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Applications Guide for the use of Barrier Isolators in Compounding Sterile Preparations in Healthcare facilities

In response to the establishment and publication of United States Pharmacopeia (USP) Chapter <797> of the U.S. standards document, USP 27/ National Formulary (NF) 22, the Controlled Environment Testing Association (CETA) published, The CETA Applications Guide for the use of Barrier Isolators in CSPs in Healthcare Facilities. The guide is intended to assist in the purchase, commission and installation of barrier isolators for pharmacy compounding.

The requirements established under USP Chapter <797> make reference to the sterile environment provided by barrier isolators and their appropriateness for use in compounding sterile preparations (CSPs). The requirements call for a sterile environment in which the end user is capable to control the risk of microbial contamination and cross contamination. Barrier isolators are credited with providing such an environment.

Barrier isolators consist of two separate chambers. A transfer chamber is used to clean the background environment of items taken from the general pharmacy area to ISO Class 5 (formerly Class 100) classification. Once the air is clean, the item is placed in an isolated, airtight chamber where the compounding is performed. The use of barrier isolators for CSPs is a, relatively, new concept. Though barrier isolators, in existence at the time of publication of Chapter <797>, were not designed for the purpose of performing sterile preparations, their operating environments make them prime candidates for compliance within Chapter <797> requirements.

The applications guide provides an overview and description of isolator types as well as minimum performance expectations and suggested applications for the various designs of isolator types. The guide specifies and defines an isolator as a unit "supplied with air through a filtration system (HEPA minimum)". The guide further specifies that the isolator:

• May vent discharged air directly in the room in which it is contained
• May provide either unidirectional or turbulent air flow distribution methods
• Must be positively pressurized in relation to its outside environment
• Must meet ISO Class 5 classifications for the cleanliness of the ozone
• Must be reproducibly decontaminated
• Must not allow exposure of the compounded product to personnel or the outside environment
• Must provide access to the compounded product through the use of gloves
• May provide methods of transfer into and out of the unit through either a closed door system or open door system

The guide specifies the design characteristics to consider when purchasing, commissioning and installing an isolator. They include airflow and control; pressurization; clean zone classification; decontamination and disinfections; gloves and sleeves; closed vs. open systems; pass through systems; construction materials; ergonomics; testing and commissioning.

Airflow

The end user of isolator systems should consider which of the two primary designs for airflow patterns and utilization best suits their needs. The two primary airflow designs include unidirectional airflow and turbulent airflow. Unidirectional airflow allows the compounding area to be continuously showered with high-speed, filtered air, which provides a method of sweeping contaminants away from the product and out of the environment through an air exhaust system. Turbulent airflow allows filtered air to be mixed with airborne contaminants, which dilute the contaminants and dispenses them through an air filtration system. This method of turbulence and dilution is dependent upon the volume of air that is cycled into the environment and larger volumes of air require more time to process. During this process, particles may be suspended in the air, some of which may become stagnate and harbor contaminated particles. The unidirectional airflow design is the more efficient design with respect to eliminating contamination. However, both designs have practical applications in the overall process of CSPs.

Unidirectional designs are best suited for delivering air to non-aseptic environments, such as those where compounding is performed. The continuous shower of filtered air sweeps away contamination, almost, immediately. Unidirectional designs offer flow control, which has traditionally been recommended at 90 fpm. The desired airflow velocity, however, is dependent upon the desired results to rid the environment of contaminates. The end user should request the manufacturer to demonstrate a capability to achieve the desired rate of airflow. The manufacturer must be capable to:

1. Provide an airflow velocity profile of the isolator. The profile should include parameters, which represent a system that does not allow for particles to cross contaminate the compounding product, during and after compounding
2. Demonstrate airflow patterns using a smoke pattern test. The test should include a visual demonstration of the airflow from filtration to dispensing. Smoke should follow a smooth even path without turbulence or backflow.

