ALARA As Low As Reasonably Achievable API Active Pharmaceutical Ingredient ASCO American Society of Clinical Oncology ASHP American Society of Health-System Pharmacists (formerly American Society of Hospital Pharmacists) ASTM American Society for Testing and Materials BSC Biological Safety Cabinet BUD Beyond-Use Date CACI Compounding Aseptic Containment Isolator CAI Compounding Aseptic Isolator CDC Centers for Disease Control and Prevention
(Department of Health and Human Services) CFR Code of Federal Regulations CSTD Closed System Drug-Transfer Device CP Cyclophosphamide C-PEC Containment Primary Engineering Control C-SCA Containment Segregated Compounding Area C-SEC Containment Secondary Engineering Control CSP Compounded Sterile Preparations DNA Deoxyribonucleic Acid DOL U.S. Department of Labor EPA U.S. Environmental Protection Agency FDA U.S. Food and Drug Administration GHS Globally Harmonized System HCS Hazard Communication
Standard HCWs Healthcare Workers HD Hazardous Drug HEPA High-Efficiency Particulate Air "or Arrestor" IARC International Agency for Research on Cancer IM Intramuscular IND Investigational New Drugs ISO International Organization for Standardization IT Intrathecal IV Intravenous ONS Oncology Nursing Society NIOSH National Institute for Occupational Safety and Health OEL Occupational Exposure Limit OSHA Occupational Safety and Health Administration (Department of Labor) PEC Primary Engineering
Control P&P Policy and Procedure PPE Personal Protective Equipment SCE Sister Chromatid Exchange SDS Safety Data Sheet (formerly Material Safety Data Sheet) SOP Standard Operating Procedure SQ Subcutaneous TJC The Joint Commission USP US Pharmacopeial Convention WHO World Health Organization The Occupational Safety and Health Administration (OSHA) first published guidelines for the management of
cytotoxic (antineoplastic) drugs in the work place in 1986 (OSHA, 1986), and the guidelines were made available in the peer-reviewed literature that same year (Yodaiken, 1986). OSHA updated the guidelines in 1995 and subsequently posted them to OSHA's website in 1999 (OSHA, 1995; OSHA, 1999). Since OSHA last updated the guidelines, governmental and professional organizations have contributed substantial quantities of scientific investigation results, "best-practices", and policy recommendations,
which broadened the evidence base underlying the current practices for safe hazardous drug (HD) handling. NIOSH and the American Society of Hospital Pharmacists (ASHP) (ASHP, 1990) redefined the term "hazardous drug" beyond directly cytotoxic drugs to include additional agents that exhibit specific characteristics in human and animal toxicity [See sec. II.A., Figure 1]. The World Health Organization (WHO) estimates that the number of cancer patients will almost double in the next two decades
(WHO, 2014), and the number of healthcare workers (HCWs) needed to care for those patients will grow commensurately. The National Institute for Occupational Safety and Health (NIOSH) estimates that somewhere around 8 million HCWs are potentially exposed (NIOSH, 2009). This informational guidance document outlines OSHA's current recommendations for addressing the health and safety hazards faced by healthcare workers who handle HDs, and the background evidence underlying those
recommendations. Although work practices and safe HD handling practices have improved in the years since OSHA first published guidance on the subject in 1986 (OSHA, 1986), workplace exposure to HDs remains a problem (Valanis, 1992; Connor, 1999; Connor, 2010). Several recent publications have documented the ongoing failure of employers to adopt, or consistently use, recommended safety practices for handling HDs (Boiano, 2014; Polovich and Martin, 2011). This failure, in conjunction with
many information requests from the public on how to safely handle HDs, and the growing population of HCWs with potential HD exposure in their work prompted OSHA to review and revise its recommendations for hazardous drug handling. Most agents that are considered HDs are covered under the Hazard Communication Standard (HCS)[29 CFR 1910.1200], which has undergone a significant update since OSHA's 1995 hazardous drug guidance was issued (OSHA, 2012b). Note that the requirements of the HCS are
superseded by those of OSHA's Laboratory Standard, 29 CFR 1910.1450, when an employer is engaged in the "laboratory use of hazardous chemicals" (i.e., use of relatively small quantities of hazardous chemicals on a non-production basis), but this document focuses on the HCS requirements that apply to most healthcare employers. These recommendations apply to all healthcare settings where employees are occupationally exposed to HDs, such as hospitals, physicians' offices, and home healthcare
agencies. Because many of the same drugs used to treat humans are also used to treat animals, this guidance is applicable to veterinary practices as well. Sections dealing with work areas and prevention of employee exposure to HDs at a workplace refer to workplaces where pharmaceuticals are used in concentrations appropriate for patient therapy. In settings where employees work with drugs in a more potentially hazardous form (e.g., a more concentrated form encountered in certain components of
pharmaceutical manufacturing), measures that afford employees a greater degree of protection from exposure are commonly employed and should be used. Many manufacturers have internal occupational exposure limits, but those limits are not generally available to regulatory agencies; workers may inquire about those limits from the manufacturers separately from the information available in this document. This review will: Anesthetic agents are not considered in this review, even though exposure to some of these agents is a well-recognized health hazard (NIOSH, 2007). A separate OSHA document on this topic is available at: https://www.osha.gov/waste-anesthetic-gases/workplace-exposures-guidelines (OSHA, 2000). While OSHA's 1986 guidelines focused on cancer chemotherapy drug safety
(OSHA, 1986), OSHA's 1995 instruction enlarged the focus to include additional agents with toxicity profiles of concern. These additional agent categories were defined as hazardous drugs ("HDs") by the American Society of Health-System Pharmacists (ASHP), formerly American Society of Hospital Pharmacists, in a 1990 publication (ASHP, 1990) based on four specific criteria, which are listed below in Figure 1. In 2004, a NIOSH work group authored a NIOSH Alert: "Preventing Occupational
Exposure to Antineoplastic and Other HDs in Healthcare Settings," (NIOSH, 2004), a now internationally-referenced guidance document that revised ASHP's definition of HDs, including adding two more characteristics, as Figure 1 depicts. The NIOSH work group split ASHP's "teratogenicity or fertility impairment" characteristic into two characteristics - "teratogenicity/developmental toxicity" and "reproductive toxicity" - to differentiate between insults that develop in offspring (such as a malformation) and impairments to reproductive function or capacity of the parent. The NIOSH work group also added a sixth criterion to address "structure and toxicity profiles of new drugs that mimic existing drugs
determined [to be] hazardous by the above criteria." Finally, the NIOSH work group added helpful refinements to one of the original criteria, "organ toxicity at low doses." Here, the work group added a qualitative and quantitative discussion of the continuum of toxicity that may be exhibited by a drug. To help readers interpret the "low dose" description, the NIOSH work group cited a series of publications authored by pharmaceutical industry toxicologists that describe industry
"performance" practices for defining "low dose" effects. The citation notes that "…a daily therapeutic dose of 10mg/day or a dose of 1mg/kg per day in laboratory animals that produce serious organ toxicity, or developmental or reproduction toxicity…" has been used by the pharmaceutical industry to develop internal "occupational exposure limits" (OELs) of less than 10µg /m3 with the application of safety factors (Sargent and Kirk, 1988; Naumann and Sargent, 1997; Sargent et al. 2002). NIOSH's
citation further notes that "in house" OELs in this range are typically established for drugs referred to in the pharmaceutical industry as "potent compounds" (NIOSH, 2004). Under the NIOSH approach, characterizing a drug as "hazardous" requires a "hazard identification" process, in which the descriptive criteria of the drug are reviewed and screened against the six HD characteristics. The presence of any one of the HD characteristics is enough to define a drug as hazardous. As such, this
analysis does not comprise a complete four-step risk assessment. It is important to understand the rationale and logic that is used to identify a drug as "hazardous" so that employers can independently assess the hazardousness of new drugs that have not yet been evaluated by NIOSH. Moreover, investigational new drugs (IND), which may be undergoing clinical trials in a given healthcare setting, are new chemicals for which there is often little information on potential toxicity. Structural
or activity similarities to other chemicals and in vitro data can be considered when determining the potential toxic effects of INDs. Investigational new drugs should be prudently handled as HDs unless adequate information becomes available to exclude them. In vitro data may also assist in determining if INDs should be considered a HD (See U.S. Environmental Protection Agency [EPA], 1986, for guidance [EPA, 1986]). When designating a drug as hazardous, professionals trained in pharmacology and toxicology have historically considered several factors (McDiarmid, 1991) that are similar to the considerations used in NIOSH's approach, including: In addition to publishing the 2004 Alert on HD safe handling, NIOSH biennially updates their HD list to reflect newly Food and Drug Administration
(FDA)-approved agents, and also to address any listings which may be modified in light of newly published scientific literature or other governmental agency determinations. See the NIOSH Alert parent document (NIOSH, 2004) and the subsequent shorter HD listing updates (NIOSH, 2010; NIOSH, 2012; NIOSH, 2014b) for further details. In the thirty years since the publication of OSHA's technical guidance on HD safe handling, the scientific literature on this topic has grown
