The Institute of Environmental Sciences and Technology (IEST) has announced that the final draft International Standard (FDIS) version of International Organization for Standardization (ISO) Standard 14644-6, Cleanrooms and controlled environments, Part 6: Vocabulary, is now available. An important resource for anyone operating a cleanroom or controlled environment, the document is an up-to-date, international dictionary of all cleanroom terms and definitions used in the ISO 14644, Cleanrooms and controlled environments, and 14698, Biocontamination, series. Each definition is followed by the standard designation and section in which it is used. It also features an index to make it easier to find a particular definition.

Working Group 6 of ISO/TC 209 undertook the task of harmonizing the terms, definitions, and units within ISO Standard series 14644 and 14698, as well as internationally used definitions.

The 34-page FDIS 14644-6 is available online at http://www.iest.org/iso/iso6.htm or by calling IEST at (847) 255-1561.

Click here to download a .pdf of the Interphex 2007 Conference and Exhibition

For products that can’t be terminally sterilized, aseptic processing offers the best solution

By Sarah Fister Gale

Advanced aseptic processing strategies offer manufacturers the best solution for protecting the quality and safety of their products and for ensuring the highest contamination control standards possible for products that cannot be terminally sterilized-but it comes at a cost. Unlike terminal sterilization, aseptic processing lines don’t involve a high-heat kill step for final products, which can mute food flavors and destroy pharmaceutical potency. But because they can’t rely on that all-powerful, microbial-destroying heat treatment, manufacturers have to put in place strict controls, in-process control testing and validation steps throughout the manufacturing process to ensure that no contaminants ever find their way into materials, components and final product.

Terminal sterilization involves filling and sealing product containers under high-quality environmental conditions to minimize the microbial and particulate content of the final product, and then subjecting the final product to a sterilization step. In most cases, the product and the container closure exhibit low bioburden going into the process, but they are not sterile until the final container is subjected to the sterilization process, such as heat or irradiation.

While terminal sterilization is an ideal choice for heat-resistant products because there are fewer opportunities for error, it’s not usually a viable solution for heat-sensitive products such as vaccines and other biologic products. The high heat used in the autoclave to eliminate microorganisms can weaken or destroy heat-sensitive pharmaceutical ingredients, particularly in the case of biotech products, which feature bioactive proteins that would be denatured under the intense heat of an autoclave.

These delicate products can be affected not only by temperature but also light, pH balance, sheer, and the velocity at which the product runs through a nozzle and hits the surface of a storage container.

“The slightest damage will destroy it,” says Jack Lysfjord, vice president of consulting for the Valicare Division of Bosch Packaging Technology (Brooklyn Park, MN).

“If you have one percent degradation in a product, the rest of it will die within days. Once it starts, you can’t stop it.”

As a result, many pharmaceutical as well as food and beverage products are manufactured using advanced aseptic processing strategies, and as the biotech industry matures, the ratio of aseptically produced products to those that are terminally sterilized continues to expand.

Separating people from product

An advanced aseptic process is one in which direct intervention with open product containers or exposed product contact surfaces by operators wearing conventional cleanroom garments is not required or permitted. Because there is no opportunity to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment.

Through aseptic processing conditions, manufacturers of pharmaceuticals, vaccines and similar products produce sterile end products by compounding and assembling sterile bulk drugs or raw materials with sterile packaging components. The key is to maintain the sterility of all the ingredients and packaging by using containers, closures and processes that are already sterile and are kept inside a high-quality environment, typically within an ISO 5 (Class 100) cleanroom.

“Aseptic processing is not a choice; it’s product dependent,” Lysfjord points out. “Regulations state that if you have a product that can be terminally sterilized, that’s what you must use.”

Unfortunately those products are limited to simple chemicals, saline and other heat-resistant substances that won’t easily degrade when exposed to heat. The rest of the industry relies on aseptic processing strategies to keep products and workers safe in the cleanroom environment.

According to the FDA’s Guidance for Sterile Drug Products Produced through Aseptic Processing (September 2004), there are basic differences between the production of sterile drug products using aseptic processing and production using terminal sterilization.

Figure 1. Image from a real-time, interactive 3D scene in a simulated cleanroom training program. Photo courtesy of 3D Solve.Click here to enlarge image

The guidance notes that because aseptic processing involves more variables than terminal sterilization, it requires more validation and controls. For example, before assembly, the individual parts of the final product must be subjected to appropriate sterilization processes, such as heat for glass containers and filtration for chemicals and liquids.

Figure 1. Image from a real-time, interactive 3D scene in a simulated cleanroom training program. Photo courtesy of 3D Solve.Click here to enlarge image

If the environment, ingredients, equipment and personnel do not meet the strict guidelines that govern the aseptic processing environment, any step in the process could introduce an error that could ultimately lead to contamination in the final product.

“Human interaction with the product is one of the biggest contamination control risks. As the involvement of operators in cleanroom activities increases, so does the risk to finished product sterility. Operators must be trained to use aseptic techniques at all times,” notes Carmen Wagner, president of Strategic Compliance International, a pharmaceutical, medical device and biotech consulting firm in Cary, North Carolina. “Problems can occur because of human error, but also as a result of natural causes, such as people shedding particulate through the performance of their daily activities.” For example, operators working within a cleanroom environment can shed millions of 0.3 μm particles in the form of skin flakes and clothing fibers. In fact, a motionless person, sitting or standing, can generate approximately 100,000 particles per minute, and with motion, as much as 500,000 to 1,000,000 particles per minute-for a grand total of up to 1 billion skin flakes per day. “There are so many things people do to contribute to contamination without ever realizing it.”

In operations in which toxic and potent chemicals are used, such as the manufacture of immune-suppressing cancer drugs, the operators also need to be protected from the product, Lysfjord says.

