ASHP REPORTS

ASHP Guidelines on Handling Hazardous Drugs

Am J Health-Syst Pharm. 2018; 75:1996- general chapter, chapter 800, Hazard- barriers to adherence to safe han- Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 2031 ous Drugs—Handling in Healthcare dling guidance remain. The purposes Settings.8 Unlike the other publica- of these updated guidelines are to (1) Luci A. Power, M.S., Power Enterprises, tions regarding HDs noted above, inform readers about new and con- San Francisco, CA. USP chapter 800 is not a guidance tinuing concerns for healthcare work- Joseph W. Coyne, B.Pharm., Coyne Consulting, Mundelein, IL. document but an enforceable stan- ers handling HDs and (2) provide in- dard, containing both best practice formation on recommendations and recommendations and mandates for requirements, including those regard- Address correspondence to Bruce Hawkins ([email protected]). reducing the occupational exposure of ing controls and equipment that have healthcare workers who handle non- been developed since the publication sterile and sterile HDs. The standards of the 2006 ASHP guidelines. Open access set by USP chapter 800 are applicable Because newer studies have shown The full text of this article is freely available at www.ajhp.org. in all settings in which HDs are com- that contamination is widespread pounded and administered and where in healthcare settings and that more

Keywords: ASHP, guidelines, hazardous, healthcare workers may come into workers than previously thought are drugs contact HD residue, not just hospitals exposed, these guidelines should be and clinics. implemented wherever HDs are re- Copyright © 2018, American Society of With the increasing number of ceived, stored, prepared, transported, Health-System Pharmacists, Inc. All rights publications on this topic, the inclu- administered, or disposed.8-11 reserved. 1079-2082/18/1202-1996. sion of older material in these guide- Comprehensive reviews of the lit- DOI 10.2146/ajhp180564 lines has been limited to landmark or erature covering anecdotal and case other crucial studies. The ASHP 1990 reports of surface contamination, technical assistance bulletin and 2006 worker exposure, and risk assess- guidelines provide historic overviews ment are available from NIOSH,6,9,12 SHP published its first guidance of this topic. Sections of USP chapter the Occupational Safety and Health Aon hazardous drugs (HDs) in 1983 800 are discussed in this document, Administration (OSHA),13,14 and indi- as part of the 1983–84 ASHP Practice but the ASHP Guidelines on Handling vidual authors.15-20 The primary goal Spotlight: Safe Handling of Cytotoxic Hazardous Drug are not intended to of this document is to provide rec- Drugs.1,2 This was followed by techni- modify, interpret, or be a substitute ommendations for the safe handling cal assistance bulletins in 1985 and for the provisions of USP chapter 800. of HDs. These guidelines represent 1990 and the ASHP Guidelines on These updated guidelines include in- the research and recommendations Handling Hazardous Drugs in 2006.3-5 formation from the literature, NIOSH, of many groups and individuals who The 2006 guidelines were created to and USP and are current to October have worked tirelessly over decades harmonize with the National Institute 2017. to reduce the potential harmful ef- for Occupational Safety and Health fects of HDs on healthcare workers. (NIOSH) Alert: Preventing Occupa- Purpose The research available to date, as well tional Exposure to Antineoplastic and Significant advances in the aware- as the opinions of thought leaders in Other Hazardous Drugs in Health Care ness of safe handling of HDs have this area, is reflected in the guidelines. Settings issued in 2004.6 The ASHP been made since the previous version Where possible, recommendations 2006 HD guidelines were current to of these guidelines was published in are evidence based. In the absence 2005. 2006. NIOSH has created a topics page of published data, professional judg- In 2007, the United States Phar- to maintain a bibliography of NIOSH ment, experience, and common sense macopeial Convention revised United HD documents, publications on oc- have been used. States Pharmacopeia (USP) chapter cupational exposure to antineoplastic 797 (Pharmaceutical Compounding— and other HDs, and research on safe Background Sterile Preparations)7 to harmonize handling drawn from the published Healthcare workers may be ex- with the NIOSH 2004 Alert. It became literature.9 After more than 30 years posed to HDs at many points during effective May 1, 2008, establishing of published guidance, international manufacture, distribution, receipt, many of the NIOSH recommenda- research indicates that occupational storage, transport, compounding, and tions as enforceable requirements. On exposure to HDs continues, negative administration, as well as during waste February 1, 2016, USP published a new reproductive outcomes continue, and handling and care of treated patients.6

1996 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS

All workers involved in these activi- International Agency for Research on mide, , , pacli- ties, as well as in equipment mainte- .30 Although the increased in- taxel, and ) in 75% of the nance and repair, have the potential cidence of for occupationally pharmacy wipe samples and 43% of for contact with uncontained drug. exposed groups has been investigat- the infusion wipe samples. The study One study of worker contact with sur- ed, with varying results,31-34 2 related confirmed that HD contamination Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 faces contaminated with HDs identi- studies described evidence of drug is generally widespread, even with fied a number of job categories not uptake (drug being incorporated into engineering controls such as class traditionally expected to be exposed.11 workers’ bodies) and chromosomal II biological-safety cabinets (BSCs); Unit clerks, transport workers, ward changes in oncology workers exposed that pharmacy areas have more con- aides, dietitians, and oncologists were to workplaces contaminated with HD taminated surfaces; and that the con- observed touching contaminated sur- residue.35,36 The DNA of exposed work- tamination is in higher concentrations faces. A follow-up study documented ers showed a statistically significant than in nursing areas. Most impor- in the urine of increase in the frequency of damage tantly, this study confirmed that there these workers, concluding that work- to chromosome 5 or 7 and an increase had been little progress in reducing ers in the drug administration setting, in frequency of damage to chromo- HD contamination in similar health- even those who were not responsible some 5 alone. As signature lesions in care settings in the United States in for administering the drugs to patients chromosomes 5, 7, and 11 have been the 10 years between the studies. (i.e., volunteers, oncologists, ward shown to be associated with chemo- A series of multisite studies on HD aides, and dietitians), had the largest therapy treatment-related myelodys- contamination was published by a re- proportion of samples exceeding the plastic syndrome and acute myeloid search team in British Columbia.11,21,43 limit of detection (LOD) for cyclo- leukemia, these results provide addi- Through interviews and observations, phosphamide.21 These results suggest tional evidence of harmful effects from 11 job categories with the potential that it is reasonable to expand the list occupational exposure to HDs.37,38 for HD exposure by dermal contact of potentially exposed workers. Recent These conclusions are bolstered by with potentially contaminated sur- studies have also begun to examine recent meta-analyses of comet assay, faces were identified within 6 medical the impact on families and caregiv- micronuclei and chromosomal aber- sites.11 In addition to those workers ers of home treatments with HDs22-24; ration data in healthcare workers that traditionally thought to be exposed, however, the scope of these guidelines have shown increases in chromosom- workers who had possible dermal is limited to workers in healthcare al damage in workers exposed to anti- contact with HDs included receiving settings. neoplastic drugs.39-41 staff, unit clerks, ward aides, and even Exposure to HDs in the workplace Continuing exposure. Before the volunteers. In investigating contami- has been associated with acute and publication of the 2004 NIOSH Alert, nated surfaces, the researchers noted short-term reactions as well as long- a 1999 study done in 3 cancer treat- that although the BSC had the high- term effects. Anecdotal and case re- ment centers in the United States and est frequency of contact in the com- ports in the literature range from skin- 3 in Canada provided strong evidence pounding area, the pen inside the BSC related and ocular effects to flu-like of surface contamination with anti- and the isopropyl alcohol spray bottle symptoms and headache.6,17 Repro- neoplastic HDs in compounding and were frequently touched.11 I.V. pumps, ductive studies on healthcare workers infusion areas.42 Measurable amounts countertops, and waste containers have shown an increase in fetal ab- of cyclophosphamide, ifosfamide, and were the most contacted surfaces in normalities, fetal loss, and fertility im- fluorouracil were detected in 75% of the infusion areas. The team collected pairment resulting from occupational the pharmacy wipe samples and 65% surface wipe samples at the participat- exposure to these potent drugs.25-28 of the infusion area wipe samples. The ing sites, using cyclophosphamide as An extensive study published in 2012 levels of contamination were higher in the marker drug.11 Of the 275 surface documented increased spontaneous the pharmacy areas than in the drug samples collected, 35% were above the abortions in nurses exposed to HDs infusion areas. The number of posi- LOD. As in the 2010 U.S. study,10 the in the workplace.26 An increase in tive wipe sampling results was related pharmacy compounding areas had learning disabilities among offspring to the amount of drug prepared and the majority of contaminated wipes as a result of occupational exposure administered. (47 of 85) and the highest concentra- to these potent drugs has also been A NIOSH-sponsored study of 3 tion of drug.11 Additional surface wipe reported.27 university-based U.S. cancer centers sampling done at the same 6 medical Antineoplastic drugs and immu- published in 2010 reexamined HD sites43 produced a total of 438 samples nosuppressants are some of the types contamination and other risk points from 55 categories of surfaces in 5 of drugs included on lists of known or from the 1999 study.10,42 The 2010 study drug handling stages (delivery, prep- suspected human by the measured surface contamination of at aration, transport, administration, National Toxicology Program29 and the least 1 of the 5 drugs (cyclophospha- and waste), with 159 (36%) having

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 1997 ASHP REPORTS HANDLING HAZARDOUS DRUGS concentrations above the LOD. The A review of studies of healthcare volved with HD compounding and most-contaminated surfaces by stage worker exposure to antineoplastic administration, support the theory were the drug delivery elevator but- HDs published in the United States, that dermal contact with contami- ton, drug preparation pen (possibly Canada, and Europe after publication nated surfaces is the primary route of from the BSC), transport bin for drug of the 2004 NIOSH HD Alert revealed exposure.18,19,21,48-50 Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 pickup, drug administration i.v. pump, no decrease in contamination.44 In ad- An alternative to dermal absorp- and waste elevator button.43 In the dition, separating the publications by tion, where HDs penetrate unpro- original study,11 the BSC was noted to origin, the review found that only 9 tected skin after contact with con- be the most frequently touched item of 71 such studies were done by U.S. taminated surfaces, is that surface in the drug preparation area; however, researchers, and most of those were contamination transferred to hands the pen used in the BSC was the most sponsored by medical device manu- may be ingested via the hand-to- contaminated. Other items such as a facturers. U.S. critics of HD safe han- mouth route.51,52 Researchers have marker and tweezers kept in the BSC dling guidance often note the lack of examined hand sampling as a mea- were also heavily contaminated, prob- evidence of exposure as well as the sure of exposure.51 Using a technique ably resulting in glove contamination recommendations to mitigate it. The of wipe sampling, similar to that done during each contact. While routine exceptionally small number of U.S. for work surfaces, healthcare work- cleaning of the BSC surface was re- studies found in this literature review ers’ hands may be swabbed to check ported, miscellaneous items, such as may indicate a basic lack of interest for HD contamination.51 One study the pen, were probably not included in conducting such research in the of workers at 6 sites analyzed a total in that cleaning. Measurable HD con- United States. of 225 wipe samples, 20% of which tamination on elevator buttons is con- Routes of exposure. Numerous were above the LOD for cyclophos- cerning for workers, and visitors may studies have shown the presence of phamide.52 Contaminated hands may also be exposed to this risk. HDs in the urine of healthcare work- transfer HD residue to other surfaces In addition, this research team ers.10,21,45-47 In a review of 20 studies and other workers as well as contrib- sought to determine whether health- from 1992 to 2011 examining biomark- ute to hand-to-mouth transfer. Hand care workers from the earlier stud- ers of exposure in healthcare work- sampling may offer an alternative to ies were at risk of cyclophosphamide ers handling antineoplastic HDs, 17 surface sampling in monitoring HD uptake through dermal contact with studies found drug in workers’ urine.19 contamination and exposure. contaminated surfaces or by other One of the studies in that review de- Hazard assessment. The risk to means.21 Participants identified from scribed no response in 50 subjects, workers from handling HDs is the re- the prior studies as potentially ex- but the study did note that all subjects sult of a combination of the inherent posed agreed to provide urine samples demonstrated postshift exposure to toxicity of the drugs and the extent to quantify the urine concentration of platinum.47 A study by Wick et al.,46 to which workers are exposed to the nonmetabolized cyclophosphamide. which was not included in the review, drugs in the course of their daily job Cyclophosphamide levels greater than demonstrated that 6 of 8 participants’ activities. Both hazard identification the LOD were found in 55% of urine 24-hour urine samples had cyclo- (the qualitative evaluation of the tox- samples.21 Participants from depart- phosphamide and ifosfamide levels icity of a given drug) and an exposure ments where drug preparation and above the LOD. Hon et al.21 collected assessment (the amount of worker drug administration do not occur (i.e., 201 urine samples from 103 subjects, contact with the drug) are required shipping/receiving, transport, nutri- including those in job categories with to complete a hazard assessment. As tion, and materials management) had low expectation of exposure; 55% had the hazard assessment is specific to the highest average urinary concen- levels exceeding the LOD for cyclo- the safety program and safety equip- tration levels of cyclophosphamide.21 phosphamide, with unit clerks having ment in place at a work site, a formal When the results were stratified by job the highest average level. hazard assessment may not be avail- title, unit clerks had the highest aver- HDs may enter the body through able for most practitioners. An alter- age urinary cyclophosphamide con- inhalation, dermal absorption, acci- native is a performance-based, ob- centration. The authors identified 2 dental injection, ingestion of contam- servational approach. Observation of factors associated with cyclophospha- inated foodstuffs, or mouth contact current work practices, equipment, mide uptake: (1) whether a worker had with contaminated hands. Inhalation and the physical layout of work areas a duty to handle antineoplastic HDs was previously suspected as the pri- where HDs are handled at any given and (2) whether a worker received mary route of exposure, but 1 or more site will serve as an initial assessment training on safe drug handling, and of these routes might be responsible of appropriate and inappropriate concluded that interventions to mini- for workers’ exposure. More recent practices.6 mize this risk should be more broadly studies, especially those looking at NIOSH defines a risk assessment as applied. healthcare workers not directly in- characterization of potentially adverse

