Pharmacies that mix drugs and other ingredients to prepare patient-specific doses, a process referred to as compounding, use engineering controls to maintain the high level of cleanliness necessary to prevent contamination of the product. These controls include air filtration, frequent air changes, and relative pressure. Differences in the relative pressure between spaces in a pharmacy help prevent contamination and control the spread of hazardous drugs (HD) from spaces where they are stored or compounded. This article describes an innovative design for managing the need to contain HD within the compounding space while also preventing the airborne infiltration of contaminants.

In the United States, the United States Pharmacopeia establishes the standards for pharmacy compounding. USP chapter <797> addresses the sterile preparation of pharmaceutical compounds, including the ventilation and environmental conditions of controlled spaces within the pharmacy. USP chapter <800> addresses the handling of hazardous drugs in a healthcare setting.

The required level of cleanliness inside a pharmacy space determines the cleanroom classification of the space. The International Organization for Standardization (ISO) classification system—ISO 14644-1, —is the primary standard for the classification of cleanrooms. In the ISO system, the cleanest spaces in a pharmacy are designated ISO 5. Pharmacy anterooms—transition spaces where materials and supplies enter the controlled spaces of the pharmacy from uncontrolled space—have traditionally been less clean (ISO 8) than the buffer rooms (ISO 7) where the compounding occurs.  Positive and negative pressure refers to the relative balance of air pressure between two adjacent spaces. Adjusting the volume of supply and return air to a space determines the space pressurization. When a space receives more supply air than is exhausted or returned to the air-handling equipment for recirculation, the space pressure will be positive. When the space receives less supply air than is exhausted or returned to the air-handling equipment for recirculation, the space pressure will be negative. Maintaining positive pressure relative to adjacent spaces helps prevent airborne contamination from entering cleaner spaces.  In the spaces where hazardous drugs are handled or stored, the use of negative pressure helps prevent the spread of drug components into adjacent spaces. The negative pressure in an ISO 7 HD buffer room relative to an adjacent space results in a requirement that the air in the pharmacy anteroom also be ISO 7 and as clean as the air in the buffer room. Having both spaces meet ISO 7 requirements prevents the airborne intrusion of contaminants from the anteroom into the HD buffer room. Supply air in a pharmacy cleanroom is through high-efficiency particulate air (HEPA) filters located in  the ceilings of the buffer and anterooms. HEPA filters remove at least 99.97 percent of airborne particles 0.3 microns in diameter. Each filter should include a test certification confirming its performance.  Air returns in buffer and anterooms are typically located low on the wall to capture particles shed by occupants near the floor rather than drawing them up though work spaces to the ceiling. Locating air returns near the likely source of particulates—for example, the garbing area of the anteroom—will facilitate the capture and control of airborne particulates. Using pass-through cabinets minimizes airborne particle movement from less clean to cleaner spaces by allowing materials to pass in and out of controlled spaces without needing to open the doors between spaces with different ISO levels. Pass-throughs have interlocking cabinet doors to prevent both doors from being open at the same time. In USP chapter <797>, the cleanest environment is the ISO 5 space within a primary engineering control (PEC) where the actual work with the drugs occurs. A PEC is a laminar flow cabinet or other device designed to provide an aseptic environment for handling drugs and other injectable products through a unidirectional flow of HEPA-filtered air. This airflow must be maintained at a sufficient velocity during use to sweep particles away from the compounding work. Airflow through the HEPA filters of the PEC may be included as a portion of the required air changes per hour (ACPH) in a controlled space. The PEC is often located in an ISO 7 buffer room. The buffer room is where the supplies for compounding the products in the PEC are prepared for use, and where the pharmacist works. Typically, staff will enter the ISO 7 buffer room from an attached anteroom. For compounding of non-hazardous drugs, the pressure in the buffer room is positive relative to the anteroom.  The anteroom is a transition space where materials and supplies enter the controlled spaces of the pharmacy from uncontrolled space. The anteroom pressure is positive relative to the adjacent uncontrolled space. This series of positive pressures in the cleaner spaces relative to less clean and uncontrolled spaces is intended to reduce the transfer of airborne contaminants from uncontrolled spaces into the anteroom, and from the anteroom into buffer rooms where compounding occurs. When pharmacy staff enter an anteroom, they carry viable and non-viable particles with them on their skin, clothing, and air from the uncontrolled space. Supplies brought into the anteroom without adequate cleaning are another source of particles that can become airborne. Staff performing hand hygiene, garbing, talking to each other, and preparing supplies brought into the anteroom are all examples of anteroom activities that can generate higher levels of airborne particulates. In recognition of the transitional role of the anteroom space, the allowable limits for airborne particles in an ISO 8 anteroom are up to 3,520,000 counts per cubic meter of particles greater than or equal to 0.5 micron in size, and up to 100 colony-forming units (CFU) of viable particles per cubic meter of air. These higher limits do not create significant concerns for the compounding process when the compounding buffer room is positively pressurized relative to the higher ISO class anteroom. However, when an HD buffer room is added, USP chapter <800> requires the HD buffer room to have a negative pressure between 0.01 and 0.03 inches of water column (inch wc) relative to adjacent spaces. The intent of this negative pressure is to contain any inadvertent airborne releases of hazardous drugs. With the ventilation pressure in the HD buffer room negative relative to the adjacent anteroom, air from the anteroom will enter the buffer room. To prevent this airflow into the buffer room, USP chapters <797> and <800> require the connected anteroom to be ISO 7 with the same air quality requirements as the ISO 7 HD buffer room (see Figure 1). The limits for airborne particles in an ISO 7 space are 352,000 counts per cubic meter for particles greater than or equal to 0.5 micron in size, and no more than 10 CFU per cubic meter of air for viable particles. These levels are an order of magnitude lower than the requirements for an ISO 8 anteroom not connected to an HD buffer room. Especially in busy pharmacies, where supplies frequently enter the space or occupancy and activity are high, compliance with the stricter ISO 7 standards can be difficult. In addition to the lower limits for airborne particulates, an ISO 7 space must receive a minimum of 30 ACPH compared to the required minimum of 20 ACPH for an ISO 8 anteroom (see Table 1).