Wagner is excited about companies such as 3DSolve, from Cary, North Carolina, which is working to develop Aseptic Cleanroom Simulator training programs that use computer-based simulations of real-world cleanroom facilities, equipment and processes to teach aseptic cleanroom operations to pharmaceutical industry workers (see Fig. 1). The course covers issues such as basic microbiology, hygiene, gowning, handling of equipment, and specific written procedures covering aseptic processing area operations. Wagner adds, “For companies that can’t afford a dedicated cleanroom for training, simulated learning gives trainees a safe place to learn, without taking risks with real facilities or products. Just as there has been tremendous progress-almost revolutionary in some cases-in aseptic processing technology, there are also emerging technologies that will facilitate the development of more effective training for aseptic processing, and 3DSolve is one of those.”

Wagner believes that teaching workers in a simulated environment allows them to practice and perfect their skills before they go into a real cleanroom. She adds, “This can be done without using expensive live space, real equipment or materials just for training purposes. This simulation approach has been used extensively with military training and it has been very successful. Operators can complete several hours in the simulated environment, honing and internalizing critical skills, prior to interacting with the actual processing line, which makes them more comfortable to experiment and learn, and helps eliminate the risks of human error posed by new employees. It offers a lot of promise.”

Isolators

However, as Wagner points out, humans can do everything right and still contribute to contamination, which is why the industry is pushing to create systems that eliminate human contact with equipment and the product. To achieve that goal, isolators and restricted access barrier systems (RABS) continue to claim their place in aseptic processing manufacturing as companies realize the benefits of adding controlled spaces and enclosed equipment in which product can be shielded from environmental and human interaction.

“The goal of isolators and RABS is to segregate people from product,” says Lysfjord, who has conducted annual global surveys of isolator and RABS use in aseptic processing lines since the mid-1990s. His survey data shows a steady increase in the use of both technologies, with the two most recent isolator surveys showing a significant jump from 2004, in which 256 facilities claimed to have isolator systems in operation, to 2006, in which 304 facilities were operating isolators. He notes that many of the isolator projects currently being planned mention protection of operators working with potent drugs as a key factor in the decision.

“A paradigm shift is building in the industry to separate people from product,” he says. “The use of isolators and RABS supports that.”

Isolators can be used in a wide variety of applications, including both large- and small-volume parenterals, lyophilized products, powder fills, combination products, and medical devices, as well as more typical liquid fills into a single container (see Fig. 2).

There are two types of isolator systems: closed and open. In closed systems, all components are gathered in batches into portable transfer isolators and moved into the sealed isolator through double-door systems and rapid transfer ports (RTPs). Open-system isolators feature mouse holes through which vials pass. Because the mouse holes are open during operation, continuous overpressure of the barrier isolator ensures separation of the environment inside the isolator from the surrounding room air.

Figure 2. Isolators can be used in a wide variety of applications. The isolator shown here features (from left to right) a vial accumulation area, a filling system, and a stoppering station, with an outfeed to a tray. Photo courtesy of Bosch Packaging Technology.Click here to enlarge image

Some facilities use isolator technology just for critical steps, such as filling vials. Others have implemented series of isolators to produce an entire line, with filling, overcapping and washing all taking place inside the isolator environment, Lysfjord says. Conveyors or robot exchange systems are used to transfer the vials between production areas.

According to Lysfjord, there are several benefits to isolator technology in the cleanroom. The sterilization level inside an isolator can be brought to a sterility assurance level (SAL) of 10-6, or one contaminated vial in a million, which in most cases is significantly higher than the sterilization rate of a conventional cleanroom space.

It also allows for extended campaigning, in which several product lots can be filled over the course of several days and for up to four weeks without shutting down the production line. “Existing technology can maintain aseptic conditions for 28 days. As long as you can validate that you can maintain sterility during that time, you can do it,” he says.

Campaigning offers significant cost savings by eliminating extended downtime for cleaning steps. However, Lysfjord warns, it is a serious business decision. If a problem occurs during a campaign, you can conceivably lose the entire product batch, and the longer the campaign, the greater the loss. “If it’s a five-cent product, it may be worth the risk, but if it’s a $5 million lot, you may want to think hard about how long to run the line.”

Using isolator technology for aseptic processing can also save facility owners a significant amount of money in the design and construction of new and retrofit facilities. Because the isolator maintains ISO 5 conditions internally, the equipment can be placed into an ISO 8 (Class 100,000) cleanroom. “The cost per square foot is much less in that scenario,” explains Lysfjord.

The operating space can also be much smaller, further reducing facility costs. “You do have to put more money into equipment, but the reduced cost for the facility far outweighs it,” Lysfjord says.

RABS

Like isolators, RABS can be used in cleanrooms to isolate product from people, although this type of system is less secure. RABS and isolators provide similar functions, but RABS offer product protection and contamination control by providing a “physical and aerodynamic barrier” over the critical process zone. Although there are some isolators that use this combination (in the form of the isolation barrier and a sterilizing tunnel), the aerodynamic barrier is restricted to transfer entry or exit zones into and out of the critical zone. The extent of separation of process, people and environment provides a sliding scale of product protection.

RABS use a combination of a barrier and a dynamic HEPA-filtered airflow to create isolated space and prevent human interventions. Compared to isolators, RABS can allow for faster start-up time and ease of changeover. However, because it is not a closed system, steps need to be taken to ensure the sterility of the process. Using restricted access barrier equipment on its own is not enough to protect the process. It must be supported by critical, validated operating procedures to ensure quality standards are met.

To clarify the use of RABS in aseptic processing, the International Society for Pharmaceutical Engineering (ISPE) worked with the FDA to produce a RABS definition paper in September 2005 with the goal of reducing confusion about the key elements of RABS and their regulatory requirements. According to the paper, in order to be classified as a RABS, a system must possess certain criteria, including: properly designed equipment; management oversight; a quality system in place; proper surrounding room design to maintain ISO 5 in the critical zone; proper gowning practice; proper training; initial high-level disinfection with a sporicidal agent; and proper SOPs for rare interventions, disinfection, appropriate line clearance, and documentation of an event.

