Q&A with James Wagner,
Controlled Environment Consulting
Pharmacy Purchasing & Products: What pharmacy applications make the best use of compounding aseptic isolators for drug compounding?
James Wagner: In general, I see compounding aseptic isolators (CAIs) most commonly used in hospital pharmacies for low-volume applications or as a solution for those facilities that have no space or means to build a cleanroom. I also have seen CAIs used in ante areas or other convenient locations for after-hours preparation of stat doses or other one-off preparations.
When considering the implementation of a CAI, it is worth taking into consideration the amount of time required to perform the kinds of compounding done in your facility. In some cases, the garbing and gowning process required for access to a cleanroom might actually take longer than the average time needed for the compounding procedure itself. Therefore, using an isolator for low- to medium-risk, low-volume compounding in such situations could be beneficial, as gowning is not necessarily required for many isolators.
PP&P: What are the functioning components of a CAI and how do they provide safety to drug compounding?
Wagner: Like any other engineering control used for sterile compounding, CAIs are designed to create a suitable clean space for drug manipulation by controlling and cleaning airflow. Air is passed through HEPA filters to create virtually particulate free air, which is then passed through a diffuser and directed to return grilles on the opposite end (top to bottom) of the work area to create unidirectional airflow. Unlike biological safety cabinets and laminar flow air workstations, CAIs also add the benefit of a physical barrier between the product and the environment. Work is performed by a pharmacist or technician via gloves attached to a sleeve, which is in turn attached to portals in the isolator’s glass view screen. CAIs operate at a slight positive pressure relative to the room in order to help keep any outside air from leaking into the chamber.
Conversely, compounding aseptic containment isolators (CACIs) operate with a slight negative pressure relative to the room. Because of this, the impact of any leaks created in the isolator glove or sleeve assembly can be dramatically more significant than with positive pressure isolators (CAIs). While USP Chapter <797> does not mandate it, I suggest operating negative pressure isolators in a cleanroom to reduce potential contamination risks.
PP&P: What types of compounding should be avoided in CAIs?
Wagner: Isolators work well for routine aseptic manipulations, but more complicated compounding operations that require the use of bulky equipment can be a challenge in a small isolator, especially if the rear of such equipment must be accessed during compounding. For example, it may be best to avoid using a larger automated compounding device inside a typical single-user CAI, because interacting with the device can be difficult.
Additionally, I have heard reports of concerns over the risk of repetitive stress injuries when working with heavier IV bags in certain isolators. Certainly, any prolonged activities inside a CAI should be performed with proper ergonomic considerations taken into account.
PP&P: What are the facility requirements for using a CAI outside of a cleanroom?
Wagner: A CAI can be placed and used outside of a cleanroom as long as it meets all of the criteria laid out in USP Chapter <797>; in essence, the interior of the isolator must be completely isolated from the room. Tests designed to prove whether the isolator is truly isolating the environment are detailed in the Controlled Environment Testing Association applications guide CAG-002 (www.cetainternational.org).
The isolator must be proven to maintain ISO Class 5 air quality during material transfer and under dynamic operating conditions. It is worth noting that for non-hazardous preparations, the chapter does not specify any detailed room conditions, but I recommend that the room at least have accommodations for hand washing and be easily cleanable. When using a CACI for hazardous preparations, the room in which the CACI is housed should be maintained with at least 0.01-inch water column negative pressure in addition to ease-of-cleaning and hand hygiene requirements. Both USP and NIOSH require external venting when compounding potentially volatile hazardous drugs regardless of isolator design. This is important because the HEPA filters used in these devices to provide environmental protection from hazardous substances are not effective against volatile agents. Some hazardous drugs have been shown to volatilize, so external venting is appropriate.
PP&P: Are there inherent risks to compounding in a CAI outside a cleanroom?