1998 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS health effects from human exposure definition from the 2004 NIOSH Alert From 2004 through 2012, NIOSH to environmental and occupational is used (Appendix A). recommended that standard pre- hazards. Risk assessment can be di- NIOSH. The NIOSH 2004 HD Alert cautions or universal precautions be vided into 5 major steps: hazard iden- contained an appendix of HD lists taken in handling HDs. In 2014, with tification, dose–response assessment, compiled from information provided the addition of many nonantineoplas- Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 exposure assessment, risk character- by 4 organizations that had gener- tic drugs and drugs in tablet and/or ization, and risk communication.4 ated lists of HDs for their respective capsule form to the list, NIOSH noted USP chapter 800 introduced the institutions, as well as a list from the that no single approach could cover term assessment of risk, which allows Pharmaceutical Research and Manu- the diverse potential occupational an entity to perform an evaluation of facturers of America.6 NIOSH adopted exposures to the drugs.54 This change risk to determine alternative contain- a mechanism both to review its HD required the development of a new ment strategies and/or work practic- criteria and to update its HD list every format for the 2014 NIOSH list of HDs, es to those described in USP chapter 2 years by reviewing the existing drugs which for the first time divided HDs 800 for some dosage forms of HDs on the HD list and examining newly into 3 groups: that may not pose a significant risk approved drugs, and drugs with new of direct occupational exposure.8 An Food and Drug Administration (FDA) • Group 1: antineoplastic drugs (AHFS assessment of risk may only be used warnings against the NIOSH HD cri- Classification 10:00) [ASHP/AHFS for drugs on the NIOSH list that are teria. The review process for the addi- DI 2013]. Many of these drugs may neither HD active pharmaceutical in- tion of the new listings is described in also pose a reproductive risk for gredients (APIs) nor antineoplastics the Federal Register.53 susceptible populations. requiring HD manipulation. Accord- ing to USP chapter 800, the assess- ment of risk must, at a minimum, consider the type of HD, the dosage Table 1. Comparison of NIOSH and ASHP Definitions of Hazardous form, the risk of exposure, the pack- Drugs aging involved, and how the drug will NIOSH6 ASHP4 be manipulated. If an assessment of risk is per- Carcinogenicity Carcinogenicity in animal models, in the patient population, or in both as formed, the entity must document reported by the International Agency the alternative containment strate- for Research on Cancer gies and/or work practices specific Teratogenicity or developmental Teratogenicity in animal studies or in to the drugs and dosage forms so as toxicitya treated patients to minimize healthcare workers’ ex- Reproductive toxicitya Fertility impairment in animal studies or posure. The assessment of risk must in treated patients be reviewed and documented at least Organ toxicity at low dosesa Evidence of serious organ or other every 12 months. An assessment of toxicity at low doses in animal models or in treated patients risk should not be confused with a risk b assessment, as the hazard identifica- Genotoxicity (i.e., mutagenicity and clastogenicity in short-term test tion step is not done by the entity. USP systems) chapter 800 describes the require- Structure and toxicity profile of new . . . ments and restrictions of an assess- drugs that mimic existing drugs ment of risk.8 determined hazardous by the above criteria Definition of HDs aThe National Institute for Occupational Safety and Health (NIOSH) definition contains the following explanation: “All drugs have toxic side effects, but some exhibit toxicity at low The 1990 ASHP technical assis- doses. The level of toxicity reflects a continuum from relatively nontoxic to production of toxic tance bulletin proposed criteria to effects in patients at low doses (for example, a few milligrams or less). For example, a daily determine which drugs should be therapeutic dose of 10 mg/day or a dose of 1 mg/kg/day in laboratory animals that produces serious organ toxicity, developmental toxicity, or reproductive toxicity has been used by considered hazardous and handled the pharmaceutical industry to develop occupational exposure limits (OELs) of less than 10 within an established safety program.4 micrograms/meter3 after applying appropriate uncertainty factors [Sargent and Kirk 1988; The technical assistance bulletin’s Nauman and Sargent 1997; Sargent et al. 2002]. OELs in this range are typically established for potent or toxic drugs in the pharmaceutical industry. Under all circumstances, an evalua- definition of HDs was revised by the tion of all available data should be conducted to protect health care workers.”6 NIOSH Working Group on Hazard- bThe NIOSH definition contains the following explanation: “In evaluating mutagenicity for ous Drugs for the 2004 alert.6 These potentially hazardous drugs, responses from multiple test systems are needed before precau- tions can be required for handling such agents. The EPA evaluations include the type of cells definitions are compared in Table 1. affected and in vitro versus in vivo testing [51 Fed. Reg. 34006-34012 (1986)].”6 For purposes of these guidelines, the

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 1999 ASHP REPORTS HANDLING HAZARDOUS DRUGS

• Group 2: nonantineoplastic drugs genicity, carcinogenicity, reproductive HDs, as CSPs, are regulated by both that meet 1 or more of the NIOSH toxicity, specific target organ toxicity USP chapters 797 and 800 for com- criteria for an HD. Some of these (single or repeated exposure), or as- pounding environments.7,8 The com- drugs may also pose a reproductive piration hazard. The criteria for de- pounding of nonsterile HDs must meet risk for susceptible populations. termining whether a chemical is clas- the criteria in USP chapter 795, Phar- Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 • Group 3: drugs that primarily pose sified as a health hazard are detailed maceutical Compounding—Nonsterile a reproductive risk to men and in Appendix A to §1910.1200—Health Preparations,61 as well as USP chapter women who are actively trying Hazard Criteria.59 In addition, the HCS 800.8 With the adoption of USP chapter to conceive and women who are requires that drugs that pose a health 800, the HD section will be removed pregnant or breast-feeding (some of hazard (with the limited exception of from USP chapter 797. these drugs may be present in breast those in solid, final forms for direct USP chapter 800 has changed the milk). administration to the patient, such requirements for HD handling, stor- as tablets or pills) be included on lists age, and compounding environments The 2016 NIOSH HD list retains of hazardous chemicals to which em- to emphasize containment, includ- this 3-group format.55 The most cur- ployees are exposed. As a federal stan- ing the containment primary engi- rent NIOSH list of HDs, along with dard, the HCS is the definitive docu- neering control (C-PEC), the device other NIOSH HD documents, may be ment establishing compliance with all in which compounding takes place, found on the NIOSH Hazardous Drug phases of this right-to-know legisla- and the containment secondary en- Exposures in Healthcare Topics Page.56 tion, including the definition of haz- gineering control (C-SEC), the room USP chapter 800. In 2016, USP ardous and the requirements for the in which the C-PEC is placed.8 Major chapter 800 adopted the NIOSH HD Safety Data Sheet (SDS). In addition, revisions in engineering controls ad- list as the list of antineoplastic and the HCS requires that the hazards of opted by USP chapter 800 include a other HDs that an organization wish- all chemicals produced or imported requirement that certain areas be un- ing to comply with USP chapter 800 into a workplace are classified and der negative pressure relative to sur- must begin with.8 This list may be that information concerning the rounding areas to contain HDs and modified to include only the drugs classified hazards is transmitted to minimize the risk of exposure.8 Ex- that they handle and must be reviewed employers and employees.57 ternal ventilation (i.e., exhausting to at least every 12 months. The list must A list of HDs in use in the facility is the outside) is advocated to achieve be dynamic: whenever a new agent required by the OSHA HCS and by USP negative pressure. Because HDs are or dosage form is used by the organ- chapter 800.8,57 The Joint Commission, also compounded in areas adjacent ization, it should be reviewed against in Elements of Performance for Medi- to patients and family members (e.g., the list. The NIOSH HD criteria must cation Management (MM).01.01.03, in infusion centers), be used to identify HDs that enter the requires that hospitals identify in writ- inappropriate environmental con- market after the most recent version ing their high-alert and hazardous tainment puts them and healthcare of the NIOSH HD list and to assess medications.60 workers at risk.8 any investigational drugs used by the organization. HDs as sterile preparations Recommendations OSHA. The OSHA Hazard Com- Many HDs are designed for paren- The recommendations below stem munication Standard (HCS) was teral administration, requiring aseptic from the dedicated and thoughtful ef- updated in 2012 to align with the reconstitution or dilution to yield a forts of numerous groups and individ- United Nations Globally Harmonized final sterile preparation. As such, the uals over many years. Where possible, System of Classification and Label- compounding of these products is reg- the recommendations are evidence ing of Chemicals.57 The revised HCS ulated as sterile pharmaceutical com- based. In the absence of published defines a hazardous chemical as any pounding by USP chapter 797.7 The data, the professional judgment and chemical that is classified as a physi- intent of USP chapter 797 is to protect opinions of thought leaders have been cal or health hazard, simple asphyxi- patients from improperly compound- relied upon. In this document, the ant, combustible dust, pyrophoric gas, ed sterile preparations (CSPs) by regu- term must is used to denote a require- or hazard not otherwise classified.58 It lating facilities, equipment, and work ment of generally applicable laws, further defines a health hazard as a practices to ensure the sterility of ex- regulations, or practice standards; the chemical that is classified as posing temporaneously CSPs. USP chapter term should indicates a generally ac- 1 of the following hazardous effects: 797 addresses not only the sterility of cepted recommendation that is not acute toxicity (any route of exposure), a preparation but also the accuracy of drawn from an authoritative refer- skin corrosion or irritation, serious its composition. Because many HDs ence. Healthcare professionals are en- eye damage or irritation, respiratory are very potent, there is little margin couraged to rely on their professional or skin sensitization, germ cell muta- for error in compounding. judgment, experience, and common

2000 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS sense in applying these recommenda- ty program must include a process for of the packing cartons and onto the tions to their unique circumstances, monitoring and updating the SDS da- package inserts placed around the vial as no set of guidelines on this topic tabase. When an HD is purchased for within the carton.68 This study found can address all the needs of every the first time, an SDS must be received cyclophosphamide contamination on healthcare facility. from the manufacturer or distributor. 100% of the cyclophosphamide vials, Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 The SDS should define the appropri- the outside outer packaging, and the Safety program ate handling precautions, including inside outer packaging that were sam- Policies and procedures for the protective equipment, controls, and pled.68 Package leaflets (inserts) were safe handling of HDs must be in place spill management associated with the also sampled, with 90–100% of samples for all situations in which these drugs drug. SDS collections are available on- found to be above the LOD. In addi- are used throughout a facility. A com- line through the specific manufactur- tion, the researchers sampled primary prehensive safety program must be er or through safety-information ser- packaging containing tablets (blister developed that deals with all aspects vices. In the event an online service is packages) of 50-mg cyclophosphamide of the safe handling of HDs. This pro- used, a proper contingency plan must tablets. Cyclophosphamide was quan- gram must be a collaborative effort, be in place to access this vital infor- tified in all wipe samples from the tab- with input from all affected depart- mation in the event of a system failure. let blister packages.68 ments, such as pharmacy, nursing, Drugs that have been identified as Such contamination on packag- medical staff, environmental services, requiring safe handling precautions ing presents an exposure risk to any- transportation, maintenance, em- should be clearly labeled at all times one opening drug cartons or handling ployee health, risk management, during their transport, storage, and the vials, including workers receiving industrial hygiene, clinical laborato- use. The HCS requires a list of hazard- open or broken shipping cartons or ries, and safety. New research indi- ous chemicals be present in the work- selecting vials to be repackaged at a cates that HD contamination is more place as part of the written hazard distribution point (e.g., a worker at widespread than generally believed communication program.64 The HCS the drug wholesaler selecting HDs and that worker exposure extends be- applies to all workers, including those for shipping containers, a pharmacy yond the primarily accepted occupa- handling HDs at the manufacturer worker dividing an HD in a multi- tions.11,21 It is important to make all af- and distributor levels. Employers are dose container for repackaging into fected workers aware of the potential required to develop and implement single-dose containers). These activi- risks and to train them in appropriate employee training programs regard- ties present risks, especially for work- safety precautions.62 ing workplace hazards and protective ers who too often receive inadequate Per USP chapter 800, each facility measures.64 safety training.62 Environmental ser- handling HDs USP chapter 800 requires that vices staff and patient care assistants who handle drug waste and patient must have a designated person all personnel who handle HDs are waste are also at risk and are not al- who is qualified and trained to be responsible for understanding the ways included in the safe handling responsible for developing and fundamental practices and precau- training required by safety programs. implementing appropriate proce- tions and for continually evaluating Safety programs must identify and in- dures; overseeing entity compli- these procedures and the quality of clude all workers who may be at risk of ance with this chapter and other final HDs to prevent harm to pa- exposure.11,43,62 applicable laws, regulations, and tients, minimize exposure to per- New packaging techniques for HD standards; ensuring competency of sonnel, and minimize contamina- vials include a film wrapper on the vi- personnel; and ensuring environ- tion of the work and patient-care als and reinforcement of the bottom mental control of the storage and environment.8 of the vials with a plastic disk. Stud- compounding areas.8 ies of specialty packaging methods The HCS and USP chapter 800 have shown that these resist breakage As many HDs are also hazards that require employee training to the and that the wrapper is less contami- are identified in the revised HCS, the tasks they will perform as part of the nated than detected in previous stud- requirements of the HCS must also be safety program.8,57 Personnel compe- ies of the glass of the vial itself.67,69 The met.57 A fundamental element of this tency must be demonstrated every 12 packaging (cartons, vials, ampules) safety program is the SDS, formerly months and documented.8 of HDs should be properly labeled by the Material Safety Data Sheet, man- The outsides of the vials of many the manufacturer or distributor with dated by the HCS.63 Employers are re- commercial HDs are contaminated a distinctive identifier that notifies quired to have an SDS available for all when the vials are received in the personnel receiving them to don ap- hazardous agents, including HDs, in pharmacy.50,65-68 In 1 study, the con- propriate personal protective equip- the workplace. A comprehensive safe- tamination extended to the inside ment (PPE) during their handling.

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Sealing these drugs in plastic bags at by OSHA, a complete respiratory pro- potential drug errors (e.g., pulling a the distributor level provides an ad- gram, including proper training and look-alike vial from an adjacent drug ditional level of safety for workers fit-testing, must be completed by all bin). To reduce transfer of HD residue who are required to unpack cartons. staff required to use respirators.70 Sur- from vials and cartons, all staff mem- USP chapter 800 requires policies gical masks do not provide adequate bers must wear gloves tested to ASTM Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 and procedures and standard oper- protection from the harmful effects of D6978 for resistance to chemotherapy ating procedures (SOPs) for labeling, these drugs. (i.e., chemotherapy gloves). NIOSH packaging, and transport of HDs.8 USP chapter 800 contains a table notes that single chemotherapy gloves It should be noted that USP chapter listing the summary of requirements are sufficient in receiving, unpacking, 800 does not apply to manufacturers for receiving and handling damaged and placing HDs into storage, unless or distributors. Distributors may pro- HD shipping containers.8 USP chap- there is a spill.55 Because many stud- vide special packaging and labeling if ter 800 prefers that damaged shipping ies have shown that HD residue on requested by their customers. containers be transported to a C-PEC the drug vial itself is routine and that designated for nonsterile compound- contamination has been reported in Labeling, packaging, storing, ing before opening.8 significant amounts,65-69 staff should and transporting of HDs from Storing HDs. Segregation of HD consider wearing double chemother- point of receipt inventory from other drug inventory apy gloves when receiving, unpack- The safety program should address improves control and reduces the ing, stocking, and inventorying these the entire lifecycle of HD handling, in- number of staff members potentially drugs and selecting HD packages for cluding receipt, storage, and transpor- exposed to the danger.5 USP chapter further handling.5,20 Per NIOSH 2016 tation. Drug packages, bins, shelves, 800 requires that HDs listed as anti- recommendations, a gown and respi- and storage areas for HDs must bear neoplastic HDs on the current NIOSH ratory protection should also be used distinctive labels identifying those HD list55,56 that require manipulation when spills or leaks are of concern drugs as requiring special handling (more than counting or repackaging (e.g., if a carton appears damaged) precautions. of final dosage forms) and HD APIs be during HD receiving, unpacking, and Receipt of HDs. According to stored separately from non-HDs.8 HDs storage activities.55 USP chapter 800, HDs listed as anti- should be stored so as to prevent con- Transport of HDs. All transport of neoplastic HDs on the current NIOSH tamination and personnel exposure. HD packages must be done in a man- HD list55,56 and all HD APIs must be These HDs must be stored in areas ner to reduce environmental contami- unpacked in areas that are neutral/ with sufficient external exhaust ven- nation in the event of accidental drop- normal or negative pressure relative to tilation (i.e., negative-pressure rooms) ping.5 HD packages must be placed in the surrounding areas.8 HDs must not having at least 12 air changes per hour sealed containers and labeled with a be removed from their external ship- (ACPH).8 The nonantineoplastic, re- unique identifier. Carts or other trans- ping containers in sterile compound- productive risk–only, and final HD port devices must be designed with ing areas or in any area that is under dosage forms of antineoplastic HDs, guards to protect against falling and positive pressure to the surrounding as contained on the current NIOSH breakage. All individuals transporting areas.8 During receipt of HDs, visual HD list,55,56 may be stored with other HDs must have safety training that examination of cartons for outward inventory per USP chapter 800 if the includes spill control and have spill signs of damage or breakage is an facility’s assessment of risk and policy kits immediately accessible.5,57 Staff important initial step in the receiv- allow it.8 handling HDs or cleaning areas where ing process. Policies and procedures HDs placed in inventory should be HDs are stored or handled must be must be in place for handling dam- protected from potential breakage by trained to recognize the unique iden- aged cartons or containers of HDs storage in bins that have high fronts tifying labels used to distinguish these (e.g., returning the damaged goods and on shelves that have guards to drugs and areas.57 Warning labels and to the distributor using appropri- prevent accidental falling.5 USP chap- signs must be clear to non-English ate containment techniques).8 These ter 800 notes that HDs must be stored readers. All personnel who work with procedures should include the use of to prevent spillage or breakage if the or around HDs must be trained to ap- PPE, which must be supplied by the container falls.8 Special care must propriately perform their jobs using employer. HD spill kits must be avail- also be taken to secure shelves and the established precautions and re- able in the receiving area.8 The spill kit other storage containers in the event quired PPE.57 should contain complete PPE, includ- of earthquakes or other natural di- ing an NIOSH-certified respirator, in sasters as appropriate. The bins must Environment the event no ventilation protection also be appropriately sized to properly It has long been shown that HD is available where damaged HD con- contain all stock. Care should be taken contamination is widespread in tainers are handled.8,70,71 As required to separate HD inventory to reduce healthcare settings, even when pri-

