The risks to health care workers handling hazardous drugs (HDs) under non-USP compliant conditions are often underappreciated. The development of the USP 800 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.
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 include:
■ Primary Engineering Controls (PECs): The Hoods
■ Secondary Engineering Controls (SECs): The Room
■ Supplemental Engineering Controls: The Tools
Hoods:
Some PECs, such as laminar airflow cabinets, simply facilitate product protection, while others, such as containment primary engineering controls (CPECs), 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.
USP 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 beyond-use dating (BUD). Considerations when choosing a PEC include:
■ Costs: Measure device acquisition cost, maintenance, power, and specialized supplies for the PEC (ie, sleeves for CACIs)
■ Methods for product ingress into the workspace and preparation egress into the SEC
■ Ergonomics for low-volume compounding (eg, 100 doses per day)
■ Ease of batching multiple doses
■ Ease of certification
■ Cost of certification
■ Product labeling requirements
■ Cleaning needs
The BSCs recommended by USP for compliant HD sterile compounding excludes some types of BSCs, that 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.
Some issues we suggest to be considered with the design of the BSCs, is that they are open to the operator, requires proper use to deliver protection. Given the design of the movable front glass damper and the protective-airflow curtain, caution must be taken to not block the intake grills located in the front (next to the operator) and back of the BSC. Blocking these grills can create turbulence, which may lead to inadvertent exposure of the operator and the environment to HD vapors and/or particles.
A Class III BSC removes all of these issues that are common with the lower class BSCs. A Class III BSC, which is totally enclosed, is designed for work with infectious microbiological agents and for handling hazardous materials. This system is rarely used in pharmacy practice sites due to its expense, the costs of maintenance, and the complexity of use.
Now let’s compare the CACI features and attributes to the USP 800 propositions.
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. Our CACI, the XLTC 800, by design, restricts ALL personnel from ALL HD handling areas. The C-PEC, C-SEC and CVE are externally vented through HEPA exhaust filters, thus creating conditions similar to those achieved by a Class III BSC. The C-PEC and C-SEC run far better that ISO Class 5, at all times, therefore meeting the standards for Sterile Compounding.
Our XLTC’s C-PEC is ISO Class 5. In fact, it runs at 0 particulate levels at virtually all times regardless of surrounding activities. It can only be opened to the adjacent C-SEC which also runs ISO class 5. Our C-SEC runs negative to the C-PEC. Aseptically, a far superior approach to having a positive pressure Ante dump into a negative pressure buffer. The attachment of a CVE (for staging & opening shipments) that is Negative to C-SEC adds another level of Aseptic protection against particulate ingress.
In the XLTC800 from the time the HD totes from your supplier are opened, until the HD preparations are ready for patient delivery, Hospital staff is protected by a comprehensive barrier that is under constant negative pressure and is externally vented.
Another additional benefit of a CACI over a BSC is the Environmental monitoring as for the XLTC800 is not just wipe sampling. The equipment enables real-time environmental monitoring and alarms if there is no negative pressure according to the requirements.
Room Configurations:
In addition to C-PEC selection, USP 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 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 does not apply, rather the BUD may not exceed 12 hours.
For more information regarding the requirements and best practices for setting up an USP compliant work areas give us a call now 800.418.9289 or contact our USP <800> Product Specialist Ken Brookfield kenb@asepticenclosures.com
References
- DHHA (NIOSH) Pub. No. 2004-165. NIOSH Alert: Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Healthcare Settings. CDC Accessed November 10, 2016.
- USP General Chapter Hazardous Drugs—Handling in Healthcare Settings https://www.usp.org/usp-nf/notices/general-chapter-hazardous-drugs-handling-healthcaresettings. Accessed November 10, 2016.
- Power L, Kastango ES, Douglass K, Kienle PC. Understanding the new proposed USP Chapter . Pharm Purch Prod. 2014;11(6):6-7,24.
- NSF/ANSI 49-2004: class II (laminar fl ow) biosafety cabinetry. Ann Arbor, MI: NSF International/American National Standard; 2004.
- LaBella CJ. Does your pharmacy have a compounding isolator? Am J Health-Syst Pharm. 2007;64:855-858.
- Appendix A – Primary Containment for Biohazards: Selection, Installation and Use of Biological Safety Cabinets. Centers for Disease Control and Prevention Web site. www.cdc.gov/biosafety/publications/bmbl5/BMBL5_appendixa.pdf. Accessed November 10, 2016.
- NSF International (The National Sanitation Foundation). NSF/ANSI 49 – 2008, Biosafety Cabinetry: Design, Construction, Performance, and Field Certifi cation. https://www.nsf.org/services/by-industry/pharma-biotech/biosafety-cabinetry/nsf-ansi49-biosafety-cabinetry-certifi cation Accessed November 15, 2016.
- USP General Chapter Pharmaceutical Compounding—Sterile Preparations. https:// www.usp.org/usp-nf/notices/general-chapter-797-proposed-revision. Accessed November 10, 2016.
- Containment Primary Engineering Controls (C-Pecs) and Containment Secondary Engineering Controls (C-Secs) For Hazardous Drug (HD) Compounding. CriticalPoint: Sterile Compounding Pearls of Knowledge – March 2016 Edition.
- Massoomi F. The evolution of the CSTD. Pharm Purch Prod. 2015;12(2):S1-S12
