Research studies over the past several decades have indicated the possible harmful effects on healthcare workers from low-level work-related exposure to any of more than 200 medications that are considered hazardous drugs. As a result, the United States Pharmacopeia (USP) — a nonprofit compendium of drug information — published the nation’s first standards on the handling of hazardous drugs from receipt to disposal. Chapter 800, titled “Hazardous Drugs — Handling in Healthcare Settings,” applies to all healthcare personnel who handle hazardous drug preparations and all entities that store, prepare, transport, or administer hazardous drugs, such as pharmacies, hospitals, clinics, and physician offices. Hazardous drugs include those used for cancer chemotherapy, antiviral drugs, hormones, and some bioengineered drugs. Most existing pharmacies will need to modify their workflow, space, and infrastructure to comply with USP 800 when it becomes effective on December 1, 2019.
USP 800 expands upon the previously published chapters USP 797 (Pharmaceutical Compounding Sterile Preparations) and USP 795 (Pharmaceutical Compounding Nonsterile Preparations) by differentiating between the handling procedures and facilities for hazardous and non-hazardous drugs, both sterile and nonsterile. Although both USP 797 and 795 focused on preventing harm to patients, they lacked standards that specifically protected the personnel who are exposed daily to hazardous drugs and the environment in which they are being handled. Facilities previously designed to comply with both USP 795 and USP 797 will likely be out of compliance with USP 800.
A key requirement of USP 800 is the separation of hazardous and non-hazardous drug spaces — for drug receiving/unpacking, storage, and compounding. Hazardous drugs must be unpacked in a dedicated room with either neutral/normal or negative air pressure to prevent the spread of hazardous drugs from packaging material. Moreover, hazardous drugs must be stored separately from all non-hazardous drugs in an externally-ventilated room with negative pressure. Also, the compounding of hazardous drugs must be performed in a room with negative pressure and external ventilation which is separate from where non-hazardous drugs are compounded. Additionally, the compounding of sterile and nonsterile hazardous drugs needs to occur in separate rooms. USP 800 refers to the room where sterile compounding or mixing occurs as a buffer room or clean room and these rooms also require an anteroom for activities such as handwashing, gowning, and various staging activities.
If a pharmacy currently complies with USP 797, and compounds sterile and nonsterile hazardous drugs, additional space will be required to comply with USP 800.
The facility requirements for USP 800 are particularly confusing because a pharmacy may have separate workflows (and spaces) for compounding nonsterile hazardous drugs, sterile hazardous drugs, and sterile non-hazardous drugs depending on the drugs that it handles and type of compounding it performs. This in turn will determine the number of receiving/unpacking rooms, storage rooms, buffer rooms, and anterooms that it needs. However, if a pharmacy currently complies with USP 797, and compounds sterile and nonsterile hazardous drugs, additional space will be required to comply with USP 800.
FIRST LET’S REVIEW SOME USP 800 TERMINOLOGY
Creating and controlling the environment for pharmaceutical compounding is typically performed through the use of primary engineering controls (PECs) — usually laminar airflow workbenches, biological safety cabinets, and compounding aseptic isolators. The buffer room in which the PEC is placed is considered the secondary engineering control (SEC).
Unlike laminar airflow workbenches (LAFWs) that simply facilitate product protection, containment primary engineering controls (C-PECs) are ventilated devices designed and operated to minimize worker and environmental exposure to hazardous drugs by controlling emissions of airborne contaminants. Examples of C-PECs include biosafety cabinets (BSCs), compounding aseptic isolators (CAIs), and compounding aseptic containment isolators (CACIs). CACIs are a specific type of CAI that are designed for compounding sterile hazardous drugs.
It is critical to note that horizontal laminar flow hoods/laminar airflow workbenches (LAFWs) and containment aseptic isolators (CAIs) must never be used for compounding hazardous drugs due to their lack of safety controls necessary for operator protection.
The International Organization for Standardization (ISO) classification system ISO 14644-1 is the primary authority in the U.S. and Canada used to determine the level of cleanliness that the buffer or clean room complies with, according to the quantity and size of particles per volume of air.
KEY USP 800 SPACES AND CONFIGURATION
USP 800 addresses the following spaces specific to the receipt/unpacking, storage, and compounding of hazardous drugs:
- Dedicated receipt/unpacking room
- Dedicated storage room
- Buffer room for compounding nonsterile hazardous drugs
- Buffer room (with anteroom) for compounding sterile hazardous drugs
- Workstation for the compounding supervisor
The configuration of the buffer room (C-SEC), equipment within the room (C-PEC), anteroom, and infrastructure requirements will depend on whether sterile or nonsterile hazardous drugs are being compounded. However, negative pressure must be provided in any buffer room where hazardous drugs are compounded and a contiguous anteroom with positive pressure must be provided where sterile hazardous drugs are processed. To comply with USP 800, the buffer room must also be externally ventilated and maintain a minimum 12 air changes per hour and negative pressure between 0.01 to 0.03 inches of water. Various spaces and their configuration are described below.
Dedicated receipt/unpacking room. A dedicated room with neutral or negative pressure must be provided for receiving and unpacking hazardous drugs before they are taken to their respective storage spaces. There are no clearly defined air change rates or pressure differential requirements. Unpacking should not done in sterile compounding areas or positive pressure areas.
