escape of dust from process equipment or ventilation systems.
• Use dust collection systems and filters.
• Utilize surfaces that minimize dust accumulation and facilitate cleaning.
• Provide access to all hidden areas to permit inspection.
• Inspect for dust residues in open and hidden areas at regular intervals.
• Clean dust residues at regular intervals.
• Use cleaning methods that do not generate dust clouds if ignition sources are present.
• Only use vacuum cleaners approved for dust collection.
• Locate relief valves away from dust hazard areas.
• Develop and implement a hazardous dust inspection, testing, housekeeping, and control program (preferably in writing with established frequency and methods).