2002 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS mary compounding controls are in in the Ventilated Engineering Controls for significant worker exposure as place.6,10,11,21,42-46 USP chapter 800 fo- section below. well as environmental contamina- cuses on containment of HD contami- Administration. Only individuals tion, as closed-system administra- nation, which is illustrated in the new trained in the administration of HDs tion is problematic. All staff members terminology of ventilation controls.8 should do so.5,6,8 Nurses who admin- who handle HDs should receive safety Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 Many prior recommendations for ister HDs and care for patients receiv- training that includes recognition of controlled, ventilated areas for storage ing chemotherapy should meet the HDs and appropriate spill response. and handling HDs will become man- requirements of the Oncology Nursing HD spill kits, containment bags, and dates when USP chapter 800 becomes Society (ONS) position statement on disposal containers must be available effective.8 Similar to NIOSH and ASHP administration.72 During administra- in all areas where HDs are handled. recommendations, USP chapter 800 tion, access to the administration area requires that HDs be handled within a should be limited to patients receiving Ventilated engineering controls program that promotes patient safety, therapy and essential personnel. Eat- Engineering controls protect worker safety, and environmental ing, drinking, applying makeup, and workers by removing hazardous con- protection.5,6,8 Facilities must iden- the presence of foodstuffs should be ditions or by placing a barrier between tify all areas where HDs are stored or avoided in patient care areas while the worker and the hazard. To safely handled.5,6,8 As staff members in some HDs are administered. For inpatient handle HDs, ventilated engineer- jobs may not be proficient in English, therapy, where lengthy administration ing controls are required for primary using signs with verbal and pictorial techniques may be required, hanging and secondary containment of sterile warnings is preferred.57 HDs should or removing HDs should be scheduled and nonsterile forms of these drugs. be handled in restricted areas where to reduce exposure of family members For compounding sterile prepara- access is limited to authorized per- and ancillary staff and to avoid the po- tions, USP chapter 797 designated sonnel trained in handling require- tential contamination of dietary trays primary engineering controls, buffer ments. Break rooms and refreshment and personnel. areas, and clean rooms as ventilated areas for staff, patients, visitors, and Because much of the compound- engineering controls that provided others should be located away from ing and administration of HDs appropriate air quality.7 USP chapter areas of potential HD contamination throughout the United States are 800 applies to both sterile and non- to reduce unnecessary exposure to done in outpatient or clinic settings sterile compounding of HDs and has staff, visitors, and others. USP chap- with patients and their family mem- modified USP chapter 797 terminol- ter 800 requires that specific areas bers near the compounding area, ogy to emphasize the key require- are designated for defined HD tasks, care must be taken to minimize en- ment in handling HDs, which is con- including receipt and unpacking, stor- vironmental contamination and to tainment.8 USP chapter 800 divides ing HDs, and compounding nonster- maximize the effectiveness of clean- ventilated engineering controls for ile and sterile HD preparations.8 USP ing (decontamination) activities. The containment as C-PEC, used for the chapter 800 also requires that certain design of such areas must include actual compounding, and C-SEC, in HD areas have negative pressure from surfaces that are readily cleaned and which the C-PEC is placed.8 These surrounding areas to contain HDs and decontaminated. Upholstered and guidelines only present a summary minimize risk of exposure.8 carpeted surfaces should be avoided, of USP chapters 797 and 800 and are Compounding. Only individuals as they are not readily cleaned. Sev- not meant to interpret the standards trained in the compounding of HDs eral studies have shown floor con- and best practices described in those should do so.5,6,8 HDs should be com- tamination and the ineffectiveness of documents. pounded in a controlled area where cleaning practices on both floors and access is limited to authorized per- surfaces.10,36,37,40,73,74 C-PECs sonnel trained in handling require- HDs may also be administered in A C-PEC is defined inUSP chapter ments.5,6 Sterile and nonsterile HDs nontraditional locations, such as the 800 as a ventilated device designed must be compounded in environ- operating room, which presents chal- and operated to minimize worker and ments that have a negative pressure to lenges in training of personnel and in environmental exposures to HDs.8 all adjacent areas.8 Positive-pressure proper containment of the drugs and A C-PEC functions by controlling environments for HD compounding drug residue. Intracavitary adminis- emissions of airborne contaminants must not be used because of the po- tration of HDs (e.g., into the bladder, through the following8: tential spread of airborne contamina- peritoneal cavity, or chest cavity) fre- tion from contaminated packaging, quently requires equipment for which • The full or partial enclosure of a poor handling technique, and spills.5 locking connections may not be avail- potential contaminant source, Ventilation controls for sterile and able. Inhalation of some HDs to treat • The use of airflow capture ve- nonsterile compounding are covered certain diseases also has the potential locities to trap and remove airborne

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 2003 ASHP REPORTS HANDLING HAZARDOUS DRUGS

contaminants near their point of ile compounding, the standards in taining HD contamination depends generation, USP chapter 797 must be followed.7 on operators’ use of proper technique • The use of air pressure relationships Sterile HDs must be compounded in and strict adherence to policies and that define the direction of airflow a C-PEC that provides ISO class 5 or procedures. into the cabinet, and better air quality and unidirectional Class II BSCs types A2, B1, and B2 Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 • The use of high-efficiency par- airflow. A class II or class III BSC or a are acceptable under USP chapter ticulate air (HEPA) filtration on all CACI is an appropriate ventilated en- 800 for compounding sterile HDs.8 potentially contaminated exhaust gineering control for compounding USP chapter 800 notes that the type streams. sterile HDs.8 C-PECs for sterile com- A2 cabinet, which recirculates a por- pounding must be located in a C-SEC tion of the HD-contaminated air The C-PEC required is dictated by that is either an ISO class 7 buffer through HEPA filters while exhaust- the type of compounding being per- room with an ISO class 7 anteroom ing the remainder to the outside, can formed, as well as other factors. (preferred) or an unclassified con- be reliably integrated with ventila- Nonsterile compounding. For tainment segregated compounding tion systems and accommodates the nonsterile HD compounding, a area (C-SCA).8 USP chapter 800 re- pressurization requirements of USP C-PEC that provides personnel and quires C-PECs used for compounding chapter 800 for the C-SEC. Class II environmental protection, such as a of sterile HDs to be externally vented type B2 BSCs exhaust all air from the class I BSC or containment ventilat- to the outside.8 cabinet through an outside ventilation ed enclosure (CVE), must be used. A Class II BSCs. Class II BSCs have system, recirculating none of the HD- C-PEC for nonsterile use does not re- been used to provide product, per- contaminated air within the cabinet.81 quire unidirectional airflow because sonnel, and environmental protec- USP chapter 800 notes that these are the critical environment does not tion while compounding sterile HDs typically reserved for use with volatile need to be International Organiza- for over 3 decades. As specific and components. Class II type A1 BSCs are tion for Standardization classified.8 A sensitive analytic methods have been not appropriate for HDs, as they are class II BSC or a compounding asep- developed to measure representative not designed for integration with an tic containment isolator (CACI) may or marker HDs, studies have shown outside ventilation system to exhaust be used if it is dedicated to nonsterile continuing HD contamination on sur- to the outside.81 Class II type A2 and compounding. The C-PECs used for faces in HD work areas and detected B1 BSCs recirculate a portion of the manipulation of nonsterile HDs must HDs in the urine of healthcare work- contaminated air but are designed either be externally vented (preferred) ers exposed to these drugs while com- to connect to an outside ventilation or have HEPA filters in series as a con- pounding in a class II BSC.10,16,42,46 The system and exhaust the predomi- tainment system to exhaust into the exact cause of contamination has yet nant amount.81 A new class II BSC, work area.8 HEPA filters do not trap va- to be determined, but it is probably a the type C1, is currently available but pors and should not be used for han- combination of issues. Studies have is not certified by NSF International dling vaporous HDs, either as nonster- shown that (1) there is contamination (NSF).82,83 The class II type C1 cabinet ile APIs or in other nonsterile forms.6,75 on the outside of vials received from is a recirculating cabinet with outside USP chapter 800 allows a C-PEC that is manufacturers and distributors,65-69 exhaust capabilities. It may be useful usually used for sterile compounding (2) work practices required to maxi- in handling HDs, but additional test- (e.g., class II BSC or CACI, as defined mize the effectiveness of the class II ing and validation are needed to docu- by USP chapter 797, as revised in 2008) BSC are neglected or not taught,78,79 ment this. to be used for occasional nonsterile and (3) the potential vaporization of Most class II BSCs recirculate HD compounding if it is decontami- HD solutions may reduce the effec- contaminated air within the cabinet nated, cleaned, and disinfected before tiveness of the HEPA filter in provid- through HEPA filters, which may not resuming sterile compounding in that ing containment.75,80 Studies of sur- trap all HDs, allowing them to pass C-PEC.8 As cleaning and decontami- face contamination have discovered into the HEPA-filtered air.75,80,83 The nating a C-PEC has not been shown deposits of HDs on the floor in front class II BSC is designed with air ple- to be very effective, this is not a pre- of the class II BSC, indicating that nums that are unreachable for surface ferred option.73,74,76,77 The C-PEC used drug may have escaped through the decontamination; the plenum under for nonsterile compounding must be open front of the BSC onto contami- the work tray collects room dirt and placed in a C-SEC that has at least 12 nated gloves or the final product, or debris that mix with HD residue when ACPH, is externally vented, and is at into the air.10,42,46 Workers must under- the cabinet is operational.4 Drafts, negative pressure relative to adjacent stand that the class II BSC does not supply-air louvers, and other laminar areas.8 prevent the generation of contamina- airflow equipment placed adjacent to Sterile compounding. To com- tion within the cabinet and that the the class II BSC can interfere with the pound sterile HDs, as with any ster- effectiveness of such cabinets in con- containment properties of the inflow

2004 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS air barrier, resulting in contamina- Where volatile HDs are prepared, the contamination, but no wipe-down tion of the work environment.81,84 Ad- exhaust air from the compounding procedures have been studied. Sur- ditional information on classes and isolator should be appropriately re- face decontamination may be more types of BSCs is available through the moved by properly designed building readily conducted in CACIs than in Centers for Disease Control and Pre- ventilation.7,8 class II BSCs; however, opening the Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 vention (CDC).81 More information on Unlike class II BSCs, which have a front of the CACI to improve access the design and use of class II BSCs is standard to which they are designed may allow surface contamination to available from NSF/American Nation- and validated,83 there have been few escape the enclosure. Cleaning the al Standards Institute (ANSI) standard performance measures for the com- enclosure through the glove ports 49.83 Recommendations for use of pounding isolator. USP chapter 797 generally requires tools and may be class II BSCs are listed in Appendix B. created performance criteria for the difficult for some operators. (See Alternatives to class II BSCs. CACI, including unidirectional air- the Decontamination, Deactivation, USP chapter 800 identifies the class flow,7 and the Controlled Environment and Cleaning section below for more III BSC and the CACI as acceptable Testing Association has established information.) ventilated engineering controls for several performance guides, testing Recirculating CACIs depend on compounding sterile HDs. These of- requirements, and servicing instruc- high-efficiency (HEPA or ultra-low fer alternatives to the open-front tions that may be used with CACIs to penetrating air) filters. These filters class II BSC.8 ensure their effectiveness for the com- may not sufficiently remove volatile Class III BSC. By definition, a class pounding of HDs.85-88 HD contamination from the airflow. III BSC is a totally enclosed, ventilated For compounding sterile prepara- CACIs that discharge air into the work- cabinet of leak-tight construction.81 tions, the filtered air and airflow must room, even through high-efficiency Operations in the cabinet are con- achieve an ISO class 5 environment filters, present exposure concerns sim- ducted through fixed-glove access. within the CACI.7,89 The totally en- ilar to those of unvented class II BSCs. The cabinet is maintained under neg- closed design may reduce the escape If there is a possibility that the HDs ative air pressure. Supply air is drawn of contamination during the com- handled in them may vaporize, they into the cabinet through HEPA filters. pounding process, and the CACI may will not be contained in a filter.USP The exhaust air is treated by double be less sensitive to drafts and other chapter 800 requires outside exhaust.8 HEPA filtration or by HEPA filtration laminar airflow equipment. Issues CACIs used for compounding HDs and incineration. Class III cabinets unique to CACIs include pressure should be at negative pressure or use a are not exhausted through the gen- changes when accessing the fixed- pressurized airlock to the surrounding eral exhaust system. The class III BSC glove assembly, pressure changes in areas to improve containment. Some is designed for use with highly toxic the main chamber when accessing compounding isolators rely on a low- or infectious material. Because of the the antechamber (compounding iso- particulate environment rather than costs of purchasing and operating a lator pass-through), and ergonomic laminar airflow technology to pro- class III BSC, it is not commonly used considerations associated with a tect the sterility of the preparations for extemporaneous compounding of fixed-glove assembly. Compounding and are not recommended for com- sterile preparations.5 isolators must be continuously mon- pounding sterile hazardous prepara- CACI. A CACI is a form of com- itored for leaks in the gloves and the tions.8 Recommendations for use of pounding isolator specifically de- fixed-glove assembly. Glove changes class III BSCs and CACIs are summa- signed for compounding pharma- must be done routinely, and facilities rized in Appendix C. ceutical ingredients or preparations must have policies for the frequen- that provides worker protection from cy of such changes. As in all sterile C-SECs exposure to undesirable levels of HD compounding, the glove closest USP chapter 800 requires that airborne drug throughout the com- to the sterile preparation must be C-PECs used to compound sterile and pounding and material transfer proc- sterile. nonsterile HDs be located in a C-SEC, esses and provides an aseptic environ- CACIs, like class II BSCs, do not which may be either an ISO class 7 ment with unidirectional airflow for prevent the generation of contami- buffer room with an ISO class 7 an- compounding sterile preparations.7,8 nation within the cabinet work- teroom (preferred) or an unclassified Air exchange with the surrounding space, and their effectiveness in con- C-SCA.8 The C-SEC must be vented to environment should not occur unless taining contamination depends on the outside, be physically separated the air is first passed through a micro- proper technique.41,90,91 The potential from non-HD preparation areas, have bial retentive filter (HEPA minimum) for the spread of HD contamination appropriate ACPH, and be at negative system capable of containing airborne from the antechamber and main pressure to all adjacent areas. If the concentrations of the physical size and chamber of the CACI to the work- negative pressure in the C-SEC is sup- state of the drug being compounded. room may be reduced by surface de- plied either all or in part by the C-PEC,

