Hazardous drugs (HDs) are any drugs that may exhibit carcinogenic, teratogenic, developmental, reproductive, or organ toxicity in humans or animals, and include genotoxic drugs or new drugs that mimic existing HDs in structure or toxicity. USP Chapter <800> Hazardous Drugs--Handling in Health Care Settings, which establishes practices and quality standards for handling HDs to promote patient safety, worker safety, and environmental protection, will become official on July 1, 2018. The chapter is comprehensive regarding proper actions related to the receipt, storage, compounding, dispensing, administration, and disposal of sterile and nonsterile HD products and preparations. A simple, common sense approach to preventing the dissemination of and exposure to HDs, as detailed in USP <800>, requires that pharmacy address facility design, monitoring, protective equipment, and personnel practices.
Effective HD control starts with a facility that has been designed and engineered to prevent the dissemination of HDs. Control begins at the point of HD receipt and continues through storage, compounding, dispensing, and administration. The receiving area should be a designated area that is neutral or negatively pressurized to the surrounding areas; this configuration will contain the HDs and minimize the spread of contamination into surrounding areas. The room’s pressure should be monitored to ensure correct airflow is maintained.
Antineoplastic HDs must be stored in negatively pressurized rooms as well. Non-antineoplastic HDs may be stored with other inventory; however, it would behoove the pharmacy to store all HDs, including those that are refrigerated, in negatively pressurized rooms to minimize the potential for cross contamination. Further, non-sterile HDs should be segregated from sterile HDs to reduce traffic into the sterile area. The storage area must be restricted to authorized personnel only.
Compounding of HDs is permitted only in a containment primary engineering control (C-PEC) within a containment secondary engineering control (C-SEC) room, which may either be an ISO Class 7 buffer room with an ISO Class 7 ante-room (preferred) or an unclassified containment segregated compounding area (C-SCA). The C-SEC must be externally vented, physically separated from other preparation areas, and have a negative pressure between 0.01 and 0.03 inches of water column relative to all adjacent areas. It must have at least 12 air changes per hour (ACPH) for non-sterile compounding, 30 ACPH for sterile compounding if the C-SEC is within an ISO Class 7 classified room, or 12 ACPH if the C-SEC is within a non-classified room. Since many hospital and compounding pharmacies will need to redesign their compounding areas to comply with USP <800>, it is preferable to design a facility wherein the C-PECs are located within an ISO Class 7 room; the additional capital expense will add an extra layer of protection against HD contamination, and may well be worth the cost when the FDA inspects the facility.
The use of additional engineering controls, such as closed-system drug-transfer devices (CSTDs), is suggested to reduce the potential for cross contamination. There are two general types of CSTDs: CSTDs that are mechanically closed, and those that rely on a carbon filter to reduce the release of HD vapors (filter-vent systems). CSTDs are considered supplemental engineering controls; as such, they do not replace the protection of primary engineering controls; rather, they improve the protective performance of the primary engineering controls.1 A variety of CSTDs have been approved for use in the United States (see TABLE 1). It is pharmacy’s responsibility to determine which one is best suited for its particular application.
To monitor the efficacy of facility design in limiting HD contamination, sampling of the surfaces used to prepare HDs must occur at least every six months, or more often as needed to verify containment. Surface wipe sampling should encompass the interior of the C-PEC and any equipment contained within it, pass-through chambers, surfaces in staging or work areas near the C-PEC, areas adjacent to C-PECs (eg, floors directly under C-PEC, staging, and dispensing areas), areas immediately outside the HD buffer room or the C-SCA, and patient administration areas. The pharmacy should have a written plan describing the monitoring process, which delineates wipe frequency, identifies specific sites to monitor, establishes acceptance criteria for residuals, and lists the types of HD markers that will be analyzed, such as cyclophosphamide, ifosfamide, methotrexate, fluorouracil, and platinum-containing drugs. Per the USP <800> section on Environmental Monitoring and Control, it is important to note that elevated levels of HD markers, such as cyclophosphamide >1.00 ng/cm2, may result in uptake of the drug in exposed workers.
Should any measurable contamination be found, a designated person must identify, document, and contain the source of contamination. Such actions should include an investigation to reevaluate work practices, personnel training, decontamination and cleaning procedures, and engineering controls. In addition, wipe sampling should be repeated upon completion of the investigation. The investigation also should reconfirm that the validation of the deactivation/decontamination and cleaning steps are effective.
A pharmacy may conduct its own surface monitoring or engage an environmental testing firm to collect samples. For those facilities that choose self-monitoring, sampling kits are available that provide instructions, measuring tape, colored dots for marking sampling areas, swab tissues for sampling, sample diluent, gloves, containers, a return shipping box, and a return label from a shipper (see TABLE 2). Alternatively, a pharmacy may use an environmental monitoring firm that collects and analyzes samples (see TABLE 3).
The risk assessment must be predicated on baseline data and exposure levels that are recognized as acceptable. To date, the National Institute for Occupational Safety and Health (NIOSH) has not published guidelines of acceptable antineoplastic agents. However, there is a published guide to sampling frequency that is based on cyclophosphamide (CP) levels.4 If CP levels are below 0.1 ng/cm, sampling would be conducted once a year (note that USP <800> will require at least twice a year). If CP levels are between 0.1 - 10 ng/cm, sampling would be conducted within 3-6 months. If CP levels are >10 ng/cm, remedial actions and additional sampling should be conducted.