Wagner: The argument for using an isolator outside of a cleanroom is based on the presence and integrity of the physical barrier and the isolator’s sleeve and glove structure. In the event of a pinhole or tear in the glove or shell of a CAI, internal positive pressure will cause air exposed to whatever materials are being compounded to leak from the critical area out into the room. If there is such a leak, the particulate levels inside the isolator should not be affected. However, in the case of a negative pressure isolator (CACI), even just a pinhole leak can result in significant contamination to the direct compounding area (DCA) within the isolator due to outside air being drawn into the DCA. Therefore, it is my opinion that the ISO classification of the room where a CACI is employed is significantly more important than a room used to house a CAI. Further to this, while it is important to change out gloves regularly on all isolators, it is especially critical for negative pressure CACIs. If possible, I recommend performing dynamic particle counts daily or even continuously when working in negative pressure isolators because of the potential contamination risk that even pinhole leaks can lead to. This may sound arduous, but small, low-volume particle counters are available at moderate cost.
Working through the defined openings in isolators can be problematic especially when you consider that several people of different sizes will likely be using the equipment. Because of this, it is beneficial to include height adjustors for all isolators. Keep in mind that if you are using a CACI, that unit must be externally vented, so a flexible vent hose connection with enough room to accommodate at least the amount of adjustment that could be made to isolator height is necessary.
Lastly, disposal chutes are often incorporated into CAIs to manage waste and sharps. They are convenient and work well for positive pressure isolators. I am concerned, though, that the potential for leakage and resulting contamination when disposal chutes are used with negative pressure isolators outweighs the advantages. If a disposal bag or container is not properly sealed on a positive pressure isolator (CAI), any air leakage will be from the inside of the isolator out, which does not create a problem for any nonhazardous compounding procedures. However, any leakage from an improperly sealed disposal container on a negative pressure isolator (CACI) will draw outside air into the isolator, and this creates a contamination potential for CSPs. To help avoid contamination, waste from a CACI can be placed in an airtight disposal vessel inside the isolator and then be safely removed through the airlock.
PP&P: How often should isolator sleeves be changed and what signs of wear should you look for?
Wagner: In general, I suggest adopting the manufacturer’s recommendation for sleeve replacement frequency, because the integrity of a sleeve and glove system is highly dependent on frequency of use. I have seen sleeves that have been in use for nine months that are still intact and sound. However, this does not imply that nine months is replacement benchmark; rather, it simply implies that the particular sleeve system on that isolator was robust or the isolator saw limited use. Obviously, if pinholes appear, the sleeves must be changed. Unfortunately, tiny tears and holes are often difficult to see and will be missed as often as they are found. The most conservative approach is to perform a daily particle count in negative pressure isolators.
PP&P: Are there productivity issues related to compounding within a CAI?
Wagner: Sterile compounding in general requires careful forethought and planning. Smaller facilities that may not have the space or budget for a cleanroom are able to use CAIs to prepare one item at a time, which helps with accuracy and supports a standardized compounding protocol, and the slower operational progress is usually offset by a reduction in gowning time. However, there are some operational challenges inherent to this equipment.
Transferring materials into and out of an isolator takes longer than the same processes using other laminar flow equipment. Materials have to be placed into the transfer box and then the technician must wait for the required purge time before introducing the materials into the main isolator workspace. When working inside the isolator, the operator’s movements can be somewhat restricted by the fixed nature of the glove portals and sleeve locations. Cleaning also can be challenging because of the difficulty in accessing all surface areas. Often, special cleaning equipment and extra time is needed to properly sanitize isolators, and enhanced environmental monitoring inside isolators also is recommended to ensure effective cleaning.
PP&P: What are the certification requirements for CAIs upon installation and periodically thereafter?
Wagner: USP Chapter <797> clearly recommends that isolators be certified in accordance with CETA CAG-002-2006 upon installation, every six months, when moved, and when a major service is performed. The reference to this applications guide is important, because when certifying a critical piece of equipment, it should be tested to industry-based guidance documents intended to truly challenge the devices. In many cases, certifiers only employ the rigorous CETA testing at the request of their customer, despite the recommendations in USP Chapter <797>. Therefore, I suggest all isolator owners demand that their certifier follow this industry based guidance document.
James T. Wagner, principal of Controlled Environment Consulting, has over 30 years’ experience evaluating facilities and primary engineering controls used for aseptic processing. He has served on many industry-standard writing committees, and was a member of the expert panel that revised USP Chapter <797>.
USP <797> Definitions:
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