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 2005 ASHP REPORTS HANDLING HAZARDOUS DRUGS the C-PEC must operate continuously.8 devices, not requiring premarket ap- able, they should meet the definition The C-PEC must also operate continu- proval.93 The FDA 510(k) process does of CSTDs established by NIOSH6 and ously if used for sterile compounding.8 not establish independent perfor- should be required to demonstrate The allowance for HD compounding mance standards for devices submit- their effectiveness in independent in a C-SCA is new, as this was not al- ted as “substantially equivalent” nor studies.8 CSTDs (or any other ancillary Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 lowed in USP chapter 797 and will be does it test or approve these devices. devices) are not a substitute for using allowed only after USP chapter 800 Based on a successful review of the a ventilated cabinet.6,8 takes effect.7,8 The beyond-use date manufacturer’s 510(k) submission, The use of ventilated engineering of all CSPs compounded in a C-SCA, FDA clears the new device for sale in controls during the compounding of however, must be limited as described the United States 93 Many devices mar- HDs provides protection for the work- in USP chapter 797.7,8 keted for i.v. compounding or admin- er as well as the sterile preparation. istration have been cleared by the FDA During the administration of HDs, Containment supplemental 510(k) process under various product there are no similar controls available. engineering controls codes. Many of the devices marketed For these reasons, USP chapter 800 USP chapter 800 describes a third and used for HD compounding are has determined that CSTDs should level of control, a containment sup- not CSTDs by definition and may not be used when compounding HDs and plemental engineering control, which be appropriate for HD use. FDA cre- that CSTDs must be used when ad- provides adjunct controls to offer an ated a product code, ONB, specifically ministering antineoplastic HDs when additional level of protection during for a closed antineoplastic and HD the dosage form allows and the device compounding or administration of reconstitution and transfer system.94 is physically or chemically compatible HDs.8 Although applications under this code with the HD to be used.8 The device most frequently dis- are not independently tested by FDA, USP chapter 800 notes that there cussed in this category is the closed- the application process is more strin- is no certainty that all CSTDs will system drug-transfer device (CSTD). gent for the manufacturer and the perform adequately, and, without a The NIOSH definition of a CSTD, ad- code specifically addresses antineo- standard for evaluating CSTD con- opted by USP chapter 800, is a drug plastics and HDs. Products that are tainment, users will have to rely on in- transfer device that mechanically pro- marketed as CSTDs but have not been dependent, peer-reviewed studies and hibits the transfer of environmental cleared by FDA under the product demonstrated contamination reduc- contaminants into the system and the code ONB should not be considered tion to evaluate performance claims.8 escape of HD or vapor concentrations CSTDs. outside the system.6,8 The continued Although some CSTDs have been PPE discovery of HD contamination in shown in peer-reviewed studies to PPE provides worker protection to compounding and administration limit the potential of generating aero- reduce exposure to HD aerosols and areas, despite adherence to HD safe sols and reduce HD contamination in residues. However, in the hierarchy handling guidelines, has generated the workplace, not all marketed CSTDs of controls, PPE is the least-effective an interest in CSTDs, especially for have been studied, and no surrogate measure for protecting workers.98 Ad- administration areas where C-PECs or marker HD has been shown to be ditional PPE may be required to han- are not available during HD adminis- superior in measuring CSTD effective- dle the HDs outside of a C-PEC, such tration. The initial CSTD, developed ness or has been universally adopted as treating a patient or cleaning a spill. in Europe, was tested in 1996–97 dur- for that purpose. The NIOSH topics The NIOSH list of antineoplastic and ing compounding and administra- page includes an expanded bibliogra- other HDs provides general guidance tion by 3 nurses for 1 year in an out- phy of publications related to CSTDs.95 on PPE for possible scenarios that patient setting. Compared to surface In the absence of a performance stan- may be encountered in healthcare contamination of similar work areas dard, NIOSH is attempting to develop settings.12 NIOSH has also created a reported in the literature, the closed protocols to test the containment per- Workplace Solution on PPE contain- system was more effective than the formance of both the physical barrier ing detailed recommendations with BSC in reducing contamination dur- type of CSTD and CSTDs designed to references.99 Disposable PPE must ing preparation.92 operate using air-cleaning technolo- not be reused. Reusable PPE, such as In originally defining the CSTD in gies.96,97 Difficulties encountered in a face shield or cartridge respirator, 2004, NIOSH did not specify design or this attempt include the selection of must be decontaminated and cleaned performance criteria for what consti- surrogates to represent HDs and the after use. USP chapter 800 has an ex- tutes an effective CSTD.6 A number of method to capture and analyze the tensive discussion of PPE and its ap- devices marketed as CSTDs have ap- surrogates. The NIOSH protocols are propriate use but requires that the peared since 2004. These devices are a positive step in evaluating these de- entity develop SOPs for PPE based on designated by FDA as class II medical vices. As other products become avail- its own safety plan and assessment of

2006 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS risk.8 The following summary of PPE tic HDs and reproductive risk–only tainer or tote for damage, as described use is not designed to replace or in- HDs and the catalog of formulations in USP chapter 800, and then deter- terpret the best practice mandates of of HDs similarly enlarged to encom- mine the appropriate PPE.8 NIOSH USP.7,8 pass APIs used in compounding, fi- also allows single gloves for handling Removal of PPE. PPE used to nal dosage forms of compounded HD intact, unit-dose oral agents when Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 compound HDs, dispose of HDs, and preparations, and manufactured HD no cutting or crushing is required.55 clean up an HD spill should be consid- products.8,55 NIOSH recommends double gloves for ered contaminated with HD residue. Although double gloving is re- spill control and for cleaning and dis- PPE used to administer HDs, perform quired by USP chapter 800 in only posal of HD waste and patient waste.55 patient care, or discard patient waste select circumstances,8 wearing 2 pairs USP chapter 800 and Table 5 of the should be considered contaminated of gloves allows removal of the outer current NIOSH HD list should be con- with HD residue and potentially con- glove while the skin of the hand and sulted for specific information about taminated with infectious material. wrist is still covered. Changing the glove use.8,55 Removal of PPE must be done cau- outer glove while retaining the in- ASTM International has developed tiously to avoid transferring contami- ner glove during any HD handling is testing standards for assessing the re- nation to skin, the environment, or a work practice that provides added sistance of medical gloves to perme- other surfaces that may be touched protection against skin contact with ation by chemotherapy drugs, ASTM with uncovered skin. Wearing double HDs. Many studies have shown that D6978-05 (2013).100 This standard tests gloves provides an additional barrier areas where HDs are handled have gloves for resistance to permeation to to possible contamination transfer as significant surface contamination a group of HDs selected for character- the hands are covered until the last and workers are at risk of absorbing istics of toxicity, diluent, and ability to item of PPE is removed. After any han- HDs through uncovered skin any time permeate standard gloving material, dling of HDs, the outer gloves should they come into contact with this con- among others. Gloves are not tested be removed 1 at a time with the con- tamination.10,11,21,43,46 A single, thicker for all known HDs because of the cost taminated glove fingers touching only glove, tested as a chemotherapy glove, and lack of assays for many drugs, so the outer surface of the other glove, may provide the same protection as 2 these drugs act as markers for perme- never the inner surface. The first glove pairs of chemotherapy gloves against ability. Gloves passing this ASTM stan- should be removed and then turned permeation during compounding and dard may be labeled as “chemotherapy inside out. Still wearing the inner, administration, but it does not pro- gloves.” ASTM F739-12e1 (2012) is also clean glove, personnel should place vide the protection of never having a permeation standard, but it is spe- the fingers underneath the wrist of the exposed skin in a contaminated area. cific neither to gloves nor to chemo- second, outer glove and roll the glove Double gloving and good work prac- therapy drugs and should not be used down, turning it carefully inside out to tices provide better protection. Facili- to test chemotherapy gloves.100-102 The avoid touching the outside. The face ties writing policies and procedures, performance requirement of ASTM shield, if worn, should be removed especially detailing work practices, F739-12e1 is only one tenth that of next, while avoiding contact with should consider requiring wearing ASTM D6978-05, and ASTM F739-12e1 the front. Personnel should then re- double chemotherapy gloves when is performed at room temperature move the gown, using care to avoid receiving and stocking HDs, select- rather than body temperature, which transfer of contamination to clothes ing HD packages for further handling, results in less drug permeation being and skin. They should then turn the handling drug waste and patient measured and less-protective gloves gown inside out, fold it tightly, and waste, cleaning spills, performing rou- to be marketed as chemotherapy discard it as trace waste. Other PPE tine cleaning with detergents and dis- gloves.100-102 Staff purchasing gloves (e.g., hair coverings, facemask, shoe infectants, and any situation in which and staff using them for handling HDs coverings) should then be carefully an exposed hand or wrist may create must verify that the gloves are tested removed, from least contaminated a risk of touch contamination with against ASTM D6978. USP chapter 800 to most contaminated. The inner HD residue on surfaces. NIOSH allows requires that chemotherapy gloves gloves should be removed last and single gloves for receiving, unpacking, must meet ASTM D6978.8 discarded in the HD disposal con- and placing HDs in storage.55 Because Many guidance documents have tainer. Hands should be washed with broken cartons and containers of HDs recommended gloves both for sterile soap and water. represent a major risk of worker expo- compounding and for any handling of Gloves. Gloves are essential when sure while receiving and unpacking, HDs be powder-free to avoid powder handling HDs. Glove use has been any package that does not appear in- particulates from contaminating ster- more clearly described by USP and tact should be handled with 2 pairs of ile processing areas and to prevent ab- NIOSH as the definition of HDs has chemotherapy gloves. Workers should sorption of HD contaminants, which expanded to include nonantineoplas- visually examine the shipping con- may increase the potential for dermal

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 2007 ASHP REPORTS HANDLING HAZARDOUS DRUGS contact.5 This issue was resolved when be sterile. Supplies of sterile ASTM When removing HD gloves, the FDA issued a ban on powdered gloves D6978-approved gloves must be kept contaminated glove fingers must only effective January 18, 2017.103 FDA near the C-PEC to allow changing of touch the outer surface of the glove, states that the use of powder on medi- the outermost glove as needed. never the inner surface. If the inner- cal gloves presents numerous risks to USP chapter 800 notes that che- most glove becomes contaminated, Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 patients and healthcare workers, in- motherapy gloves should be worn for both pairs of gloves must be changed. cluding inflammation, granulomas, handling all HDs, including nonan- Both the innermost and outermost and respiratory allergic reactions.103 tineoplastic HDs and for reproduc- gloves should be considered contami- As latex sensitivity is a concern tive risk–only HDs, and that 2 pairs of nated, and glove surfaces must never to healthcare workers and patients, chemotherapy gloves are required for contact the skin or any surface that gloves made of nitrile and neoprene administering antineoplastic HDs.8 may be touched by the unprotected have been tested against different Gloves should be inspected for visible skin of others. HD contamination may HDs, with nitrile demonstrating a defects before donning. When double be distributed to other surfaces dur- high resistance to permeation by mul- gloves are worn with a gown, the inner ing compounding, other handling, or tiple HDs.104-106 In a review of glove glove should be placed underneath glove removal and may be a source standards and studies done in the the gown cuff and the outer glove over of surface contamination and subse- European Union and United States, the gown cuff. There should be no skin quent dermal absorption of HDs by Landeck et al.107 determined that for exposed at the wrist. workers not actively involved in the gloves used for extended exposure to Based on the ASTM D6978 perme- compounding, administration, or HDs, double gloving, the use of thicker ability testing, the maximum recom- other tasks involving HDs or who are gloves, and frequent glove changes in- mended wear time for gloves is 30 not wearing PPE.11,21,109 Gloves used creased worker protection. They rec- minutes. Certain drugs may permeate to compound HDs in the class II BSC ommend regular glove changes every more quickly (e.g., , thio- should be placed in a sealable plastic 15–20 minutes with constant exposure tepa).100 When handling these drugs, bag for containment within the C-PEC to chemotherapy drugs.107 gloves should be changed according before disposal as contaminated USP chapter 800 requires that to the permeation time listed on the waste. The outermost glove attached gloves selected for use with HDs must glove packaging. Gloves should be to the class III BSC or CACI fixed glove meet ASTM D6978-05 (or its succes- removed immediately if torn, punc- or gauntlet must be removed from sor) and requires that 2 pairs of che- tured, or knowingly contaminated. the assembly and placed in a sealable motherapy gloves are used for com- The same wear-time restrictions ap- plastic bag for containment within the pounding sterile and nonsterile HDs. ply to the outermost glove in the C-PEC before disposal as contaminat- For sterile compounding, the out- class III BSC or CACI. ed waste. During compounding, HD ermost glove must be sterile.7,8 Dur- When compounding in a class II contamination may be transferred to ing sterile compounding in a class II BSC, gloves (at minimum the outer- the gloves or gauntlets and then trans- BSC, 2 pairs of ASTM D6978-approved most gloves) must be changed when- ferred to the surfaces of all items with- gloves are required, with the outer- ever it is necessary to exit and reenter in the C-PEC. Fixed-glove and gaunt- most pair being sterile. During sterile the BSC. Gloves worn during the ad- let surfaces must be cleaned after HD compounding in a class III BSC and ministration of HDs must be removed compounding to avoid the potential a CACI, both of which are equipped at the completion of administration, if spread and cross-contamination of with attached gloves or gauntlets, gloves are visibly damaged or contam- HD residue to other surfaces. All fi- the gauntlet, sleeve and fixed-glove inated, and before leaving the admin- nal preparations must be surface de- assembly must be cleaned and dis- istration area to prevent the spread contaminated while wearing ASTM infected before sterile compound- of HD residue to other areas. For the D6978-approved gloves to avoid ing using an appropriate cleaner and aseptic protection of sterile prepa- spreading contamination, and the disinfectant applied with a sterile rations, the outermost sterile gloves clean inner glove must be used to ap- wiper. The fixed glove, if disposable, must be sanitized with an appropri- ply labels. must be changed before compound- ate disinfectant (e.g., sterile isopropyl Proper hand hygiene must be ing and sanitized per the manufac- alcohol 70%) by wiping with a sterile practiced before donning and after turer’s instructions. A pair of sterile wiper saturated with the disinfectant removing any PPE. Hands should be ASTM D6978-approved gloves must when reentering the BSC. Personnel cleaned with soap and water after PPE be placed in the pass-through and should never spray anything on con- is removed. Sanitizing gels should not brought into the C-PEC work area and taminated gloves or any other poten- be used until hands are thoroughly donned over the glove connected to tially contaminated surface, as this cleaned of HD residue, as rubbing gels the gauntlet or over the fixed-glove may generate aerosols and spread HD into hands may increase the dermal assembly. The outermost glove must contamination.108 absorption of any HD residue.110

2008 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS

Recommendations for use of tamination, potentially contaminated HDs.111 Of a total of 18 contamination gloves are summarized in Appendix D. clothing must never be taken home.8 spots detected, 5 were present on the Gowns. Gowns are worn during There is no specific standard for gowns of nurses after drug adminis- the compounding of HD preparations gowns or gowning materials to be tration. No spots were discovered on to protect the preparation from the tested for permeation by HDs. ASTM the gowns of pharmacists after com- Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 worker, the worker from the prepara- F739-12e1 is a test method for per- pounding. In contrast, researchers tion, or both.5 Any sterile compound- meation by liquids and gases through using a more sensitive assay placed ing requires PPE to protect the asep- protective clothing materials under pads in various body locations, both tic compounding environment from conditions of continuous contact, but over and under the gowns used by the biological contamination that is it does not specify drugs or concen- the subjects during compounding presented by the worker. The require- trations to be tested and has no per- and administration of cyclophospha- ments of both USP chapters 797 and formance standard for an acceptable mide and ifosfamide.112 Workers wore 800 must be met for sterile compound- resistance to HD permeation.101 Some short-sleeved nursing uniforms, dis- ing.7,8 USP chapter 800 requires gowns; gowns are tested using the ASTM posable or cotton gowns, and vinyl or head, hair, and shoe covers; and 2 F739 parameters and the chemother- latex gloves. More contamination was pairs of chemotherapy gloves for com- apy drugs and concentrations from found during compounding than ad- pounding sterile and nonsterile HDs.8 D6978.100 This practice has not been ministration. Contamination found HD compounding in an enclosed en- studied for effectiveness or safety. HD on the pads placed on the arms of vironment, such as a class III BSC or a gowns should be coated and labeled as preparers was consistent with the de- CACI, has not been exempted from the impervious per manufacturer testing. sign and typical work practices used gowning requirement. USP chapter 800 Gowns should be changed per the in a class II BSC, where the hands and further requires that gowns that show manufacturer’s recommendations. If arms are extended into the contami- resistance to permeability by HDs be there is no specific information, coat- nated work area of the cabinet. Re- worn when administering injectable ed gowns should be changed every markably, 1 preparer had contamina- antineoplastic HDs. Additional policies 2–3 hours.5,8 Gowns must be changed tion on the back of the gown, possibly for gowns, as for other PPE, must be es- immediately after a spill or splash. indicating touch contamination with tablished by the entity and delineated Contamination of gowns during glove the class II BSC during removal of the in the procedures. changes must be a consideration. final product. Pads were used in 2 ad- The selection of gowning materi- If the inner pair of gloves requires ditional studies to assess HD contam- als depends on the goal of the proc- changing, a gown change may be ination on the workers’ bodies.113,114 ess. Personal protective gowns are needed. Gowns worn as barrier pro- Pads placed on the arms and chest recommended during the handling tection in the handling of HDs must of workers involved in compounding of HD preparations to protect the never be worn outside the immedi- and administration showed evidence worker from inadvertent exposure to ate handling areas. Gowns worn dur- of touch contamination with HD extraneous drug particles on surfaces ing administration should be changed residue on the studied areas. Without or generated during the compound- when leaving the patient care area protective gowns, the HD residue may ing process and leakage of any liquid and immediately if contaminated. have contaminated skin or worker forms of HDs. HD gowns must be dis- Gowns should be removed carefully clothing, resulting in drug uptake or posable and shown to resist HD per- and properly disposed of as trace- transfer. meability. Disposable gowns made contaminated waste to avoid becom- Recommendations for the use of of polyethylene-coated polypropyl- ing a source of contamination to other gowns are summarized in Appendix E. ene (e.g., spunbond/meltblown/ staff and the environment.5,6 Gowns Eye and face protection. Many spunbond) provide better protection used for cleaning or spill management HDs are irritating to the eyes and mu- than uncoated gowns.5,8 Basic char- may be more heavily contaminated. cous membranes. Appropriate eye and acteristics for HD gowns include that These gowns should be contained in face protection must be worn when they close in the back with no open sealable bags and discarded as bulk there is a risk of spills or splashes, front, have long sleeves with tight- hazardous waste. when HD waste materials are handled, fitting elastic or knit cuffs to fit over Researchers have looked at or when working outside of a C-PEC gloves, and have no seams or closures gown contamination with fluores- (e.g., administration in the surgical to allow powder or liquid HD residue cent scans, high-performance liquid suite, working at or above eye level, to pass through.5,8 Washable garments chromatography, and tandem mass cleaning a spill). Face shields should (e.g., laboratory coats, scrubs, cloth spectrometry.111,112 In 1 study, re- be used in combination with goggles gowns) absorb fluids and provide no searchers scanned nurses and phar- to provide a full range of protection barrier against HD absorption and macists wearing gowns during the against splashes to the face and eyes. permeation.5,8 To avoid spreading con- compounding and administration of Although face shields provide im-

