By James T. Wagner

The Importance of Eliminating Contamination in Your Barrier Isolator

BARRIER ISOLATORS ARE USED TO COMPOUND BOTH HAZARDOUS AND
non-hazardous sterile preparations. USP chapter <797> and the NIOSH Alert for Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings are both based on the assumption that isolators prevent the exchange of unfiltered air between the isolator work chamber and the room in which the isolator is housed. Following is the background you will need to decide whether or not to place an isolator in a cleanroom, and factors to consider when determining your isolator’s ability to actually isolate its work area from the room in which it is placed.

The current version of USP chapter <797> makes the following statements: “A well-designed positive-pressure barrier isolator, supported by adequate procedures for its maintenance, monitoring, and control, may offer an acceptable alternative to the use of conventional LAFWs in cleanrooms for aseptic processing...The contamination-reduction conditions and procedures in this section include LAFWs located within buffer or cleanroom areas that maintain at least an ISO Class 8. It is preferred, but not necessary to locate barrier isolators within such a buffer air quality area.” While we do not yet know the changes to be made to the USP chapter, we can be sure that additional guidance will be forthcoming. In the pharmacy, it seems most people forget the phrase “it is preferred,” and choose to only remember the words “but not necessary.”

Guidance documents have historically required the placement of an isolator in an ISO Class 7 or 8 environment. The most recognized of these is the non-binding FDA document, released in 2004, “Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice,” which states, “The interior of the isolator should meet Class 100 (ISO 5) standards. The classification of the environment surrounding the isolator should be based on the design of its interfaces (e.g., transfer ports), as well as the number of transfers into and out of the isolator. A Class 100,000 (ISO 8) background is commonly used based on consideration of isolator design and manufacturing situations. An aseptic processing isolator should not be located in an unclassified room.” This language is quite clear and strong.

The Importance of Material Transfer Protection Material transfer in and out of isolators during pharmaceutical manufacturing is recognized as the stage most vulnerable to contamination. The same is true for isolators used in the hospital pharmacy. In fact, material transfer poses a bigger threat to the internal chamber of a compounding isolator than most pharmaceutical manufacturing isolators, because pharmacy isolators typically rely on “pass-through” systems rather than the more robust “direct interface” or “rapid transfer ports” typically associated with pharmaceutical manufacturing.

Pharmaceutical manufacturers place isolators in cleanrooms to reduce the total contamination potential during material transfer. In hospital pharmacies, isolators are often placed in uncontrolled rooms, increasing the susceptibility to transferred contamination, and thus potentially compromising the sterility of the preparations being compounded in the isolator.

Decontamination with a validated system such as Vapor Phase Hydrogen Peroxide or Chlorine Dioxide is considered standard practice in pharmaceutical manufacturing settings. Procedures are developed to ensure full exposure of all isolator surfaces to the chemical decontamination agent. A breach of isolator integrity, such as that caused by entry of room air into the isolator is usually justification for decontamination. Pharmacy isolators, on the other hand, are usually decontaminated by spraying and wiping surfaces with a chemical agent, but the process is seldom validated to be effective. As such, pharmacy assumes substantial risks by rejecting the practice of placing isolators in a cleanroom while not fully embracing all of the other safeguards employed by other industries using isolators. Therefore, it is imperative that we take steps to eliminate the contamination transferred from the room during material transfer, and to maintain strict attention to aseptic technique during product manipulation.

USP Chapter <797> has made us aware of the fact that traditional clean air devices placed outside of a cleanroom are not always adequate protection to sterile products. Cleanroom technology, along with laminar flow equipment, will certainly provide appropriate atmospheres for compounding sterile preparations. In some cases, however, cost or space constraints do not allow for building of proper cleanroom facilities. In these case, the argument has been made that properly designed positive pressure isolators that prohibit the exchange of unfiltered room air with the isolator are suitable alternatives to the cleanroom option.

Isolators are intended to isolate the work chamber from the room at all times during operation and transfer. However, you cannot simply purchase any system, place it in a room, and then expect it to provide the protection needed for sterile compounding. Understanding the importance of eliminating contamination, most isolator manufacturers have engineered material transfer protection into their product through the use of airflow and HEPA filtration. In its simplest form, a static passthrough is a box attached to the isolator with two doors. At least one of the doors is closed at all times. While this will prevent the isolator’s working chamber from being directly exposed to the room, it will not prevent the transfer of particulate contamination from the room; room-particulate load enters the pass-through when materials are transferred into the passthrough from the room. Particulate matter is then transferred from the pass-through to the isolator.

