Current and Future Considerations for the Safe Handling of Hazardous Drugs

Occupational exposure to oncology medications and other hazardous drugs has been a mounting public health concern for several decades. Health care workers may be exposed to hazardous drugs while preparing, administering, or disposing of drugs or while handling bodily fluids of treated patients.

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Occupational exposure to oncology medications and other hazardous drugs has been a mounting public health concern for several decades.1,2 According to the National Institute for Occupational Safety and Health (NIOSH), more than 5.5 million workers may be exposed to hazardous drugs in the United States.3 Other estimates suggest that about 8 million US health care workers may be exposed to hazardous drugs every year.4 These estimates include shipping and receiving personnel, pharmacists, and health care workers.3 Hazardous drugs are defined as chemicals that exhibit 1 or more of the following characteristics: carcinogenicity, genotoxicity, teratogenicity, reproductive toxicity, or organ toxicity.5 Many antineoplastic drugs, antiviral agents, bioengineered drugs, and antibiotics interrupt cell growth or DNA synthesis, causing adverse reproductive effects in patients and medical professionals.6 Health care workers may be exposed to hazardous drugs while preparing, administering, or disposing of drugs or while handling bodily fluids of treated patients.5 Often, needlestick injuries or contaminated or broken vials/ampoules are sources of hazardous drug exposure.7 Results from several studies have detected metabolites of chemotherapy drugs in the urine of health care workers, confirming that hazardous drug exposure is a widespread problem.7

Exposure to hazardous drugs may cause acute and chronic health effects. Acute effects include skin irritation, hair loss, nausea, liver and kidney damage, hearing loss, cardiac toxicities, and decreases in blood cell counts.8 Adverse skin effects are common.7 For example, a health care worker developed a rash after emptying containers of urine from oncology patients treated with vincristine and doxorubicin.9 Both drugs are associated with localized and systemic allergic reactions in patients and health care workers handling the medications.9

There are fewer studies of chronic health effects associated with hazardous drug exposure in health care workers, but the chronic effects in patients treated with these are better known.8 It was the observation of secondary cancers in treated patients that triggered concerns about health care workers involved in handling anticancer drugs.2 According to National Cancer Institute data from 1973 to 2000, cancer survivors have a 14% greater risk of developing a new malignancy compared with the general population.10 Many individuals who develop a new cancer do so in a separate organ system than the first cancer. This suggests that cancer treatments are potentially carcinogenic.10 Other chronic health effects include those affecting reproductive and fertility outcomes in men and women. Most of the medications on the NIOSH list of hazardous drugs negatively affect the reproductive system, and many can be passed through breast milk. Because many antitumor drugs prevent cell division, the danger to a rapidly growing fetus can be considerable.2 For women, exposure to antineoplastic drugs may cause damage to ovarian follicles, decreased ovarian volume, and ovarian fibrosis, which may lead to amenorrhea and menopausal symptoms.11 Pregnant women should be especially careful to avoid exposure to hazardous drugs. One study demonstrated an increased risk of spontaneous abortion in nurses who reported occupational exposure to antineoplastic drugs compared with nurses who did not report such exposure.12 Men may experience primary or secondary hormonal changes and can pass hazardous drugs to a female or a developing fetus via contamination on clothing or skin or during sexual intercourse.11

Current guidelines suggest that a comprehensive safety program is necessary to reduce hazardous drug exposure in the workplace. A successful safety program should integrate personal protective equipment (PPE) with administrative, engineering, and work practice controls.13 Recent updates to the United States Pharmacopeia (USP) Chapter General <800> will require implementation of additional safety standards for hazardous drug handling. These updates aim to improve safety for all health care workers.13 However, safety practice gaps are problematic. A recent online NIOSH survey investigated current practices used to reduce chemical exposures.13 Overall, survey results showed deficiencies in training and in awareness regarding procedures and national guidelines. Survey results also indicated that health care workers do not always adhere to hazardous drug safety guidelines.13

