Highlighting the Risk of Occupational Exposure to Hazardous Drugs in the Health Care Setting

SPECIAL REPORT: SAFE HANDLING | PART TWO OF A THREE-PART SERIES

For additional information, please read Part 1 and Part 3 of the Safe Handling publication series.

This article is supported by Sun Pharma.

The health care setting has the largest and most diverse array of agents that are hazardous to humans—more than any other occupational setting—ranging from medications that produce acute symptoms to those linked to reproductive toxicity and cancer.¹ As described in

Table 1

, the National Institute for Occupational Safety and Health (NIOSH) defines drugs as hazardous if they exhibit at least 1 of the following characteristics in humans or animals: carcinogenicity; teratogenicity or other developmental toxicity; reproductive toxicity; organ toxicity at low doses; genotoxicity; or, in the case of new drugs, structure and toxicity profiles that imitate existing drugs deemed hazardous by any of the above criteria.²

Commonly used drugs in the health care setting that are classified as hazardous include antineoplastic agents such as chemotherapy; non-antineoplastic agents such as immunosuppressive agents and endocrine receptors; and other miscellaneous drug products.

Table 2

includes a select list of NIOSH-defined antineoplastic and non-antineoplastic drugs used in health care settings and notes their classification of risk.²

Many hazardous oncology drugs, such as alkylating antineoplastic agents (eg, cyclophosphamide), can bind to and cause irreversible DNA damage in humans.² Additionally, drugs other than those used to treat cancer may have toxic properties similar to antineoplastic drugs.² Other chemotherapeutic agents (eg, methotrexate, hydroxyurea, paclitaxel, and fluorouracil), some antivirals (eg, abacavir and ribavirin), anti-epileptic drugs (eg, carbamazepine, valproic acid, and phenytoin), and bioengineered drugs can interfere with cell growth or proliferation, or with DNA synthesis and repair.^1-3 Nonselective actions of these drugs disrupt the growth and function of healthy cells, resulting in toxic effects to health care workers who are inadvertently exposed to hazardous drugs.² For some hazardous drugs, adverse reproductive effects are the primary concern with occupational exposure.² Health care providers conduct a risk versus benefit assessment that occurs prior to patient exposure to treatment with these medications, where the potential therapeutic benefits of hazardous drugs must outweigh the risk of adverse effects. In contrast, exposed health care workers are at risk of these AEs during occupational exposure without any therapeutic benefit.¹

Surface contamination with hazardous drugs in the health care setting may put those who come in contact with a particular site at risk for accidental exposure, which may lead to unintentional AEs.^4,5 Thus, in addition to health care workers who handle hazardous drugs and patients who receive hazardous drugs, adverse effects from hazardous drug exposure may occur in other health care workers and patients who come in contact with the contaminated surfaces. Workplace contamination represents a major risk to health care workers, patients, and their loved ones. If medication vials and the external surfaces of compounded intravenous (IV) hazardous drug products are contaminated, this contamination can transfer to work surfaces. It is likely through this means that healthcare workers are exposed, including those not directly handling the medications. Environmental exposure in health care settings can represent a risk of cross contamination for patients, as well as contamination during visits. However, health care workers are at the greatest risk, as they may be exposed to a variety of agents each day at work, compounded by the decades of their career.^4,5

A NIOSH Alert issued in 2004 warned providers about the risk of AEs with exposure to hazardous drugs, stating that “working with or near hazardous drugs in health care settings may cause skin rashes, infertility, miscarriage, birth defects, and possibly leukemia or other cancers.”¹ Acute health effects reported in hospital workers exposed to hazardous drugs include abdominal pain, nausea, vomiting, diarrhea, coughing, facial flushing, hair thinning, hair loss, dermatitis, irritation of skin and eyes, irritation of mucous membranes, menstrual cycle disruption, and fetal loss.^1,6-9 As evidenced by several studies of health care workers who handle antineoplastic agents, chronic occupational exposures to these drugs have been associated with effects on fertility, reproductive health, and cancer.^1,6,8

A meta-analysis of studies evaluating reproductive health risks of health care workers who handle antineoplastic drugs found an association between adverse reproductive outcomes and occupational exposure to these drugs.⁹ In a multicenter survey of female nurses who worked as oncology nurses or in preselected reference departments (n = 1519), those who were occupationally exposed to antineoplastic drugs had a higher risk of prolonged time to pregnancy compared with nonexposed nurses (adjusted hazard ratio [HR], 0.9; 95% CI, 0.6-0.9), with an increased median time to pregnancy of 1 month. Moreover, nurses who were highly exposed (>0.74 μg/week) to antineoplastic drugs were at an increased risk of delivering a child of low birth weight compared with nonexposed nurses (adjusted odds ratio [OR], 2.1; 95% CI, 0.9-4.7).¹⁰ A historical prospective study of a cohort of female registered nurses from British Columbia, Canada between 1974 and 2000 found a significantly higher risk of congenital anomalies of the eye in the offspring of the nurses who were employed in oncology units or cancer centers compared with other female nurses (adjusted OR, 3.46; 95% CI, 1.08-11.14), and an elevated risk of cleft palate or lip (adjusted OR, 1.84; 95% CI, 0.75-4.49) with exposure that occurred for 10 years prior to the pregnancy.¹¹