tremendously. In the years since the 2004 NIOSH Alert was issued, over 400 papers on HDs have been published in the peer-reviewed literature. These reports document how vial contamination, preparation, administration, disposal, and other HD handling activities may expose pharmacists, nurses, physicians, and other HCWs to potentially significant workplace levels of these chemicals. It is difficult to set safe levels of exposure to HDs on the basis of current scientific information because
the degree of absorption that takes place during work, and the significance of early biological effects on each individual, are difficult to assess and may vary depending on the HD. However, several lines of evidence support the toxic potential of these drugs if handled improperly. In addition, most HCWs are exposed to multiple agents during any work shift, yielding a "mixed exposure" scenario. Therefore, it is essential to minimize exposure to all HDs. Summary tables of much of the data
presented below can be found in the scientific literature (Sorsa, 1985; Rogers, 1987; Connor and McDiarmid, 2006). While most commonly used HDs are members of several chemically unrelated classes of agents, most of those used for anti-cancer chemotherapy exert their action by binding to cellular macromolecules, including deoxyribonucleic acid (DNA), or through disruption of DNA and protein synthesis (Skeel, 1987; Chabner
and Longo, 2010). The potential fates of a cell exposed to a HD include transformation to malignant potential, mutation, cell death, or, through repair, a normal cell may remain (Harris, 1976). Importantly, HDs do not distinguish between normal and cancerous cells, thus normal cells are often affected during treatment. Numerous studies document the carcinogenic, mutagenic, and teratogenic effects of HD exposure in animals. They are well
summarized in the pertinent International Agency for Research on Cancer (IARC) publications (IARC, 1975; IARC, 1976; IARC, 1981; IARC, 1982; IARC, 1987; IARC, 1990; IARC, 2012). Alkylating agents present the strongest evidence of carcinogenicity (e.g., cyclophosphamide, mechlorethamine hydrochloride [nitrogen mustard]). However, other classes, such as the Topoisomerase II inhibitors (Pedersen-Bjergaard, 2002) and some anthracycline antibiotics, have been implicated as well. Extensive evidence
for mutagenic and reproductive effects can be found in all antineoplastic classes. The antiviral agent ribavirin has additionally been shown to be teratogenic in all rodent species tested (Harrison, 1988; Kilham and Ferm, 1977). The ASHP recommends that drugs that are carcinogenic and/or teratogenic in animals and those that exhibit reproductive toxicity or organ toxicity at low doses in animals be considered potential human occupational hazards (ASHP, 1990). Many HDs are known carcinogens for which there is no safe level of exposure. The development of secondary malignancies in cancer patients is a well-documented side effect of chemotherapy treatment (Sieber, 1975; Weisburger, 1975; Pedersen-Bjergaard, 2002; Choi, 2014). Leukemia is the most frequent adverse outcome, but other secondary malignancies, such as bladder cancer and lymphoma, have been documented in patients treated for other primary malignancies
(Socie, 1991; Bermejo, 2009; Krishnan, 2007). Chromosomal aberrations can result from chemotherapy treatment as well (Chabner and Longo, 2010). Numerous case reports have linked chemotherapeutic treatment to adverse reproductive outcomes (reviewed in NTP, 2013). Testicular and ovarian dysfunction, including permanent sterility, has occurred in male and female patients who have received anti-cancer HDs, either singly or in combination (Chapman, 1984; Ajala, 2010). In addition, most antineoplastic
agents are known or suspected to be present in breast milk (Briggs, 2014). The literature also documents the effects of these HDs on other organ systems. Extravasation of some agents can cause severe soft-tissue injury, consisting of necrosis and sloughing of exposed areas (Duvall and Baumann, 1980; Perry, 2008; Rudolph, 1979). Other HDs, such as zidovudine (formerly AZT), are known to have significant side effects (i.e., hematologic abnormalities) and some monoclonal antibodies
(biologics) may cause malignancy and reproductive effects in treated patients (Anderson, 1982; Henderson and Gerberding, 1989; Hansel, 2010). Serum transaminase elevation has also been reported in treated patients (Anderson, 1982; Henderson and Gerberding, 1989). Initial air sampling results often showed very low concentrations of measurable HDs. However, they were questioned because of evidence
suggesting that sampling methods were not sufficiently robust to capture drug that existed not only as a particulate, but also in gaseous form emanating from high efficiency particulate arrestor (HEPA) filters (Larson, 2003; Kiffmeyer, 2002) through sublimation. In addition, scientific interest in work surface contamination grew following the initial observation of work surface contamination in early studies, and observations using the biologic evidence of exposure (described below). With
the development of sensitive assays for certain marker HDs, the past several decades have seen a large effort to assess HD work environments using wipe samples of work surfaces, such as BSCs and countertops, and of the wider work environment, such as floors and door handles. These studies frequently found widespread contamination (Minoia, 1998; Connor, 1999; Hedmer, 2004; Nygren and Aspman, 2004). While the concentrations of drug measured were often not high, the frequency of positive
(measurable) results, the frequency of positive (measurable) results suggested extensive contamination, and thus exposure opportunities for workers. For example, one multi-site study in the U.S. and Canada found that 75 percent of samples in pharmacies and 65 percent in nursing treatment areas showed measurable results of HDs (Connor, 1999). More than 80 studies of the ambient work environment have been published during the past few decades, with the majority having yielded detectable
results for at least one of several drugs for which sampling was performed. See NIOSH website: https://www.cdc.gov/niosh/topics/antineoplastic/sampling.html. Several studies also linked environmental sampling results to bio-monitoring results of drug levels in workers' urine, documenting an uptake of drug levels in contaminated work environments (Minoia, 1998; Wick, 2003; Mason, 2005; Connor, 2010; Hon, 2015). These studies raise the question of whether the skin contact pathway may be not
only a common but also biologically important exposure route of absorption for under-protected workers for at least some agents (Kromhout, 2000). Even prior to drug compounding, exposure opportunity exists for oncology workers, as studies have documented that drug contamination can occur from handling the outside of new, unopened drug vials (Connor, 2005; Nygren, 2002a; Sessink, 1992a; Power, 2014). The special case of administration of drugs via aerosol nebulizer treatment can lead
to measurable air concentrations in the breathing zone of workers who provide the treatment (Harrison, 1988) and, depending on the medication, air concentrations may result in symptoms in exposed workers (Balmes, 1995). Aerosolized medication safety recommendations are available from the Society of Infectious Disease Pharmacists (Le, 2010). In the past thirty years, bio-monitoring studies have become quite commonplace, with more than 100 reports in the literature, about two-thirds of which documented drug uptake by measuring these drugs or their metabolites in the urine of at least some exposed HCWs. Bystander uptake of drug in non-drug handling health workers, including support staff, has also been reported (Sessink, 1992b; Hon, 2015). More recent evidence suggests that structural chromosomal damage
(e.g., gaps, breaks, translocations and copy number differences (aneuploidy)) may be prognostic of an increased cancer risk at least when considered on a population basis (i.e., exposed vs. non-exposed, groups), thus making it a more potentially meaningful marker of effect (Hagmar, 1998). Micronuclei frequency, a count of chromosome remnants that mark flawed chromosomal segregation during cell division (Fenech, 2008), are also considered to be epidemiologically prognostic of a future cancer risk
at the group level (Bonassi, 2007; Bonassi, 2008; Bonassi, 2011). Importantly, specific chromosomal markers of HD damage, typically observed in therapeutically treated cancer patients, have also been reported in oncology pharmacy and nursing personnel as a function of drug handling frequency (McDiarmid, 2010; McDiarmid, 2014). The concern regarding reproductive risks associated with occupational exposure to HDs derives from both the mechanism of action of many of the drugs (interference with DNA replication or protein synthesis) and from the well-documented reproductive and developmental toxicity observed in therapeutically treated patients (Perry, 2008). While the focus of concern has been on pregnancy, several HDs have significant male mediated
reproductive effects as well (Chapman, 1984; Roche, 1996). With the advent of safe handling controls in the mid-1980s, the hope was that these adverse reproductive outcomes, which, unlike a cancer risk, could theoretically result from a brief, acute exposure, would be eliminated. To be sure, outcome studies conducted after safe handling guidelines were issued have shown some decrease in exposure (Connor & McDiarmid, 2006), but several recent studies still have shown excess reproductive
loss even with the use of BSCs (Martin, 2003; Lawson et al., 2012, reviewed in Connor et al., 2014). In the most recent study on this topic, using the Harvard Nurses' Study cohort, NIOSH investigators found a statistically significant, two-fold increase in the risk of spontaneous abortion in nurses who reported first trimester HD exposure from 1990 through 2001 (Lawson, 2012). A review of the reproductive health risks associated with occupational exposure to HDs can be found in Connor