HANDLING OF HAZARDOUS DRUGS

Hazardous drugs pose exposure and health risks to health care workers involved in drug preparation and administration. Millions of medications are compounded each year in the United States. Compounding is often necessary to obtain tailored dosages of a drug or for the treatment of rare diseases.14 By providing access to individualized medicine, pharmacy compounding plays an important role in treating patients with unique medical needs.15 Thus, guidelines to protect pharmacy workers involved in the compounding of nonsterile and sterile preparations containing antineoplastic drugs were put into standard pharmacy practice in 2007.16 In general, the guidelines recommend the use of engineering controls, administrative controls, work practice controls, and PPE to reduce occupational exposure to hazardous drugs.16

Both the USP and the International Society of Oncology Pharmacy Practitioners (ISOPP) publications on standards of practice for the safe handling of hazardous drugs discuss the above categories of safety controls at length. There is a hierarchy of efficiency in these protection measures. The top level recommends the elimination or substitution of the hazardous drug. However, this is not often feasible with antineoplastic drugs.16 Engineering controls, such as biological safety cabinets, isolators, or ventilation tools that filter or control airflow, are another line of protection.17 Administrative controls include organization of work so that the number of workers exposed to a hazard is reduced or the duration of exposure is decreased.17 PPE is considered the lowest (ie, most basic) level of protection; it is to be used after other control measures have been tried and/or found to be insufficient. According to the USP, appropriate PPE, such as gloves, masks, gowns, goggles, and face shields, should be used during all phases of hazardous drug handling. These include receipt, storage, transport, compounding, administration, decontamination, and waste disposal.18 The ISOPP guidelines highlight using PPE made from materials proven to block the substance(s) in question. This knowledge is preferably gained by thorough testing of the PPE, taking into account the activities that will be performed and environmental conditions such as temperature.17

US guidelines on the safety and handling of hazardous drugs have been updated. The revised version of USP General Chapter <800>: Hazardous Drugs — Handling in Healthcare Settings is expected to become official on December 1, 2019.18 Building on 2008 USP standards, USP General Chapter <800> aims to protect all health care workers (including those in the veterinary field), patients, and the general public from hazardous drug exposure.19 Whereas previous standards in the USP General Chapter <797> were aimed at minimizing drug contamination during preparation, the new USP General Chapter <800> is much broader in scope. Included requirements may affect anyone involved in the storage, transport, preparation, or administration of hazardous drugs.19

In addition to the aforementioned mandates on PPE use, USP General Chapter <800> proposes other significant safety upgrades. Many of the new requirements are focused on pharmacies. According to experts, pharmacies that were compliant with USP General Chapter <797> requirements will generally meet USP General Chapter <800> standards.19 However, entities must now appoint a compounding supervisor who is qualified and trained to be responsible for all parts of hazardous drug handling.20 Updates to packaging and labeling guidelines indicate that hazardous drugs must be labeled as such at all times during transit in order to be clearly identifiable and that appropriate packing containers should be selected carefully to prevent contamination.20 Storage requirements have been updated to reflect the 2014 NIOSH guidelines on hazardous drug stratification (Table 1).20 The new guidelines also require entities to have a written hazard communication plan that covers safety during all phases of hazardous drug handling.18 USP General Chapter <800> also discusses the concept of medical surveillance to help identify and follow up on workers who have potentially been exposed to hazardous drugs.20

New facilities requirements specify that hazardous drugs must be unpacked in a room with either neutral/normal or negative air pressure to prevent the spread of hazardous drugs from packaging material.20 Additionally, compounding of hazardous drugs must be performed in containment primary engineering control devices with external ventilation, located in walled-off rooms that function as containment secondary engineering controls.19 In USP General Chapter <800>, the negative air pressure requirements are more stringent, specifying an acceptable range of 0.01 to 0.03 inches of water column relative to all adjacent areas.19 Furthermore, separate areas for compounding sterile and nonsterile hazardous drugs are needed.19 Moreover, PPE should include gowns, head/hair covers, shoe covers, and 2 pairs of chemotherapy gloves for compounding both sterile and nonsterile hazardous drugs. Two pairs of gloves are also needed for administering antineoplastic drugs.19