Globalization

While much of the industry is focused on improving its aseptic processes, it is also struggling with the need to adhere to differing regulations for globally marketed products. “The vast majority of sterile drug products being produced are being distributed globally, thus they are impacted by multiple regulatory requirements,” says Douglas Stockdale, president of Stockdale Associates, an aseptic fill/finish and sterile packaging consulting company (Rancho Santa Margarita, CA). “The principal aseptic regulatory issue is that global requirements are not fully harmonized.”

In the United States, the two FDA regulatory groups primarily concerned with aseptic processing are the Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER). In most of Europe, the European Agency for the Evaluation of Medicinal Products (EMEA) provides the regulatory overview for aseptic processing according to Annex 1 of the EU GMP guidelines. In Japan, the Ministry of Health and Welfare (MHW), along with the relatively new Pharmaceutical and Medical Devices Evaluation Center (PMDEC), is the principal regulatory agency. For the rest of the world, individual regulatory agencies exist, but as a general rule they recognize the regulatory requirements of ISO, FDA or EMEA.

Although the fundamentals of aseptic processing strategies are similar across regions, the EU and the U.S. have different requirements, and they use different terminology to define their terms, including how they classify active and inactive rooms. The inconsistency in language alone makes having discussions around harmonization complicated, Stockdale points out. For example, according to Annex 1, the Grade B cleanroom requirement for particulate is the same as Class 100 without activity, but the same as Class 10,000 with activity.

This translates into challenges for processing facilities that produce global products, says Glenn Jennings, director of AAIPharma’s manufacturing center in Charleston, South Carolina, which is dedicated to the manufacture of sterile drug products as well as aseptic liquid and lyophilized products. “All of the regulations are different in their approach,” he says. “One of the biggest differences between the U.S. and the EU is that the U.S. allows more procedural controls, while the EU requires engineering controls.”

That means that U.S. facilities can use systems such as airflow design and procedural steps to cascade toward stricter cleanroom conditions, moving from Class 100,000 to Class 10 at the core; while in the EU, regulations require rigid structures, such as airlocks in gowning areas, to delineate these zones as an added level of protection. The EU also establishes classification in common-use hallways between compound areas, which may not be classified in a U.S. facility.

Non-viable particle monitoring requirements also differ. U.S. facilities sample one cubic foot of air and only sample for 1- and 0.5-micron particles, while EU facilities sample one cubic meter and test for 5-micron particles in addition to 1- and 0.5-micron particles. “The rationale is that a particle that big could act as a host to a viable particle,” Jennings says of the differing regulations. Jennings does agree that testing a cubic meter of air increases the confidence level of the room.

Regardless of which standards are better, facilities such as AAIPharma’s that manufacture products for the global market deal with the differences by adhering to the highest standards among all the regulations, which adds costs and extra steps to the process but gives them, and their clients, the assurance that products are marketable worldwide.

To achieve this goal, two years ago the AAIPharma facility began capping vials in a Class 100 filling room, which adheres to the EU expectations and exceeds U.S. requirements (see Fig. 3). In its latest facility renovation, the company added airlocks between rooms to make its Charleston plant EU-compliant.

“Striving for the strictest regulations adds a lot of extra expense,” Stockdale notes. For some companies, making such decisions becomes a purely financial consideration: When it is not economically viable for certain products, they may not be marketed in particular regions of the world. Unfortunately, this reduces financial success for the company and prevents consumers from having access to important drugs. For other companies, it means decentralizing the manufacture of critical drugs, with regional facilities handling local production.

Figure 3. A capper in AAIPharma’s manufacturing facility in Charleston, SC. Photo courtesy of AAIPharma.Click here to enlarge image

Ideally, all of these regions would come together and develop a single global set of regulations, but experts agree that much work still needs to be done.

“When it happens, harmonization will only be a positive thing,” Jennings says. Moving toward a single standard for aseptic processing “eliminates the need to select the strictest requirements from each set of regulations and then meld them into a single global approach for the facility. That’s a positive thing for the industry.”

Jennings admits, though, that at this juncture harmonization won’t have a significant impact on his facility. “Because we are a global company, we’ve had to make changes to our facilities to satisfy the needs of clients all over the world,” he says. “It gives them an added level of comfort to know we meet requirements in the U.S. and the EU.”

I don’t usually, if ever, review industry trade shows on this page, even when they’re our own events. However, I am going to talk about the Food Safety and Security Summit held earlier this month in Washington, DC, because I think there were some important things going on there that would be of general interest to the contamination control industry and certainly to contamination control professionals already involved in, or looking at, opportunities in the food industry.

The first thing I noticed is that there were in fact “contamination control” people at the event-both exhibiting and attending. And, there were also food industry people speaking the language of contamination control. In the past, my experience at food industry shows, and with the food industry in general, has been that the language-or at least much of the terminology-used is different. For example, where we talk about contamination control, sanitization and disinfection, they generally talk about cleaning, sanitation and hygiene. Where we talk about contamination and cross-contamination control and verification, they talk about quality control and hazard analysis. I believe that the not-so-subtle differences in mindset associated with these different terms are slowly beginning to change. And that is good.

The food industry also appears to be more openly accepting of and honestly attempting to address the very real problems of contamination control it clearly faces. This is also a welcome change from the often knee-jerk defensiveness, denial, and sometimes outright belligerence shown in response to even mild criticism of its practices, or lack thereof, in the past.

