Anteroom Ventilation Design for Pharmacies Compounding Hazardous Drugs
BY LEWIS JOHNSON
Transition Space
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.
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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, Cleanrooms and Associated Controlled Environments—Part 1: Classification of Air Cleanliness by Particle Concentration—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.  PRESSURIZATION 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. TYPICAL VENTILATION 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). 
Table 1. Comparing ISO Classifications of Cleanliness
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AN ALTERNATIVE DESIGN Three of the four drawings in USP chapter <800> that depict suggested pharmacy layout for sterile compounding of hazardous drugs with an anteroom show an arrangement where the anteroom connects directly to the HD buffer room. In this design, the anteroom must be an ISO 7 space. One example shows the HD buffer room accessed from the anteroom via a non-hazardous buffer room. This layout has the potential to increase traffic in the non-hazardous buffer room. USP chapter <800> does not recommend this design and cautions that measures may be needed to avoid contamination of the positive-pressure buffer room. An alternative design to allow for an ISO 8 anteroom with an HD buffer room is the addition of a small secondary gowning room between the anteroom and HD compounding room with a door to each. Such a gowning room provides a convenient location for staff to don and doff personal protective equipment for work with hazardous drugs, but the principal purpose of this room is to isolate the ventilation of the anteroom from the HD buffer room (see Figure 2). I’ve implemented this design to facilitate maintenance of the prescribed anteroom air quality limits while still providing the required conditions for safe, sterile compounding.
Figure 1. A typical pharamacy design. The arrows depict airflow. Proper pressurization requires the anteroom air to have the same cleanliness (ISO 7) as the buffer room for compounding of hazardous drugs.
Figure 2. An alternative pharmacy design. The addition of a gowning room maintains proper pressurization relative to the buffer rooms while allowing the anteroom to be ISO 8.
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The ventilation pressure design for this gowning room must be at least 0.02 inch wc or greater relative to the anteroom, and the HD buffer room must be -0.01 to -0.03 inch wc relative to the gowning room. With this gowning room positive to the HD buffer room, the pressure in the HD buffer room remains negative relative to the adjacent space. This design requires the gowning room to be ISO 7, but because the gowning room is a smaller space than the anteroom with lower traffic and occupancy, it is easier to maintain at ISO 7.  The gowning space is also positive to the anteroom, preventing air from the ISO 8 anteroom from entering the ISO 7 gowning room or the ISO 7 HD buffer room. This allows the anteroom, with its typically higher particle levels due to traffic and activity, to remain ISO 8 with higher limits for airborne particles and a lower number of required ACPH.  As an ISO 7 space, the gowning room must have a minimum of 30 ACPH, which experience has shown to be adequate to manage the viable and non-viable particulate loads created in this low-traffic and low-occupancy space. Establishing this gowning room as the location for donning and doffing impervious gowns, shoe covers, and other PPE for the HD buffer room helps reinforce the behavior of keeping only one door to this room open at a time. CONTROLLED VS. UNCONTROLLED Trying to maintain an anteroom as an ISO 7 space can be challenging considering its role as a transition from uncontrolled to controlled spaces. As traffic levels and occupancy increase, so too do the difficulties of maintaining ISO 7 air quality in an anteroom.
In a pharmacy, the control of airborne particulates to levels specified for ISO classes requires a balanced combination of ventilation design and good work practices. The use of a gowning room as an isolation area between an anteroom and an HD buffer room can help balance these issues and allow the anteroom to return to its traditional role as a transition space from uncontrolled to ISO-controlled spaces.   LEWIS JOHNSON, MS, CIH, CIC, is an industrial hygienist with Lee Health System in Fort Myers, Florida. Send feedback to The Synergist.

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RESOURCES
United States Pharmacopeial Convention: USP General Chapter <797>, “Pharmaceutical Compounding—Sterile Preparations,” in United States Pharmacopeia and National Formulary (2019). United States Pharmacopeial Convention: USP General Chapter <800>, “Hazardous Drugs—Handling in Healthcare Settings,” in United States Pharmacopeia and National Formulary (2019).
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Disadvantages of being unacclimatized:
  • Readily show signs of heat stress when exposed to hot environments.
  • Difficulty replacing all of the water lost in sweat.
  • Failure to replace the water lost will slow or prevent acclimatization.
Benefits of acclimatization:
  • Increased sweating efficiency (earlier onset of sweating, greater sweat production, and reduced electrolyte loss in sweat).
  • Stabilization of the circulation.
  • Work is performed with lower core temperature and heart rate.
  • Increased skin blood flow at a given core temperature.
Acclimatization plan:
  • Gradually increase exposure time in hot environmental conditions over a period of 7 to 14 days.
  • For new workers, the schedule should be no more than 20% of the usual duration of work in the hot environment on day 1 and a no more than 20% increase on each additional day.
  • For workers who have had previous experience with the job, the acclimatization regimen should be no more than 50% of the usual duration of work in the hot environment on day 1, 60% on day 2, 80% on day 3, and 100% on day 4.
  • The time required for non–physically fit individuals to develop acclimatization is about 50% greater than for the physically fit.
Level of acclimatization:
  • Relative to the initial level of physical fitness and the total heat stress experienced by the individual.
Maintaining acclimatization:
  • Can be maintained for a few days of non-heat exposure.
  • Absence from work in the heat for a week or more results in a significant loss in the beneficial adaptations leading to an increase likelihood of acute dehydration, illness, or fatigue.
  • Can be regained in 2 to 3 days upon return to a hot job.
  • Appears to be better maintained by those who are physically fit.
  • Seasonal shifts in temperatures may result in difficulties.
  • Working in hot, humid environments provides adaptive benefits that also apply in hot, desert environments, and vice versa.
  • Air conditioning will not affect acclimatization.
Acclimatization in Workers