In 1990, the American Society of Health-System Pharmacists (ASHP) published its revised technical assistance bulletin (TAB) on handling cytotoxic and hazardous drugs.1 The information and recommendations contained in that document were current to June 1988. Continuing reports of workplace contamination and concerns for health care worker safety prompted the Occupational Safety and Health Administration (OSHA) to issue new guidelines on controlling occupational exposure to hazardous drugs in 1995.2,3 In 2004, the National Institute for Occupational Safety and Health (NIOSH) issued the “NIOSH Alert: Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings.”4 The following ASHP Guidelines on Handling Hazardous Drugs include information from these recommendations and are current to 2004.
The purpose of these guidelines is to (1) update the reader on new and continuing concerns for health care workers handling hazardous drugs and (2) provide information on recommendations, including those regarding equipment, that have been developed since the publication of the previous TAB. Because studies have shown that contamination occurs in many settings, these guidelines should be implemented wherever hazardous drugs are received, stored, prepared, administered, or disposed.2–7
Comprehensive reviews of the literature covering anecdotal and case reports of surface contamination, worker contamination, and risk assessment are available from OSHA,2,3 NIOSH,4 and individual authors.5–7 The primary goal of this document is to provide recommendations for the safe handling of hazardous drugs.
These guidelines represent the recommendations of many groups and individuals who have worked tirelessly over decades to reduce the potential harmful effects of hazardous drugs on health care workers. The research available to date, as well as the opinions of thought leaders in this area, is reflected in the guidelines. Where possible, recommendations are evidence based. In the absence of published data, professional judgment, experience, and common sense have been used.
Workers may be exposed to a hazardous drug at many points during its manufacture, transport, distribution, receipt, storage, preparation, and administration, as well as during waste handling and equipment maintenance and repair. All workers involved in these activities have the potential for contact with uncontained drug.
Early concerns regarding the safety of workers handling potentially hazardous drugs focused on antineoplastic drugs when reports of second cancers in patients treated with these agents were coupled with the discovery of mutagenic substances in nurses who handled these drugs and cared for treated patients.8,9 Exposure to these drugs in the workplace has been associated with acute and short-term reactions, as well as long-term effects. Anecdotal and case reports in the literature range from skin-related and ocular effects to flu-like symptoms and headache.4,5,10–17 Two controlled surveys have reported significant increases in a number of symptoms, including sore throat, chronic cough, infections, dizziness, eye irritation, and headaches, among nurses, pharmacists, and pharmacy technicians routinely exposed to hazardous drugs in the workplace.18,19 Reproductive studies on health care workers have shown an increase in fetal abnormalities, fetal loss, and fertility impairment resulting from occupational exposure to these potent drugs.20–23 Antineoplastic drugs and immunosuppressants are some of the types of drugs included on lists of known or suspected human carcinogens by the National Toxicology Program24 and the International Agency for Research on Cancer.25 Although the increased incidence of cancers for occupationally exposed groups has been investigated with varying results,26,27 a formal risk assessment of occupationally exposed pharmacy workers by Sessink et al.28 estimated that cyclophosphamide causes an additional 1.4–10 cases of cancer per million workers each year. This estimate, which considered workplace contamination and worker contamination and excretion in combination with animal and patient studies, was based on a conservative exposure level. Connor et al.29 found greater surface contamination in a study of U.S. and Canadian clinical settings than had been reported in European studies conducted by Sessink and colleagues.30–32 Ensslin et al.33 reported an almost fivefold greater daily average excretion of cyclophosphamide in their study than that reported by Sessink. These later findings could add 7–50 additional cancer cases per year per million workers to Sessink’s estimate. From these and other studies that show variations in work practices and engineering controls,34,35 it may be assumed that such variations contribute to differences in surface and worker contamination.
Routes of Exposure. Numerous studies showed the presence of hazardous drugs in the urine of health care workers.30–34,36–41 Hazardous drugs enter the body through inhalation, accidental injection, ingestion of contaminated foodstuffs or mouth contact with contaminated hands, and dermal absorption. While inhalation might be suspected as the primary route of exposure, air sampling studies of pharmacy and clinic environments have often demonstrated low levels of or no airborne contaminants.30–32,40 Recent concerns about the efficacy of the sampling methods42 and the possibility that at least one of the marker drugs may be volatile42–45 and thus not captured on the standard sampling filter leave the matter of inhalational exposure unresolved. Surface contamination studies do, however, suggest that dermal contact and absorption may be a primary route of exposure.31,46 While some hazardous drugs are dermally absorbed, a 1992 report showed no detectable skin absorption of doxorubicin, daunorubicin, vincristine, vinblastine, or melphalan.47 An alternative to dermal absorption is that surface contamination transferred to hands may be ingested via the hand-to-mouth route.48,49 One or more of these routes might be responsible for workers’ exposure.