Finally, and perhaps more important and telling than anything else I noted, was the amount of intelligent questioning going on, and the clear desire of many food industry professionals to learn everything possible about available contamination control technology and established contamination control standards and practices, as well as proven contamination control testing, validation and monitoring programs. And that’s definitely good.

To ensure a safe food supply, the contamination control professionals within the food industry must work aggressively to advance a policy of dramatic improvement in food processing and packaging operations as well as enforceable standards across the board, and to eschew those who would instead advocate denial, avoidance or reticence.

CleanRooms will continue its efforts to bring our industry’s experts and technology together with those food industry professionals responsible for product safety. And we will also continue to encourage increased collaboration between those government agencies responsible for regulation, inspection and enforcement of critical food safety protocols and practices.

John Haystead,
Editor-in-Chief

Innovation, agility, flexibility and personalized service enable IEST to pursue its mission

By Julie Kendrick, CAE, Executive Director, IEST

Giant conglomerates and mergers dominate today’s corporate world. Therefore, it is not surprising that not-for-profit organizations too are feeling economic and marketing pressures to follow the path of expansion into new areas. The challenge is to build on existing strengths while avoiding the often ruinous temptation to become all things to all people. The Institute of Environmental Sciences and Technology (IEST) is an example of technical growth based on a well-established foundation of expertise. IEST possesses four major advantages in its mission to provide outstanding education, standards, and recommended practices to the industries served by it: innovation, agility, flexibility, and personalized service.

Innovation

Based on its experience and stature stemming from a long relationship with the International Organization for Standardization (ISO) as the Secretariat of ISO Technical Committee (TC) 209, Cleanrooms and associated controlled environments, IEST petitioned the American National Standards Institute (ANSI) for admission as a founding member of the United States Technical Advisory Group (U.S. TAG) to ISO Technical Committee 229, Nanotechnologies (ISO/TC 229).

Ably represented by its delegate to the U.S. TAG to ISO/TC 229, Dr. David S. Ensor, IEST Fellow and director of its Nanotechnologies Standards and Practices Committee, IEST speaks for the interests of the contamination control industries that it serves and provides ISO/TC 229 with expertise gained from IEST’s global leadership in publishing standards and recommended practices.

Nanotechnology, as defined by ISO, is the science of engineering matter at the atomic and molecular scale, about 10,000 times smaller than the thickness of a human hair. It was used in the production of $30 billion in manufactured goods last year-a number expected to grow to $2.6 trillion by the year 2014. The use of nanoscience expands daily into new fields and new products so disparate that unsafe practices, misdirection of efforts, and waste of resources are among the likely end results of such rapid and unstructured growth.

To paraphrase author Lewis Carroll, “If you don’t know where you are going, then any road will take you there.” The nanoscience world desperately needs to define where it’s going and the best routes to take. Therefore, IEST has begun intensive work on a “Nanotechnology Roadmap” to establish a detailed plan for the guidelines, best practices, and standards that will be needed for the myriad disciplines that are-or will be-involved in nanotechnology. To this end, IEST has established a new working group of experts and other interested parties, which recently convened at the 2006 IEST Fall Conference.

“Although nanoscience is extremely diverse, the IEST ‘Roadmap’ will not deal wholly in generalities. It will definitely be meaty and have a great degree of specificity,” commented Chuck Berndt, IEST Fellow and communications vice president. “Some of the finest minds in the world gathered in November and spent two days brainstorming, writing down ideas, and taking on assignments. It was exciting.” The next meeting is scheduled in conjunction with the annual meeting of IEST (ESTECH 2007), April 29-May 2, in Bloomingdale, Illinois, and is open to all those interested in the development of nanotechnology.

Agility

Another IEST strength is its agility. ISO/TC 142, Cleaning equipment for air and other gases, was reactivated to address the various standards in the world dealing with the same topics in gas cleaning technologies. The large number of different national standards worldwide is a serious problem in that the proliferation of standards often forms a barrier to trade and prevents fair competition. The filtration and separation industry needed to be represented by an active ISO Technical Committee producing standards for the benefit of end users, manufacturers, designers and governmental authorities.

The ability of IEST to “turn on a dime” without losing footing, stability, or forward motion came into play upon learning that ISO/TC 142 was being revitalized after many years of inactivity. IEST used its nimbleness to act quickly and successfully apply to ANSI for accreditation as the Administrator of the U.S. TAG to ISO/TC 142-just in time to send a delegation from the United States to the first meeting of ISO/TC 142 in Milan, Italy, in early 2006. IEST Senior Member and former Education Vice President Philip Winters chairs the U.S. TAG to ISO/TC 142 and is the head of the United States delegation to ISO/TC 142.

Flexibility

IEST is a technical society founded more than 50 years ago; therefore, flexibility does not always come easily. Traditional ways of doing things can be both a blessing and a curse in a world where change is constant. Fortunately, a commitment by its volunteer and staff leadership to keep current with technology has allowed IEST to offer many of its same services and educational opportunities, but in ways that fit today’s workplace and lifestyles.

For example, the venerable peer-reviewed Journal of the IEST, which has been published continuously for nearly 50 years, has become an exclusively online publication. Moving beyond print media was the result of in-depth study that focused on three questions: Who are the Journal readers? How can writers of technical papers be assured that their work is available to a large readership? And how can IEST incorporate into the Journal 24/7 access to technical material needed by students and researchers?

The Journal of the IEST is published online twice a year. Subscriptions, which are free of charge to IEST members, include access to archived technical papers from past issues. The most recent 20 years of archived papers are available, with 10 additional years of papers scheduled to be posted each year until all papers are online, providing a wealth of information and a well-documented history of technical developments.

IEST has also maintained a fluid approach to change in establishing its online “Access the Experts” short courses, and in the evolution of ESTECH into a compact yet comprehensive educational experience-with ESTECH 2007 marking the event’s 53rd consecutive year.