To avoid this risk, most isolators utilize HEPA filtration to purge the pass-through. These HEPA-purged pass-throughs are able to eliminate virtually all particle transfer. Furthermore, the use of unidirectional airflow in the pass-through allows for the transfer of materials directly from the room to the isolator chamber with practically no purge time. I do not suggest transferring materials without at least a short purge time, but it is reassuring that the purge times can be short enough that even busy pharmacies will be able to use the system properly.

Laminar Air Flow
When thinking through the process of using the isolator for sterile compounding, remember that we need to prevent the ingress of contamination into the isolator. Your isolator will most likely not be in a cleanroom and the outside of the packages used in the isolator are most likely not going to be sterile. Do you really want to take these packages into the isolator without some type of preparation?

Some isolators are equipped with a laminar air flow pass-through, allowing users to remove the outer packaging or to wipe down the outside of packages in an ISO Class 5 unidirectional zone prior to entry into the work chamber. By removing the contaminated outer packaging in an ISO Class 5 pass-through and wiping down with the appropriate disinfectant, you can greatly reduce or possibly even eliminate the transfer of contamination into the isolator.

Aseptic technique is generally associated with the use of “first air” concepts. Combining unidirectional isolator airflow with sound technique and a unidirectional passthrough will most likely provide the protection needed for pharmacy. Quoting the FDA aseptic processing guide again, “There are two types of aseptic processing isolators: open and closed. Closed isolators employ connections with auxiliary equipment for material transfer. Open isolators have openings to the surrounding environment that are carefully engineered to segregate the inner isolator environment from the surrounding room via overpressure. Turbulent flow can be acceptable within closed isolators, which are normally compact in size and do not house processing lines. Other aseptic processing isolators employ unidirectional airflow that sweeps over and away from exposed sterile materials, avoiding any turbulence or stagnant airflow in the area of exposed sterilized materials, product, and container closures. In most sound designs, air showers over the critical area once, and then is systematically exhausted from the enclosure. The air-handling system should be capable of maintaining the requisite environmental conditions within the isolator.”

Because of the potential for particulate transfer into them, isolators used for pharmacy compounding are considered “open” systems by the FDA’s standards. In an open isolator system, unidirectional airflow is needed to accommodate good aseptic technique. I am quite confident that a welldesigned laminar flow isolator with HEPA-filter-purged pass-throughs can provide at least the same level of cleanliness to the work area as a traditional laminar flow bench in a cleanroom. However, attention must be paid to the isolator’s design. Think through your process for prepping materials and your method for bringing them into the isolator without introducing contamination to the isolator. Then match that thought process to the appropriate isolator design.

Compounding Hazardous Drugs
When considering how well the isolator isolates, we must also consider the isolators used for compounding hazardous drugs. Unlike biological safety cabinets, isolators are not certified to an industry standard by an independent agency. Every isolator is tested to criteria established by that manufacturer. The Controlled Environment Testing Association (CETA) is in the final stages of developing a standard that will at least give the end user a method of establishing consistent testing protocols. That should available by the end of the year. The same concerns that are important for transferring material into an isolator are even more important when removing materials from an isolator used to contain hazardous drugs.

Unidirectional isolator airflow will prevent a build up of processgenerated aerosols that may provide a risk to the room during material egress. Additional isolation is provided by HEPA-purged pass-throughs. The NIOSH Alert suggests specific isolators for use with volatile drugs. It should be noted that even HEPA-purged pass-throughs will not prevent the transfer of volatile contamination, as HEPA filters do not filter gases and vapors. Isolators and their associated pass-throughs should be vented outside the building if used to contain volatile contamination. Much more work is needed to understand containment isolators and that process has just begun. As such, for now, make sure you look at all the isolator options and understand how they utilize airflow and HEPA filtration to accomplish their stated goals. With a combination of proper aseptic technique and the use of a barrier isolator with a unidirectional pass-through and work area, you will most likely achieve the level of protection your pharmacy needs. However, one should remember that although it is acceptable to use a barrier isolator outside of a controlled environment, to minimize the potential for contamination in the isolator work area, the isolator should be validated to prevent contamination during material transfer and cross contamination during operation or it should be located in an ISO Class 8 or cleaner environment.

James T. Wagner, principal of Controlled Environment Consulting, has over 25 years' experience evaluating facilities used for aseptic processing. He has served on many industry-standard writing committees, and is currently a member of the committee revising USP Chapter <797>.