Hazard Assessment. The risk to health care personnel from handling hazardous drugs is the result of a combination of the inherent toxicity of the drugs and the extent to which workers are exposed to the drugs in the course of their daily job activities. Both hazard identification (the qualitative evaluation of the toxicity of a given drug) and an exposure assessment (the amount of worker contact with the drug) are required to complete a hazard assessment. As the hazard assessment is specific to the safety program and safety equipment in place at a work site, a formal hazard assessment may not be available for most practitioners. An alternative is a performance-based, observational approach. Observation of current work practices, equipment, and the physical layout of work areas where hazardous drugs are handled at any given site will serve as an initial assessment of appropriate and inappropriate practices.4
Hazardous Drugs as Sterile Preparations
Many hazardous drugs are designed for parenteral administration, requiring aseptic reconstitution or dilution to yield a final sterile preparation. As such, the compounding of these products is regulated as pharmaceutical compounding by the United States Pharmacopeia (USP), chapter 797.50 The intent of chapter 797 is to protect patients from improperly compounded sterile preparations by regulating facilities, equipment, and work practices to ensure the sterility of extemporaneously compounded sterile preparations. Chapter 797 addresses not only the sterility of a preparation but also the accuracy of its composition. Because many hazardous drugs are very potent, there is little margin for error in compounding.
The initial version of chapter 797, released in early 2004, provided only minimal guidance for the handling of hazardous drugs, limiting this issue to a short discussion of chemotoxic agents in the document’s section on aseptic technique. The chapter referred to standards established by the International Organization for Standardization (ISO)51 that address the acceptable air quality (as measured by particulate counts) in the critical environment but failed to discuss airflow, air exchanges per hour, or pressure gradients of the ISO standards for cleanrooms and associated environments for compounding sterile products. The chapter did not describe the containment procedures necessary for compounding sterile hazardous agents, leaving it to the practitioner to simultaneously comply with the need to maintain a critical environment for compounded sterile products for patient safety while ensuring a contained environment for worker safety. The use of positive-pressure isolators for compounding hazardous drugs or placement of a Class II biological-safety cabinet (BSC) for use with hazardous drugs in a positive-pressure environment may result in airborne contamination of adjacent areas. Engineering assessment of designs of areas where this may occur should be done to address concerns of contaminant dissemination. Because hazardous drugs are also compounded in areas adjacent to patients and their family members (e.g., in chemotherapy infusion centers), inappropriate environmental containment puts them, as well as health care workers, at risk. Because USP review is a dynamic and ongoing process, future revisions are likely to address these concerns. Practitioners are encouraged to monitor the process and participate when appropriate.
Definition of Hazardous Drugs
The federal hazard communication standard (HCS) defines a hazardous chemical as any chemical that is a physical or health hazard.52,53 A health hazard is defined as a chemical for which there is statistically significant evidence, based on at least one study conducted in accordance with established scientific principles, that acute or chronic health effects may occur in exposed employees. The HCS further notes that the term health hazard includes chemicals that are carcinogens, toxic or highly toxic agents, reproductive toxins, irritants, corrosives, sensitizers, and agents that produce target organ effects.
A 1990 ASHP TAB proposed criteria to determine which drugs should be considered hazardous and handled within an established safety program.1 OSHA adopted these criteria in its 1995 guidelines, which were posted on its Web site in 1999.2,3 The TAB’s definition of hazardous drugs was revised by the NIOSH Working Group on Hazardous Drugs for the 2004 alert.4 These definitions are compared in Table 1.