(2014). Several of these studies, including the Harvard Nurses' Study, report on a period after the initial safe handling guidance was promulgated in the mid-1980s and imply that some safe handling practices were being implemented. Notably of the 184 drugs that NIOSH identifies as HDs in its 2014 list (NIOSH, 2014), about 80 percent are classified by the FDA as Pregnancy Category D or X, which indicates a potential for fetal harm when used during pregnancy (FDA, 1997). This categorization
has been changed to the Pregnancy and Lactation Labeling Rule (PLLR) that became effective June 2015. However, a drug's characteristics that allowed it to be designated as D or X remain unchanged and thus these older designations may be helpful to organizations assembling their own HD list (see https://womensmentalhealth.org/posts/fdas-new-labeling-rule-clinical-implications/). In addition, the secretion of HDs into human milk of treated patients suggests an additional concern for
exposed and pregnant workers who plan to breast feed (MotherRisk, 2014). Epidemiologic data assessing occupational cancer in oncology workers, however, has been difficult to obtain, primarily because the U.S. lacks a national cancer registry. A fragmented set of state registries collects cancer data, but the
occupation of patients is not typically included. The best studies performed to date were in Denmark, where linkage of health and employment records allowed this question to be studied. An increased risk of leukemia was found for physicians with at least six months of exposure, but this excess did not reach statistical significance and participant numbers were small (Skov, 1990). A subsequent publication by these same investigators found an increased risk among oncology nurses in the Danish
registry, and these excesses did reach significance (Skov, 1992). While not specifically targeting oncology workers, other types of available epidemiologic evidence bolsters the Danish cancer registry reports described above. For example, a Danish study of female pharmacy technicians found a statistically significant increased risk of non-Hodgkin's lymphomas (Hansen, 1994), a cancer seen in excess in cancer patients following certain therapies (Krishnan and Morgan, 2007). A study of
occupational risk factors for breast cancer among nurses found a non-statistically significant raised odds ratio of 1.65 (95 percent CI 0.53-5.17) among nurses working with cytotoxic HD drugs (Gunnarsdottir, 1997). A large U.S. cancer mortality study of HCWs in 24 states found a 30 percent excess of myeloid leukemia among nurses and a two-fold excess in pharmacists (Petralia, 1999). Other cancers were also observed to be in excess in these workers. A population-based study of worker occupation
and leukemia in two Midwestern U.S. states also found an increased risk of leukemia in nursing and health care workers (HCW) (Blair, 2001). A series of case reports of possible occupational cancer risks have also been published, including bladder cancer in a female pharmacist (Levin, 1993) and naso-pharyngeal cancer in an oncology nurse (Gabriele, 1993). In both cases, no safe handling precautions were used. Generally, the same effects of HDs on the target organs of treated patients may also be observed in under-protected employees. For example, hepatocellular damage has been reported in nurses working in an oncology ward, and the damage appeared to be related to the intensity and
duration of their work exposure to HDs (Sotaniemi, 1983). The use of nebulizers to administer HDs presents a specific challenge to the respiratory system and exposes HCWs to the "fugitive" aerosol of the drug. For example, pentamidine was associated with reversible respiratory dysfunction in one worker who administered aerosol treatment and subsequently experienced a decrease in diffusing capacity of the lung that improved after exposure ceased (Gude, 1989). The onset of bronchospasm in a
pentamidine-exposed worker has also been reported (Doll, 1989). Employees involved in the aerosol administration of ribavirin have noted symptoms of respiratory tract irritation (Lee, 1988). With the potential increase in aerosol administration of HDs, exposure controls should be applied to minimize widespread environmental contamination and protect HCWs. A number of medications, including some HDs, psyllium, and various antibiotics, are known respiratory and dermal sensitizers. Exposure
in susceptible individuals can lead to asthma or allergic contact dermatitis (Kusnetz and Condon, 2003). Risks to personnel working with HDs are a function of the drugs' inherent toxicity and the extent of exposure. Early speculation noted inhalation was the primary route of exposure. However, with the advent of more sensitive drug assays, surface wipe sampling of a number of "marker" HDs has provided a method of
examining work areas for HD residue (Sessink, 1992a & b; Sessink, 1997; Kopp, 2013; Fransman, 2005; Fransman, 2007). Numerous studies have shown that surfaces in areas where HDs are stored, mixed, administered, and wasted, as well as where patients are cared for, are contaminated with measurable levels of HD residue (Connor, 1999; Connor 2002; Acampora, 2005; Connor, 2010; Hon, 2013). Studies have detected the presence of HDs in the urine of HCWs who have handled these drugs, and in others
who did not work directly with the drugs but who were only in the work area (Sessink, 1997; Wick, 2003; Fransman, 2004; Suspiro, 2011; Hon, 2015). Current belief is that dermal absorption of HD residue from contaminated surfaces is the primary route of exposure for at least some agents, such as cyclophosphamide (Kromhout, 2000; Fransman, 2004; Fransman, 2005). Inhalation, especially of drugs that vaporize, is an additional exposure route, and at least one study of automatic dispensing machines
of oral tablets indicates that these devices may generate dust of active pharmaceutical ingredients (APIs) during the counting and dispensing process (Fent, 2014). Exposure is also likely to result from ingestion of contaminated food or drink or through mouth contact with contaminated hands or cigarettes. Accidental injection from the use of needles or contact with broken glass fragments is also of concern. Opportunity for exposure to HDs may occur at many points in the process of handling
these drugs. NIOSH has included pharmacy and nursing personnel, physicians, operating room personnel, environmental services workers, workers in research laboratories, veterinary care workers, and shipping and receiving personnel in the workers who handle HDs (NIOSH, 2004). The US Pharmacopeial Convention (USP) is a scientific nonprofit organization that sets standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured,
distributed and consumed worldwide. USP's drug standards are enforceable in the United States by the Food and Drug Administration. USP chapter 797 ("Pharmaceutical Compounding—Sterile Preparations"), notes that when compounding sterile preparations of HDs, they should be handled with caution at all times during receiving distribution, stocking, inventorying, preparation, and disposal (USP 797, 2012). USP's general chapter 800 ("Hazardous Drugs—Handling in Healthcare Settings" published 2/1/2016
in USP 39-NF 34, First Supplement) cautions that both clinical and nonclinical personnel may be exposed to HDs when they create or use aerosols, generate dust, clean up spills, or touch contaminated surfaces during the receipt, preparation, administration, cleaning, or disposal of HDs (USP 800, 2016). NIOSH, ASHP, and others have reported on studies that found drug residue on the outside of HD vials when they arrive at the workplace from the manufacturer or distributor (NIOSH, 2004; ASHP, 2006;
Power, 2014). Packing cartons have also been identified as sources of measurable HD contamination (Kiffmeyer, 2000). Evaluation of
these preparation techniques, using fluorescent dye solutions, has shown contamination of bag ports, gloves, and the sleeves and chest of gowns (Stellman, 1987; Spivey and Connor, 2003). HD contamination has also been identified and quantified on gloves and other PPE through the use of sensitive assays of marker drugs of cyclophosphamide, fluorouracil, and methotrexate. (Sessink, 1992a; Sessink, 1992b; Sessink, 1997; Minoia, 1998; Fransman, 2004; Fransman, 2005; Mason, 2005). Administration of HDs to patients is generally performed by nurses or physicians. The potential for occupational
exposure exists for every route of drug administration. Common methods include injection (e.g., intravenous, intra-arterial, intramuscular, subcutaneous), IV infusion, oral or enteral tube, intracavitary (e.g., intravesicular, intraperitoneal, or intrapleural), topical, intraspinal, and inhalation (Polovich, 2011). HDs and contaminated materials should be disposed of in accordance with federal, state, and local laws. Any discarded HDs greater than residue amounts should be evaluated as to whether they are a hazardous waste under federal U.S. EPA regulations, and if so, be disposed of in accordance with 40 CFR part 261 (EPA, 1991a
and b). In addition, any discarded antineoplastic HDs should be managed as hazardous waste as a best practice, and as required by some states. Since the EPA lists of hazardous wastes have not been updated since the 1980s, EPA's Office of Inspector General has strongly recommended that EPA conduct a review of drugs that have entered the market since that time, particularly chemotherapy agents, to determine which drugs should be managed as hazardous waste, in order to protect human health and the
environment EPA OIG, 2012). An independent commentary article on the EPA report (Eckstein, 2012), provides context to the issue of the future regulation of pharmaceutical waste. Overtly contaminated materials, such as may occur during a spill or the cleanup of a spill, should also be managed as a hazardous waste (EPA, 2008). Trace contaminated materials used in the preparation and administration of HDs, such as gloves, gowns, syringes and vials, also present a hazard to clinical support