HEALTH CARE WORKERS AND OTHERS AT RISK OF EXPOSURE TO HAZARDOUS DRUGS IN THE HEALTH CARE SETTING

In the United States, approximately 8 million health care workers are potentially exposed to hazardous drugs or drug waste at their worksites.¹² Both clinical and nonclinical health care workers as well as patients in any setting where hazardous drugs are handled, may be at risk of hazardous drug exposure and contamination during the life cycle of hazardous drugs—from shipping and receiving, transport and distribution, compounding, administration, and waste disposal (

Figure

).^1,12-14

Clinical health care workers who may be directly and indirectly exposed to hazardous drugs include nurses, pharmacists and pharmacy technicians, physicians and physician assistants, veterinarians and veterinary technicians, and operating room personnel.¹² Pharmacists, pharmacy technicians, and nurses responsible for preparing or administering hazardous drugs have the highest potential exposure to antineoplastic agents.^5,13 However, several studies support that contamination occurs in personnel who are not responsible for compounding or administering hazardous drugs.^5,7,13 Nonclinical hospital staff who may be exposed to hazardous drugs include shipping and receiving personnel, environmental services workers (eg, housekeeping, laundry, and maintenance), and workers involved in the transport or disposal of hazardous drugs or waste (

Figure

).^1,12-14 Patients, caregivers and family members of patients, visitors, and secondary contacts of patients are also at increased risk of unintentional hazardous drug exposure through contact with contaminated surfaces in health care settings or items contaminated with the excreta (eg, urine, stool, and sweat) of patients who received hazardous drugs.^4,13

Potential Routes of Exposure

Exposure to hazardous drugs may be caused by the creation of aerosols or dust, improper cleaning of spills, or touching contaminated surfaces during the preparation, administration, and disposal of hazardous drugs. Contact can occur through several routes, including inhalation, skin contact and subsequent dermal absorption, ingestion, or injection. The most common routes of exposure are skin contact with hazardous drug-contaminated workplace surfaces and inhalation of drug aerosols generated during compounding or administration of hazardous drugs. However, unintentional ingestion from hand-to-mouth transfer of hazardous drug particles or dust and injection from a needle stick or sharps injury are also possible.¹²

Both clinical and nonclinical workers in the health care setting may be exposed to hazardous drugs through various routes during the preparation, administration, or disposal of these agents.¹ High-risk tasks that may expose health care workers to hazardous drugs in the workplace are defined by United States Pharmacopeia (USP) Chapter <800> and are presented in

Table 3

.¹⁴

EVIDENCED HAZARDOUS DRUG EXPOSURE IN THE HEALTH CARE SETTING

Health Care Worker Exposure

Several studies have documented health care worker exposure to antineoplastic agents, as measured with biological end points, including urine mutagenicity, chromosomal damage, and DNA damage.¹ Urinary concentrations of antineoplastic drugs and their metabolites are commonly measured in health care workers as a method of quantifying the occupational uptake of antineoplastic drugs and to provide biomarkers for exposure.^7,15,16

In a meta-analysis of data from 20 studies published between 1992 and 2011 about health care workers who handle antineoplastic hazardous drugs, biomarkers of exposure were found in the urine of health care workers in 17 of the studies. Measurable levels of antineoplastic drugs or their metabolites were found in urine samples of health care workers (eg, pharmacists and nurses), indicating substantial unintended exposure and uptake of antineoplastic agents despite protective measures.¹⁶ Some of the studies reported measurable urinary levels of antineoplastic drugs in as many as 40% to 100% of the health care workers.^7,15

Notably, detectable urinary levels of antineoplastic agents have been reported in health care workers who did not handle and/or administer those antineoplastic agents, implying that environmental contamination with hazardous drugs may be widespread.^15,17 In a study of exposure to antineoplastic agents across different health care occupations and settings, the concentration of nonmetabolized cyclophosphamide was assessed from urine samples (n = 201). The mean urinary cyclophosphamide concentration was 0.156 ng/mL, and more than half (55%) of the total urine samples contained cyclophosphamide levels greater than the limit of detection (LOD) of 0.05 ng/mL. Among the study participants, those who worked in the drug administration unit, but who were not responsible for administering drugs to patients, had the highest proportion of urine samples exceeding the LOD.¹⁷ Moreover, compared to urine samples from health care workers from an acute care setting, urine samples from workers at a cancer center were more often above the LOD and had higher average cyclophosphamide concentrations.¹⁷