Comparison of 2004 NIOSH and 1990 ASHP Definitions of Hazardous Drugsa
Carcinogenicity in animal models, in the patient population, or both as reported by the International Agency for Research on Cancer
Teratogenicity or developmental toxicityb
Teratogenicity in animal studies or in treated patients
Fertility impairment in animal studies or in treated patients
Organ toxicity at low dosesb
Evidence of serious organ or other toxicity at low doses in animal models or treated patients
Genotoxicity (i.e., mutagenicity and clastogenicity in short-term test systems)
Structure and toxicity profile of new drugs that mimic existing drugs determined hazardous by the above criteria
aNIOSH = National Institute for Occupational Safety and Health, ASHP = American Society of Health-System Pharmacists.
bNIOSH’s definition contains the following explanation: “All drugs have toxic side effects, but some exhibit toxicity at low doses. The level of toxicity reflects a continuum from relatively nontoxic to production of toxic effects in patients at low doses (for example, a few milligrams or less). For example, a daily therapeutic dose of 10 mg/day or a dose of 1 mg/kg/day in laboratory animals that produces serious organ toxicity, developmental toxicity, or reproductive toxicity has been used by the pharmaceutical industry to develop occupational exposure limits (OELs) of less than 10 micrograms/meter3 after applying appropriate uncertainty factors. OELs in this range are typically established for potent or toxic drugs in the pharmaceutical industry. Under all circumstances, an evaluation of all available data should be conducted to protect health care workers.”
cNIOSH’s definition contains the following explanation: “In evaluating mutagenicity for potentially hazardous drugs, responses from multiple test systems are needed before precautions can be required for handling such agents. The EPA evaluations include the type of cells affected and in vitro versus in vivo testing.”
Each facility should create its own list of hazardous drugs based on specific criteria. Appendix A of the NIOSH alert contains related guidance and a sample list.4 When drugs are purchased for the first time, they must be evaluated to determine whether they should be included in the facility’s list of hazardous drugs. As the use and number of hazardous drugs increase, so too do the opportunities for health care worker exposure. Investigational drugs must be evaluated according to the information provided to the principal investigator. If the information provided is deemed insufficient to make an informed decision, the investigational drug should be considered hazardous until more information is available.
Safety Program. Policies and procedures for the safe handling of hazardous drugs must be in place for all situations in which these drugs are used throughout a facility. A comprehensive safety program must be developed that deals with all aspects of the safe handling of hazardous drugs. This program must be a collaborative effort, with input from all affected departments, such as pharmacy, nursing, medical staff, housekeeping, transportation, maintenance, employee health, risk management, industrial hygiene, clinical laboratories, and safety. A key element of this safety program is the Material Safety Data Sheet (MSDS) mandated by the HCS.52,53 Employers are required to have an MSDS available for all hazardous agents in the workplace. A comprehensive safety program must include a process for monitoring and updating the MSDS database. When a hazardous drug is purchased for the first time, an MSDS must be received from the manufacturer or distributor. The MSDS should define the appropriate handling precautions, including protective equipment, controls, and spill management associated with the drug. Many MSDSs are available online through the specific manufacturer or through safety-information services.
Drugs that have been identified as requiring safe handling precautions should be clearly labeled at all times during their transport and use. The HCS applies to all workers, including those handling hazardous drugs at the manufacturer and distributor levels. Employers are required to establish controls to ensure worker safety in all aspects of the distribution of these drugs.
The outside of the vials of many commercial drugs are contaminated by the time they are received in the pharmacy.30,54,55 Although the possibility has not been studied, the contamination may extend to the inside of the packing cartons and onto the package inserts placed around the vial within the carton. Such contamination would present an exposure risk to anyone opening drug cartons or handling the vials, including workers receiving open or broken shipping cartons or selecting vials to be repackaged at a distribution point (e.g., a worker at the drug wholesaler selecting hazardous drugs for shipping containers or a pharmacy worker dividing a hazardous drug in a multidose container for repackaging into single-dose containers). These activities may present risks, especially for workers who too often receive inadequate safety training. Housekeepers and patient care assistants who handle drug waste and patient waste are also at risk and are not always included in the safe handling training required by safety programs. Safety programs must identify and include all workers who may be at risk of exposure.