and housekeeping staff. These items should be disposed of in properly labeled, covered, and sealed disposal containers and handled by trained and protected personnel. Since sharps and potentially infectious materials may also be included in the trace contaminated materials, such containers should be managed as biohazardous waste under the Bloodborne Pathogens Standard [29 CFR 1910.1030(d)(4)(iii)] (OSHA, 2012a). Treatment should occur at a regulated medical waste incinerator rather than an
autoclave or microwave to prevent aerosolization. Spills involving HDs can also represent a hazard, and employers should ensure that all employees are familiar with appropriate spill procedures, as outlined in the Chemotherapy Safety Standards issued by the American Society of Clinical Oncology/Oncology Nursing Society (ONS, 2013). Recent studies of HD handling practices have found deviations from the recommendations
for personnel training, use of work practices, and personal protective equipment. Formal training for HD handlers is not universally provided. For example, among nurses and pharmacists responsible for HD preparation, 9-13 percent reported never having received HD training, and for those who had received training, most reported that it was more than a year earlier (Boiano, 2014). Individuals responsible for HD preparation reported failure to wear protective gowns 20-36 percent of the time and
failure to wear chemotherapy gloves 8-10 percent of the time (Polovich, 2012; Boiano, 2015). For HD administration, use of protective gowns ranged from 50-65 percent, use of chemotherapy gloves ranged from 78-85 percent, and double-gloving was particularly low, at only 11-20 percent (Polovich, 2011, 2012; Boiano, 2014). Such failure to use appropriate precautions results in occupational exposure, with 4-17 percent of employees reporting known skin or mucous membrane contact with HDs in the
previous year (Friese, 2012; Boiano, 2014; Boiano, 2015). These findings demonstrate that employers have failed to sufficiently protect all personnel potentially exposed to HDs. Healthcare workers may be occupationally exposed to HDs in many different types of settings. Drug preparation can take place in pharmacies (hospital, retail, mail-order, or compounding) or clinic settings. Drug administration occurs in hospital inpatient and
outpatient units, operating rooms, interventional radiology departments, respiratory therapy departments, treatment centers, physician offices, veterinary clinics or hospitals, extended care facilities, and home care agencies. Exposure potential is related to the manipulations required to prepare and administer HDs, the type of equipment available in the specific setting, the work practices, and personal protective equipment used by the personnel. Specialized settings (e.g.,
operating room or interventional radiology departments) may infrequently be involved in HD handling. Procedures should be evaluated step-by-step for the likelihood of drugs being released into the environment so that exposure can be minimized. Settings where HDs are administered by inhalation or nebulizer should be equipped with appropriate engineering controls to prevent workers' inhalation of fugitive aerosols (CDC, 2003). Additionally, drug aerosols may be deposited on skin and
surfaces, resulting in dermal exposure. Where HDs are used in the workplace, sound practice dictates that employers develop a written Hazardous Drug Safety and Health Plan. As many HDs are also hazards that are identified in the revised HCS, the requirements of the HCS must also be met [29 CFR 1910.1200] (OSHA,
2012b). Such a plan assists in: The HD Safety Plan should be readily available and accessible to all employees, including temporary employees, contractors, and trainees. The comprehensive plan should address all aspects of safe handling of HDs throughout the facility, be developed using a collaborative effort including all affected
departments, and specify measures that the employer is taking to ensure employee protection. The Joint Commission (TJC) released a monograph in 2012 to stimulate greater awareness of the potential synergies between patient and worker health and safety activities by comparing TJC standards and OSHA mandates and guidance (TJC, 2012). This monograph will help employers to develop a HD Safety Plan that includes both patient and worker safety under a generalized "culture of safety." OSHA has also
prepared a comparison of the OSHA Safety and Health Management Systems and Joint Commission Standards to further assist employers to develop comprehensive safety programs (OSHA, 2013). The NIOSH 2004 Alert on HDs and the ASHP 2006 HD Guidelines provide recommendations for similar safety programs that also include these elements (NIOSH, 2004; ASHP, 2006): Standard operating procedures (SOPs) or policy and procedures (P&Ps) that provide a comprehensive safety program to deal with all
aspects of the safe handling of HDs should be in place. These SOPs and P&Ps should address receiving, storage, transport, preparation, administration, spill cleanup, handling HD waste, handling patient waste, and disposal of HDs in order to protect the safety and health of all health care workers who are responsible for handling HDs. The NIOSH HD Alert of 2004, ASHP HD Guidelines of 2006, USP <797> of 2012, and USP <800> of 2016 all address the need to handle HDs using containment facilities, special equipment, and appropriate ventilation (NIOSH, 2004; ASHP, 2006; USP 797, 2012; USP 800, 2016). HD handling areas should be established for sterile and non-sterile compounding: NIOSH, USP, and ASHP recommend that HD compounding be performed in a restricted and preferably centralized area. USP <800> states that sterile and non-sterile HDs should be compounded within a Containment Primary Engineering Control (C-PEC) located in a Containment Secondary Engineering Control (C-SEC) (USP 800, 2016). USP <800> has identified C-PECs as the appropriate ISO Class 5 cabinets for sterile compounding (USP 800, 2016). C-PECs
for compounding sterile HDs include Class II and Class III BSCs and ISO Class 5 CACIs that meet or exceed the standards set in USP <797> (USP 797, 2012). Class II Biological Safety Cabinets (BSC) that meet the current NSF/ANSI standard 49 (NSF 49, 2012) should reduce exposure to HDs during preparation. A study done in 1982 showed that the Class II BSC reduced the exposure of pharmacy compounding staff to HDs as measured by
urine mutagenicity detected by the Ames test (Anderson, 1982). More recent studies, using analytical methods specific to HDs and significantly more sensitive than the Ames test, have shown environmental and worker contamination occurs in HD workplaces despite the use of a Class II BSC (Connor, 1999; ASHP, 2006; Connor, 2010; Wick, 2003). Contamination with marker HDs has been found on the work surface, front lip and grill of the BSC, on areas around the BSC, and on the floor in front of the
Class II BSC. Marker HDs have also been measured in the urine of workers where a Class II BSC is the PEC (Wick, 2003). The exact cause of HD contamination is undetermined and there are a number of issues that could contribute to the apparent failure of the BSC to contain HD residue. When used in a total safety program that includes good work practices, excellent technique, and consistent cleaning and decontamination, Class II BSCs are a valued tool for reducing occupational exposure to HDs during compounding. Per ASHP's 2006 guidelines, workers should 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 HD contamination depends on operators' use of proper technique (ASHP, 2006). Four main types of Class II BSCs are available. They all have downward airflow and HEPA filters. They are differentiated by the amount of air recirculated within the cabinet, whether this air is vented to the room or the outside, and whether contaminated ducts are under positive or negative pressure. These four types are described below: Class III BSCs are totally enclosed with gas tight construction. The entire
cabinet is under negative pressure, and operations are performed through attached gloves. All air is HEPA filtered. All exhaust is to the outside. The exhaust air is treated by double HEPA filtration or single HEPA filtration/incineration. Passage of materials in and out of the cabinet is generally performed through pass-through chambers that can be decontaminated between uses. Class II BSC types A2, B1, or B2 are acceptable for compounding HDs. For most known HDs, type A2 cabinets offer a
simple and reliable integration with the ventilation and pressurization requirements of the C-SEC. Class II type B2 BSCs are typically reserved for use with volatile components (USP 800, 2016). The exhaust fan or blower of the Class II or Class III BSC should be on at all times, except when the cabinet is being mechanically repaired or moved. If the blower is turned off, the BSC should be decontaminated before reuse (ASHP, 2006). Each BSC should be equipped with a continuous monitoring
device to allow confirmation of adequate air flow and cabinet performance. Open front Class II BSCs should preferably be placed in ISO 7 buffer areas with minimal air turbulence (USP 797, 2012). If the Class II BSC is placed in a C-SCA, the beyond use date (BUD) of all compounded sterile preparations (CSPs) so prepared should be limited as described in USP <797> for CSPs prepared in a SCA (USP 800, 2016). USP <797> defines a CACI as a form of isolator specifically designed for compounding pharmaceutical ingredients or preparations, designed to provide worker protection from exposure to undesirable levels of airborne drug throughout the compounding and material transfer processes, and designed to provide an aseptic environment for compounding sterile preparations (USP 797, 2012). Air exchange with the surrounding environment should not occur unless the air is
first passed through a microbial retentive filter (HEPA minimum) system capable of containing airborne concentrations of the physical size and state of the drug being compounded. Where volatile HDs are prepared, the exhaust air from the isolator should be appropriately removed by properly designed building ventilation. USP <797> has specific performance criteria for the CACI (USP 797, 2012): The manufacturer of the CACI should provide documentation that the device will meet this standard when located in environments where the background particle counts exceed ISO Class 8 for 0.5-mm and larger particles. When CACI are used for sterile compounding, the recovery time to achieve ISO Class 5 air quality should be documented and internal procedures developed to ensure that adequate recovery time is allowed after