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 2009 ASHP REPORTS HANDLING HAZARDOUS DRUGS proved skin protection, face shields iting the compounding area. Gloves Luer-Lok connections on syringes and alone do not deliver full eye and face are required, and care must be taken, on all compounding and ancillary de- protection.8,99 Goggles must be used when removing hair or shoe covers, to vices must be used whenever possible when eye protection is required.8 prevent contamination from spread- for manipulating HDs, as they are less Eyeglasses alone or safety glasses ing to uncontaminated areas. Hair likely to separate during compound- Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 with side shields do not sufficiently and shoe coverings used in the HD ing and administration. protect the eyes from splashes and handling areas must be contained, Spiking an i.v. set into a solution therefore are not suitable when han- along with used gloves, and discarded containing HDs or priming an i.v. set dling HDs. A full-face piece respira- as trace contaminated waste in the ap- with HD solution in an uncontrolled tor provides complete eye and face propriate waste receptacle. Shoe cov- environment must be avoided. One protection.8 erings that are overtly contaminated, recommendation is to attach and Respirator protection. Staff un- as in spill cleanup, should be disposed prime the appropriate i.v. set to the packing HDs that are not contained of as hazardous waste. final container in the C-PEC before in plastic should wear an elastomeric adding the HD. CSTDs should achieve half-mask with a multigas cartridge Work practices a dry connection between the ad- and P100 particulate filter.8 All work- Compounding sterile HDs. Work ministration set and the HD’s final ers who may use a respirator must be practices for the compounding of ster- container. This connection allows the fit-tested by a certified fit tester and ile HDs differ somewhat with the use container to be spiked with a second- instructed on the use of the appropri- of a specific C-PEC. Good organiza- ary i.v. set and the set to be primed by ate respirator according to the OSHA tional skills are essential to minimize backflow from a primary non-HD so- Respiratory Protection Standard.70,71 contamination and maximize pro- lution. This process may be done out- A respirator of the correct size and ductivity. All activities not requiring side the C-PEC, reducing the potential suitable to the aerosol size, physical a critical environment (e.g., check- for surface contamination of the i.v. state (i.e., particulate or vapor), and ing labels, performing calculations) set during the compounding process. concentration of the airborne drug should be completed before accessing Only CSTDs that have been tested to must be available at all times. Surgi- the C-PEC. All items needed for com- achieve a dry connection may be con- cal masks do not provide respiratory pounding must be gathered before sidered for use with this technique. protection and therefore should on beginning work to eliminate the need Personnel should avoid placing the i.v. no occasion be used when respirato- to exit the C-PEC once compounding set on the surface of the C-PEC during ry protection is required for HDs.6,8 has begun. Two pairs of ASTM D6978- compounding to reduce the trans- N95 respirators offer no protection approved gloves should be worn to fer of HD residue from the surface against gases and vapors and negli- gather HD vials, due to the frequent of the C-PEC to the surface of the i.v. gible protection against direct liquid findings of HD residue on vials, and set. Care must also be taken to avoid splashes.71 A surgical N95 respirator 1 or 2 pairs of ASTM D6978-approved contaminating the tubing with HD provides the respiratory protection of gloves may be worn to gather other residue from the surface of the gloves. an N95 respirator and, like a surgical supplies. All areas where HDs are re- A new i.v. set must be used with each mask, provides a barrier to splashes, ceived, stored, handled, and wasted dose of HD. Once attached, the i.v. set droplets, and sprays around the nose have been shown to be contaminated must never be removed from an HD and mouth.8 with HD residue. Prudent practice is dose, thereby preventing the residual Shoe and hair coverings. Shoe to wear 2 pairs of gloves.6,8,10,11,20,21,43 Af- fluid in the bag, bottle, or tubing from and hair coverings must be worn ter tasks are completed, these gloves leaking and contaminating personnel throughout the sterile compounding should be carefully removed and dis- and the environment. process to minimize particulate con- carded as contaminated waste. Fresh In order to avoid inadvertent con- tamination of the critical work zone ASTM D6978-approved gloves must tamination of the outer surface of the and the preparation.7 With the poten- be donned before aseptic manipula- bag by transfer of HD residue, trans- tial for HD contamination on the floor tion. For the compounding of sterile port bags must never be placed in the in the compounding and administra- HDs, the ASTM D6978-approved glove C-PEC work area during compound- tion areas, donning of 2 pairs of shoe closest to the sterile preparation must ing. Final HD preparations must be coverings, as the contamination- be sterile. surface decontaminated after com- control mechanism, must occur. Con- Only supplies and drugs essential pounding is complete. In any type of taminated shoe covers must never be to compounding the dose or batch C-PEC, clean ASTM D6978-approved worn outside of the immediate HD should be placed in the work area gloves must be worn when labeling area to avoid spreading contamina- of the C-PEC. C-PECs should not be and placing the final HD preparation tion.8 The outer shoe covers must be crowded to avoid unnecessary HD into the transport bag. Handling final removed with gloved hands when ex- contamination and disrupting airflow. preparations and transport bags with

2010 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS gloves contaminated with HD residue near the class II BSC to allow changes use of a large pad that might block the will result in the transfer of the con- of gloves during sterile HD compound- front or rear grilles must be avoided. In tamination to other workers. Person- ing. The class II BSC work surface addition, because a pad may absorb nel should don clean ASTM D6978- should be cleaned of surface contami- small spills, it may become a source approved gloves whenever there is a nation with detergent, sodium hypo- of HD contamination for anything Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 doubt as to the cleanliness of the inner chlorite, and neutralizer or an inde- placed upon it. Preparation pads are or outer gloves. pendently tested alternative cleaner. not readily decontaminated and must Working in any C-PEC. With Between cleanings, the compounding be replaced and discarded after prep- or without ancillary devices (e.g., surface must be disinfected with ster- aration of each batch and frequently CSTDs), none of the available ventilat- ile 70% isopropyl alcohol applied with during compounding. The mat should ed engineering controls can provide a sterile wiper, never using a spray. be changed immediately if a spill oc- 100% protection for the worker. Per- For the class II BSC, the front shield curs.8 Equipment for HD compound- sonnel must recognize the limitations must be lowered to the proper level to ing must be dedicated. Work practices of the equipment and address them protect the face and eyes. The opera- for sterile compounding of HDs must through appropriate work practices.4,5 tor should be seated so that his or her adhere to USP chapters 797 and 800.7,8 PPE use with C-PECs is addressed by shoulders are at the level of the bottom More information on the design and USP8 and NIOSH55 (see also the PPE of the front shield. All drugs and sup- use of class II BSCs is available from section above). The effectiveness of plies needed to aseptically compound the CDC81 and NSF/ANSI Standard C-PECs in containing HD contamina- a dose or batch should be gathered 49-2016.83 tion depends on proper technique.47 and disinfected with sterile 70% iso- Class III BSCs and CACIs. At least 1 HD contamination from the work propyl alcohol before being placed in pair of ASTM D6978-approved gloves area of the CACI (e.g., on the surfac- the direct compounding area (DCA) of should be worn to prepare for work es of the final preparation) may be the C-PEC. Exiting and reentering the in a class III BSC or a CACI. Using 2 brought into the antechamber or air- work area should be avoided. Being pairs of gloves allows changing only locks of the CACI and ultimately into careful not to place any sterile objects the outer pair while handling vials the workroom environment. Surface below them, i.v. bags and bottles may and supplies. Wearing gloves, work- decontamination of the preparation be hung from the bar. All items must ers must gather all drugs and supplies before removal from the CACI’s main be placed well within the class II BSC, needed to aseptically compound chamber should reduce the HD con- away from the unfiltered air at the an HD dose or batch, sanitize them, tamination that could be transferred front barrier. By design, the intended and ready them for placement into to the workroom, but no wipe-down work zone within the class II BSC is the antechamber of the compound- procedures for final preparations have the area between the front and rear air ing isolator. Supplies and drugs in been studied. Surface contamination grilles. The containment characteris- the antechamber are disinfected with may be removed by using isopropyl tics of the class II BSC are dependent sterile 70% isopropyl alcohol when alcohol, sterile water, peroxide, or so- on the airflow through both the front taken into the main chamber (the dium hypochlorite solutions on dis- and back grilles; these grilles should DCA) of the compounding isolator, posable pads and wiping the surface never be obstructed. Due to the design where the drug and supplies are used of the final preparation, provided the of the class II BSC, the quality of HEPA- to compound the dose. The contami- packaging is not permeable to the so- filtered air is lowest at the sides of the nated supplies are removed using lution and the labels remain legible work zone, so manipulations should the closed trash system of the com- and intact. be performed at least 6 inches away pounding isolator, if so equipped, Recommendations for working in from each sidewall in the horizontal or sealed into a transport bag and C-PECs are summarized in Appendix F. plane. A small waste-sharps contain- removed via the antechamber for Class II BSCs. Class II BSCs use er may be placed along the sidewall disposal as contaminated waste. The unidirectional, vertical-flow, HEPA- toward the back of the BSC. Per USP dose is then labeled and placed into a filtered air (ISO class 5) as their con- chapter 800, a plastic-backed prepara- sealable bag for transport in the ante- trolled aseptic environment. Be- tion mat should be placed on the work chamber. The transport bag is never fore beginning an operation in a surface of a C-PEC before compound- placed in the DCA of the compound- class II BSC, personnel should follow ing HDs.8 One study has suggested that ing isolator to avoid contaminating the hand-washing and PPE require- a plastic-backed absorbent prepara- the outer surface. ments of USP chapters 797 and 800.7,8 tion pad in a class II BSC may inter- For sterile compounding, the For cleaning the class II BSC, non- fere with airflow,112 but another study gloves closest to the sterile prepara- sterile ASTM D6978-approved gloves determined that use of a flat firm pad tion must also be sterile.7,8 Sterile are appropriate. Sterile ASTM D6978- that did not block the grilles of the gloves must be placed into the ante- approved gloves must be available cabinet had no effect on airflow.115 The chamber to be transferred into the

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 2011 ASHP REPORTS HANDLING HAZARDOUS DRUGS

DCA. Additional work practices may barrel.116 For reconstitution, once the with sterile 70% isopropyl alcohol, include cleaning off the gloves or diluent is drawn up, the needle is care- a 5-µm filter needle or straw should gauntlets and final preparation after fully inserted into the upright HD vial be attached to a syringe that is large initial compounding and before han- stopper, being careful not to core the enough that it will be not more than dling the label and sealable transport stopper. The syringe plunger is then three-fourths full when holding the Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 bag. Care must be taken when trans- pulled back (to create a slight nega- drug. The fluid should then be drawn ferring products out of the antecham- tive pressure inside the vial), so that through the filter needle or straw and ber and disposing of waste through air is drawn into the syringe. Small cleared from the needle and hub. After the antechamber or trash chute to amounts of diluent should be trans- this, the needle or straw is exchanged avoid accidental contamination. ferred slowly into the HD vial as equal for a needle of similar gauge and Aseptic technique. Stringent volumes of air are removed. The nee- length; any air and excess drug should aseptic technique, described by dle should be kept in the vial, and the be ejected into a sterile vial (leaving Wilson and Solimando116 in 1981, contents should be swirled carefully the desired volume in the syringe); remains the foundation of any pro- until dissolved. For a liquid HD, the aerosolization should be avoided. The cedure involving the use of needles vial is kept upright while a syringe and drug may then be transferred to an and syringes in manipulating ster- needle are prepared. A slightly smaller i.v. bag or bottle. If the dose is to be ile dosage forms. This technique, amount of air than the amount of the dispensed in the syringe, the plunger when performed in conjunction with required HD dose is drawn into the sy- should be drawn back to clear fluid negative-pressure technique, mini- ringe. The needle is inserted into the from the needle and hub. The needle mizes the escape of drug from vials vial stopper, being careful not to core should be replaced with a locking cap, and ampules. Needleless devices have the stopper, and the vial is inverted and the syringe should be surface de- been developed to reduce the risk with the syringe and needle inserted. contaminated and labeled. of blood-borne pathogen exposure The proper amount of drug solution Training and demonstration of through needle sticks. None of these should be gradually withdrawn while competence. The OSHA HCS and devices has been tested for reduction equal volumes of air are exchanged USP chapter 800 require employee of HD contamination, and the appro- for solution. The exact volume needed training for the tasks that will be priateness of these devices in the safe must be measured while the needle is performed as part of the safety pro- handling of HDs has not been deter- in the vial, and any excess drug should gram.8,57 The HCS details the require- mined. CSTDs have been developed remain in the vial. With the vial in the ments for worker information and to reduce the release of HD residue upright position, the plunger should training in paragraph H of the HCS during compounding, but not all HDs be drawn back past the original start- regulation.57 In the 2008 revision of or all types of sterile compounding ing point to again induce a slight USP chapter 797, which includes HDs, are compatible with CSTDs. Stringent negative pressure before removing the training requirements note that aseptic technique using needles and the needle. The needle hub should be compounding personnel of reproduc- syringes is a necessary skill, especially clear of drug solution before the nee- tive capability must confirm in writing for those occasions when no ancillary dle is removed. that they understand the risks of han- device is available or appropriate. If an HD is transferred to an i.v. dling HDs.7 This requirement is also In reconstituting HDs in vials, it is bag, care must be taken to puncture in USP chapter 800.8 ONS provides an critical to avoid pressurizing the con- only the septum of the injection port excellent example of a worker agree- tents of the vial. Pressurization may and avoid puncturing the sides of the ment to handle HDs in the 3rd edi- cause the drug to spray out around port or bag. After the drug solution is tion of Safe Handling of Hazardous the needle or through a needle hole injected into the i.v. bag, the i.v. port, Drugs.110 or a loose seal, aerosolizing the HD container, and set (if attached by phar- Personnel must be trained before into the work zone. Pressurization macy in the C-PEC) should be surface handling HDs as part of their job re- can be avoided by creating a slight decontaminated. Wearing clean gloves sponsibilities.8,57 Staff handling HDs negative pressure in the vial. Too (or the inner glove), personnel should must demonstrate competency before much negative pressure, however, label the final preparation, including commencing responsibilities and at can cause leakage from the needle an auxiliary warning, and cover the in- least every 12 months thereafter.8 All when it is withdrawn from the vial. jection port with a protective seal. The staff who will be compounding HDs The safe handling of HD solutions in final container should be placed into must be trained in the stringent asep- vials or ampules requires the use of a sealable bag to contain any possible tic and negative-pressure techniques a syringe that is no more than three- leakage.4 necessary for working with sterile HDs fourths full when filled with the solu- To withdraw HDs from an ampule, as well as all primary, secondary, and tion, which minimizes the risk of the the neck or top portion should be gen- supplementary engineering controls.8 plunger separating from the syringe tly tapped.116 After the neck is wiped Once trained, staff must demonstrate