Personalized service

Above all, IEST considers personalized service to be its primary strength. IEST knows that information exists in numerous locations and in limitless quantities easily accessible to its members and colleagues. Therefore, the volunteer and professional leadership of IEST work in partnership with one another to answer questions, mentor, and assist workers in the disciplines IEST represents. IEST leaders are approachable through the many networking opportunities provided by IEST. Our mantra: IEST members are not an interruption of our business; they are our business.

Click here to enlarge image

Julie Kendrick is the executive director of IEST, a position she has held since 1997. She earned a bachelor’s degree from Illinois Wesleyan University, and has attained the distinction of Certified Association Executive (CAE) from the American Society of Association Executives. Kendrick is a member of the Association Forum of Chicagoland, for which she conducts study groups in association policy and governance for CEOs working toward obtaining CAE recognition. She is also a member of the Council of Engineering and Scientific Society Executives.

Attendee questions from the CleanRooms Webcast are answered

On January 30, 2007, CleanRooms hosted its second Webcast focused on USP <797>. With participation from members of the USP <797> Expert Committee, now evaluating proposed revisions to the Chapter, the presentation put to rest some of the “urban legends” surrounding the standard and provided attendees with practical information and answers to the immediate and real-world challenges and questions they have today. Remaining questions that could not be answered during the one-hour Webcast are presented and answered here.

When will the final version of USP be published?

The final version will be published after the USP Sterile Compounding Committee has had time to adequately review all of the comments received.

What is the difference between validation and certification of cleanrooms?

Validation of a cleanroom or a primary engineering control is based on the specific needs of a particular facility as determined by that facility. Validation performed at one facility is often very dissimilar to that done at a different facility. Certification is the application of industry-based protocols to specific applications in an attempt to assure repeatable tests are performed using the same methods and instrumentation on every piece of equipment. Certification of primary and secondary engineering controls is often a component of an overall facility validation. Primary engineering controls should be certified to industry-based protocols such as the Controlled Environment Testing Association’s (CETA) application guides and National Sanitation Foundation (NSF) International Standard 49. The secondary engineering controls, such as cleanrooms, are often validated to the owner’s specific criteria that will include certification.

Where can we find a list of companies that are certified to validate or certify cleanrooms?

A list of qualified certifiers for validation of sterile compounding facilities currently does not exist. CETA is in the process of developing an accreditation program for this.

Where can we find a list of laboratories that measure surface contamination from hazardous drugs?

To our knowledge no such list exists. Environmental sampling is a relatively new approach used to determine the level of workplace contamination by antineoplastic agents. The procedure has been used extensively in other situations, especially for monitoring contamination from radioactive materials. Typically, work surfaces are sampled with a moistened wipe and the material is extracted and analyzed for specific antineoplastic agents. Currently, it is possible to identify and quantitate six to eight agents with this technique. Often, analytical labs will work with potential clients to incorporate new analytical methods if one can be identified, so don’t hesitate to inquire even if a particular lab doesn’t advertise this capability. There are a few labs and methods mentioned in the research literature; these might be a good place to start. Some references to aid in this search can be found at: http://www.cdc.gov/niosh/topics/antineoplastic/sampling.html#a. You might also check similar trade literature reports by certifiers, pharmacists and equipment manufacturers.

When do you think these proposed changes will become effective?

The Sterile Compounding Expert Committee is carefully reviewing and considering all comments received on or before the August 15, 2006, public commentary deadline. There are approximately 2,500 pages of comments from over 300 participants including hospitals, professional associations, vendors, stakeholders, and individual practitioners (pharmacists, nurses, physicians, etc.).

Due to the volume and criticality of these comments, it is not known when the review will be completed and the proposed revisions finalized. The committee is working hard to get a revised chapter out later this year.

How will these guidelines be enforced?

The USP has no enforcement authority. The primary responsibility of enforcement falls to the state boards of pharmacy. Many states are in the process of rewriting their laws and regulations to enhance existing sterile and nonsterile compounding regulations to harmonize with USP <797>. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) still requires a gap analysis and action plan during survey but has neither the authority nor the trained surveyors to survey to USP chapter requirements.

Can you have an open concept in a negative room?

A negative pressure cleanroom must be maintained at a minimum pressure of 0.01 in./WC. It seems unlikely that this can be maintained in an open-concept cleanroom.

Do you need a dedicated air-handling unit (AHU) for the cleanroom or can you share one from another area? If so, must you still meet the air-changes-per-hour (ACPH) requirements?

You do not need a dedicated AHU if the existing HVAC system can handle the additional load. You still need to meet the ACPH requirements regardless of which HVAC system you employ.

Should you design the function and equipment of the room first, trying to predict the particle generation, and then design the HVAC system?

Ideally, the ACPH requirements are based on particle generators, heat load considerations, personnel traffic and other considerations and should be taken into account when determining HVAC requirements. The USP ACPH recommendations are minimum requirements and should not be looked at as specific numbers. USP states: “More air changes may be required based on the number of personnel and processes.”

Can you store supplies in the cleanroom?

Ideally, supplies in the cleanroom should be limited. The cleanroom should be as spartan as possible, containing only the supplies and inventory needed for that compounding day. Excessive amounts of supplies and inventory in the cleanroom are a hassle when performing daily, weekly and monthly cleaning procedures.

Can you compound IVs and chemo in the same room?

As stated in USP <797>: “The ISO Class 5 BSC [biosafety cabinet] or CAI [compounding aseptic isolator] shall be placed in an ISO Class 7 room that is physically separated, i.e., in a different room, from other preparation areas…”

Do you need pressure-locked doors into the anteroom and/or buffer room?

No.

How do the standards relate to oncology offices?