The packaging (cartons, vials, ampuls) of hazardous drugs should be properly labeled by the manufacturer or distributor with a distinctive identifier that notifies personnel receiving them to wear appropriate personal protective equipment (PPE) during their handling. Sealing these drugs in plastic bags at the distributor level provides an additional level of safety for workers who are required to unpack cartons. Visual examination of such cartons for outward signs of damage or breakage is an important first step in the receiving process. Policies and procedures must be in place for handling damaged cartons or containers of hazardous drugs (e.g., returning the damaged goods to the distributor using appropriate containment techniques). These procedures should include the use of PPE, which must be supplied by the employer. As there may be no ventilation protection in the area where damaged containers are handled, the use of complete PPE, including an NIOSH-certified respirator, is recommended.56,57 As required by OSHA, a complete respiratory program, including proper training and fit testing, must be completed by all staff required to use respirators.56 Surgical masks do not provide adequate protection from the harmful effects of these drugs.
Labeling and Packaging from Point of Receipt. Drug packages, bins, shelves, and storage areas for hazardous drugs must bear distinctive labels identifying those drugs as requiring special handling precautions. Segregation of hazardous drug inventory from other drug inventory improves control and reduces the number of staff members potentially exposed to the danger. Hazardous drugs should be stored in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.4 Hazardous drugs placed in inventory must be protected from potential breakage by storage in bins that have high fronts and on shelves that have guards to prevent accidental falling. The bins must also be appropriately sized to properly contain all stock. Care should be taken to separate hazardous drug inventory to reduce potential drug errors (e.g., pulling a look-alike vial from an adjacent drug bin). Because studies have shown that contamination on the drug vial itself is a consideration,30,54,55 all staff members must wear double gloves when stocking and inventorying these drugs and selecting hazardous drug packages for further handling. All transport of hazardous drug packages must be done in a manner to reduce environmental contamination in the event of accidental dropping. Hazardous drug packages must be placed in sealed containers and labeled with a unique identifier. Carts or other transport devices must be designed with guards to protect against falling and breakage. All individuals transporting hazardous drugs must have safety training that includes spill control and have spill kits immediately accessible. Staff handling hazardous drugs or cleaning areas where hazardous drugs are stored or handled must be trained to recognize the unique identifying labels used to distinguish these drugs and areas. Warning labels and signs must be clear to non-English readers. All personnel who work with or around hazardous drugs must be trained to appropriately perform their jobs using the established precautions and required PPE.52
Environment. Hazardous drugs should be compounded in a controlled area where access is limited to authorized personnel trained in handling requirements. Due to the hazardous nature of these preparations, a contained environment where air pressure is negative to the surrounding areas or that is protected by an airlock or anteroom is preferred. Positive-pressure environments for hazardous drug compounding should be avoided or augmented with an appropriately designed antechamber because of the potential spread of airborne contamination from contaminated packaging, poor handling technique, and spills.
Only individuals trained in the administration of hazardous drugs should do so. During administration, access to the administration area should be limited to patients receiving therapy and essential personnel. Eating, drinking, applying makeup, and the presence of foodstuffs should be avoided in patient care areas while hazardous drugs are administered. For inpatient therapy, where lengthy administration techniques may be required, hanging or removing hazardous drugs should be scheduled to reduce exposure of family members and ancillary staff and to avoid the potential contamination of dietary trays and personnel.
Because much of the compounding and administration of hazardous drugs throughout the United States is done in outpatient or clinic settings with patients and their family members near the compounding area, care must be taken to minimize environmental contamination and to maximize the effectiveness of cleaning (decontamination) activities. The design of such areas must include surfaces that are readily cleaned and decontaminated. Upholstered and carpeted surfaces should be avoided, as they are not readily cleaned. Several studies have shown floor contamination and the ineffectiveness of cleaning practices on both floors and surfaces.29,30,46 Break rooms and refreshment areas for staff, patients, and others should be located away from areas of potential contamination to reduce unnecessary exposure to staff, visitors, and others.
Hazardous drugs may also be administered in nontraditional locations, such as the operating room, which present challenges to training and containment. Intracavitary administration of hazardous drugs (e.g., into the bladder, peritoneal cavity, or chest cavity) frequently requires equipment for which locking connections may not be readily available or even possible. All staff members who handle hazardous drugs should receive safety training that includes recognition of hazardous drugs and appropriate spill response. Hazardous drug spill kits, containment bags, and disposal containers must be available in all areas where hazardous drugs are handled. Techniques and ancillary devices that minimize the risk of open systems should be used when administering hazardous drugs through unusual routes or in nontraditional locations.