Biomarkers of genotoxicity have been measured in exposed health care workers for biological monitoring of the genotoxic effects of antineoplastic agents, including primary DNA damage, chromosomal aberrations, and micronuclei in peripheral blood lymphocytes.^16,18,19 More recent studies have utilized the micronucleus test and comet assay (for primary DNA damage) to quantify the extent of DNA damage caused by occupational exposure to antineoplastic agents.^18-20

The primary concern related to genotoxic effects of antineoplastic exposure is the risk of secondary cancers, namely leukemia.¹⁹ Two recent meta-analyses revealed a significant increase in genotoxic risk among health care workers occupationally exposed to antineoplastic agents.^18,19 A meta-analysis of data from 24 studies published between 1988 and 2015 evaluated the use of the lymphocyte cytokinesis-block micronucleus assay as a biomarker of genotoxic risk in occupationally exposed health care workers.¹⁸ Results demonstrated a significantly increased risk of genotoxicity in health care workers exposed to antineoplastic agents, with a meta-estimate for frequency of micronuclei in peripheral blood lymphocytes of 1.67 (95% CI, 1.41-1.98).¹⁸ A second meta-analysis of data from 17 studies published through February 2017 evaluated chromosomal aberrations and abnormalities in health care workers. When health care workers were compared with control subjects, results demonstrated that occupational exposure to antineoplastic agents was associated with a significantly higher level of chromosomal aberrations, with a pooled standardized mean difference of 1.006 (P <.001).¹⁹

A study evaluated the use of the comet assay in identifying a biomarker of early DNA damage in nurses and pharmacy technicians exposed to low levels of antineoplastic drugs. All health care workers exposed to antineoplastic drugs wore personal protective equipment (PPE). Although statistical significance was not reached, the mean value of exfoliated buccal cells was greater in day hospital nurses compared with the control group of healthy subjects who worked in the administrative office at the same hospital (43.2 vs 28.6; P = .2). The slight increase may indicate early DNA damage in exfoliated buccal cells potentially due to exposure of antineoplastic drugs via inhalation.²⁰

Patient and Community Exposure

Measurable levels of contamination with hazardous drugs have been reported in patient care areas, including floors, tables, and chairs, and other areas throughout the hospital, which unduly increases the risk of exposure through skin contact.^1,13,21 In addition to patients treated in the health care setting, family members and other visitors may also be exposed to hazardous drugs through contact with any contaminated surfaces. Moreover, secondary contacts of patients, who are not directly exposed to contaminated surfaces, may also be at risk of exposure to hazardous drugs. The urine, stool, and sweat of patients treated with certain hazardous drugs may contain varying amounts of these agents, which creates a potential route of exposure for caretakers, family, and friends of patients. In a pilot study from Japan, detectable levels of cyclophosphamide were discovered in urine samples of family members who lived with patients receiving cyclophosphamide, with varying concentrations (range, 17-252 ng per member). Importantly, of 6 family members enrolled, the urine from 4 family members contained comparable amounts of cyclophosphamide to the amount excreted by the patients (≥101.5 ng). This risk of secondary exposure may be attributed to direct and indirect contact with the patient and the lack of appropriate PPE.⁴

Increasing concern for the safety of health care workers and patients who may be exposed to hazardous drugs has prompted further investigation into the extent of occupational exposure in the health care setting and potential methods to reduce the risk of exposure to these agents.¹ Although patients may be exposed to hazardous drugs during a finite treatment period and environmental contamination, health care workers are exposed to multiple agents daily and over decades of their career. However, as detailed later in this article, nonadherence to best practices is a continuing challenge in the health care setting and additional support with commercially available products is needed to minimize exposure.

POTENTIAL OPPORTUNITIES FOR EXPOSURE TO HAZARDOUS DRUGS DURING HIGH-RISK OCCUPATIONAL ACTIVITIES IN THE HEALTH CARE SETTING

Occupational Activities Associated With Exposure Risks Compounding

Pharmacists and nurses who prepare hazardous drugs and administer them are the 2 occupational groups who have the highest potential exposure to antineoplastic agents. The risk of occupational exposure to oral hazardous drugs varies depending on the formulation and the tasks required to prepare and dispense the doses.^2,14,22 Certain oral hazardous drugs may not directly pose substantial risk of occupational exposure because of their formulation (eg, coated tablets or capsules); however, exposure risk may increase when formulations are manipulated.^2,14 For example, coated tablets or solid capsules of intact medications that are administered to patients without modification of the formulation are associated with less exposure risk compared with formulations that are altered, such as those that require the compounding of potent powders into custom-dosage capsules or the crushing of tablets for oral solutions.^23,24

Compounding of hazardous drugs into their final dosage form may generate aerosols or dust particles that may result in surface contamination and occupational exposure.^1,22 Crushing tablets, opening capsules, and other drug manipulations outside of a controlled environment may cause contamination of the site with hazardous drug residue and increase the risk of inhalation or skin contact.^14,22 Pressed-powder uncoated tablets (eg, methotrexate) may present a risk of exposure from dust when the tablets are counted either manually or in automated dispensing machines, as this liberates dust particles causing surface contamination and creating airborne drug dust that can be directly inhaled by employees and can contaminate the work area.¹⁴