The standards in USP Chapter 797 are intended to apply to all persons who prepare compounded sterile preparations (CSP) and all places where CSPs are prepared, e.g., hospitals and other healthcare institutions, patient treatment clinics, pharmacies, physicians’ practice facilities, and other locations and facilities in which CSPs are prepared, stored, and transported. Persons who perform sterile compounding include pharmacists, nurses, pharmacy technicians, and physicians. These terms recognize both that most sterile compounding is performed by or under the supervision of pharmacists in pharmacies and that this chapter applies to all healthcare personnel who prepare, store, and transport CSPs. In Virginia, the Board of Medicine adopted emergency regulations requiring all physician offices that engage in compounding (which is broadly defined) to meet USP Chapter 797-Sterile Compounding Rule emergency regulations. Oncology offices that don’t have a licensed pharmacy area are regulated by the state board of medicine and may be required to comply with other local, state and federal (e.g., OSHA, NIOSH) requirements.

Will JCAHO, FDA or state boards of pharmacy survey my facility for compliance?

Possibly any or all of those organizations will survey your facility, depending on your state. You should contact your state board of pharmacy directly for more information.

Can two people work and compound under the same laminar bench and still maintain ISO 5?

If that device has been designed for that operation and particle count testing confirms that ISO Class 5 is maintained, two people can work at the same time.

How many of the changes in the proposed revisions will be accepted and become a requirement?

That will be determined by the committee based on the review of the comments received.

In chemo rooms, how can you maintain ISO 5 on the bench if you are pulling dirty air (ISO 7 or 8) across the bench, based on airflow? Shouldn’t the chemo bench be in an ISO buffer room as well?

Work in a chemo room should only be done in a BSC or compounding aseptic containment isolator (CACI) specifically designed to provide ISO Class 5 and to contain at the same time. Work should never be performed on a bench in a chemo application.

How often do you need to do particle and bioburden counts?

Particle counting or nonviable sampling occurs every six months. Depending on your risk level, you are required to sample either monthly (low- and medium-risk level) or weekly (high-risk level). If you haven’t already, download a copy of the proposed changes to USP Chapter 797. Visit http://www.usp.org/USPNF/pf/generalChapter797.html to obtain a copy. The specifics can be found in this document.

State boards of pharmacy have full legal compliance such that fines can be imposed. Should we not have to follow their laws, regardless of USP <797>?

There are some state laws that are not harmonized with USP Chapter 797. The principle of preemptive law applies and pharmacists have to follow the stricter of the two laws (state vs. federal). It is best to contact your state board of pharmacy for more complete guidance. USP standards have been used in lawsuits as national standards of practice.

Can you elaborate on viable sample requirements?

Viable sampling is the collection of air, surface or personnel samples with the express purpose of detecting microbial contamination.

How are HEPA filters tested after installation (in situ)?

For cleanrooms, every application is slightly different. Ideally, the cleanroom contractor has made accommodations for field-testing. An aerosol challenge (typically polyalphaolefin [PAO]) is introduced upstream of the HEPA filters and the filters are scanned downstream with an aerosol photometer. Ceiling-mounted HEPA filters are usually easier to test than remotely located banks of filters.

What are the deadlines for facility implementation?

Technically, USP Chapter 797 has been in effect since January 1, 2004. JCAHO initially published 2008 deadlines but has since backed down on those dates, unless mandated by state boards of pharmacy.

Is there any historical data to justify 30 ACPH vs. the normal 60 ACPH for ISO 7 areas?

The rate of 30 ACPH is based on the minimum suggestions in the ISO 14644-4 document. Remember, USP specifically states: “More air changes may be required based on the number of personnel and processes.” It is interesting to note that, when discussing this document with people familiar with cleanrooms, they invariably comment on the concern that 30 ACPH might not be adequate to maintain ISO Class 7. When you discuss this with people less familiar with cleanrooms, they wonder why we require so much air. The final number of air changes will need to be determined on an individual basis but, with the amount of HEPA-filtered air added to the room from the primary engineering controls (except for an exhausted chemo hood), 30 ACPH will be a good starting point.

Is it true that all work surfaces and storage surfaces must be stainless steel in the cleanroom?

No, as long as they are smooth, impervious, free from cracks and crevices, nonshedding, cleanable, and will stand up to the disinfectants.

What is a reasonable date to expect the completed revision of USP <797>?

All USP chapters are dynamic and subject to change. The goal of the USP Sterile Compounding Committee is to get through the comments from the proposed changes and issue a revised chapter as soon as feasible.

Is coving necessary in a cleanroom?

Coving is ideal, but as long as cleaning can be accommodated and seams are sealed and caulked, it should be sufficient.

Please comment on the ability of an operator to shut off a laminar flow bench (LFB) and therefore change the effective ACPH. Wouldn’t it be better to have the primary airflow be at a minimum of 30 ACPH or, even better, 60 ACPH?

The primary engineering controls should never be turned off in a cleanroom. They are designed for continuous operation. I understand your concern that an operator can make a mistake and therefore affect the operation of the cleanroom. If you feel that concern is real for your institution, I recommend you bypass the on/off switch on the hood. That will be a much cheaper solution than ignoring the value of the HEPA-filtered air delivered to the cleanroom. This allowance by USP was intended as a cost-saving consideration.

Are open-concept cleanrooms a better alternative to traditional design? Where can I find more information on open-architecture designs?

Open architecture cleanrooms are not a better design, nor are they cheaper. Factoring in the air needed to achieve 40 FPM across the interface between two spaces, this becomes an expensive option. The open architecture design is acknowledged in ISO 14644-4, thus it is acknowledged by USP. There is not a lot of precedent in the U.S. for this type of design outside the pharmacy industry. You will also find that most of the early discussions regarding open architecture cleanrooms were conducted without consideration for engineering criteria: Just place a line on the floor, and the room magically works. Once criteria become part of the discussion, the costs seem to make this design impractical.