In addition to the above protective measures, closed-system transfer devices (CSTDs) are useful outside the manufacturing realm for the handling and administration of hazardous drugs. As defined by NIOSH, a closed-system drug-transfer device mechanistically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapor concentrations outside the system.3 CSTDs decrease the potential for aerosol generation and reduce worker exposure to sharps.3 PhaSeal was one of the first CSTDs available in the United States, but the market has grown over the past decade to include numerous CSTDs (Table 2).21-23 After 15 years of data collection, the USP recommended the integration of CSTDs for safe handling of hazardous drugs, encouraging their use in compounding and requiring them for drug administration in the proposed USP General Chapter <800>.18,21

Available CSTDs have been tested using a 2015 NIOSH protocol designed to determine whether CSTDs are effective in preventing drug vapors or liquids from escaping into the environment.24 The CSTDs studied were Equashield, PhaSeal, ChemoClave, ChemoLock, VialShield, and OnGuard with Tevadaptor.25 Tests showed that only 2 of the 6 tested CSTDs (Equashield and PhaSeal) had a vapor release of less than 0.3 ppm—the detection limit of the MIRAN SapphIRe Portable Ambient Analyzer (Thermo Fisher Scientific) used to measure vapor levels.26 In terms of liquid leaks, only the Equashield CSTD had 0 leaks when tested with the antineoplastic drug fluorouracil (also known as 5-FU). PhaSeal also performed well, with minor leaks in only a few samples.27 However, it should be noted that these tests were performed prior to the 2016 NIOSH protocol updates. Specifically, 70% isopropanol was used as a surrogate compound for testing the effectiveness of barrier-type CSTDs in the 2015 NIOSH protocol. In correspondence to NIOSH dated March 2016, the manufacturer of OnGuard/Tevadaptor recommended 1% isopropanol as a surrogate compound instead of 70% isopropanol.28 Devices such as OnGuard are designed to filter aqueous medications, and 70% isopropanol (a primarily organic solution) may not have physiochemical properties representative of hazardous drugs.29 The 2016 NIOSH protocol states that isopropanol is not an appropriate surrogate compound because of its high volatility, which may result in vapor breakthrough that does not accurately reflect the behavior of current hazardous drugs due to their lower vapor pressures. Thus, surrogates with lower vapor pressures, which are more representative of known hazardous drugs, are now recommended. Nine surrogates with a range of vapor pressures (0.002-0.393 mm Hg) are under consideration.30 As such, additional testing of CSTDs according to the 2016 NIOSH protocol is needed before decisions on CSTD efficacy can be made.30

One concern surrounding the new USP General Chapter <800> guidelines is the cost associated with the necessary upgrades. Several health care systems estimate that the cost of redesigning their pharmacy facilities could surpass $1 million per compounding area.19 Additionally, the cost of implementing CSTDs is relatively high and may be a barrier for hospitals struggling to meet USP General Chapter <800> standards.31 However, some costs for compounding and administration may be offset by the use of cost-effective CSTD systems. Results from a study published in 2012 examined the overall CSTD cost using the advertised price of the product along with calculated costs of disposal.32 Based on an average of 1276 monthly hazardous drug infusions over a 5-month period, ChemoClave (ICU Medical, Inc) was found to be the least expensive system. Compared with the second most cost-effective system, Texium/Smart Site (CareFusion Corp), ChemoClave saved $38,739. The most expensive system was PhaSeal (Carmel Pharma, Inc).32 For compounding, some companies may offer pharmacies volume discounts, lower-cost specialty kits, or discounts on frequently used components.31 For facilities that compound a high volume of material, savings may be realized by using automated compounding technology. For example, costs may be decreased by substituting automated reusable CSTD components for high-volume preparations of the same medication (Table 3).31

Besides safety and cost, it is important to select a CSTD that will maximize efficiency for a given compounding or drug administration process. Also, comparative time-in-motion assessments are useful for determining the CSTD efficiency of a process.33 These assessments can help managers better understand the timing of each process and adjust staff and workload requirements accordingly.33 Consideration should also be given to other features, such as simple connections for easier training and consistent use. Prebonded components and uncomplicated packaging also contribute to greater efficiency. Features such as prepurging displacement air in the system and the wetting potential of filters should also be taken into account.33