Many hazardous drugs require reconstitution, transfer from one container to another, or other manipulations during preparation and dispensing.^1,6 Powdered or lyophilized drugs may also require reconstitution or further dilution of concentrated liquid forms of hazardous drugs.²⁵ Manipulations such as using syringes and needles for drug transfer, breaking open ampules, and expelling air from syringes may result in hazardous drug residue escaping by splattering, spraying, or aerosolizing. Several studies documented that hazardous drug residue was found on IV bags and PPE, such as gloves and gowns.^1,6 Even with precautionary measures, the opportunity for absorption through inhalation or direct eye or skin contact exists.⁶ Other activities that may be high risk during compounding include pouring liquids, weighing/mixing components, and withdrawing drugs from containers.

Administration

Administration of hazardous drugs poses a potential risk of occupational exposure for every route of administration (eg, parenteral, oral, and topical).⁶ Routes of administration for injectable hazardous drugs, including intramuscular, subcutaneous, IV, intraperitoneal, and intrathecal routes, carry the additional risk of exposure through unintended self-needle stick, puncture injury, or vial breakage, especially during complex and specialized procedures such as intraperitoneal or intrathecal injections.^1,6

Because aerosols may be generated during the administration of drug, by direct IV push or IV infusion, or when expelling air from syringes filled with hazardous drugs, patients and health care workers may be exposed to unnecessarily high amounts of hazardous drugs during treatment, especially if there are any deviations from normal procedures. To prevent additional patient exposure to hazardous drugs, nurses administering medications in the uncontrolled environment at the patient bedside, including the priming or spiking of IV sets with hazardous drug solutions for use at the patient bedside should be performed inside the primary engineering controls available in the pharmacy setting.^1,22

Leakage of hazardous drugs during administration (eg, connecting/disconnecting tubes or syringes) can lead to contamination of work surfaces and administration apparatuses, which increases the risk of patient and occupational exposure to hazardous drugs via dermal and hand-to-mouth contact.^1,6 Contamination may also occur during the dispensing of drugs in prepared dosage forms (eg, tablets and capsules) or administering drugs orally, topically, or via nebulizer or inhaler to patients.

Spill Generation, Spill and Waste Management, and Disposal

Health care workers may also be exposed to hazardous drugs when handling bodily fluids or bodily fluid-contaminated materials from patients who received hazardous drugs.^1,6 Proper handling and disposal of bodily fluids or contaminated clothing, dressings, linens, and other materials should be performed to limit occupational exposure to hazardous drugs.¹

To appropriately handle hazardous drug spills or contaminated bodily fluids, exposed surfaces should be deactivated, decontaminated, and disinfected. Contaminated materials that may result from a spill or during clean up should be treated as hazardous waste. As best practice, health care workers should be familiar with appropriate spill procedures.⁶ Settings that may be exposed to hazardous drugs and require cleaning and decontamination include the compounding area, pharmacy, nursing station, patient room, and hallways. Collection and disposal of hazardous drug materials, including PPE used to handle hazardous drugs or antineoplastic drugs, should be handled in accordance with federal, state, and local laws.⁶

ENVIRONMENTAL AND SURFACE CONTAMINATION WITH HAZARDOUS DRUGS

Environmental Contamination

Environmental contamination of areas where hazardous drugs are prepared, administered, and handled in health care facilities has been extensively studied in the United States and several other countries.^1,6 Environmental studies of patient care areas have documented measurable concentrations of drug contamination, even in facilities thought to be following recommended handling guidelines. Environmental monitoring studies of health care facilities have continually found measurable levels of hazardous drugs in the air, on surfaces, on PPE, and on workers.¹⁸

Environmental contamination may arise from contact with measurable concentrations of drugs present on drug vial exteriors or with final drug products, such as bottles, bags, and syringes, after preparation or compounding as exteriors of these products may be contaminated during preparation. Some of the highest concentrations of contamination have been found inside the biologic safety cabinets (BSCs) and the floor directly in front of them. Contamination can also occur on numerous surfaces, including counters, floors, cabinets, drawers, hallways, elevators, sinks, workstations, paperwork (eg, charts, discharge papers, and prescriptions), bins for drug storage or transport, and personal items belonging to health care workers or patients. Additionally, spills or waste from hazardous drugs or waste from patients who have been treated with hazardous drugs may also contaminate areas within a health system.^8,13,15,22