Ventilation Controls. Ventilation or engineering controls are devices designed to eliminate or reduce worker exposure to chemical, biological, radiological, ergonomic, and physical hazards. Ventilated cabinets are a type of ventilation or engineering control designed for the purpose of worker protection.4 These devices minimize worker exposure by controlling the emission of airborne contaminants. Depending on the design, ventilated cabinets may also be used to provide the critical environment necessary to compound sterile preparations. When asepsis is not required, a Class I BSC or a containment isolator may be used to handle hazardous drugs. When sterile hazardous drugs are being compounded, a Class II or III BSC or an isolator intended for aseptic preparation and containment is required.4 Recommendations for work practices specific to BSCs and isolators are discussed later in these guidelines.
Class II BSCs. In the early 1980s, the Class II BSC was determined to reduce the exposure of pharmacy compounding staff to hazardous preparations, as measured by the mutational response to the Ames test by urine of exposed subjects.58,59 Studies in the 1990s, using analytical methods significantly more specific and sensitive than the Ames test, indicated that environmental and worker contamination occurs in workplace settings despite the use of controls recommended in published guidelines, including the use of Class II BSCs.29–35,37–41,60,61 The exact cause of contamination has yet to be determined. Studies have shown that (1) there is contamination on the outside of vials received from manufacturers and distributors,30,54,55 (2) work practices required to maximize the effectiveness of the Class II BSC are neglected or not taught,32,46 and (3) the potential vaporization of hazardous drug solutions may reduce the effectiveness of the high-efficiency particulate air (HEPA) filter in providing containment.42–45 Studies of surface contamination have discovered deposits of hazardous drugs on the floor in front of the Class II BSC, indicating that drug may have escaped through the open front of the BSC onto contaminated gloves or the final product or into the air.29–32
Workers must understand that the Class II BSC does not prevent the generation of contamination within the cabinet and that the effectiveness of such cabinets in containing hazardous drug contamination depends on operators’ use of proper technique.
Some Class II BSCs recirculate airflow within the cabinet or exhaust contaminated air back into the work environment through HEPA filters.62 The Class II BSC is designed with air plenums that are unreachable for surface decontamination; the plenum under the work tray collects room dirt and debris that mix with hazardous drug residue when the BSC is operational.1 Drafts, supply-air louvers, and other laminar flow equipment placed near the BSC can interfere with the containment properties of the inflow air barrier, resulting in contamination of the work environment.63 More information on the design and use of Class II BSCs is available from the NSF International (NSF)/American National Standards Institute (ANSI) standard 49–04.62 Recommendations for use of Class II BSCs are listed in Appendix A.
Alternatives to Class II BSCs. Alternatives to the open-front Class II BSC include the Class III BSC, glove boxes, and isolators. By definition, a Class III BSC is a totally enclosed, ventilated cabinet of leak-tight construction.64 Operations in the cabinet are conducted through fixed-glove access. The cabinet is maintained under negative air pressure. Supply air is drawn into the cabinet through HEPA filters. The exhaust air is treated by double HEPA filtration or by HEPA filtration and incineration. The Class III BSC is designed for use with highly toxic or infectious material. Because of the costs of purchasing and operating a Class III BSC, it is seldom used for extemporaneous compounding of sterile products.