2012 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS competence by an objective method, tion. A class I BSC or CVE is accept- sterile HDs, measurable drug levels and competency must be reassessed able equipment for this task. A CACI have been found in workers, most on a regular basis.117 Additional train- or a class II BSC may also be used if it likely due to contact of uncovered ing should be carried out whenever is dedicated to nonsterile compound- skin with drug-contaminated surfac- new equipment or procedures are put ing. USP chapter 800 allows a C-PEC es.21,46 Drug residue generated in any Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 in place. All training and competency used for sterile HD compounding to task may be found on work surfaces testing must be clearly documented as be used for nonsterile HD compound- and result in a potential occupational part of the worker’s safety record.8,57 ing, provided that the C-PEC is decon- exposure. Work practices and clean- Compounding and handling of taminated, cleaned, and disinfected ing procedures must be in place to at nonsterile HD dosage forms. Non- before resuming sterile compounding least reduce this exposure. Procedures sterile compounding of HD dosage in that same device. As noted above, for nonsterile HD compounding and forms must adhere to USP chapter 795 cleaning and decontaminating a other handling, as well as the appro- and USP chapter 800.8,61 Best practices C-PEC has not been shown to be very priate use of equipment (C-PECs and and mandates for other activities in- effective, making this an undesirable other devices) for this purpose, must volved in handling of nonsterile HD solution.73,74,76,77 be developed to avoid the release of forms (e.g., tablets, oral liquids) are Nonsterile HD dosage forms, like aerosolized powder or liquid into the provided in USP chapter 800.8 Guid- oral HD capsules or tablets, vary in environment during manipulation of ance for PPE when handling nonster- their risk of causing occupational HDs. ile HD dosage forms is available from exposure. The level of risk, however, Recommendations for preparation NIOSH.55 depends on the tasks required to pre- and handling of nonsterile HD dosage Although nonsterile dosage forms pare and dispense the doses. Manual forms are summarized in Appendix G. of HDs contain varying proportions counting of solid medications may be Decontamination, deactivation, of drug to nondrug (nonhazardous) problematic if, for example, repeated cleaning, and disinfection. All components, there is the potential handling of a large container of tablets guidelines agree that decontamina- for personnel exposure to and envi- has created a loose powder or residue tion of areas where HDs are stored, ronmental contamination with the of tablet dust. Exposure to the dust compounded, administered, wasted, hazardous components if HDs are or residue may present a risk of pow- or otherwise handled is critical to handled (e.g., packaged) by pharmacy der inhalation or skin contact. USP reduce the levels of HD residue on staff. Most HDs are not available in chapter 800 notes that an assessment various surfaces.5,6,8,110,120 All areas liquid formulations; however, such of risk should be conducted to deter- where HDs are handled and all reus- formulations are often prescribed for mine the appropriate containment able equipment and devices must be small children and adults with feed- strategies for the HD tasks required of decontaminated. Decontamination ing tubes. Recipes for extemporane- the worker.8 occurs by inactivating, neutralizing, or ously compounded oral liquids may There are risks associated with au- physically removing HD residue from start with the parenteral form or an tomatic pill counters, especially high- nondisposable surfaces (e.g., stain- API, or they may require that tablets speed delivery devices. One study less steel C-PECs) and transferring it be crushed or capsules opened. Tablet studied a number of drugs dispensed to absorbent, disposable materials trituration has been shown to cause in this manner and found measur- (e.g., wipes, pads, towels) appropriate fine dust formation and local environ- able drug dust concentrations in the to the area being cleaned. The decon- mental contamination.118 Healthcare air surrounding such devices.119 Pill taminating, deactivating, cleaning, personnel should avoid manipulating dust was generated in a variety of and disinfecting agents selected must HDs (e.g., crushing tablets, opening worker-related tasks, such as empty- be appropriate for the type of HD con- capsules) if possible. Liquid formula- ing and refilling the drugs in the de- taminants, location, and surfaces to tions are preferred if solid oral dosage vice canisters.119 Cleaning the device be cleaned. Consult manufacturer or forms are not appropriate for the pa- or the canisters using compressed air supplier information for compatibil- tient. If HD dosage forms do require produced the highest amount of con- ity with cleaning agents used.8 Agents manipulation such as crushing tablets tamination in the air. The researchers used for decontamination, deactiva- or opening capsules for a single dose, found that workers directly involved tion, and cleaning should be applied personnel must don appropriate PPE with the automatic pill counters and through the use of wipes wetted with and use a plastic pouch to contain any those who hand-filled prescriptions appropriate solution and not deliv- dust or particles generated. were exposed to higher air concen- ered as a spray to avoid aerosolizing USP chapter 800 requires that trations of tablet fillers, like lactose, and/or spreading HD residue. compounding of nonsterile HDs be than workers who did other jobs such Cleaning processes must be vali- performed in a C-PEC that provides as administrative or office work.119 In dated for solutions and methods by environmental and personnel protec- studies of surface contamination with surface wipe sampling of HDs that

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 2013 ASHP REPORTS HANDLING HAZARDOUS DRUGS have appropriate assays.73,74,76,77,121-124 tralizer was used in this study). Solu- Decontamination of C-PECs In addition, sterile compounding (ISO tions containing anionic surfactants should be conducted per manufac- 5) areas and devices must be subse- were very effective cleaners and had turer recommendations. The SDS for quently disinfected.7,8 Appropriate a high safety ratio but did not deacti- many HDs recommends sodium hy- preparation of materials used in com- vate any HD. A second research team pochlorite solution as an appropriate Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 pounding before introduction into the used similar solutions on deactivating agent.125,126 Research- C-PEC, including spraying (for non- and fluorouracil and found that these ers have shown that strong oxidizing HD-contaminated supplies) or wiping cleaning procedures were able to re- agents, such as sodium hypochlorite, with sterile 70% isopropyl alcohol or duce HD contamination but did not are effective deactivators of many appropriate disinfectant, is also nec- completely eliminate it.124 These re- HDs.125 There are commercially avail- essary for sterile compounding.7 searchers concluded that it might be able products that provide a system All personnel who perform decon- more effective to adapt cleaning pro- for decontamination and deactivation tamination, deactivation, cleaning, cedures to the variety of drug com- using sodium hypochlorite, detergent, and disinfection activities must be pounds and surface types rather than and thiosulfate to neutralize the hypo- trained in appropriate procedures to continue with a singular approach.124 chlorite and deactivate other HDs.73 protect themselves and the environ- The 2 studies also examined re- Other nonchlorine bleach commer- ment from contamination.7,8 Proper moving HD contamination from glass cial disinfectant and sporicidal clean- PPE must be worn when perform- surfaces.76,124 The cleaning agents and ers may provide appropriate decon- ing these tasks (see the PPE section application methods may be useful tamination from HDs.127,128 Although above). All disposable materials must in decontaminating HD vials before it is not possible to perform analysis be discarded to meet state and fed- placing them into the C-PEC. The out- for all of the HDs, a selection of dif- eral Environmental Protection Agen- er surface of HD vials has been shown ferent chemical HDs with different cy (EPA) regulations and the entity’s to be contaminated with HD resi- diluents may provide sufficient mark- policies.8 due.65-69 The amount of HD contami- ers of the type of contaminants on a Decontamination, deactivation, and nation placed into the C-PEC may be given surface. The manufacturer of cleaning. Decontamination may be reduced by surface decontamination the deactivating cleaner should pro- defined as cleaning or deactivating. (i.e., wiping down) the HD vials. Care vide independent laboratory analysis Deactivating an HD is preferred, but must be taken to avoid damaging the and documentation of effective clean- no single process has been found information on the vial label. ing. A decontamination (cleaning/ to deactivate all currently available In a 2015 study, 70% isopropyl al- deactivating) process should include HDs from different surface materi- cohol was compared to sodium do- 1 or more cleaning or deactivating als.76,77,121 A 2013 study created terms decyl sulfate in 20% isopropyl alcohol agents and the method used to apply to clarify the types of HD decontami- for the routine decontamination of 10 it and the use of a neutralizer or rinse nants tested on glass and stainless antineoplastic agents from the surfac- step, if needed. The entire process steel as elimination type (cleaners) es of U.K.-designed BSCs.77 This study should be validated by wipe sampling and degradation type (deactivators).76 concluded that 70% isopropyl alcohol the various surfaces to determine Elimination-type solutions dissolve was only 49% efficient at achieving de- whether the HD has been removed. As chemical products on surfaces, and contamination for the 10 antineoplas- there are many types of chemical HDs, degradation-type solutions react with tic agents tested. The sodium dodecyl analysis of a number of them, prefer- the chemical structure of HD com- sulfate–20% isopropyl alcohol solu- ably various types, would be needed pounds, leading to their degradation tion averaged 82% overall; however, to validate a given process. and formation of noncytotoxic com- and demon- A ventilated cabinet that runs pounds. Elimination-type detergents, strated cleaning efficacies lower than continuously should be cleaned be- solutions, solvents, and surfactants 20% to both tested solutions. There- fore the day’s operations begin and and degradation-type cleaners were fore, the use of alcohol for disinfect- at regular intervals or when the day’s applied to stainless steel and glass ing stainless steel surfaces may result work is completed. USP chapter 800 surfaces that were contaminated with in the spread of contamination rather further states that the work surface of 10 HDs and removed.76 Wipe samples than any actual cleaning.77 Additional the C-PEC must be decontaminated were collected from the surfaces and considerations with sodium dodecyl between the compounding of differ- analyzed for HD residue. All tested sulfate–isopropyl alcohol 20% include ent HDs.8 The C-PEC must be decon- decontamination agents reduced the whether a rinse is needed with sodium taminated at least daily (when used), HD residue on the surfaces, but none dodecyl sulfate and that 20% isopro- anytime a spill occurs, before and af- totally removed it. Sodium hypochlo- pyl alcohol is insufficient as a disinfec- ter certification, anytime power inter- rite was found to be very effective but tant, requiring additional application ruption occurs, and if the ventilation damaged the stainless steel (no neu- of an effective disinfecting solution. device is moved.8 Ventilated C-PECs

2014 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS

(i.e., class II and III BSCs and some HDs found the incidence and amount eas even though they are transported CACIs) have air plenums that handle of contamination from marker drugs in a sealable plastic bag or container. contaminated air. These plenums are cyclophosphamide and fluorouracil If HDs are being prepared or admin- designed for fumigation of the con- were higher than previously reported istered in a nontraditional area (e.g., tamination from biological agents in studies that examined overall con- home setting, operating room, pro- Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 traditionally handled in the BSCs. The tamination in the infusion area.10,42 cedure area, radiology or unusual plenums are not designed for surface Practices for administration of HDs patient care area), a spill kit and res- decontamination of drug or nonbio- must protect patients, workers, and pirator must be obtained by the drug logical residue, and many of the con- the environment.6,8,110,120 The need for handler. Signs must be available to taminated surfaces (plenums) cannot more protection in the infusion area is warn of restricted access to the spill be reached for surface cleaning.4,5,81 addressed in USP chapter 800, which area.8 The area under the C-PEC work tray provides direction on improved prac- Only trained workers with ap- should be cleaned at least monthly to tices, including the required use of a propriate PPE and respirators should reduce the contamination level in the CSTD for administration of antineo- attempt to manage an HD spill. All BSCs and CACIs where appropriate.4 plastic HDs when the dosage form workers who may be required to clean Disinfection. The selection and use allows.8 up a spill of HDs must receive proper of disinfectants in healthcare facilities Policies and procedures govern- training in spill management and in are guided by several properties, such ing the administration of HDs must the use of PPE and NIOSH-certified as microbicidal activity, inactivation be jointly developed by nursing and respirators.70,71 Policies and proce- by organic matter, residue, and shelf pharmacy for the mutual safety of dures should describe how to estab- life. Many disinfectants registered by healthcare workers. These policies lish access to workers trained to the EPA are 1-step disinfectants, formu- should supplement policies designed OSHA Hazardous Waste Operations lated to be effective in the presence to protect patient safety during ad- and Emergency Response Standard of light-to-moderate soiling without a ministration of all drugs. All policies who may provide spill management precleaning step. However, when the affecting multiple departments must in the event of a large spill.130 surface to be disinfected has heavy be developed with input from man- The circumstances and handling soiling, a cleaning step is recommend- agers and workers from the affected of spills should be documented. Staff ed before the application of the dis- areas. Extensive nursing guidelines for and nonemployees exposed to an HD infectant. Trained compounding per- the safe and appropriate administra- spill should also complete an incident sonnel are responsible for developing, tion of HDs have been developed by report or exposure form and report to implementing, and practicing the pro- ONS110,120 and USP.8 Guidance on best the designated emergency service for cedures for cleaning and disinfecting practices for HD administration may initial evaluation. the DCAs written in the SOPs.7 A 2013 also be found on the OSHA safety and All spill cleanup materials, includ- study demonstrated the importance health topics page on HDs.13,14 ing PPE used for spill management, of SOPs by demonstrating that the ef- Recommendations for reducing must be disposed of as hazardous ficacy of chemical decontamination of exposure to HDs during administra- waste in accordance with EPA Resource HD work surfaces depends not only tion in all practice settings are listed in Conservation and Recovery Act (RCRA) on the cleaning solution used but also Appendix H. regulations.131,132 Spill cleanup materi- on the cleaning protocol.122 It is neces- Spill management. Policies and als must not be discarded as chemo- sary to adapt the protocol to the sur- procedures must be developed to at- therapy waste or biohazard waste. Ad- face to clean, and it must be standard- tempt to prevent spills and govern the ditional information on spill control ized and validated.124 Cleaning and cleanup of HD spills. Written proce- practices is available on the OSHA disinfecting agents are to be used with dures must specify who is responsible Safety and Health Topics page.13,14 careful consideration of compatibili- for spill management and must ad- Recommendations for spill clean- ties, effectiveness, and inappropriate dress the size and scope of the spill. up procedure are summarized in or toxic residues.7 Spills must be contained and cleaned Appendix J. Administration of HDs. Studies of up immediately by trained workers. Worker contamination. Pro- infusion areas where HDs are admin- Spill kits containing all of the cedures must be in place to address istered have demonstrated significant materials needed to clean up spills worker contamination, and protocols HD surface contamination, which cre- of HDs should be assembled or for medical attention must be devel- ates exposure risks for nurses, other purchased (Appendix I). These kits oped before the occurrence of any workers, patients, and visitors to these should be readily available in all areas such incident. OSHA requires suit- areas.10,11,21,46,129 A 2017 study129 that where HDs are routinely handled. A able facilities for quick drenching or measured surface contamination di- spill kit should accompany delivery flushing of the eyes and body where rectly related to the administration of of injectable HDs to patient care ar- workers may be exposed to injurious