Certainly, the areas with the highest risk exposure need to be sampled, such as the compounding and dispensing areas. Beyond these, consider sampling locations immediately outside the HD buffer room or the C-SCA, as well as patient administration areas. Other areas with potentially lower risk should also be sampled; these would include the receiving, storage, patient unit delivery, nurse administration, patient, and housekeeping areas. To address the second risk component (ie, the types of HDs the pharmacy handles) ensure that the sampling kit or environmental firm can detect the marker drugs from various surface types found in the sampled areas.
Personal Protective Equipment (PPE)
Appropriate PPE must be worn during HD receipt, storage, transport, compounding, administration, cleaning, disinfecting, deactivation, decontamination, spill control, and waste disposal. The pharmacy must develop standard operating procedures (SOPs) for PPE based on the risk of exposure and activities performed; these SOPs must describe the appropriate PPE to be worn based on the pharmacy’s occupational safety plan and assessment of risk. Generally, disposable PPE must not be reused and reusable PPE must be decontaminated and cleaned after use. Head, hair, and shoe covers, gowns, and two pairs of chemotherapy gloves are required for compounding sterile and nonsterile HDs. Gowns must resist permeability by HDs when administering injectable antineoplastic HDs. Two pairs of chemotherapy gloves are required for administering antineoplastic HDs.
Gloves must be inspected for physical defects before use, particularly for pinholes or weak spots, and chemotherapy gloves must be powder-free because powder can contaminate the work area and can adsorb and retain HDs. Gowns must be seamless, long sleeved, closed in the back, resistant to HD permeability, and not fabricated from cloth; the preferred materials are polyethylene-coated polypropylene or other laminates. If reusable gowns are used, they may be washed based upon written policies. It is preferable that scrubs, rather than regular clothing, be worn under the gowns; regular clothing has the potential to become contaminated and must not be taken home under any circumstances if worn during operations.
Head, hair, beard and moustache (if applicable), and shoe covers are required when handling HDs. A second pair of shoe covers must be worn during compounding and must be removed before entering other areas. If disposable sleeve covers are used to protect the wrist area, they should be made of polyethylene-coated polypropylene or other laminate. Eye and face protection must be worn both within a C-PEC and outside of it, when there is a risk for spills or splashes of HDs. A full facepiece, chemical cartridge-type respirator, or powered air-purifying respirator (PAPR) should be worn under the following circumstances:
A fit-tested NIOSH-certified N95 particle-filtering facepiece respirator is sufficient to protect against airborne particles. However, it does not protect against gases, vapors, or direct liquid splashes; the CDC has published recommendations for these alternative types of respirators.5
Personnel exert more influence over HD containment than any other factor and represent the weakest link in the containment of HDs. Facility design, monitoring, and PPE have one common thread: To minimize the dissemination of HDs by people. Similar to the manner in which both USP <797> and cGMPs provide details to prevent people from adversely affecting the safety and efficacy of sterile products, USP <800> provides guidance to assure that personnel are properly trained to work with HDs.
To start, a pharmacy must have a robust training and evaluation program for its employees. Specifically for HDs, the program should include training on the receipt, storage, compounding, repackaging, dispensing, administrating, and disposing of HDs. Training must occur before the employee independently handles HDs and each employee must demonstrate training effectiveness and competency. Personnel must also be trained prior to the introduction of a new HD or new equipment, and prior to a new or significant change in process or SOPs.
Ongoing training competency must be reassessed at least every 12 months and this must be documented. The training program should include an overview of the pharmacy’s list of HDs and their risk, a review of the SOPs related to handling of HDs, the proper use of PPE, equipment and devices (eg, engineering controls), the proper response to known or suspected HD exposure, spill management, and the proper disposal of HDs and trace-contaminated materials. A comprehensive training program that is overseen by the quality assurance department will help to minimize the dissemination of HDs by individuals who work with them.
As the July 1, 2018 deadline approaches, USP <800> will become official and pharmacies must be ready to implement practices to prevent the dissemination of and exposure to HDs. Utilizing a common-sense approach to facility design, contamination monitoring, PPE, and personnel practices will facilitate compliance with the USP requirements. Procedural and physical controls such as negatively pressurized facilities, CSTD implementation, robust wipe sampling programs, broad use of PPE, and ongoing competency training programs, all serve to address the weakest link in the containment of HDs: People. USP <800> compliance can be achieved once a pharmacy commits to implementing and performing these controls.
Frank Settineri, BS, MS, has over 30 years’ experience working with a range of entities from compounding pharmacies to pharmaceutical companies, focusing on investigations, root cause analysis, microbiological data deviations, particulate matter mitigation, and cGMP compliance. He is particularly adept in writing responses to 483s and warning letters that result in both interim controls and sustained cGMP compliance. Frank is president and founder of Veracorp LLC, a consulting firm with a client base including compounding pharmacies, sterile facilities, API manufacturers, oral dosage manufacturers, and microbiology laboratories.