Less rigorous equipment with similar fixed-glove access include glove boxes and isolators. Although standardized definitions and criteria exist for glove boxes, these guidelines currently focus on applications in the nuclear industry and not on compounding hazardous drugs.65 There are no standardized definitions or criteria for pharmaceutical compounding applications for this equipment and no performance standards determined by an independent organization to aid the purchaser in the selection process. NIOSH recommends that only ventilated engineering controls be used to compound hazardous drugs and that these controls be designed for containment.4 NIOSH defines these controls and details their use and selection criteria as well as recommendations for airflow, exhaust, and maintenance. NIOSH further differentiates between ventilated engineering controls used for hazard containment that are intended for use with sterile products (aseptic containment) and those for use with nonsterile handling of hazardous drugs.4
An isolator may be considered a ventilated controlled environment that has fixed walls, floor, and ceiling. For aseptic use, supply air must be drawn through a high-efficiency (minimum HEPA) filter. Exhaust air must also be high-efficiency filtered and should be exhausted to the outside of the facility, not to the workroom. Workers access the isolator’s work area, or main chamber, through gloves, sleeves, and air locks or pass-throughs. Currently available isolators have either unidirectional or turbulent airflow within the main chamber. For compounding sterile preparations, the filtered air and airflow must achieve an ISO class 5 (former FS-209E class 100) environment within the isolator.50,51,66,67 Isolators for sterile compounding have become increasingly popular as a way to minimize the challenges of a traditional cleanroom and some of the disadvantages of the Class II BSC.50,68–70 The totally enclosed design may reduce the escape of contamination during the compounding process. The isolator may be less sensitive to drafts and other laminar-airflow equipment, including positive-pressure environments. Issues unique to isolators include pressure changes when accessing the fixed-glove assembly, pressure changes in the main chamber when accessing the antechamber or pass-through, positive- versus negative-pressure isolators used to compound hazardous drugs, and ergonomic considerations associated with a fixed-glove assembly. Many isolators produce less heat and noise than Class II BSCs.68 The Controlled Environment Testing Association has developed an applications guide for isolators in health care facilities.71
Isolators, like Class II BSCs, do not prevent the generation of contamination within the cabinet workspace, and their effectiveness in containing contamination depends on proper technique.72 The potential for the spread of hazardous drug contamination from the pass-through and main chamber of the isolator to the workroom may be reduced by surface decontamination, but no wipe-down procedures have been studied. Surface decontamination may be more readily conducted in isolators than in Class II BSCs. (See Decontamination, deactivation, and cleaning for more information.)
Recirculating isolators depend on high-efficiency (HEPA or ultra-low penetrating air [ULPA]) filters. These filters may not sufficiently remove volatile hazardous drug contamination from the airflow. Isolators that discharge air into the workroom, even through high-efficiency filters, present exposure concerns similar to those of unvented Class II BSCs if there is a possibility that the hazardous drugs handled in them may vaporize. Isolators used for compounding hazardous drugs should be at negative pressure or use a pressurized air lock to the surrounding areas to improve containment. Some isolators rely on a low-particulate environment rather than laminar-airflow technology to protect the sterility of the preparations. Recommendations for use of Class III BSCs and isolators are summarized in Appendix B.
Closed-system drug-transfer devices. Closed-system drug-transfer devices mechanically prevent the transfer of environmental contaminants into the system and the escape of drug or vapor out of the system.4 ADD-Vantage and Duplex devices are closed-system drug-transfer devices currently available for injectable antibiotics. A similar system that may offer increased environmental protection for hazardous drugs is a proprietary, closed-system drug-transfer device known as PhaSeal. This multicomponent system uses a double membrane to enclose a specially cut injection cannula as it moves into a drug vial, Luer-Lok, or infusion-set connector.
Several studies have shown a reduction in environmental contamination with marker hazardous drugs during both compounding and administration when comparing standard techniques for handling hazardous drugs with the use of PhaSeal.73–78 It should be noted, however, that PhaSeal components cannot be used to compound all hazardous drugs.
In 1984, Hoy and Stump79 concluded that a commercial air-venting device reduced the release of drug aerosols during reconstitution of drugs packaged in vials. The testing was limited to visual analysis. The venting device does not lock onto the vial, which allows it to be transferred from one vial to another. This practice creates an opportunity for both environmental and product contamination. Many devices labeled as “chemo adjuncts” are currently available. Many feature a filtered, vented spike to facilitate reconstituting and removing hazardous drugs during the compounding process. However, none of these devices may be considered a closed-system drug-transfer device, and none has been formally studied with the results published in peer-reviewed journals. As other products become available, they should meet the definition of closed-system drug-transfer devices established by NIOSH4 and should be required to demonstrate their effectiveness in independent studies. Closed-system drug-transfer devices (or any other ancillary devices) are not a substitute for using a ventilated cabinet.
Personal Protective Equipment. Gloves. Gloves are essential for handling hazardous drugs. Gloves must be worn at all times when handling drug packaging, cartons, and vials, including while performing inventory control procedures and when gathering hazardous drugs and supplies for compounding a batch or single dose. During compounding in a Class II BSC, gloves and gowns are required to prevent skin surfaces from coming into contact with these agents. Studies of gloves indicate that many latex and nonlatex materials are effective protection against penetration and permeation by most hazardous drugs.80–84 Recent concerns about latex sensitivity have prompted testing of newer glove materials. Gloves made of nitrile or neoprene rubber and polyurethane have been successfully tested using a battery of antineoplastic drugs.82–84 The American Society for Testing and Materials (ASTM) has developed testing standards for assessing the resistance of medical gloves to permeation by chemotherapy drugs.85 Gloves that meet this standard earn the designation of “chemotherapy gloves.” Gloves selected for use with hazardous drugs should meet this ASTM standard.