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 2015 ASHP REPORTS HANDLING HAZARDOUS DRUGS corrosive materials.133 Limitations on handling, containment, and disposal organization is no longer disposing of having running water and drains in as RCRA hazardous waste. any waste drugs by discarding them HD compounding areas conflict with Every state except Iowa and Alaska down the sewer drain, those listed in these requirements. An alternative is is authorized to implement its own table 2, group 2, and table 3, group 3, to have a portable emergency eyewash hazardous waste program, and these of the NIOSH HD list55 could be man- Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 station or emergency kits containing programs may be more stringent than aged as nonhazardous pharmaceuti- isotonic eyewash supplies and soap EPA. State and local regulations must cal waste through incineration at a immediately available in areas where be considered when establishing a permitted regulated medical waste or HDs are handled. Workers who are hazardous waste and HD disposal pol- waste-to-energy facility. To emphasize contaminated during the spill or spill icy for a given institution.138 the difference between HDs and haz- cleanup or who have direct skin or eye The RCRA allows for the exemp- ardous waste, the term chemotherapy contact with HDs require immedi- tion of empty containers from haz- will be used to denote antineoplas- ate treatment. OSHA-recommended ardous waste regulations. Empty con- tic HDs. The healthcare organization steps for treatment are outlined in tainers are defined as those that have always has the option to manage all Appendix K.133 Additional information held U-listed or characteristic wastes NIOSH HDs as hazardous waste, of on personnel contamination is avail- and from which all wastes have been course, if sorting is problematic. It is able on the OSHA Safety and Health removed that can be removed using important to review state regulations Topics page.13,14 the practices commonly employed for stricter definitions of hazardous to remove materials from that type waste; in Minnesota, for example, Hazardous waste containment of container and no more than 3% these drugs must be managed as haz- and disposal by weight of the total capacity of the ardous waste.143 In 1976, the RCRA was enacted container remains in the container.139 Trace-contaminated chemother- to provide a mechanism for tracking Disposal guidelines developed by the apy drug waste. By the NIH defini- hazardous waste from its generation National Institutes of Health (NIH) tion of trace chemotherapy waste,140 to disposal.134 Regulations promul- and published in 1984 coined the term “RCRA-empty” containers, needles, gated under the RCRA are enforced “trace-contaminated” waste using the syringes, trace-contaminated gowns, by EPA and apply to pharmaceuticals 3% rule.140 Note that a container that gloves, pads, and empty i.v. sets may be and chemicals discarded by pharma- has held an acute hazardous waste collected and incinerated at a regulated cies, hospitals, clinics, and other com- listed in §261.33(e), such as arsenic medical waste incinerator. Sharps used mercial entities. The RCRA outlines trioxide, is not considered empty by in the preparation of chemotherapy 4 characteristics of hazardous waste the 3% rule141 and that spill residues should not be placed in red sharps con- (D codes)135 and contains lists of agents from cleanup of hazardous agents are tainers, since sharps are most frequent- that are to be considered hazardous considered hazardous waste.132 ly disinfected by autoclaving or micro- waste when they are discarded (P and It is important that distinctions be waving, not by incineration, and pose a U codes).132 Any discarded drug that drawn between HDs from an OSHA risk of aerosolization to waste-handling is on 1 of the lists (a “listed” waste) or (HCS) and NIOSH employee exposure employees. meets 1 of the criteria (a “characteristic” perspective and hazardous waste from Bulk chemotherapy and RCRA waste) is considered hazardous waste. an EPA perspective. USP chapter 800 drug waste. Although the termi- EPA has provided some relief for phar- uses antineoplastic hazardous drugs nology is not official, the terms bulk maceuticals over the years by exclud- to refer to those HDs generally used chemotherapy and RCRA drug waste ing epinephrine salts and weak medici- as chemotherapy in oncology treat- have been used to differentiate con- nal nitroglycerin from the list, though ment.8 For example, antineoplastic tainers that have held either (1) RCRA- epinephrine base and other forms of drugs listed in table 1, group 1, of the listed or characteristic hazardous nitroglycerin are still listed.136 Not all NIOSH 2016 HD list55 are both em- waste or (2) any chemotherapy drugs states have adopted these exemptions, ployee hazards and hazardous to the that are not RCRA empty or any ma- so state hazardous waste regulations environment based on their acknowl- terials from chemotherapy or hazard- and interpretations should be con- edged toxicity. EPA hazardous waste ous waste drug spill cleanups. These sulted. In addition to a few others, the regulations have not kept up with drug wastes should be managed as hazard- listed drugs include warfarin, nicotine, development, with over 100 chemo- ous waste. dalfampridine (4-aminopyridine), and therapy drugs not listed by EPA.142 Dual infectious–hazardous waste. physostigmine, as well as 7 current The recommendation, therefore, is If a situation arises where a syringe chemotherapy drugs: arsenic triox- to manage all antineoplastic drugs as with a needle containing a listed che- ide, , cyclophosphamide, hazardous waste through a permitted motherapy drug cannot be used, it daunomycin, , mitomycin hazardous waste treatment, storage, should be managed as a dual waste. C, and streptozocin.137 They require and disposal facility. Assuming that an A black needle box labeled for both

2016 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS hazardous and biohazardous wastes status by the total amount of hazard- of the rule is published, it will be im- should be used for containment. The ous waste generated per calendar portant for organizations to review contract with the hazardous waste dis- month.148 Small- and large-quantity and modify their programs accord- posal company should have this waste generators are determined by the ingly, as the proposed rule contained stream listed on the waste profile. The amount of P-, U-, and D-listed wastes very significant hazardous pharma- Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 cost of this waste stream is typically that are discarded on a monthly ba- ceutical waste management changes, higher than others, so it should be used sis. The Hazardous Waste Generator many of them beneficial to healthcare only when needed. Improvements Rule took effect fed- facilities. Once hazardous waste has been erally on May 30, 2017.148 States had identified, it must be collected, stored, until July 1, 2018, to adopt it or have Medical screening and and transported according to specific until July 1, 2019, if legislation is re- surveillance and alternative EPA and Department of Transporta- quired.148 The rule changes the name duty tion (DOT) requirements.134,144 Prop- of “conditionally exempt small quan- Many drugs described in this erly labeled, leakproof, and spill-proof tity generators” to “very small quantity document as hazardous are acutely containers of nonreactive plastic generators” (VSQGs). Waste manage- toxic or are known or suspected hu- are required for areas where hazard- ment requirements are more stringent man carcinogens; many more cause ous waste is generated. DOT packing for large-quantity generators than for adverse reproductive outcomes.55 group II containers are required for small-quantity generators (SQGs) and Decades of literature show that HD transportation.145 Needles, scalpels, VSQGs.149 The removal of epinephrine contamination in the healthcare work and waste contaminated with blood salts and medicinal nitroglycerin from environment is absorbed into health- or other body fluids must not be the P-list is a tremendous benefit to care workers.6,9-12,15,19 Marker HDs have mixed with hazardous waste. healthcare facilities, since only 1 kg been measured in the urine of workers Only individuals who meet OSHA- (2.2 lb) of P-listed waste per calendar who routinely handle HDs during the mandated hazardous waste aware- month causes the organization to be- course of patient care.10,21,46,48,49 HD lev- ness training may transport the haz- come a large-quantity generator. els have also been found in the urine ardous waste containers from satellite In the past, healthcare facilities of workers not directly responsible for accumulation areas in the pharmacy had to count the weight of the con- HD compounding or administration.21 and nursing units to the storage accu- tainers that held P-listed waste to- This continued worker exposure has mulation sites.146,147 Hazardous waste ward their generator status. In a 2011 prompted many groups to advocate must be properly manifested and memo, EPA provided additional op- that healthcare workers tasked with transported by a federally permitted tions, including counting only the res- handling HDs be identified and en- hazardous waste transporter to a fed- idue of the waste.149 Since most of the rolled in medical screening programs erally permitted hazardous waste stor- P-listed waste containers are warfarin before job placement and periodically age, treatment, and disposal facility.131 stock bottles, warfarin unit-dose blis- during employment and that they be A licensed contractor may be hired to ter packs, or nicotine wrappers, hos- maintained in a systematic medical manage the hazardous waste program. pitals can use the residue calculation surveillance program.6,13,14,27,110,120 The waste generator, however, may in the memo to document that their Medical screening and surveil- be held liable for mismanagement of P-listed waste does not exceed 1 kg in lance should be part of the compre- hazardous waste. Investigation of a a calendar month or 1 kg of stored P- hensive safety program for controlling contractor, including verification of listed waste. This practice may enable workplace exposure to HDs, which possession and type of license, should the facility to remain a VSQG or SQG, must include engineering controls, be completed and documented before depending on the volume of other training, work practices, and PPE. a contractor is engaged. hazardous waste generated. If an or- Such safety programs must be able to In addition to determining what ganization is documenting P-listed identify potentially exposed workers types of containers and what methods residues only and total hazardous and those who might be at higher risk of sorting an organization will imple- waste generation per month (not just of adverse health effects due to this ex- ment to properly manage both OSHA pharmacy waste) is below 100 kg, it is posure. Guidance on medical surveil- and EPA HD wastes, it is important to a VSQG; if the total is 100–1,000 kg, it lance programs is available from USP,8 understand how generating hazard- is an SQG. Again, some states have not OSHA,14 and NIOSH.151 ous waste impacts an organization as accepted this option, so state regula- Because reproductive risks have a whole. Additional departments need tions must be consulted. been associated with exposure to to be involved, such as laboratory and On September 25, 2015, EPA pub- HDs, alternative duty (work assign- maintenance, which may also gener- lished its Proposed Rule: Management ments that do not involve handling ate other types of RCRA hazardous Standards for Hazardous Waste Phar- HDs) should be offered to individu- wastes. EPA defines waste generation maceuticals.150 When the final version als who are pregnant, breast-feeding,

AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 2017 ASHP REPORTS HANDLING HAZARDOUS DRUGS or attempting to conceive or father a state board of pharmacy, and these compounding over a 4-day period.158 a child.14,28 Employees’ physicians devices must also meet provisions of The detection rate for cyclophospha- should be involved in making these USP chapter 797 when used for ster- mide contamination was 70% of sur- determinations. Guidance on alterna- ile compounding.7,153 face samples in the BSC versus 15% tive duty is available from NIOSH.28 Studies have examined the accu- using the robot. Overall, cyclophos- Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 All workers who handle HDs racy of robotic devices compounding phamide contamination was quite should be routinely monitored in a HDs for patient safety but did not in- low for both settings compared to that medical surveillance program.6,8,14,28,110 clude environmental contamination found in the literature. Medical surveillance involves the col- or worker safety considerations.154,155 These studies demonstrate that lection and interpretation of data for Limited studies have been published robotic HD compounders are depen- the purpose of detecting changes in examining the ability for robotics to dent on work practices surrounding the health status of working popula- reduce HD surface contamination the actual compounding to achieve tions. Medical surveillance programs during sterile compounding or to im- the lowest levels of contamination involve assessment and documenta- pact the safety of healthcare workers and the best protection for workers tion of symptom complaints, physi- interacting with the robot during HD and the environment. Additional re- cal findings, and laboratory values compounding. One study reported on search is needed to evaluate the place (such as a blood count) to determine observed work practices where the ro- of robotic HD compounders in patient whether there is a deviation from the bot was found to produce a significant and worker safety. Information about expected norms. NIOSH encourages reduction in the number of potentially robotics in sterile compounding is employees who handle HDs to partici- harmful staff safety events during available from ASHP.159 pate in medical surveillance programs compounding; however, no marker of that are provided in the workplace.6 exposure of staff was used during the Environmental sampling for Limited resources may preclude the study and neither robot cleaning nor HDs implementation of a comprehensive waste disposal tasks were addressed.156 Surface wipe sampling of health- medical surveillance program for Environmental contamination has care settings for HD contamination healthcare workers who are exposed been evaluated by wipe sampling for is advocated as a means of environ- to HDs. Workers handling HDs are cyclophosphamide during robotic mental quality and control.6,8 Surface encouraged to inform their personal compounding by different manufac- wipe sampling should be done rou- healthcare providers of their occupa- turers’ robots. In the first study, cyclo- tinely, first to determine a benchmark tion and possible HD exposure when phosphamide was measured on work of contamination and then to moni- obtaining routine medical care.6 surfaces, in air samples, and in urine tor the effectiveness of safe handling samples of workers.157 Wipe samples of programs. As no acceptable levels of Robotics the subjects’ hands were also collect- HD surface contamination have been Robotics may be defined as me- ed. Cyclophosphamide was detected determined by any regulatory agency, chanical devices that perform pro- on most surfaces inside the robot in surface wipe sampling should deter- grammed, complex, and repetitive small amounts, and the outer glove mine an operational baseline of at manipulations that mimic human had the most contamination. The vials least several marker HDs from which behavior without continuous input and ports of the i.v. bags where cyclo- a facility action level may be deter- from an operator. Robotic i.v. auto- phosphamide was injected had higher mined. Surface wipe sampling pro- mation presents an opportunity for and more consistent contamination. vides a way to determine the efficacy improving safety and efficiency in the No cyclophosphamide was detected of HD handling equipment, ancillary compounding process by increasing on the personal air samplers or in the devices, work practices, cleaning accuracy and consistency for patients 14 urine samples of the 2 technicians. methods, and disposal and is current- and reducing HD direct exposure for Although the contamination detected ly the method of choice to determine compounding staff.152 There are cur- in the robot was low, the study iden- surface contamination of the work- rently a number of robots and au- tified work practices that needed im- place with these drugs.160 Wipe sam- tomated devices that are marketed provement, such as cleaning HD vials pling should also be done if a lapse for sterile HDs, and manufacturers before placing them into the robot, in the safe handling program occurs, should provide evidence-based data which may have resulted in cyclo- which may result in an excursion be- to support the use of any of these phosphamide transfer to gloves and yond a predetermined action level of devices in compounding sterile HD final products. HD surface contamination.6,8,161,162 doses to provide patient safety and In a second study, wipe samples Since it has been postulated that worker safety. There may also be legal were used to compare measured cy- dermal uptake is the most likely route requirements when using these de- clophosphamide surface contamina- of occupational exposure to most vices in a pharmacy licensed through tion in a BSC and robot after similar HDs in healthcare settings, especially

2018 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS low-molecular-weight antineoplastic in the urine for median surface levels ing these recommendations to their drugs, surface wipe sampling is a use- below 0.01 ng/cm2. This value, as the unique circumstances and to take ful tool to evaluate contamination of others, is not based on endpoints of into account evolving federal, state, the healthcare facility with HDs.48,79 any measurable health effect. and local regulations, as well as the re- Wipe-sampling methodology can be Guidance values and action levels quirements of appropriate accrediting Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 used for most classes of drugs. Pub- are dependent on the methods used institutions. As additional research is lished studies have focused on sev- for wipe sampling and analytic assays, needed in this area, healthcare work- eral sentinel antineoplastic drugs, which have varied greatly in studies.9 ers must act as their own advocates most commonly cyclophosphamide, The basic methodology that should be and encourage studies that look at ad- ifosfamide, fluorouracil, methotrex- common to all protocols for wipe sam- verse health outcomes as well as prac- ate, and , though others pling was reviewed by Connor et al.160 tice standards that improve worker are reported in the literature.9 As ana- They stressed that proper validation of safety. lytic methods become more sophis- the sampling method is critical to ob- ticated, more drugs can be analyzed taining reproducible results and being Acknowledgments simultaneously. able to compare results across studies. The contributions of Charlotte Smith, No standards exist for acceptable USP notes there are currently no cer- B.S.Pharm., M.S., and Wendy M. Wong, Pharm.D., BCOP, to these guidelines are ac- or allowable surface concentrations tifying agencies for vendors of wipe knowledged. ASHP also acknowledges the 8 for HDs in the healthcare setting. Sur- sample kits. Therefore, individuals following individuals for their contribu- face contamination levels for cyclo- purchasing or specifying the selection tions to previous versions of these guide- phosphamide in early studies led USP of a kit must be responsible for verify- lines: CAPT (ret.) Joseph H. Deffenbaugh to describe a 1-ng/cm2 action level for ing its effectiveness. Factors to consid- Jr., M.P.H.; CDR Bruce R. Harrison, M.S., BCOP; Dayna McCauley, Pharm.D., BCOP; cyclophosphamide, above which drug er when selecting a wipe-sampling kit Melissa A. McDiarmid, M.D., M.P.H.; and uptake was believed to occur. More re- or a laboratory to perform the analysis CAPT Kenneth R. Mead, Ph.D., PE. cent studies looking at a large number include validated sampling and ana- ASHP gratefully acknowledges the follow- of samples done with standardized lytic methods, extraction efficiency ing individuals for reviewing the current sampling and assay techniques have of drug from surface material, recov- version of the guidelines (review does not proposed hygienic guidance values ery of drug from sampling material, imply endorsement): Thomas H. Connor, for surface wipe sampling that are LOD, limit of quantification, and the Ph.D.; Ryan Forrey, Pharm.D., M.S., FASHP; Patricia C. Kienle, B.S.Pharm., M.P.A., based on reporting 50th and 75th per- qualifications and certifications of the FASHP; and Martha Polovich, Ph.D., RN, 161 108,162 160 centiles or 90th percentiles of laboratory. AOCN. samples. Hygienic guidance values are No regulations or standards exist not based on endpoints of either HD for allowable or acceptable HD surface Disclosures uptake by workers or any measurable concentrations in healthcare settings, The authors have declared no potential health effect. The Monitoring-Effect and many questions remain about the conflicts of interest. Study of Wipe Sampling in Pharma- potential health risks associated with Additional information cies (MEWIP) method conducted in exposure to existing levels of environ- 130 German pharmacies looked at mental surface contamination. How- Developed through the ASHP Council on Pharmacy Practice and approved by the surface contamination with cyclo- ever, prudent practice dictates that ASHP Board of Directors on July 30, 2018. phosphamide, , , levels of HD surface contamination fluorouracil, gemcitabine, ifosfamide, should be reduced to as low as reason- These guidelines supersede the ASHP , and .108 Based ably achievable.15,110 guidelines on handling hazardous drugs dated January 12, 2006 (Am J Health-Syst on the 90th percentile of the contam- Pharm. 2006; 63:1172-93). ination values, they recommend a Conclusion substance-independent performance- These guidelines represent the rec- References based guidance value of 0.1 ng/cm2 as ommendations of many groups and 1. Stolar MH, Power LA, Viele CS. the action level.108 This is significantly individuals who have worked diligent- Recommendations for handling cy- more stringent than USP’s observa- ly over decades to reduce the potential totoxic drugs in hospitals. Am J Hosp Pharm. 1983; 40:1163-71. 8 163 tion. Kibby conducted a review of of harmful effects on healthcare work- 2. Stolar MH, Power LA. The 1983–84 studies with concurrent surface wipe- ers exposed to HDs. No set of guide- ASHP practice spotlight: safe han- sampling and urine monitoring for lines on this topic, however compre- dling of cytotoxic drugs. Am J Hosp sentinel HDs and noted that no sta- hensive, can address all the needs of Pharm. 1983; 40:1161. tistically significant correlation was every healthcare facility. Healthcare 3. American Society of Hospital Phar- macists. ASHP technical assistance found between the 2 types of studies. professionals are encouraged to rely bulletin on handling cytotoxic drugs He further noted that none of the re- on their professional judgment, expe- in hospitals. Am J Hosp Pharm. 1985; viewed studies found detectable HDs rience, and common sense in apply- 42:131-7.