material transfer before and during compounding operations. CACIs should be certified to CAG-002-2006 or current (CETA, 2008; USP 797, 2012). When a CACI is placed in a C-SCA, the beyond use date (BUD) of all compounded sterile preparations (CSPs) so prepared should be limited as described in USP <797> for CSPs prepared in a SCA (USP 800, 2016). The CACI is no more resistant to HD contamination than the Class II BSC as the same limitations (vial contamination, technique,
cleaning and decontamination) apply. Transfer of contaminated items into or out of the CACI will result in contamination on outside surfaces. The CACI, like all isolators, should have the fixed gloves changed multiple times per day to perform HD compounding. Sleeves, gauntlets, and glove assemblies develop pinholes and other damage and should be monitored for this. As the CACI is negative pressure to the surrounding area, damage to gloves or sleeves will bring particulates into the ISO 5 work
area, creating a risk of microbial contamination of sterile preparations. USP <797> standards and other guidance documents do not exempt the CACI from the use of appropriate PPE for HD compounding (USP 797, 2012; ASHP, 2006; NIOSH, 2004). Gowns and additional gloves should be worn by HD compounders using a CACI. The C-PECs used to compound HDs should be cleaned according to the manufacturer's
instructions. Additional cleaning information may be found in the SDS for specific drugs. Per ASHP, decontamination may be defined as cleaning or deactivating (ASHP, 2006). Per USP <800>, all areas where HDs are handled and all reusable equipment and devices should be deactivated, decontaminated, and cleaned (USP 800, 2016). Sterile compounding areas and devices should be subsequently disinfected (USP 800, 2016). Deactivating a hazardous substance is preferred, but no single process has
been found to deactivate all currently available HDs. The use of alcohol for disinfecting (deactivating microbial contamination) the C-PEC will not deactivate any HDs and alcoholic solutions may result in the spread of contamination rather than any actual cleaning (Sessink, 1992b; Dorr, 1992; ASHP, 2006; Le, 2013). Disinfection should be done routinely when using C-PEC for sterile compounding. Attempts to remove marker HD contamination with detergents and vaporized hydrogen peroxide have
been met with mixed success depending on the HD and the cleaning method (Roberts, 2006). Several studies examining cleaning techniques in HD compounding and administration areas have found residual HD contamination after cleaning in most instances (Acampora, 2005; Hedmer, 2008b; Touzin, 2010; Turci, 2011; Chu, 2011). One study found a commercial sodium hypochlorite/sodium thiosulfate product to be more successful at removing cyclophosphamide (CP) when compared to other cleaning solutions
(Touzin, 2010). Combining various cleaning techniques, however, resulted in even less residual concentration of CP after cleaning was performed (Touzin, 2010). This success in reducing CP contamination, however, may have limited usefulness when attempting to clean other drugs. A recent study of 10 HDs, which were divided into "hydrophilic" or "hydrophobic" groups, assessed the potential of several chemical solutions to decontaminate stainless steel and glass work surfaces (Lamerie, 2013).
The authors chose to test "elimination type" solutions (cleaners), whose main action is to dissolve chemical products on the surface, and "degradation type" (deactivating) solutions, which react with the chemical structure of compounds leading to their degradation and, possibly, the formation of expected non-cytotoxic compounds. Sodium hypochlorite 0.5 percent, a degradation type solution, showed the highest overall effectiveness, with removed 98 percent contamination all 10 drugs from both
surfaces. The authors did not report using detergent or neutralizer with this bleach solution. One elimination type surfactant, dish washing liquid, was found to be an effective cleaning solution (91.5 percent of contaminants removed), but the exact formulation of the solution was unknown. Solutions containing 10-2 M anionic surfactants and 20 percent isopropyl alcohol had the highest global effectiveness at around 90 percent. Their efficacy was the highest for the most hydrophilic
compounds and around 80 percent effective for anthracyclines. Another interesting finding was that adding isopropyl alcohol to surfactant solutions enhanced their decontamination efficiency on the least hydrophilic molecules. Additional research is needed, but this study provides much needed information on the cleaning of C-PECs, as well as drug vials. When cleaning C-PECs, one must ensure that they appropriately rinsed, and that the cleaning and rinsing materials are collected and disposed of
as contaminated waste. Per ASHP, a C-PEC that runs continuously should be cleaned before the day's operations begin, at regular intervals, or when the day's work is completed (ASHP, 2006). For a 24-hour service, the cabinet should be cleaned two or three times daily (ASHP, 2006). Initial decontamination (cleaning) should consist of surface cleaning with water and detergent followed by thorough rinsing. Detergents, as surfactants, may assist in removing HD residue from the C-PEC (Lamerie,
2013). No single accepted method of chemical deactivation for all HDs has been identified (Castegnaro, 1985; Benvenuto, 1993; Castegnaro, 1997). Several studies have shown standard cleaning methods may leave HD residue or result in moving the residue to other areas (Sessink, 1992b; Turci, 2011). Cleaning systems that provide decontamination and deactivation using sodium hypochlorite, detergent, and thiosulfate neutralizer have shown some success (Touzin, 2010). Newer agents, such as high level
disinfectants containing hydrogen peroxide and peracetic acid, may provide alternatives to bleach when used in HD equipment cleaning programs. C-PECs used for sterile compounding should be disinfected routinely, per USP <797> (USP 797, 2012). Class II BSCs and CACIs that have laminar flow in the work area may have a removable work tray as the work surface. The area under this tray should be physically cleaned routinely. USP <800> describes a cleaning process and recommends at
least a monthly clean of this area (USP 800, 2016). The interior of the Class II BSC and the CACI should be thoroughly cleaned and rinsed prior to accessing the area under the tray. During cleaning, the worker should wear PPE similar to that used for spills. The sash on the Class II BSC should remain down during cleaning and the front of the CACI should remain closed. The exhaust fan/blower should be left on. Cleaning should proceed from the least to the most contaminated areas. Any trough area
should be cleaned at least twice since it can be heavily contaminated. All materials from the decontamination process should be handled as HDs and disposed of in accordance with federal, state and local laws (ASHP, 1990; ASHP, 2006). Vial cleaning and decontamination of storage areas should be done routinely to reduce HD residue in the work area. The outer surface of HD vials has been shown to be contaminated with HD residue in numerous studies (Sessink, 1992b; Kiffmeyer, 2000; Connor,
2005; Touzin, 2008; Power, 2014). This residue may transfer to workers when receiving HDs, storing HDs, performing inventory control, selecting HDs for compounding, and all other times when workers interact with potentially contaminated vials. Limited studies have been done to select an appropriate and successful cleaning procedure for HD vials (Touzin, 2008; Lamerie, 2013). Cyclophosphamide (CP) was removed, to varying extents, from vial surfaces by using several methods of wiping with a tissue
wetted with soapy water, followed by a dry wipe and a wipe down with a pre-wetted commercial wiper (Touzin, 2008). A larger study used wipers wetted with selected cleaning solutions to wash off vials of 10 different HDs (Lamerie, 2013). Sodium hypochlorite 0.5 percent solution in water, dish washing liquid in water, and anionic surfactants in 20 percent isopropyl alcohol all achieved greater than 90 percent removal of most of the 10 drugs (Lamerie, 2013). Wiping solutions for both studies were
selected due to their ease of use and lack of toxicity. Though more studies are needed, these methods of wiping HD vials would remove much of the initial contamination and reduce the transfer of HD residue to storage and compounding areas. Storage areas should be cleaned and decontaminated routinely to avoid transfer of HD residue to gloves and other surfaces. Sodium hypochlorite solution, detergent, neutralizer and rinsing have been shown to be effective on hard surfaces (Touzin, 2010). USP <797> notes that a C-PEC used for sterile compounding be certified by a qualified technician every six months using an approved procedure, such as the Controlled Environment Testing Association (CETA)-approved procedure. Contract workers certifying or servicing these devices should be made aware of the HD risks posed by these tasks and should use the same PPE that compounding staff uses when cleaning HD spills (USP 797,
2012). ASHP recommends that BSCs be serviced and certified by a qualified technician every six months, or any time the cabinet is moved or repaired (ASHP, 1990; ASHP, 2006). Technicians servicing these cabinets or changing the HEPA filters should be aware of HD risks through hazard communication training from their employers and should use the same PPE as recommended for large spills. CACIs should be serviced and certified, per the CETA guidance (CETA, 2008). The C-PECs generally used for handling HDs require personal protective equipment (PPE) to provide a barrier between the worker and the HD during episodes of potential contact, and OSHA requires employers to provide and to require the use of PPE that protects employees against the hazards to which they are exposed [29 CFR 1910.132]. Multiple studies show that workers have continued physical contact with HD contaminated surfaces in the many work areas where HDs are