Connor and Xiang86 studied the effect of isopropyl alcohol on the permeability of latex and nitrile gloves exposed to antineoplastic agents. During the limited study period of 30 minutes, they found that the use of isopropyl alcohol during cleaning and decontaminating did not appear to affect the integrity of either material when challenged with six antineoplastic agents.
In most glove-testing systems, the glove material remains static, in contrast to the stressing and flexing that occur during actual use. In one study designed to examine glove permeability under static and flexed conditions, no significant difference in permeation was reported, except in thin latex examination gloves.87 Another study, however, detected permeation of antineoplastic drugs through latex gloves during actual working conditions by using a cotton glove under the latex glove.88 The breakthrough time for cyclophosphamide was only 10 minutes. The authors speculated that the cotton glove may have acted as a wick, drawing the hazardous drug through the outer glove. Nonetheless, under actual working conditions, double gloving and wearing gloves no longer than 30 minutes are prudent practices.
Permeability of gloves to hazardous drugs has been shown to be dependent on the drug, glove material and thickness, and exposure time. Powder-free gloves are preferred because powder particulates can contaminate the sterile processing area and absorb hazardous drug contaminants, which may increase the potential for dermal contact. Hands should be thoroughly washed before donning gloves and after removing them. Care must be taken when removing gloves in order to prevent the spreading of hazardous drug contaminants.
Several studies have indicated that contamination of the outside of gloves with hazardous drug is common after compounding and that this contamination may be spread to other surfaces during the compounding process.30–33,39 Studies have also shown that hazardous drug contamination may lead to dermal absorption by workers not actively involved in the compounding and administration of hazardous drugs.30,88 The use of two pairs of gloves is recommended when compounding these drugs. In an isolator, one additional pair of gloves must be worn within the fixed-glove assembly.68
Once compounding has been completed and the final preparation surface decontaminated, the outer glove should be removed and contained inside the BSC. The inner glove is worn to affix labels and place the preparation into a sealable containment bag for transport. This must be done within the BSC. In the isolator, the fixed gloves must be surface cleaned before wiping down the final preparation, placing the label onto the preparation, and placing it into the pass-through. The inner gloves should be worn to complete labeling and to place the final preparation into a transport bag in the pass-through. The inner gloves may then be removed and contained in a sealable bag within the pass-through. If the final check is conducted by a second staff member, fresh gloves must be donned before handling the completed preparation.
During batch compounding, gloves should be changed at least every 30 minutes. Gloves (at least the outer gloves) must be changed whenever it is necessary to exit and re-enter the BSC. For aseptic protection of sterile preparations, the outer gloves must be sanitized with an appropriate disinfectant when reentering the BSC. Gloves must also be changed immediately if torn, punctured, or knowingly contaminated. When wearing two pairs of gloves in the BSC, one pair is worn under the gown cuff and the second pair placed over the cuff. When removing the gloves, the contaminated glove fingers must only touch the outer surface of the glove, never the inner surface. If the inner glove becomes contaminated, then both pairs of gloves must be changed. When removing any PPE, care must be taken to avoid introducing hazardous drug contamination into the environment. Both the inner and outer gloves should be considered contaminated, and glove surfaces must never touch the skin or any surface that may be touched by the unprotected skin of others. Gloves used to handle hazardous drugs should be placed in a sealable plastic bag for containment within the BSC or isolator pass-through before disposal as contaminated waste.
If an i.v. set is attached to the final preparation in the BSC or isolator, care must be taken to avoid contaminating the tubing with hazardous drug from the surface of the gloves, BSC, or isolator.
Class III BSCs and isolators are equipped with attached gloves or gauntlets. They should be considered contaminated once the BSC or isolator has been used for compounding hazardous drugs. For compounding sterile preparations, attached gloves or gauntlets must be routinely sanitized per the manufacturer’s instructions to prevent microbial contamination. Hazardous drug contamination from the gloves or gauntlets may be transferred to the surfaces of all items within the cabinet. Glove and gauntlet surfaces must be cleaned after compounding is complete. All final preparations must be surface decontaminated by staff, wearing clean gloves to avoid spreading contamination.68 Recommendations for use of gloves are summarized in Appendix C.