Which particle counter flow rates are applicable for environmental monitoring?

Most particle counters are available in 0.1 CFM, 1.0 CFM, and sometimes even larger sample volumes are available. Any sample volume will work depending on how much time can be allocated to particle counting. I assume most professional certifiers will use at least a 1.0 CFM counter, simply based on the amount of time needed when using a 0.1 CFM counter. A pharmacy looking for a particle counter might value the lower cost of a 0.1 CFM counter more than the implications of sample time. In this case, the particle counter can be set up for longer sample times while pharmacists go about their day.

What media requirements do you recommend for viable sampling?

Proposed revisions in USP recommend tryptic soy agar (TSA) and malt extract agar (MEA).

When it states that a cleanroom must meet the specification for 0.5 micron or greater, does that mean that more than one particle size should be monitored, or is monitoring only 0.5 micron sufficient?

Setting the counter for the cumulative mode will count all particles that size and larger. Reading in the differential mode will count that specific size range.

Are there any studies indicating the impact of venting hazardous drugs to the outside air?

I assume the questioner is concerned about negative impact to the outdoor environment or positive impact (in terms of disease reductions) to the indoor environment. In either case, I am unaware of any studies that enacted this change and then evaluated the results upon the respective environments.

I understand that cleanroom certification for nonviable particles is recommended every 6 months at a minimum: How do I know I’m in compliance between certifications?

Technically, you only “know” for a fact that you are in compliance when you perform the counts. However, with a properly designed unidirectional-airflow primary engineering control, you know what control points (proper velocity, unidirectional airflow, leak-free HEPA filter, good return locations) provided the ISO Class 5 conditions that were observed while you took the counts in dynamic operating conditions. If you know your control points and you prove that you will maintain class when those control points are maintained, you should have confidence that you will maintain class reliably between tests. The same is true for the room itself: If you know that your control points (adequate ACPH of HEPA-filtered air) provided ISO Class 7 when the test was performed, you will likely maintain ISO Class 7 between tests. Continuous monitoring is the best solution but it is often outside the realm of possibility for most compounding operations.

How can isolators be advocated for use with hazardous drugs when little third-party validation of this equipment has been performed? At least BSCs have third-party review through NSF.

The adoption of containment isolators as an acceptable primary control for protection against hazardous drug exposures was based upon a number of factors, including their similarity of design with respect to Class III BSCs, the use of similar protective concepts within the pharmaceutical manufacturing industry, a small number of research studies favorably reporting their use for hospital pharmaceutical compounding, and the announced intention to reference the use of isolators in USP <797> as an alternative primary engineering control for CSP compounding. Admittedly, the big risk with this reference is a lack of industrywide performance and testing standards for pharmacy compounding isolators. Unlike Class II BSCs, isolators do not have the advantage of an independent industry organization setting the standards, testing the designs, and setting criteria for field certification. There are many different isolator designs and not all of them perform the same. This lack of testing standards can result in a potentially dangerous situation in which consumers are limited in their ability to compare and select such equipment, thus becoming potentially vulnerable to selective performance claims unverified by independent testing organizations. Until performance and testing standards are adopted, consumers are encouraged to insist that their new isolator, as a procurement requirement, meet the test and performance criteria in CETA’s application guide CAG-002-2006. Hopefully, manufacturers will begin to voluntarily and uniformly adopt this or a similarly rigorous and comprehensive test and performance protocol.

Should we wait to renovate our pharmacy until the new regulations are finalized?

That is a decision each facility must make based on the needs of their operation.

CleanRooms would like to thank the experts who served on the Webcast panel: Jim Wagner, president of Controlled Environment Consulting; Eric Kastango, president and CEO of Clinical IQ; and Kenneth R. Mead, MS, PE, research mechanical engineer at the Centers for Disease Control and Prevention. Please visit www.cleanrooms.com for information on the next CleanRooms Webcast, as well as access to The plain truth about USP <797> in its entirety.

Comparing and contrasting requirements for facilities, components and gowning

By Hank Rahe, Containment Technologies Group

The following statement by the FDA highlights the critical factors that are required to perform aseptic manipulations, whether it is in pharmaceutical manufacturing or compounding preparations in a pharmacy setting: “In an aseptic process, the drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together. Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment. Aseptic processing involves more variables than terminal sterilization. Before aseptic assembly into a final product, the individual parts of the final product are generally subjected to various sterilization processes. For example, glass containers are subjected to dry heat; rubber closures are subjected to moist heat; and liquid dosage forms are subjected to filtration. Each of these manufacturing processes requires validation and control. Each process could introduce an error that ultimately could lead to the distribution of a contaminated product. Any manual or mechanical manipulation of the sterilized drug, components, containers, or closures, prior to or during aseptic assembly, poses the risk of contamination and thus necessitates careful control.”

Aseptic manipulations in either manufacturing or compounding are difficult. The level of success in delivering a drug that is safe to use on a patient is described as the sterility assurance level (SAL) of the final package. Sterility assurance is a theoretical number set so that the probability of a nonsterile product making it through the validated sterilization process is one unit per million sterilized. This is referred to as a SAL of 10-6.

In many ways, aseptic manufacturing, as it occurs in pharmaceutical facilities, can be contrasted and compared to compounding preparations in pharmacy. The major areas of each activity are the facilities, components and gowning used. The FDA guidance for aseptic manufacturing is presented in the form of non-binding recommendations that support compliance to cGMPs, while the aseptic compounding of sterile preparations requirements come in the form of a standard issued by the U.S. Pharmacopeia (USP). A USP standard is not a regulation or law but can be adopted into law. As a standard it must be followed as written.

Facilities

The facilities for pharmaceutical processing can be of several different configurations, from conventional ISO Class 7 cleanrooms, supporting a critical manufacturing zone of ISO Class 5 where the combining of all components come together to provide a sealed package, to an ISO Class 8 environment surrounding and supporting an isolator. The FDA guidance regarding facilities is described in Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice (2004): “This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic… You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.”

