The risks to health care workers handling hazardous drugs (HDs) under non-USP compliant conditions are often underappreciated. NIOSH’s landmark 2004 alert underscored the importance of preventing occupational exposure to HDs and played a key role in the development of USP Chapter <800> Hazardous Drugs—Handling in Healthcare Settings.2,3 This new chapter provides a framework of 18 sections that guide HD compounding practices to ensure the safety not only of patients, but also of the health care workers who prepare and administer these products.
A keen understanding of compounding personnel responsibilities is not sufficient to ensure safe HD preparation. Rather, pharmacy must develop expertise in facility design and engineering controls that encompasses the dynamics of airflow and air quality. Specifically, a comprehensive understanding of USP <800> requirements for engineering controls is critical to safe HD compounding. Nevertheless, it is important to note that USP chapters describe the minimal requirements for compounding, and are not intended to be all-inclusive; other references, including peer-reviewed literature, must be considered when developing a comprehensive HD safety program.
Until the advent of USP <797> and the 2004 NIOSH alert, information describing the engineering controls required for sterile compounding was not included in most didactic educational programs for pharmacists. USP <800> was developed to provide guidance pertaining to the proper engineering controls for safely handling and preparing HDs. Specific engineering controls detailed in USP <800> include:
Some PECs, such as laminar airflow cabinets, simply facilitate product protection, while others, such as containment primary engineering controls (C-PECs), are designed to use ventilation to protect the product, the operator, and the environment. C-PECs include biological safety cabinets (BSCs) and compounding aseptic containment isolators (CACIs), which are designed to ensure safe HD compounding. These systems mitigate exposure to HDs while protecting the product by integrating the required air management systems and controls, ISO 5 compounding environment, containment/enclosure, and HEPA filtration and specialized exhaust systems designed for the attributes of the HDs, such as vaporization, spills, and sprays. C-PECs required for compounding HDs are broadly classified into ducted cabinets, such as BSCs and CACIs.
It is critical to note that horizontal laminar flow hoods/laminar airflow workbenches (LAFWs) and compounding aseptic isolators (CAIs) must never be used for compounding HDs due to their lack of safety controls necessary for operator protection.
Considerations for Choosing C-PECs
USP <800> does not specify whether to use a BSC or a CACI for compounding HDs. Many conditions for use are identical for both devices, including personal protective equipment (PPE) garbing, the recommended facility design, air quality requirements, negative pressure requirement, use of a closed system drug-transfer device (CSTD), cleaning protocols, and USP <797> beyond-use dating (BUD).
Considerations when choosing a PEC include:
The PEC should be constructed with materials that can withstand multiple cleanings with harsh chemicals (ie, stainless steel, high-grade plastics) and yet maintain protective integrity under constant pressure.
Another consideration is the standards of design and testing. BSC designs are formally submitted for verification to NSF International/American National Standard, and are field tested to a set of acceptable standards,4 while CACI design specifications are not required to be submitted for verification, and testing standards are provided by device manufacturers for field-testing. (See testing recommendations for isolators used in pharmacy developed by the Controlled Environment Testing Association [CETA]5).
With all PECs, it is important not to turn them off, as they are designed to operate continuously. Switching the C-PEC off and on again increases wear and tear and may impact the overall pressure gradients within the SEC. Additionally, some systems may require a purge time to get in sync with manufacturer’s specifications prior to use.
Attributes and Classification of BSCs
The BSCs recommended by USP <800> for compliant HD sterile compounding include Class II, Type A2; Class II, Type B2; and Class III. Compounding sites with dated equipment (>10 years old) should verify that their BSCs are one of these types; do not consider the generic term biological safety cabinet to be definitive of USP <800> compliance, since some types of BSCs were not designed for handling highly volatile, toxic HDs, including cyclophosphamide.
BSCs are designed to provide three types of protection: operator protection, product protection to avoid contamination, and environmental protection from contaminants contained within the cabinet (see TABLE 1 on page 16).6
NSF International provides minimum standards for cabinet classifications and certification, as defined by NSF within NSF/ANSI 49 - 2008, Biosafety Cabinetry: Design, Construction, Performance, and Field Certification.7
Approximately 70% of the air is recirculated through a filter to the workspace and 30% is exhausted. All air going through the ducts should be considered contaminated and must be under negative pressure. The cabinet ducts must be exhausted externally from the building and away from any fresh air intakes.