Additional benefits of CSTDs include potential reductions in medication waste and decreased levels of hazardous drug contamination. For example, a 2011 study demonstrated that the PhaSeal CTSD prevented contaminants from entering sterile solutions during drug preparation and that if the device was used properly, a solution could be expected to remain sterile for up to 7 days.34 Another study focused on the potential increase in health care worker safety and decrease in environmental contamination using the PhaSeal CSTD. Surface contamination of pharmacies in 22 hospitals was assessed using wipe samples, both before and after the introduction of PhaSeal.35 A significant decrease in contamination levels for all 3 chemotherapy drugs analyzed was observed after introduction of the CSTD (P <.05 for all).35

Other technological advances, such as ready-to-administer (RTA) injectables, may improve safety and efficiency. The American Society of Health-System Pharmacists recommends that medications be dispensed using RTA forms whenever possible.36 One reason for this recommendation is that RTA medications require less handling. For instance, RTA medications do not need vial transfers, vial cleaning, repackaging, or assembly of separate components. This improves safety by reducing the number of opportunities for the introduction of contamination and by lowering the risk of medication errors.36 RTA medications may also improve pharmacy and nursing workflows by decreasing the amount of time needed to prepare medications.36 In addition, nurses may report greater job satisfaction because of RTA medication use. As RTA dosage forms require less time to prepare and administer, nurses may have more time to devote to other, more satisfying clinical activities.36 Furthermore, RTA medications generally require less staff training, as additional education is necessary only in cases of products using safety needles, special packaging, and security devices.36 Finally, RTA medications save time in the pharmacy because they arrive from the manufacturer with clear, bar-coded labels. This helps improve labeling standardization and ensures that labels are compliant with USP General Chapter <800>.36

HAZARDOUS DRUGS IN HOSPITALS AND HEALTH SYSTEMS

Despite all the safety guidelines, engineering controls, and protective equipment available, minimizing hazardous drug exposure and contamination remains challenging. For example, in a study of 252 oncology nurses about PPE use and spills of hazardous drugs, 22% to 44% of surveyed nurses reported “never” using CTSDs or PPE items such as disposable gowns, double gloves, eye protection, and respirators.37 Additionally, the study determined that nurses who had more manageable workloads and good leadership and support from their managers were less likely to report a hazardous drug spill.37 This suggests that hospitals need to encourage a commitment to a safety culture, and improve the use and practice of administrative and engineering controls.37

Nonetheless, efforts to improve safety and reduce workplace exposure to hazardous drugs are progressing. NIOSH, the Occupational Safety and Health Administration, and the Joint Commission are working together to boost awareness of safety among employers and employees. In addition, the NIOSH website offers up-to-date information on workplace safety, health topics, and hazardous drug exposure to help improve awareness.13

Many individuals involved in pharmacy leadership understand that they have an obligation to ensure the safety of their staff members. Thus, leaders must know safety regulations and guidelines, and help to develop approaches that best protect everyone involved in handling hazardous drugs.20 To that end, pharmacy departments should prepare for potential USP General Chapter <800> compliance challenges by proactively examining their organizations’ safety practices and compliance.20 In many cases, personnel will need education and training on the updated guidelines.20 From a practical standpoint, the new USP Chapter <800> regulations will require nurses to make substantial modifications to their PPE, drug transport, and drug preparation practices.38

Hospitals and health care systems should be working now to prioritize projects and resources for compliance with USP General Chapter <800> guidelines. Although USP does not enforce hazardous drug guidelines, state pharmacy boards are usually responsible for regulating drug compounding practices. The FDA may also enforce USP compounding standards.20 Recently, several states have begun to address occupational exposure to hazardous drugs by passing new legislation related to the issue.39 Nonetheless, hazardous drug safety and compliance is everyone’s responsibility. Guidelines and access to compliant facilities do not guarantee protection unless workers at all levels engage in the safety culture and practice appropriate techniques.20

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.

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