The facility requirements for aseptic compounding of preparations as described in USP <797> are a work in progress. The USP process allows for annual revisions to its standard and has presented a moving target to healthcare institutions falling under the standard. USP <797> was first published and became enforceable as a standard of practice in 2004. The facility requirements outlined in the chapter mirror the physical requirements for cleanrooms outlined in the FDA 2004 guidance in terms of materials of construction. The USP standard calls for ISO Class 8 for air quality and uses an example showing two options for construction style, the first being a conventional anteroom and the second a single room with no physical separation between the ante-area and the compounding area.

Acceptable ISO Class 5 environments identified in the USP <797> chapter are laminar flow benches, Class II biological safety cabinets (BSC) and barrier isolators. The barrier isolators are not required to be supported by an ISO Class 8 environment.

In 2006, as part of the annual revision process, USP issued a number of revisions to USP <797>, including major changes in the physical requirements. One major change was the requirement for ISO Class 7 cleanrooms and a series of facilities for hazardous drugs. The proposed requirements for hazardous drugs include negative-pressure cleanrooms with cascading pressure differentials leading to an adjacent positive-pressure cleanroom.

Components

In aseptic manufacturing processes, the vials, syringes and patient delivery bags are also produced, in many cases, by aseptic processing. Those products that are able to withstand it are terminally sterilized. In the majority of cases, after being filled, the vials are not terminally sterilized.

The supporting components for filled vials, including the glass vial and stoppers, are sterilized and the liquids are sterile filtered. The SAL of vials is documented to be from 10-3 to 10-5. Syringes, needles and patient delivery bags are typically terminally sterilized to a SAL of 10-6.

The components used in aseptic compounding of preparations have a high SAL on the inside of the packages. However, the outside of the packages are not enclosed in a protective aseptic environment and, after manufacture, are held in corrugated shippers in a warehouse before being then shipped to a wholesaler’s warehouse until they are ordered by and shipped to a healthcare institution. Neither the facilities nor the shippers are aseptically protecting the exterior of the packages. Upon arrival at the healthcare institution, the packages containing the “sterile” components may be placed in another warehouse or general storage area. The net result is that the exterior of the components used in aseptic compounding are likely to have been contaminated with microorganisms.

The decontamination processes for compounding components is typically either a wipe- or spray-down with nonsterile alcohol. Nonsterile alcohol is the environment used to support spores and is documented as not being an effective decontaminant. FDA has discouraged manual sanitization because it is not a consistent and repeatable process. However, in the USP <797> chapter, the definition of decontamination excludes spores.

A major difference between aseptic manufacturing and aseptic compounding is the starting point, in terms of the sterility assurance level, of the components being placed into the ISO Class 5 environment.

Several studies have shown that it is likely that touch contamination is the leading factor in the dramatic differences in the sterility assurance levels between aseptic manufacturing and aseptic compounding. Two studies published in the American Journal of Heath-System Pharmacy (AJHP) help to support this conclusion.1, 2

The first study showed a 5.2 percent contamination rate of medium-risk simulations and that the use of sterile gloves greatly reduced the rate of contamination. Manipulation of contaminated components would, however, result in contamination of the sterile glove after the first contact. The second study compared simulations in and out of a conventional cleanroom. It showed a similar contamination rate of less than 10-3 in both cases.

Both studies indicate a difference in individual performance that would seem to invalidate the idea that good aseptic technique is the answer to reducing the high contamination rates. There is no means to assure good aseptic technique when the contamination rate is dependant on individuals performing the activity in the same way.

Gowning

Gowning requirements for aseptic manufacturing facilities require that individuals working in the aseptic core be fully covered with a “bunny suit.” Individuals are trained in proper gowning and degowning technique and it should be noted that gowns are sterile and intended for one-time use.

USP <797> allows for a much lower level of personal gowning, including the use of nonsterile gowns and the reuse of gowns.

Summary

Biodecontamination of the exterior of materials used in aseptic manipulations is the major factor in determining the SAL, given a properly maintained and sanitized ISO Class 5 environment.

Isolators have increased the dependability of the ISO Class 5 environment for aseptic processing by minimizing personnel contact during processing. This has been demonstrated in studies showing increased sterility assurance levels as compared to conventional cleanrooms.

Biodecontamination by automated decontamination systems has made it possible for pharmaceutical manufacturers to sterilize components and environments and has enabled them to aseptically produce products having a SAL greater than 10-4.

Compounded preparations, on the other hand, are not routinely tested for sterility due to the nature of the activities surrounding their preparation. Feedback on the lack of sterility comes in the form of adverse patient reaction, reported as secondary infections. An indication of contamination rate can be determined by simulated media activities if repeated a number of times.

The surfaces of components used in compounding must be properly decontaminated, as well as the ISO Class 5 environment, including any glass, sleeves or body parts entering the environment. If we are to see a reduction in the number of contaminated IVs going to patients, standards such as USP<797> must focus on the biodecontamination of preparations.

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Hank Rahe is director of technology for Containment Technologies Group and is a member of the CleanRooms Editorial Advisory Board. He can be contacted at [email protected].

References

1. Thomas, M., M. Sanborn, R. Couldry. “I.V. admixture contamination rates: Traditional practice site versus a class 1000 cleanroom,” American Journal of Health-System Pharmacy, Vol. 62 , Issue 22, pp. 2386-2392.
2. Trissel L., J. Gentempo, R. Anderson, J. Lajeunesse. “Using a medium-fill simulation to evaluate the microbial contamination rate for USP medium-risk-level compounding,” American Journal of Health-System Pharmacy, Vol. 62, Issue 3, pp. 285-288.