Attributes and Unique Features of CACIs
The term isolator is frequently used in the industry to describe enclosures used to compound sterile hazardous or non-HDs (see SIDEBAR 2). Such enclosures cover a wide range of configurations, sizes, features, and performance. Below is a list of the requirements that define an enclosure as a CACI (see FIGURE 4).
An advantage of a CACI is that this primary C-PEC isolates the operator from potential exposure to HDs during preparation. In addition, a CACI, compared with a Class II BSC, minimizes the potential for contamination of the room’s air during product preparation, as there is no chance of an operator’s contaminated gloves or arm covers moving into and out of the containment device.
There are strong similarities between Class III BSCs, which are primarily used for handling highly infectious microbiological agents such as viruses, and CACIs. Class III BSCs and CACIs share similar construction, features, operational requirements, and functional performance. Moreover, Class III BSCs include additional HEPA filtration of the exhaust and higher air velocity.
Key design features of CACIs that differentiate them from Class II, Type A2 BSCs include:
SEC: The Room
In addition to C-PEC selection, USP <800> describes the proper placement of compounding equipment within the designated rooms, which is important because C-PEC devices depend upon the room in which they operate to function correctly. A Class II BSC or CACI must be placed in an ISO Class 7 area that is physically separated, with a minimum of 12 ACPH, and with a minimum negative pressure of 0.01-inches of water column to the adjacent positive pressure ISO Class 7 (or better) ante-areas. This room setup ensures an inward airflow to contain any airborne drug that may result from spills, broken vials, off-gassing of waste containers with residues, and from residue on vials/packaging. A pressure indicator must be installed and continuously monitored to ensure correct room pressurization. The Class II BSC and CACI should be 100% exhausted to the outside air through HEPA filtration. Note that USP <800> does offer the option to place a C-PEC in a compounding segregated compounding area (C-SCA) that does not meet ISO 7 quality air for the compounding of low- and medium-risk HDs; but in this scenario, the guidance for BUD as defined in USP <797> does not apply, rather the BUD may not exceed 12 hours.
For more information regarding the requirements and best practices for setting up the SEC, review USP <800> and visit the CriticalPoint Web site.2,9
Supplemental Engineering Controls: The Tools
There are currently nine devices, broadly categorized as closed-system drug-transfer devices (CSTDs), on the US market cleared by the FDA to supplement C-PECs and SECs in the effort to minimize operator exposure to HDs during compounding and administration (see TABLE 2).10
USP <800> states that CSTDs should be used in HD drug preparation, regardless of the C-PEC used (ie, Class II BSC or CACI), and CSTDs must be used during drug administration. During drug preparation, CSTDs should be used within the ISO Class 5 environment of a Class II BSC or CACI and not alone. Choosing the right CSTD for your facility should occur with input from nursing and pharmacy; in addition, consider peer-reviewed articles and ease of use as part of the evaluation process.
As the official implementation date of July 1, 2018, for USP <800> compliance is rapidly approaching, organizations must examine their engineering controls and create a plan for achieving compliance with the chapter. Multiple factors must be taken into account when choosing a PEC for use within the SEC, and complementary CSTDs must be considered as supplemental engineering controls to maximize safety when compounding and administering HDs. Input from frontline staff utilizing these devices, as well as continuous monitoring to ensure best practices, are crucial to continued safety.
Fred Massoomi, PharmD, FASHP, is a senior pharmacist consultant at Visante, Inc. He received his doctorate from the University of Kansas School of Pharmacy.
David A. Kvancz, MS, RPh, FASHP, is the senior vice president for strategic client relationships for Visante, Inc, as well as president of Valore Healthcare Consulting.
Contamination in the Plenum
The plenum represents a separate space between the PEC and a building’s heating, ventilation, and air-conditioning (HVAC system), and usually is in the space between the structural ceiling and a drop-down ceiling. The plenum can be the interface into a common space where both ducts meet, or it can be hard ducting between the PEC and the building’s exhaust system. In either case, wherever HD compounding occurs, the ductwork and plenum should be considered contaminated with HD residue.
Avoiding C-PEC Isolator Terminology Confusion
In 2015, USP published the proposed revision to USP <797> for comment. Within the proposed document was the introduction of a new cabinet definition for compounding: restricted access barrier systems (RABS). RABS, which are widely used in aseptic pharmaceutical manufacturing, have almost identical design features as CACIs, with the exception that they are normally operated under positive pressure with the primary function of aseptically filling sterile products. USP <800> does not mention RABS, which may lead to confusion with the term isolator for compounding. However, it is important that pharmacists understand the purpose of RABS and how they differ from CACIs.
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