handled. A recent study used pre-moistened tissue to wipe the hands of workers who were preparing or checking HDs, as well as workers who were in the preparation area but were not involved in preparing the HDs (Hon, 2011). Of 18 wipes tested, 28 percent had measurable levels of the marker drugs, including those not directly involved with preparing HDs. A study of ambulatory care oncology nurses was conducted in 2010 to examine self-reported skin or eye contact with HDs during the previous work
year (Friese, 2012). The survey found that the overall rate of exposure to the skin or eyes was 16.9 percent. NIOSH prepared a Workplace Solution in 2009 on Personal Protective Equipment for Health Care Workers Who Work with HDs to provide guidance on the PPE needed to safely handle HDs (NIOSH, 2009). PPE is especially important during administration, spill control, handling of drug waste, and handling of patient waste because no C-PECs are in place for these activities. During sterile
compounding of HDs, barrier garments should be worn to prevent the shedding of human skin and hair cells, and the deposition of mucus or respiratory residue into the compounding area. USP <797> specifies that compounding garb for sterile doses should include the following (USP 797, 2012): NIOSH has recommended the following practices to provide eye and face protection to employees working with HD (NIOSH, 2009): Follow these recommended work practices when wearing gowns: Whenever respirators are used, OSHA's Respiratory Protection Standard (RPS) [29 CFR 1910.134] (OSHA, 2011b) must be followed, which includes requirements for respirator
selection, medical evaluation, fit testing and training. NIOSH and ASHP have provided the following guidance on the selection respirators to protect against exposure to HD: All gowns, gloves, and disposable materials used in HD preparation should be disposed of according to the facility's HD waste procedures and as described under
this review's section on Waste Disposal (Section IV. C.). Goggles, face shields, and respirators, except the filter elements, may be cleaned with mild detergent and water for reuse by wiping reusable items with wetted wipers. Discard all cleaning materials as hazardous waste. In 2004, NIOSH formulated a generic definition to describe a device used in the compounding and administration of sterile HD
doses that was designed to reduce the aerosol and drug residue that may escape during a traditional needle and syringe and open IV set technique (NIOSH, 2004). A "closed system drug-transfer device" is a drug transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapor concentrations outside the system (NIOSH, 2004). This device has been abbreviated in the literature as CSTD, although NIOSH never used this
acronym. A CSTD is classified by FDA as a Class II Medical Device and is cleared through the 510(k) process, which requires a submitted device to have "substantial equivalence" to another legally U.S.-marketed device, commonly known as the "predicate" device (FDA, 2014). The FDA's 510(k) process does not establish independent performance standards for devices submitted as "substantially equivalent." Some CSTDs have been shown to limit the potential for generating aerosols during compounding and
to avoid leakage and disconnects during administration, which results in less measurable HD surface contamination in HD work areas. There are a number of devices marketed as CSTDs but there is currently no performance standard by which all CSTDs are evaluated for containment. Until a protocol or evaluation method is established, users should carefully evaluate performance claims associated with marketed CSTDs (USP 800, 2016). Some CSTDs have been shown in peer-reviewed studies to reduce HD
contamination in the workplace (Connor, 2002; Clark, 2013; Harrison, 2006; Nygren, 2002 b; Nygren, 2008; Nyman, 2007; Sessink, 2011; Sessink, 2013; Tans, 2004; Wick, 2003; Zock, 2011). The persistent presence of HD contamination in compounding and administration areas, despite adherence to HD safe handling guidelines, has generated an interest in supplemental containment controls, especially for administration areas where primary engineering controls are not available. CSTDs are not a substitute
for good work practices or pre-cleaning of HD vials. Worker exposure to HDs may occur in handling both sterile and non-sterile doses. Work equipment for HDs should be suitable for the task and reduce the risk of exposure to the HD. Equipment should either be disposable as HD contaminated waste, or, if reusable, should be able to be decontaminated with a suitable chemical without adding exposure risk to the
worker and contamination risk to the environment (USP 800, 2016). For sterile compounding, only supplies and drugs essential to compounding the dose or batch should be placed in the work area of the C-PEC (USP 800, 2016). BSCs and CACIs should not be overcrowded to avoid unnecessary contamination with HD residue and possible interference with laminar flow for puncturing critical sites (ASHP, 2006; USP 797, 2012; USP 800, 2016). For non-sterile compounding, the ventilated controls should be
cleared of unnecessary supplies to avoid transfer of HD contamination to them during compounding tasks (USP 800, 2016). All items placed in C-PECs should be able to be decontaminated or discarded as HD contaminated waste (ASHP, 2006; USP 800, 2016). Plastic-backed absorbent pads are commercially available and may be used to cover work surfaces in the C-PECs or other areas to absorb HD leaks or small spills. In a Class II BSC, one
study suggested the use of such a pad may interfere with the airflow through the open front or block exhaust grills (Minoia, 1998). Another study determined that a flat, firm pad did not block the grills of the Class II BSC and had no effect on airflow (NuAire, 2003). The use of a pad that is large enough to block the front and/or rear grills of a Class II BSC or a CACI should be avoided. As such a pad may absorb small spills, it may become a source of HD contamination, and that contamination
may be transferred to other surfaces (ASHP, 2006). Preparation pads should be replaced and discarded after the preparation of each batch and frequently during extended batch compounding (ASHP, 2006; USP 800, 2016). Pads that are used outside of the C-PEC should be replaced regularly and monitored for excessive contamination, such as a spill. Preparation pads should be discarded as HD contaminated waste. A small waste/sharps
container may be placed along the sidewall toward the back of the C-PEC as long as it does not interfere with airflow in the ventilated cabinet or negatively impact on the particle count within an ISO 5 PEC (ASHP, 2006). Studies show HD contamination on the floor in front of the Class II BSC could occur when workers reach out of the cabinet to discard waste in receptacles located on the floor (Connor, 1999; Connor, 2010). Closed front cabinets, like the CACI, may have chutes from the cabinet
work area that go directly to waste containers. Waste handling, especially sharps waste, presents a risk of HD exposure. Care should be taken in manipulating sharps at all times. Waste containers stored inside the C-PEC should be sealed and decontaminated before removing from the C-PEC for discard, due to the potential HD contamination on the outside of the container (ASHP, 2006). HD containment bags are a valuable tool for containing contaminated gloves, wipers, preparation pads, and other things that should not be discarded directly into large waste containers. These bags should be sealed and then discarded. As the larger waste containers are frequently not covered, or the cover is opened throughout the day, the containment bag provides additional protection from exposure. ASHP advocates the use of these bags for waste containment and for transport (ASHP, 2006). Transport bags should never be placed in the BSC or the isolator work chamber during compounding to avoid inadvertent contamination of the outside surface of the bag (ASHP, 2006). Use Luer-Lock fittings for all needleless systems, syringes, needles, infusion tubing, and pumps. Luer-Lock fittings avoid separation during use for HD compounding and during administration. Syringe size should be large enough so that they are only 3/4 full when containing the entire drug dose to prevent loss of the plunger during manipulation and to allow space to manage the dose. Per ASHP, many devices labeled as "chemo adjuncts" are currently available (ASHP, 2006). Many feature a filtered, vented spike to facilitate reconstituting and removing HDs during the compounding process. These devices do not lock onto the HD vial, allowing them to be transferred from one vial to another, creating an opportunity for both environmental and product contamination (ASHP, 2006). Many of the "chemo adjunct devices" have large spikes that damage the septum of the HD vials. None of these devices may be considered a CSTD, and none has been formally studied with results published in peer-reviewed journals to demonstrate that they reduce exposure to the worker (ASHP, 2006). NIOSH, ASHP, and USP state that CSTDs (or any other ancillary devices) are not a substitute for using a ventilated cabinet (NIOSH, 2004; ASHP, 2006; USP 800, 2016). Correct work practices are essential to worker protection. Without appropriate compounding work practices, both workers and patients are at risk. Protective equipment and environments should be accompanied by a stringent program of work practices, including operator training and demonstrated competence, contamination reduction, and decontamination (ASHP, 2006).
HDs are administered through many different routes, in several types of settings, and for numerous disease states. Safe handling is required for all HDs no matter how they are used. Precautions include using personal protective equipment, work equipment, and work practices designed for safety.
Patient excreta that is contaminated by HDs should be handled in such a way as to protect health care workers from exposure.