Widespread contamination of work surfaces makes the potential for skin contamination highly probable in pharmacy and patient areas. Contaminated surfaces can be found in several health care settings, including the storage and compounding areas of the pharmacy, nursing carts or stations, and patient rooms or patient care areas.¹ Surface contamination with hazardous drug residue is a common source of occupational exposure.⁶ Since the 1990s, numerous studies have documented that work areas where hazardous drugs are stored, mixed, administered, and wasted are contaminated with measurable levels of hazardous drug residue.^6,15 Surface contamination with hazardous drugs can occur at every stage of the hospital medication system—from receipt, transport, and storage of hazardous drugs to preparation, administration, and disposal of hazardous drugs and bodily fluids/waste from patients who have received hazardous drugs.^1,13 More recent studies have revealed that hazardous drug contamination is widespread in health care settings, even where primary compounding controls are used.^13,15,16,22

The concern for persistence of contamination and personnel exposure to antineoplastic agents is well documented. In a study by Wick et al, 20% of urine samples collected from health care workers had detectable levels of ifosphamide, including samples from those who were not directly involved in compounding. Urine samples were collected over a 2-week period, and the last time ifosphamide was compounded in the pharmacy was over 3 weeks prior to the start of urine testing. The results of this study suggest that the pharmacy was a substantial source of indirect contamination with enough magnitude to yield positive biomarkers of exposure above the level of detection.²⁶

Hazardous Drug Surface Contamination Is Prevalent in the Pharmacy Setting

In a study of 3 university hospital-based cancer centers across the United States, wipe samples were used to determine detectable concentrations of hazardous drugs in various locations. These areas included BSCs, surfaces, floors, countertops, checking areas, and locations adjacent to drug handling spaces within pharmacy areas. Patient or nursing areas included counters, floors, carts, drug storage units, waste receptacles, and tables and chairs in patient treatment areas. Detectable concentrations of at least 1 of the 5 antineoplastic drugs evaluated (cyclophosphamide, ifosfamide, fluorouracil, paclitaxel, and cytarabine) present on wipe samples from pharmacy areas showed a higher level of surface contamination and higher concentrations of contamination compared to wipe samples from nursing and patient areas.¹⁵ Antineoplastic drug handling events in pharmacy, nursing, and patient areas may provide insight into high-risk activities that may lead to greater levels of contamination in the pharmacy. Compounding and checking of the drug are exclusive to pharmacy, whereas priming, spills, and splashes may occur in pharmacy, nursing, and patient areas.¹⁵ Notably, each cancer center followed current recommendations for safe-handling practices in compounding and administering antineoplastic agents as recommended by NIOSH, in addition to using engineering controls such as BSCs and closed-system drug transfer devices (CSTDs) for preparing antineoplastic drugs.¹⁵ CSTDs are pieces of equipment that contain hazardous drugs when they are transferred from one container to another (eg, from vial to syringe or IV container). This confirmed previously reported findings that little progress has been achieved in reducing hazardous drug contamination in health care settings, despite the use of safe-handling practices and proper engineering controls.^15,22

In a multi-site study, antineoplastic drug surface contamination was assessed across 5 major acute care hospitals and 1 cancer treatment center. Levels of hazardous drugs were measured by surface wipe samples, using cyclophosphamide as the marker drug, at each of the 6 steps in the medication process where dermal exposure is the primary route of occupational exposure to antineoplastic drugs: (1) delivery of the antineoplastic drugs to the facility; (2) drug preparation; (3) transport to the floor; (4) drug administration; (5) disposal; and (6) waste management.¹³ Notably, the pharmacy compounding areas had the greatest number of highly contaminated surfaces and the highest concentration of cyclophosphamide contamination. The surfaces with the highest frequency of contact were the BSCs in the compounding area and the IV pumps in the infusion area where the hazardous drugs were administered.¹³

Widespread Prevalence of Contamination in the Health Care Setting

Patients and heath care workers who do not directly handle hazardous drugs and antineoplastic agents are at risk of unnecessary exposure through environmental contamination. The risk of dermal and surface exposure to antineoplastic drugs may be possible through the contamination of surfaces by administration nurses and pharmacy personnel. In a recent study designed to assess the dermal contamination levels of cyclophosphamide across a range of health care job categories, researchers swabbed workers’ hands and found that volunteers, oncologists, dieticians, and aides who worked in a unit where cyclophosphamide was administered had exposure that was equal to that of the nurses who directly handled the drugs.⁵ In a second study, researchers further explored exposure risk to cyclophosphamide by health care workers not involved in the direct handling of antineoplastic drugs. Cyclophosphamide was detected in the urine of workers whose duty is to handle antineoplastic drugs. However, the highest proportion of samples that exceeded the LOD for cyclophosphamide came from participants (eg, volunteers, oncologists, ward aides, and dietitians) who worked in the drug administration unit but who were not responsible for administering drugs to patients.¹⁷ The results of these studies highlight the risk of exposure to antineoplastic drugs throughout institutions and demonstrate that this risk encompasses a wide array of health care workers. Subsequent studies have reported that surface contamination with hazardous drugs may be more widespread than just the pharmacy and nursing areas, but throughout the health care facility.¹³ This finding implies that surface contamination not only puts those who handle hazardous drugs at risk but also any health care worker who comes in contact with a contaminated surface. In addition, patients and visitors may potentially be at risk if surface contamination in patient care areas spreads to communal areas.^1,5,7,13