Turbulent airflow designs are best suited for aseptic environments, such as those environments that surround a compounding area. Turbulent airflow designs offer dilution control, where filtered air is used to dilute and eliminate contamination over time. The time frame necessary to replace unconditioned air with filtered air is known as recovery time. Dilution is measured as the number of air changes that are achievable in one hour or air changes per hour (ACPH). A well-designed turbulent airflow system should be capable to achieve dilution control in excess of 160 ACPH. The actual number of ACPHs to achieve recovery is dependent upon several factors, which include:

1. The number and frequency of items to be compounded. The time period to recover from the completion of one item before introducing another must be defined.
2. The effectiveness of the product pass-through system in isolating the work area from outside contamination. If the pass-through method allows contaminants to enter the work area, a recovery period to filter the air, must be allowed before work can begin.
3. The cleanliness of items bought into the work area. If items, particularly packaged items, are brought into the work area and unpackaged, the packaging is likely to introduce contaminants into the work area. A recovery period must be allowed, to clean the air, before work can begin.

Recovery periods to address all of the above should be documented and specified by the manufacturer.

Pressurization

Positive air pressure must be used to physically separate the isolator work area from the outside environment. Positive air pressure reduces the chance of introducing contaminants during product transfers to the isolator as well during the compounding process. This pressure is measured and documented as a positive air pressure differential. Minimum values of positive air pressure differential are, typically, 0.05 inches, as measured by a water gauge Manufacturers should be capable to validate differential minimums, specific to the design of their particular isolator system.

Air Classifications

USP <797> requires that the compounding environment of isolators meet ISO Class 5 classification. The requirements, however, do not specify classification requirements for the area surrounding the compounding area. The requirements only suggest that the isolator be housed in an environment that is as clean and sterile as possible. Draft Guidance for Industry, developed by the U.S. Food and Drug Administration (FDA) in 2003, however, specifies that aseptic-processing isolators be placed in a classified room.

Decontamination and Disinfections

The manufacturer must be responsible to provide documented procedures for the decontamination and disinfections of its isolation unit. The unit should be designed with surfaces that facilitate easy cleaning. The entirety of the interior surface should accessible through the unit's supplied gloves and be designed with smooth seams. If the interior surface does not permit physical access to all surfaces, a gaseous decontamination process should be validated and documented by the manufacturer.

Gloves and sleeves

Isolator units are provided with either a 1-part or 2-part design of the glove and sleeve used to access items inside of the unit. The 1-part glove and sleeve design is such that the glove and sleeve are attached to the unit as a single physical part. In the 2-part design, the glove and sleeve are separate physical parts, attached by some type of sealed system. The 2-part design offers the advantage of being able to change gloves without having to change the sleeve. The type of work to be performed and the glove's chemical resistance to decontamination and disinfecting agents as well as materials used in compounding process determine the glove material and glove life. It is common practice for end-users to institute a double glove system, which allows ordinary latex gloves to be worn underneath the manufacturer-supplied glove for extra protection.

Closed and Open Systems

Closed systems provide for the transfer of items to and from the isolator's work area through decontaminated interfaces. Open systems allow for the transfer of items through specially engineered openings, typically pressurized pass through systems.

Pass Through Systems

Pass through systems are used to isolate the work area from the surrounding atmosphere during the transfer of items into and out of the work area. Open system isolators may be designed with either static air, unidirectional airflow or dilution airflow. A static pass through system is a physical container, sealed to the isolator and used to transfer items from the general pharmacy area to the isolator's main work area. The pass through has two interlocked doors, one opening to the general pharmacy and the other opens to the main isolator area. The interlock provides that only one door is opened at a time. Open isolators, with unidirectional or dilution pass through systems, provide methods to filter and reduce or eliminate the particulate matter from items before transferring them to the main work area of the isolator.

Construction Materials

The isolator should be constructed of stainless steel, glass and high resistant plastic materials, which are durable, functional and suitable for easy cleaning.

Ergonomics

Isolator use may require long periods of relatively still positioning of the arms. Some isolators provide methods to adjust the height of isolator units to accommodate the various heights of individuals and adjustable foot pedals to rest the foot comfortably.

Testing and commissioning

There are no established standards for the testing of isolators. The end users must rely upon the manufacturer's documented procedures for use and criteria for acceptance. Current requirements, as specified by Chapter <797>, insist that the pharmacist be responsible to perform environmental monitoring and process validation for CSP processes. Also, pharmacy certification and accreditation sources have established criteria that pharmacist and pharmacies must adhere to. The end user should seek a manufacturer that has considered these issues, which put demand on the pharmacist, and choose a manufacturer that is capable to provide documented evidence of procedures that address these issues as well as anticipated changes in technology and requirements.