Emergency procedures to address spills or inadvertent release of HDs should be included in the facility's overall health and safety program (ASHP, 2006; USP 800, 2016). Incidental spills and breakages should be cleaned up immediately by a properly protected person trained in the appropriate procedures (ASHP, 2006; USP 800, 2016). The area should be identified with a warning sign to limit access to the area (ASHP, 2006; USP 800, 2016). The circumstances and management of HD spills should be documented (ASHP, 2006; USP 800, 2016). Incident reports should be filed to document the spill and persons exposed (ASHP, 2006; USP 800, 2016). Information should be included in a confidential data base that the organization manages to track exposures as a formal log.
As discussed below in more detail below in the section on Hazard Communication, OSHA's Hazard Communication Standard requires all employees to be trained in the hazards of HDs used their work area, the means used to detect HD presence or release, the procedures employers have implemented to protect employees from HDs, and the employer's hazard communication program [29 CFR 1910.1200(h)]. Staff who may be required to wear respirators must be fit tested and trained in accordance with OSHA's RPS (OSHA, 2011b; NIOSH, 2009). This section summarizes additional published guidance on training for workers in work area where HDs are present. All staff who will be handling HDs should be fully trained in the receipt, storage, handling, and disposal of these drugs (USP 800, 2016). Compounding staff should be trained in the stringent aseptic and negative-pressure techniques necessary for working with sterile HDs. Once trained, staff should demonstrate competence by an objective method, and competency should be reassessed on a regular basis (ASHP, 2006; Harrison, 1996). Per USP <800>, training should occur prior to preparing or handling HDs, and its effectiveness should be demonstrated by HD handling competencies (USP 800, 2016). Personnel competency should be reassessed every 12 months (USP 800, 2016). This training should include didactic overview of HDs, including mutagenic, teratogenic, and carcinogenic properties, and it should include ongoing training for each new HD (USP 800, 2016). USP <800> states that compounding personnel of reproductive capability should confirm in writing that they understand the risks of handling HDs. The training should include at least the list of HDs; review of HD handling policies; proper use of PPE, equipment and devices; response to known or suspected HD exposure; spill management; proper disposal of HDs and trace contaminated equipment (USP 800, 2016). NIOSH recommends that regular training reviews be conducted with all potentially exposed workers in workplaces where HDs are used. Seek ongoing input from workers who handle HDs and from other potentially exposed workers regarding the quality and effectiveness of the prevention program. Use this input from workers to provide the safest possible equipment and conditions for minimizing exposures. This approach is the only prudent public health approach, since safe concentrations for occupational exposure to HDs have not been conclusively determined (NIOSH, 2004). NIOSH also recommends establishing procedures and providing training for handling HDs safely, cleaning up spills, and using all equipment and PPE properly. Inform workers about the location and proper use of spill kits. Make these kits available near all potential sources of exposure. In addition, establish procedures for cleaning and decontaminating work areas and for proper waste handling and disposal of all contaminated materials, including patient waste (NIOSH, 2004). VI. MEDICAL SCREENING AND SURVEILLANCELike workers who are potentially exposed to other chemical hazards in healthcare, such as ethylene oxide and formaldehyde, those exposed to HDs, which include agents known to be human carcinogens, as well as those which are reproductive and developmentally toxic, should be monitored in a medical surveillance program (ASHP, 1990; ASHP, 2006; OSHA, 1995; ISOPP, 2007; Polovich, 2011; NIOSH, 2013). Medical screening and surveillance is one part of a comprehensive approach for minimizing hazardous exposures, which also includes training, engineering and work practice controls, and use of PPE. The purpose of screening is to identify the earliest reversible biologic effects so that exposure can be reduced or eliminated before the employee sustains irreversible harm. The occurrence of exposure-related disease or other adverse health effects should prompt immediate reevaluation of primary preventive measures (e.g., engineering controls, work practices, and use of PPE). Separately, OSHA views surveillance as the formal evaluation of groups of workers; in this manner, medical surveillance acts as a check on the efficiency and appropriateness of controls already in use (OSHA, 2015). For detection and control of work related health effects, screening is typically performed at specific intervals:
In addition to review of individual worker results obtained during a screening, the data obtained should be analyzed in a systematic fashion to allow early detection of disease patterns in groups of workers. Such surveillance requires systematic collection of information and, usually, some form of electronic data management system, ideally with exposure tracking.
VII. HAZARD COMMUNICATIONThis paragraph is for informational purposes only and is not a substitute for the requirements of the Hazard Communication Standard (HCS) [29 CFR 1910.1200] (OSHA, 2012b). Note that the requirements of the HCS are superseded by those of OSHA's Laboratory Standard, 29 CFR 1910.1450, when an employer is engaged in the "laboratory use of hazardous chemicals" (i.e., use of relatively small quantities of hazardous chemicals on a non-production basis), but this document focuses on the HCS requirements that apply to most healthcare employers.
VIII. TRAINING AND INFORMATION DISSEMINATION
IX. RECORDKEEPINGEmployee exposure records, including workplace monitoring, biological monitoring, and SDSs, as well as employee medical records related to drugs posing a health hazard, must be maintained and access to them provided to employees in accordance with 29 CFR 1910.1020 (OSHA, 2011a). That is, records created in connection with HD handling shall be kept, transferred, and made available for at least 30 years, and medical records shall be kept for the duration of employment plus 30 years. In addition, the HCS does not require training documentation, but sound practice dictates that training records should be created, and include the following information:
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[http://labeling.pfizer.com/showlabeling.aspx?id=490#section-11.3]. Yodaiken RE and Bennett D. OSHA work practice guidelines for personnel dealing with cytotoxic [antineoplastic] drugs. Am J Hospit Pharm 1986;43:1193-204 Zock MD, Soefje S, Rickabaugh K. Evaluation of surface contamination with cyclophosphamide following simulated hazardous drug preparation activities using two closed-system products. J Oncol Pharm Pract. 2011;17:49-5 GLOSSARYActive pharmaceutical ingredient (API) - Any substance or mixture of substances intended to be used in the compounding of a drug preparation, thereby becoming the active ingredient in that preparation and furnishing pharmacological activity or other direct effect in the diagnosis, cure, mitigation treatment, or prevention of disease in humans and animals or affecting the structure and function of the body. Alternative Duty - Performance of other tasks that does not include the direct handling of HDs. Ante Area - Transition area between the general area and the segregated area containing the CPEC. Hand-hygiene, garbing, staging of components, order entry and other particle-generating activities are performed in the ante area. For sterile compounding, the ante area should meet ISO 7 characteristics and also provides assurance that pressure relationships between rooms are constantly maintained (USP 797, 2012; USP 800, 2016). Batch - More than one unit of a compounded preparation that is intended to have uniform character and quality within specified limits, prepared in a single process, and completed during the same and limited time period. Beyond-use date - The date or time after which a compounded preparation should not be stored or transported. See Pharmaceutical Compounding - Non-sterile Preparations USP <795> and Pharmaceutical Compounding - Sterile Preparations USP <797> for additional details. Biohazard - A biological agent, such as a virus or a condition that constitutes a threat to humans. Biological Safety Cabinet (BSC) - A ventilated cabinet for CSPs, personnel, product, preparation, and environmental protection having an open front with inward airflow for personnel protection, downward high efficiency particulate air (HEPA) filtered laminar airflow for product and preparation protection, and HEPA filtered exhausted air appropriately removed by properly designed building ventilation for environmental protection. Buffer Area - Part of the compounding area where the primary containment engineering control (CPEC) is physically located. Activities that occur in this area are limited to the preparation and staging of components and supplies used when compounding HDs. Chemotherapy glove - A medical glove that meets the American Society for Testing and Materials (ASTM) Standard Practice (D6978-05(2013)) for Assessment of Resistance of Medical Gloves to Permeation by Chemotherapy Drugs. Cleanroom - A room in which the concentration of airborne particles is controlled to meet a specified airborne particulate cleanliness class. Microorganisms in the environment are monitored so that a microbial level for air, surface, and personnel are not exceeded for a specified cleanliness class (See USP 36, Chapter <1116>, "Microbiological Control and Monitoring of Aseptic Processing Environments," and also the definition of "Buffer Area"). Cleaning - The removal of soil (e.g., organic and inorganic material) from objects and surfaces normally accomplished manually or mechanically using water with detergents or enzymatic products. Closed system transfer device (CSTD) - A drug transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapors concentrations outside the system. Compounded Preparation - A sterile or non-sterile drug or nutrient preparation that is compounded in a licensed pharmacy or other healthcare-related facility pursuant to the order of a licensed prescriber. Compounding personnel - Individuals who participate in the compounding process who are competent and knowledgeable, and responsible for the preparation of