Contamination From Manufacturing

External contamination of vials and packaging containing hazardous drugs starts at the site of manufacturer. Safe handling precautions begins with receiving products, and ensuring that proper education includes at least wearing gloves before touching these containers, including administering oral medications.^22,27 Results from several studies have demonstrated that the outer surfaces of vials of many commercial hazardous drugs are contaminated prior to arrival in the pharmacy.^22,27,28 Contamination extending to packing cartons, package inserts, and shipping totes has also been reported.^22,29

Contamination of the exterior surface of hazardous drug vials is a safety concern in hospitals worldwide.²⁷ Several European studies found varying levels of contamination on the surfaces of vials after receipt from the manufacturer, prompting similar studies in the United States.^30,31 The results of 3 subsequent US studies showed comparable external contamination of antineoplastic drug vials from the manufacturer, with cyclophosphamide, ifosfamide, fluorouracil, or cisplatin detected on sampled vials.³⁰ Reasons for contamination could be associated with leakage during filling, inadequate vial cleaning after filling, or accidental leakage during transport and distribution.^22,27

Commercially manufactured hazardous drugs may be associated with the potential for contamination due to leakage or breakage, especially in the case of glass vials. The International Society of Oncology Pharmacy Practitioners (ISOPP) issued standards of practice in the safe handling of cytotoxics, which advise that hazardous products be supplied in vials made of unbreakable plastic or in glass vials protected by an overlay of plastic. ISOPP also recommends that care be taken during packaging and transportation of hazardous drugs.³² Although manufacturers of hazardous drugs have explored methods for reducing the risk of surface contamination, precautionary measures, such as donning PPE and unpacking materials in neutral or negative pressure areas, should still be taken when opening the outer packaging of hazardous drug products.^22,27

Microbial Contamination

Concern exists regarding microbial contamination of drug products either at the site of manufacture or during the preparation or administration of sterile hazardous products.³³ Aseptic manufacturing is employed to mitigate the risk of contamination from the environment and from operating personnel, both of which have the potential to introduce pathogens into the finished drug product.³⁴ Manually compounded sterile preparations of antineoplastic agents pose an additional risk for microbial contamination to patients, because the compounding process has the potential to introduce pathogens into the final drug product at any step, such as during reconstituting, combining, mixing, diluting, pooling, or administering. Commercial products supporting aseptic processes are essential to prevent microbial contamination of parenteral drug products from manufacture to final use in the health care setting.³³

NONADHERENCE TO BEST PRACTICES FOR REDUCING CONTAMINATION AND EXPOSURE

The first publication in this series, Current and Future Considerations for the Safe Handling of Hazardous Drugs, published in March 2018, discussed guidelines and regulations on the safety and handling of hazardous drugs, including the enforcement of USP General Chapter <800> (expected effective date: December 1, 2019). The following section details both the real-world application of guidelines and regulations and the barriers to adherence to best practices for reducing contamination and exposure.

Given the complexity and interdisciplinary nature of hazardous drug preparation and administration, the risk of error is considerable and the consequences can substantially affect the health of all patients and health care workers involved.³⁵ Precautionary guidelines for the safe handling of hazardous drugs in health care settings have been promulgated and updated by various government agencies, such as the Occupational Safety and Health Administration, and professional associations, such as the American Society of Health-System Pharmacists, to reflect current literature and best practices over the past 3 decades.^6,22 Although safe handling practices to reduce the risk of occupational hazards have improved since the publication of the first guidelines, adherence to safe handling practices has been less than ideal.^8,16,36-38

To characterize current practices in the handling of hazardous drugs and identify barriers to adherence to the use of protective measures, NIOSH collaborated with health care professional practice organization to conduct a nationwide survey of health care workers who regularly came in contact with selected hazardous drugs. The Health and Safety Practices Survey of Healthcare Workers, which was an Internet-based survey that took place in 2011, was designed to gather data about the scope and circumstances surrounding health care worker exposure to hazardous drugs in the workplace. Over a period of 2 months, more than 12,000 health care workers were enrolled across 21 health care professional practice organizations, including nurses, technicians, technologists, anesthesiologists, dentists, dental hygienists, respiratory therapists, pharmacists, and pharmacy technicians. Respondents were included if they came into contact with at least 1 targeted hazardous chemical within the previous 7 calendar days. The survey consisted of a screening module, a core module, and 7 hazard modules; each respondent could complete up to 2 hazard modules.³⁹ The Health and Safety Practices Survey of Healthcare Workers was the largest federally sponsored survey of its kind, and the information collected provided valuable data for subsequent analyses of specific subgroups of workers.^36-39