Dedicated storage room. Hazardous drugs must be stored separately from all non-hazardous drugs in an externally-ventilated room that maintains a minimum 12 air changes per hour and negative pressure between 0.01 to 0.03 inches of water. No pressure differential is specified. Additionally, hazardous drug storage within a sterile compounding buffer room (negative pressure) is limited to those drugs used in sterile compounding. If a refrigerator is placed in the negative pressure buffer room, an exhaust for its compressor is also recommended.
Buffer room for compounding nonsterile hazardous drugs. To comply with USP 800, the buffer room must be externally ventilated and maintain a minimum 12 air changes per hour and negative pressure between 0.01 and 0.03 inches of water. An anteroom is not required for the compounding of nonsterile hazardous drugs.
Buffer room (with anteroom) for compounding sterile hazardous drugs. The buffer room must maintain a minimum of 30 air changes per hour (to meet ISO Class 7) and a negative pressure between 0.01 and 0.03 inches water. Because sterile drugs are compounded, an anteroom is also required. The anteroom requires positive pressure of 0.02 inches of water relative to all adjacent unclassified areas and must also maintain a minimum of 30 air changes per hour to meet ISO Class 7. Both the buffer room and the C-PEC need to be externally vented. Although the compounding of sterile hazardous drugs can occur in a space that is not maintained at ISO Class 7, depending on the type of C-PEC used and drugs processed, designing to an ISO Class 7 is the most conservative approach and ensures compliance with USP 800.
Compounding both sterile and nonsterile hazardous drugs in the same room is acceptable under USP 800 if C-PECs are placed at least a meter apart, if the buffer room maintains ISO 7 classification, and if particle-generating activities are stopped when sterile compounding is in process. However, it is recommended to use separate rooms for compounding sterile and nonsterile hazardous drugs because of the challenge of keeping a room sterile while nonsterile processes occur in the same room.
Workstation for the compounding supervisor. USP 800 requires that any compounding facility must provide a dedicated staff member who is uniquely responsible for training on compounding, record keeping, and assuring competencies, among other duties. This may require creation of an additional workstation.
IMPACT ON SPACE
The additional space needed for a pharmacy to comply with USP 800 can be substantial. For a pharmacy that compounds hazardous drugs, the additional net square feet (NSF) of space required to separate hazardous drugs from non-hazardous drugs may include:
- Dedicated receipt/unpacking room with a minimum of 50 NSF
- Dedicated storage room with 100 NSF per PEC
- Buffer room with at least 120 NSF, or 50 to 100 NSF per PEC
- Anteroom with a minimum of 80 NSF
- Workroom to accommodate office activities with 80 to 120 NSF per PEC
To accommodate a single PEC for compounding sterile hazardous drugs, a pharmacy will need to provide over 500 gross square feet of additional space.
IMPACT ON BUILDING INFRASTRUCTURE
Modifications to the building infrastructure could be even more extensive than expansion and reconfiguration of the existing space. The existing air handling systems serving the pharmacy may need to be modified to accommodate differing air pressurization requirements as well as a dedicated exhaust system to achieve negative pressurization for the hazardous drug buffer room. Routing new exhaust ductwork through existing space to evacuate the potentially contaminated air to the outside of the building may be particularly challenging. The exhaust system for the hazardous drug compounding area must lead to a roof-mounted fan location discharging at a minimum of 10 feet above the roof level and 30 feet away from outdoor intakes. Routing the hazardous exhaust throughout the existent facility sometimes includes passing these ducts through rated fire and smoke walls. When a hazardous exhaust duct penetrates a rated area, the duct requires enclosures in a fire-resistant rated shaft. Constructing a rated-shaft enclosure around a duct can add significant cost to a project.
UPDATE OF USP 797 and USP 795 ALSO HAS FACILITY IMPLICATIONS
Pharmacies must also comply with the new updates to USP 797 (Pharmaceutical Compounding Sterile Preparations) and USP 795 (Pharmaceutical Compounding Nonsterile Preparations) by December 1, 2019 which may require additional facility renovation. In 2008, USP 797 outlined three categories of compounded sterile products — low-risk, medium-risk, and high-risk — while the new update consolidates those into a Category 1 or Category 2. This shift will likely have the greatest impact on facilities that were formerly categorized as medium-risk compounders which describes the majority of hospitals in the U.S. Many of these will now graduate to a higher level of compounding risk as they transition to Category 2 which requires a separate anteroom with hard walls and a door. Additionally, the updated USP 795 redefines what constitutes nonsterile compounding. This could mean that facilities that previously did not consider themselves to compound drugs would now be subject to USP 795 standards. This may require that a separate room be created solely for nonsterile compounding.
An ISO Class 7 buffer room with positive pressure is required for compounding sterile non-hazardous drugs with a laminar flow workbench or compounding aseptic isolator. As with the compounding of sterile hazardous drugs, an anteroom is also required when sterile non-hazardous drugs are compounded.
It is possible for a sterile hazardous drug buffer room and a sterile non-hazardous buffer room to share the same anteroom as shown below.
The entire USP Chapter 800 can be downloaded from the United States Pharmacopeia website and Appendix 2 provides examples of compliant buffer room and anteroom configurations for hazardous drug compounding.