HDs, using information from Chapter <797> and <800>, the entity's SOPs, and instructions from the compounding supervisor. Compounding supervisor - The individual who is responsible for developing and implementing appropriate procedures, overseeing facility compliance with Chapter <797> and <800> and other applicable laws, regulations, and standards, ensuring competency of personnel, and assuring environmental control of the compounding areas. Compounding Aseptic Containment Isolator (CACI) - A compounding aseptic isolator (CAI) designed to provide worker protection from exposure to undesirable levels of airborne drugs throughout the compounding and material transfer processes and to provide an aseptic environment for compounding sterile preparations (See USP 797, 2012). Air exchanged from the surrounding environment should not occur unless it is first passed through a microbially retentive filter (HEPA minimum) system capable of containing airborne concentrations of the physical size and state of the drug being compounded. Exhaust air from the isolator should be appropriately removed by properly designed building ventilation. Compounding Aseptic Isolator (CAI) - A primary engineering control designed for use for non-HDs. A laminar airflow workbench (LAFW) or compounding aseptic isolator (CAI) should not be used for the compounding of an antineoplastic HD (USP 800, 2016). Containment Primary Engineering Control (C-PEC) - A ventilated cabinet, designed to establish primary containment and to minimize worker exposures by controlling emissions of airborne contaminants through the following techniques:
A C-PEC may be further defined by its task or use and have other characteristics such as providing ISO 5 air quality in an engineering control used for sterile compounding. Such devices for use with HDs include, but may not be limited to, Class I BSCs (for non-sterile agents only), Class II BSCs, and compounding aseptic containment isolators (CACIs). C-PECs used for sterile compounding should have ISO 5 air quality. C-PECs used for non-sterile compounding do not need to have ISO 5 air quality. Containment Secondary Engineering Controls - The design and operation of the room in which the C-PEC is placed. Restricted access, barriers, special construction technique, ventilation and room pressurization are components of the secondary control strategy. Containment Segregated Compounding Area (CSCA) - A segregated room that is restricted to preparing low-risk HD CSPs with a 12-hour or less BUD or a segregated room that is restricted to preparing non-sterile HDs. Such area should contain a Containment Primary Engineering Control that meets the specifications of USP <797>. Containment Supplemental Engineering Control - Adjunct controls used in concurrence with Primary and Secondary Control Strategies. Supplemental controls offer additional levels of protection and may facilitate enhanced occupational protection as the HD is handled outside of the protective controls of primary and secondary control environments. Containment Ventilated Enclosure (CVE) - A C-PEC used for manipulation of non-sterile HDs. Controlled Environment Testing Association (CETA). CETA, the Controlled Environment Testing Association, is a non-profit trade association devoted to promoting and developing quality assurance within the controlled environment testing industry. http://cetainternational.org/. Deactivation - Treatment of a hazardous drug with another chemical, heat, ultraviolet lights, or other agent to create a less hazardous agent. Decontamination - Inactivation, neutralization, or removal of HDs, usually by chemical means. Disinfectant - A chemical agent that destroys or inhibits the growth of microorganisms that cause disease. Engineering Control - Primary, secondary, and supplemental devices designed to eliminate or reduce worker exposure to a chemical, biological, radiological, ergonomic, or physical hazard. Examples include laboratory fume hoods, retracting syringe needles, sound-dampening materials to reduce noise levels, safety interlocks, and radiation shielding. Entity - A pharmacy, hospital, physician office, clinic, veterinary office, or other location wherever HDs are procured, stored, prepared, dispensed, and distributed to a final user or healthcare personnel who will administer the HD. Expiration date/expiry date -The expiration date identifies the time during which the article may be expected to meet the requirements of the compendia monograph, provided it is kept under the prescribed storage conditions (See USP 34, Labeling in General Notices and Requirements, Section 10.40.100). Globally Harmonized System of Classification and Labeling of Chemicals (GHS) - A system for standardizing and harmonizing the classification and labeling of chemicals. Goggles - Tight-fitting eye protection that completely cover the eyes, eye sockets and the facial area immediately surrounding the eyes and provide protection from impact, dust, and splashes. Some goggles will fit over corrective lenses. Hazard Communication Standard (HCS) - A U.S. government regulation designed to ensure that the hazards of all chemicals produced or imported are classified, and that information concerning the classified hazards is transmitted to employers and employees [29 CFR 1910.1200(a)(1)]. Hazardous Drug (HD) - Any drug identified by at least one of the following six criteria:
Laminar Air Flow Workbench (LAFW) - A primary engineering control designed for use for compounding non-HDs. A laminar airflow workbench (LAFW) or compounding aseptic isolator (CAI) should not be used for the compounding of an antineoplastic HD (USP 800, 2016). Labeling - A term that designates all labels and other written, printed, or graphic matter on an immediate container of an article or preparation or on, or in, any package or wrapper in which it is enclosed, except any outer shipping container. The term "label" designates that part of the labeling on the immediate container [See General Notices and Requirements, 21 U.S.C. 321 (k) and (m)]. Negative Pressure Room - A room that is at a lower pressure than the adjacent spaces and, therefore, the net flow of air is into the room. Personal protective equipment (PPE) - Items such as gloves, gowns, respirators, goggles, face shields, and others that protect individual workers from hazardous physical or chemical exposures. Pharmaceutical product - A commercially manufactured drug or nutrient that has been evaluated for safety and efficacy by the FDA. Products are accompanied by full prescribing information, which is commonly known as the FDA approved manufacturer's labeling or product package insert. Positive Pressure Room - A room that is at a higher pressure than the adjacent spaces and, therefore, the net flow of air is out of the room. Safety Data Sheet (SDS) - An informational document that provides written or printed material concerning a hazardous chemical that is prepared in accordance with the HCS (previously known as a Material Safety Data Sheet (MSDS)). Spill Kit - A container of supplies, warning signage, and related materials used to contain the spill of a HD. Sterilization - A process that destroys or eliminates all forms of microbial life (including spores) and is carried out in healthcare facilities by physical or chemical methods. 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Exposures to pharmaceutical dust at a mail order pharmacy - Illinois. December 2011. Chemotherapy drug evaluation at a veterinary teaching hospital - Michigan. April 2012. Chemotherapy drug exposures at an oncology clinic - Florida. June 2012. Medical Surveillance for Healthcare Workers Exposed to Hazardous Drugs. [DHHS (NIOSH) Publication No. 2013-103]. Department of Health and Human Services. November 2012. Workplace solutions: medical surveillance for healthcare workers exposed to hazardous drugs. [DHHS (NIOSH) Publication No. 2013-103]. Department of Health and Human Services. November 2012. Evaluation of Pharmaceutical Dust Exposures at an Outpatient Pharmacy. [DHHS (NIOSH) Report No. 2010-0078-3177]. April 2013. Evaluation of safety climate, health concerns, and pharmaceutical dust exposures at a mail order pharmacy. [DHHS (NIOSH) Report No. 2012-0044-3199]. Department of Health and Human Services. December 2013. Evaluation of Chemotherapy Drug Exposure in an Outpatient Infusion Center. [DHHS (NIOSH) Report No. 2013-0019-3205]. March 2014. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. [DHHS (NIOSH) Publication No. 2014-138]. Department of Health and Human Services. September 5, 2014. The National Personal Protective Technology Laboratory (NPPTL). Respirator trusted-source information. Section 3: ancillary respirator information. Department of Health and Human Services. September 9, 2014. National Sanitation Foundation (NSF) National Sanitation Foundation. NSF/ANSI 49-2011. Biosafety cabinetry: design, construction, performance, and field certification. Annex E. 2011. Occupational Safety and Health Administration (OSHA) OSHA Summary Publication on Personal Protective Equipment. 2004. OSHA, The Joint Commission, and NIOSH joint letter to hospitals, dated 4 April 2011, on hazardous drugs. A Guide to the Globally Harmonized System of Classification and Labeling of Chemicals (GHS). Occupational Safety and Health Standards: Hazard Communication Resources Page. Occupational Safety and Health Standards: Respiratory Protection [29 CFR 1910.134]. Which PPE must be worn when cutting or crushing hazardous tablets?Manipulating tablets and capsules (cutting, crushing) will increase the risk of exposure to workers. Wear appropriate personal protective equipment including non-permeable gowns and double gloves if a hazardous drug needs to be compounded.
What personal protective equipment is worn for handling hazardous drugs?OSHA's Personal Protective Equipment (PPE) standard [29 CFR 1910.132] requires employers to provide appropriate PPE (e.g., gloves, goggles, splash aprons) for workers who may handle or be otherwise exposed to hazardous drugs.
What is the minimum PPE required when compounding hazardous drugs?Reusable PPE must be decontaminated and cleaned after use. Gowns, head, hair, shoe covers, and two pairs of chemotherapy gloves are required for compounding sterile and nonsterile HDs. Two pairs of chemotherapy gloves are required for administering antineoplastic HDs.
What PPE is required to be worn during chemo compounding quizlet?PPE should include gowns, face masks, eye protection, hair covers, shoe covers or dedicated shoes and double gloving with sterile chemo-type gloves." An N95 respirator is only required when working outside of a control device (e.g., BSC/CACI).
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