An analysis of the data collected from the hazard module of the Health and Safety Practices Survey of Healthcare Workers that focused on administration of antineoplastic agents was conducted. The main objective of this module was to characterize antineoplastic drug administration practices and to identify the magnitude of use of exposure controls and impediments to PPE use among susceptible health care workers who administer these drugs. A total of 2069 respondents completed the survey, and demographic data was available for 1954 (94%) respondents. Although the survey was available to any health care worker who administered antineoplastic drugs, the majority of respondents (98%) were nurses. Results from the analysis revealed a lack of universal adherence to safe handling guidelines by health care workers, including inconsistent compliance with guideline recommendations for activities that were associated with increased exposure risk to hazardous drugs. PPE use was especially deficient. While most respondents (85%) reported always wearing chemotherapy gloves, only 20% always wore double gloves. Additionally, almost 80% of respondents admitted to never wearing eye or face protection, and over 90% stated that they never wore respirators, shoe covers, or head covers. Respondents also reported that IV tubing arrived from the pharmacy without being primed in about 20% of cases, which often led to the IV tubing needing to be primed at the bedside prior to administration. Researchers concluded that the failure of health care workers to adhere to recommended safe handling practices increased the risk of contamination of work surfaces, which placed other health care workers and patients who may come in contact with these surfaces at an unnecessary risk of exposure.³⁷

A separate evaluation was conducted to analyze the information collected from the hazard module of the Health and Safety Practices Survey of Healthcare Workers that focused on compounding of antineoplastic agents. This hazard module focused on describing antineoplastic compounding practices with the goal of better understanding current practices in exposure control and barriers to using PPE among health care workers who compound and handle antineoplastic drugs. Because this hazard module focused on compounding, which is a task that more often involves pharmacists, pharmacists comprised a larger proportion of this survey population than the previous module. A total of 424 respondents completed this module, including 241 nurses and 183 pharmacists and pharmacy technicians.³⁶ Although the use of BSCs and designated compounding rooms was common (in the range of 75% to 90% among both nurses and pharmacy personnel, use was not universal. When transfering liquid antineoplastic drugs from vials to infusion bags, approximately one-third of pharmacy personnel and almost half of nurses reported that they did not use CSTDs, a needleless system, or glove boxes.³⁶ Although training and education are considered fundamental administrative controls, 9% of nurses and 13% of pharmacy practitioners reported that they had never received training in the safe handling of antineoplastic agents, and nearly half of respondents stated that they had not received training in safe handling within the previous 12 months.³⁶ Rates of noncompliance to recommendations for the use of PPE (eg, chemotherapy gloves and gown) were consistent with reports from prior studies.³⁶ Troublingly, respondents admitted to many risky practices that deviated from the safe handling guidelines, such as reusing gloves, contacting various work surfaces with gloves after handling antineoplastic drugs, not always changing gloves that were damaged or contaminated, and not always washing their hands after removing gloves.³⁶ These practices unnecessarily increase the risk of hazardous drug exposure for all health care workers who come in contact with those surfaces, including coworkers who are not involved in antineoplastic drug compounding.³⁶

Both hazard modules gathered information about reasons for noncompliance with safe handling guideline and recommendations. Some of the most common reasons reported by respondents to these two modules were the belief that exposure risk was minimal and that safe handling guidelines were not part of their institution’s protocol. For pharmacy practitioners specifically, a common reason reported for not wearing protective gowns was the erroneous belief that engineering controls (eg, BSC or isolator) precluded the need for such measures.³⁶ These responses suggest a lack of awareness of the substantial risk of exposure to antineoplastic drugs within manyhealth systems.^36,37

In response to growing concern regarding the lack of universal adherence to safe handling guidelines, many researchers have sought to identify common barriers to adherence. These studies often highlight an unmet need for comprehensive training and education about the risk of exposure to hazardous drugs, the availability of PPE and engineering controls to reduce the risk of exposure to hazardous drugs, and factors that contribute to a safer work climate.^36,38,40-42 Addressing barriers to adherence to safe handling guidelines is essential to improve the safety of health care workers exposed to hazardous drugs, especially with the impeding enforcement of USP General Chapter <800>.⁴³

Results from several studies among pharmacy practitioners who handle antineoplastic drugs demonstrate a general lack of adherence to safety guidelines and gaps in best practices leading to exposure. In a study of compliance to USP General Chapter <800> from a single institution, the University of North Carolina Medical Center (UNCMC) recently implemented a USP General Chapter <800> pharmacy-led collaborative initiative in an effort to foster safety for patients and workers and achieve hospital compliance with USP General Chapter <800> prior to its effective date.⁴³ Assessment of baseline compliance with USP General Chapter <800> prior to implementation of policy changes revealed that the 2 areas with the highest volumes of hazardous drug handling had 51% compliance with USP General Chapter <800> at baseline.⁴³ The study identified 3 major areas of noncompliance: (1) outdated policies and procedures regarding development and maintenance of a hazardous drug list; (2) inconsistent and outdated policies on the preparation, administration, and delivery of hazardous drugs; and (3) omission of detailed policy and procedures regarding receipt of hazardous drugs.⁴³ With months of preparation and interdepartmental collaboration, the medical center was able to update their policies and procedures to align with the requirements of USP General Chapter <800>.⁴³ Although the UNCMC encountered several operational, clinical, and financial challenges, they found that the pharmacy department-led compliance collaborative allowed departments to align while implementing standards that would improve patient and worker safety.⁴³