Gowns. Gowns or coveralls are worn during the compounding of sterile preparations to protect the preparation from the worker, to protect the worker from the preparation, or both. The selection of gowning materials depends on the goal of the process. Personal protective gowns are recommended during the handling of hazardous drug preparations to protect the worker from inadvertent exposure to extraneous drug particles on surfaces or generated during the compounding process.
Guidelines for the safe handling of hazardous drugs recommend the use of gowns for compounding in the BSC, administration, spill control, and waste management to protect the worker from contamination by fugitive drug generated during the handling process.1–4,89,90 Early recommendations for barrier protective gowns required that they be disposable and made of a lint-free, low-permeability fabric with a closed front, long sleeves, and tight-fitting elastic or knit cuffs.1 Washable garments (e.g., laboratory coats, scrubs, and cloth gowns) absorb fluids and provide no barrier against hazardous drug absorption and permeation. Studies into the effectiveness of disposable gowns in resisting permeation by hazardous drugs found variation in the protection provided by commercially available materials. In an evaluation of polypropylene-based gowns, Connor91 found that polypropylene spun-bond nonwoven material alone and polypropylene–polyethylene copolymer spun-bond provided little protection against permeation by a battery of aqueous- and nonaqueous- based hazardous drugs. Various constructions of polypropylene (e.g., spun-bond/melt-blown/spun-bond) result in materials that are completely impermeable or only slightly permeable to hazardous drugs. Connor91 noted that these coated materials are similar in appearance to several other nonwoven materials but perform differently and that workers could expect to be protected from exposure for up to four hours when using the coated gowning materials. Harrison and Kloos92 reported similar findings in a study of six disposable gowning materials and 15 hazardous drugs. Only gowns with polyethylene or vinyl coatings provided adequate splash protection and prevented drug permeation. In a subjective assessment of worker comfort, the more protective gowns were found to be warmer and thus less comfortable. These findings agree with an earlier study that found that the most protective gowning materials were the most uncomfortable to wear.93 Resistance to the use of gowns, especially by nurses during administration of hazardous drugs, has been reported.94 The lack of comfort could cause resistance to behavioral change.
Researchers have looked at gown contamination with fluorescent scans, high-performance liquid chromatography, and tandem mass spectrometry.39,95 In one study, researchers scanned nurses and pharmacists wearing gowns during the compounding and administration of hazardous drugs.95 Of a total of 18 contamination spots detected, 5 were present on the gowns of nurses after drug administration. No spots were discovered on the gowns of pharmacists after compounding. In contrast, researchers using a more sensitive assay placed pads in various body locations, both over and under the gowns used by the subjects during compounding and administration of cyclophosphamide and ifosfamide.39 Workers wore short-sleeved nursing uniforms, disposable or cotton gowns, and vinyl or latex gloves. More contamination was found during compounding than administration. Contamination found on the pads placed on the arms of preparers is consistent with the design and typical work practices used in a Class II BSC, where the hands and arms are extended into the contaminated work area of the cabinet. Remarkably, one preparer had contamination on the back of the gown, possibly indicating touch contamination with the Class II BSC during removal of the final product. While early guidelines do not contain a maximum length of time that a gown should be worn, Connor’s91 work would support a two- to three-hour window for a coated gown. Contamination of gowns during glove changes must be a consideration. If the inner pair of gloves requires changing, a gown change should be considered. Gowns worn as barrier protection in the compounding of hazardous drugs must never be worn outside the immediate preparation area. Gowns worn during administration should be changed when leaving the patient care area and immediately if contaminated. Gowns should be removed carefully and properly disposed of as contaminated waste to avoid becoming a source of contamination to other staff and the environment.
Hazardous drug compounding in an enclosed environment, such as a Class III BSC or an isolator, may not require the operator to wear a gown. However, because the process of handling drug vials and final preparations, as well as accessing the isolator’s pass-throughs, may present an opportunity for contamination, the donning of a gown is prudent. Coated gowns may not be necessary for this use if appropriate gowning practices are established. Recommendations for use of gowns are summarized in Appendix D.