TECHNOLOGIC ADVANCES TO IMPROVE SAFETY AND REDUCE UNINTENDED EXPOSURE

Given the growing awareness of occupational hazards associated with exposure to hazardous drugs, regulations and guidelines are rapidly evolving to incorporate emerging data pertinent to the safety of health care workers who are exposed to hazardous drugs.⁴⁰ In line with efforts to reduce occupational exposure to hazardous drugs, technological advances in engineering controls are also emerging. For example, CSTDs and other containment supplemental engineering controls have been developed over the past 2 decades.²² Supplemental engineering controls have adjunct controls that provide additional protection during compounding or administration, which are recommended in addition to required containment primary and secondary engineering controls by USP General Chapter <800> guidelines.¹⁴ Studies have shown that the use of supplemental engineering controls in addition to primary and secondary engineering controls has the potential to reduce spills and leaks, thereby reducing the risk of contamination and occupational exposure.^38,44

Evidence supporting CSTD use with hazardous drugs has demonstrated reduced surface contamination and possibly worker exposure; however, CSTDs do not eliminate exposure risks entirely.^14,22,45,46 Given that CSTDs are relatively novel, USP General Chapter <800> and relevant guidelines caution that there is no certainty that all CSTDs will perform adequately and, until a universal performance standard for evaluation of CSTD efficacy is available, professional judgement should be used when evaluating performance claims.¹⁴

Manufacturers continue to research innovative systems that further reduce the risk of contamination during preparation and administration of hazardous drugs. To reduce the possibility of microbial contamination of parenteral drug products, pharmaceutical companies have access to technology that supports aseptic processing at the site of manufacture, essentially eliminating the risk associated with this step in the process. Commercial products are designed to support the sterile filling of final packaging for pharmaceutical products, including vials and infusion bags. Studies examining the effectiveness of INTACT technologies confirm their utility in preventing microbial contamination of drug products by the manufacturer.⁴⁷

Technological advances in manufacturing, such as ready-to-administer (RTA) products may offer solutions to many problems associated with the use of hazardous drugs in the health care setting. RTA products may alleviate the contamination problems associated with compounding hazardous drugs by eliminating the need to transfer hazardous drugs from primary packaging or vials to IV bags. RTA products may also reduce the risk of contamination from spills and leaks during administration by reducing the number of steps needed to administer the hazardous drug. Infugem (gemcitabine) is an RTA infusion of gemcitabine that eliminates the need for reconstitution and dilution of drug prior to administration. Infugem eliminates the issue of unintended exposure to this hazardous drug during preparation of IV infusions. Infugem is supplied in premixed infusion bags containing 10 mg/mL of gemcitabine in 0.9% sodium chloride for IV use. It does not require any further preparation and reduces the possibility of medication errors, especially with regard to concentration and dosing.⁴⁸ This RTA product eliminates the possibility of microbial contamination during the preparation process. Infugem is supplied as a sterile solution in a singledose premixed IV infusion bag with aluminum overlap. Because gemcitabine is a cytotoxic drug, special handling and disposal procedures should be followed, including wearing gloves and exercising caution.⁴⁸

CONCLUSIONS

Compared with any other occupational setting, the health care setting uses the largest and most diverse array of agents that are hazardous to humans. Both clinical and nonclinical health care workers as well as patients may be at risk of hazardous drug exposure and contamination during the life cycle of hazardous drugs. Moreover, contamination with hazardous drugs may extend beyond pharmacy and nursing areas to the entire health care facility. Patients, caregivers and family members of patients, visitors, and secondary contacts of patients are also at increased risk of unintentional hazardous drug exposure through contact with contaminated surfaces or items contaminated by patients who received hazardous drugs. Nonadherence to safe handling guidelines is a continuing challenge in the health care setting. Many studies have demonstrated a lack of compliance among health care workers to guideline recommendations, leading to increased exposure risk. Addressing barriers to adherence of safe handling guidelines is essential to improve the safety of health care workers exposed to hazardous drugs, especially with the upcoming implementation of USP General Chapter <800>. Technologic advances, such as RTA products, may offer solutions to improve safety and reduce exposure risk with hazardous drugs in the health care setting.

Jeffrey Lombardo, PharmD, BCOP, is a research assistant professor at the Center for Integrated Global Biomedical Sciences, Translational Pharmacology Research Core, at the University at Buffalo School of Pharmacy and Pharmaceutical Sciences in New York.Christine Roussel, PharmD, BCOP, is the director of pharmacy at Doylestown Hospital and an adjunct professor at University of the Sciences in Philadelphia in Pennsylvania.

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