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Int Pharm Purch Prod. 2015. www. liquid chromatography/tandem Arch Occup Environ Health. 2013; pppmag.com/download. mass spectrometry in the environ- 86:333-41. php?file=documents/V12N1/pdfs/ mental and biological monitoring 123. Hon CY, Chua PP, Danyluk Q et al. ppp_1501_ppe.pdf (accessed 2018 of health care personnel occupa- Examining factors that influence the Feb 28). tionally exposed to cyclophos- effectiveness of cleaning antineo- 103. Food and Drug Administration. phamide and ifosfamide. Rapid plastic drugs from drug prepara- Banned devices; powdered Commun Mass Spectrom. 1998; tion surfaces: a pilot study. J Oncol surgeon’s gloves, powdered 12:1485-93. Pharm Pract. 2014; 20:210-6. patient examination gloves, and 113. Turci R, Minoia C, Sottani C et al. 124. Bohlandt A, Groeneveld S, Fischer E absorbable powder for lubricating Occupational exposure to antineo- et al. Cleaning efficiencies of three a surgeon’s glove (effective January plastic drugs in seven Italian hospi- cleaning agents on four different 18, 2017). www.federalregister.gov/ tals: the effect of quality assurance surfaces after contamination by documents/2016/12/19/2016- and adherence to guidelines. J Oncol gemcitabine and 5-fluorouracil.J 30382/banned-devices-powdered- Pharm Pract. 2011; 17:320-32. Occup Environ Hyg. 2015; 12:384-92. surgeons-gloves-powdered-patient- 114. Sottani C, Porro B, Imbriani M et al. 125. Johnson EG, Janosik JE. Manufac- examination-gloves-and- Occupational exposure to antineo- turers’ recommendations for han- absorbable-powder (accessed 2018 plastic drugs in four Italian health dling spilled antineoplastic agents. Feb 28). care settings. Toxicol Lett. 2012; Am J Hosp Pharm. 1989; 46:318-9. 104. Wallemacq PE, Capron A, Vanbinst 213:107-15. 126. Gonzalez R, Massoomi F. Manufac- R et al. Permeability of 13 different 115. NuAire. Containment capabilities turers’ recommendations for han- gloves to 13 cytotoxic agents under of a class II, type A2 BSC using a dling spilled hazardous drugs. Am J controlled dynamic conditions. Am chemo pad on the work surface. Health-Syst Pharm. 2010; 67:1985-6. J Health-Syst Pharm. 2006; 63:547- Technical bulletin GTB0131. www. 127. Contec Healthcare. PeridoxRTU 56. nuaire.com/media/wysiwyg/ sporicidal disinfectant for 105. Dolezalova L, Odraska P, Gorna L et bulletins-general/biological-safety- decontaminating hazardous drugs. al. [Evaporation of selected cytotoxic cabinets/GTB0131%20Contain- www.contechealthcare.com/files/ drugs and permeation of protective ment%20Capabilities%20of%20 documents/HCA001_Peridox_

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HazardousDrugs.pdf (accessed 2018 66f980852579ea0067cd97!OpenDoc regulations. www.fmcsa.dot.gov/ Feb 28). ument (accessed 2018 Feb 28). regulations/hazardous-materials/ 128. Contec Healthcare. Peridox RTU. 137. U.S. Environmental Protection how-comply-federal-hazardous- Hazardous drug cleaning removal Agency. Hazardous waste. materials-regulations (accessed test report. www.contechealthcare. Defining hazardous waste: 2018 Feb 28). com/files/documents/Peridox_ listed, characteristic and mixed 146. Occupational Safety and Health Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 RTU_Hazardous-Drug-Cleaning- radiological wastes. www.epa. Administration. OSHA standards. Removal-Test-Summary.pdf gov/hw/defining-hazardous- Hazardous waste operations and (accessed 2018 Feb 28). waste-listed-characteristic-and- emergency response. Initial training. 129. Bartel SB, Tyler TG, Power LA. mixed-radiological-wastes#PandU 29 C.F.R. 1910.120(e)(3)(i). www.ecfr. Multicenter evaluation of a new (accessed 2018 Feb 28). gov/cgi-bin/text-idx?&node=se29.5. closed system drug-transfer device 138. U.S. Environmental Protection 1910_1120&rgn=div8 (accessed 2018 in reducing surface contamination Agency. State authorization under Feb 28). by antineoplastic hazardous drugs. the Resource Conservation and 147. Occupational Safety and Health Am J Health-Syst Pharm. 2018; Recovery Act (RCRA). www.epa. Administration. OSHA standards. 75:199-211. gov/rcra/state-authorization- Hazardous waste operations and 130. Occupational Safety and under-resource-conservation-and- emergency response. Emergency Health Administration. OSHA recovery-act-rcra (accessed 2018 response to hazardous substances standards. Hazardous waste Feb 28). releases. 29 C.F.R. 1910.120(q)(1-6). operations and emergency 139. U.S. Environmental Protection www.ecfr.gov/cgi-bin/text-idx?&n response. 29 C.F.R. 1910.120. Agency. Residues of hazardous ode=se29.5.1910_1120&rgn=div8 www.osha.gov/pls/oshaweb/ waste in empty containers. 40 (accessed 2018 Feb 28). owadisp.show_document?p_ C.F.R. 261.7. www.ecfr.gov/cgi-bin/ 148. U.S. Environmental Protection table=STANDARDS&p_id=9765 retrieveECFR? &n=pt40.28.261&r Agency. Hazardous waste generator (accessed 2018 Feb 28). =PART&ty=HTML#se40.28.261_17 regulatory summary. www.epa.gov/ 131. U.S. Environmental Protection (accessed 2018 Feb 28). hwgenerators/hazardous-waste- Agency. Protection of environ- 140. Vaccari PL, Tonat K, DeChristoforo generator-regulatory-summary ment. Hazardous waste manage- R et al. Disposal of antineoplastic (accessed 2018 Feb 28). ment system: general. 40 C.F.R. 260. wastes at the National Institutes 149. U.S. Environmental Protection www.ecfr.gov/cgi-bin/text-idx? of Health. Am J Hosp Pharm. 1984; Agency. Memo: containers that &node=pt40.28.260&rgn=div5 41:87-93. once held P-listed pharmaceuticals (accessed 2018 Feb 28). 141. U.S. Environmental Protection (November 4, 2011). https:// 132. U.S. Environmental Protection Agency. Residues of hazardous yosemite.epa.gov/osw/rcra.nsf/0/ Agency. Discarded commercial waste in empty containers— 57B21F2FE33735128525795F00610 chemical products, off-specification definition of “empty.” 40 C.F.R. F0F/$file/14827.pdf (accessed 2018 species, container residues, and 261.7(b)(1)-(3). www.ecfr.gov/cgi- Feb 28). spill residues thereof. 40 C.F.R. bin/retrieveECFR? &n=pt40.28.261& 150. U.S. Environmental Protection 261.33. www.ecfr.gov/cgi-bin/text- r=PART&ty=HTML#se40.28.261_17 Agency. Proposed rule: management idx?node=se40.26.261_133 (accessed (accessed 2018 Feb 27). standards for hazardous waste 2018 Feb 28). 142. U.S. Environmental Protection pharmaceuticals (September 25, 133. Occupational Safety and Agency Office of Inspector General. 2015). www.epa.gov/hwgenerators/ Health Administration. OSHA Report: EPA inaction in identifying proposed-rule-management- standards. Medical and first hazardous waste pharmaceuticals standards-hazardous-waste- aid. 29 C.F.R. 1910.151(c). may result in unsafe disposal. www. pharmaceuticals (accessed 2018 www.osha.gov/pls/oshaweb/ epa.gov/office-inspector-general/ Feb 28). owadisp.show_document?p_ report-epa-inaction-identifying- 151. National Institute for Occupa- table=STANDARDS&p_id=9806 hazardous-waste-pharmaceuticals- tional Safety and Health. Medical (accessed 2018 Feb 28). may-result (accessed 2018 Feb 28). surveillance for healthcare workers 134. Resource Conservation and 143. Minnesota Pollution Control exposed to hazardous drugs. DHHS Recovery Act of 1976. U.S. Code Title Agency. Alternate method to evalu- (NIOSH) publication no. 2013–103 42. Chapter 82, solid waste disposal. ate pharmaceutical waste for the (2012). www.cdc.gov/niosh/docs/ www.gpo.gov/fdsys/pkg/USCODE- lethality characteristic. March 2015. wp-solutions/2013-103/ (accessed 2011-title42/html/USCODE-2011- www.pca.state.mn.us/sites/default/ 2018 Feb 28). title42-chap82.htm (accessed 2018 files/w-hw4-45b.pdf (accessed 2018 152. Fox BI, Felkey BG. Automated Feb 28). Feb 28). intravenous preparation: robots for 135. U.S. Environmental Protection 144. Pipeline and Hazardous the pharmacy. Hosp Pharm. 2009; Agency. Characteristics of hazard- Materials Safety Administration. 44:255-6,264. ous waste. 40 C.F.R. 261.20-24. www. Hazardous materials table, special 153. Volpe G, Cohen S, Capps RC et al. ecfr.gov/cgi-bin/text-idx?&node=p provisions, hazardous materials Robotics in acute care hospitals. Am t40.28.261&rgn=div5#sp40.28.261.c communications. 49 C.F.R. 172.1- J Health-Syst Pharm. 2012; 69:1601- (accessed 2018 Feb 28). 172.123. www.ecfr.gov/cgi-bin/retrie 3. 136. U.S. Environmental Protection veECFR?&n=pt49.2.172&r=PART&ty 154. Yaniv AW, Knoer SJ. Implementa- Agency. Memorandum excluding =HTML (accessed 2018 Feb 28). tion of an i.v.-compounding robot epinephrine salts. http://yosemite. 145. Federal Motor Carrier Safety in a hospital-based cancer center epa.gov/osw/rcra.nsf/ea6e50dc6214 Administration. How to comply pharmacy. Am J Health-Syst Pharm. 725285256bf00063269d/9c30209e14 with federal hazardous materials 2013; 70:2030-7.

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155. Masini C, Nanni O, Antaridi S et treatment, or prevention of disease in Chemotherapy drug: A chemical agent al. Automated preparation of che- humans and animals or affecting the used to treat diseases. The term usually motherapy: quality improvement structure and function of the body.8 refers to a drug used to treat cancer.6 and economic sustainability. Am J Alternative duty: Performance of other Chemotherapy glove: A medical glove Health-Syst Pharm. 2014; 71:579- tasks that do not include the direct that meets the ASTM Standard 85. handling of HDs.8 Practice for Assessment of Resistance Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 156. Seger AC, Churchill WW, Keohane Antechamber: Chamber in a compound- of Medical Gloves to Permeation by CA et al. Impact of robotic anti- ing isolator that leads to the main com- Chemotherapy Drugs (D6978) or its neoplastic preparation on safety, pounding chamber. The antechamber successor.8 workflow, and costs.J Oncol Pract. is used to load supplies and drugs into Chemotherapy waste: Discarded items 2012; 8:344-9. the isolator and unload final prepara- such as gowns, gloves, masks, i.v. 157. Sessink PJ, Leclercq GM, Wouters tions and waste. tubing, empty bags, empty drug vi- DM et al. Environmental contami- Anteroom: An ISO class 7 or cleaner room als, needles, and syringes used while nation, product contamination and where personnel hand hygiene, garb- preparing and administering antineo- workers exposure using a robotic ing procedures, and other activities plastic agents.6 system for antineoplastic drug that generate high particulate levels Classified space: An area that maintains preparation. J Oncol Pharm Pract. are performed. The anteroom is the an air cleanliness classification based 2015; 21:118-27. transition room between the unclassi- on ISO.8 158. Schierl R, Masini C, Groeneveld S et fied area of the facility and the buffer Cleaning: The process of removing soil al. Environmental contamination room.8 (e.g., organic and inorganic material) by cyclophosphamide preparation: Antineoplastic drug: A chemotherapeutic from objects and surfaces, normally ac- comparison of conventional manual agent that controls or kills cancer cells. complished by manually or mechani- production in biological safety cabi- Drugs used in the treatment of cancer cally using water with detergents or net and robot-assisted production are cytotoxic but are generally more enzymatic products.8 by APOTECAchemo. J Oncol Pharm damaging to dividing cells than to rest- Closed system: A device that does not ex- Pract. 2016; 22:37-45. ing cells.6 change unfiltered air or contaminants 159. Erickson BA, Boyce CA. Sterile com- Aseptic: Free of living pathogenic organ- with the adjacent environment.6 pounding technology. In: Buchanan isms or infected materials.6 Closed-system drug-transfer device EC, Schneider PJ, Forrey RA, eds. Assessment of risk: Evaluation of risk to (CSTD): A drug-transfer device that Compounding sterile preparations, determine alternative containment mechanically prohibits the transfer of 4th ed. Bethesda, MD: American So- strategies and/or work practices. environmental contaminants into the ciety of Health-System Pharmacists; Beyond-use date (BUD): The date or system and the escape of HD or vapor 2017:363-407. time beyond which a compounded concentrations outside the system.6 160. Connor TH, Zock MD, Snow AH. preparation cannot be used and must Compounded preparation: A nonsterile Surface wipe sampling for antineo- be discarded (see USP chapters 795 or sterile drug or nutrient prepara- plastic (chemotherapy) and other and 797).7,61 The date or time is deter- tion that is compounded in a licensed hazardous drug residue in health- mined from the date or time when the pharmacy or other healthcare-related care settings: methodology and preparation was compounded. facility in response to or anticipation recommendations. J Occup Environ Biological safety cabinet (BSC): BSCs of a prescription or a medication order Hyg. 2016; 13:658-67. or biosafety cabinets are used as the from a licensed prescriber.8 161. Schierl R, Bohlandt A, Nowak D. primary means of containment for Compounding aseptic containment Guidance values for surface moni- working safely with infectious micro- isolator (CACI): A specific type of toring of antineoplastic drugs in organisms. Biosafety cabinets are de- compounding aseptic isolator (CAI) German pharmacies. Ann Occup signed to prevent biological exposure that is designed for the compounding Hyg. 2009; 53:1-9. to personnel and the environment and of sterile HDs. The CACI is designed to 162. Hedmer M, Wohlfart G. Hygienic may also protect experimental mate- provide worker protection from expo- guidance values for wipe sampling rial from being contaminated when sure to undesirable levels of airborne of antineoplastic drugs in Swedish appropriate practices and procedures drugs throughout the compounding hospitals. J Environ Monit. 2012; are followed. Class II BSCs have and material transfer processes and to 14:1968-75. been adopted for use in compound- provide an aseptic environment with 163. Kibby T. A review of surface wipe ing HDs as they protect the product, unidirectional airflow for compound- sampling compared to biologic the worker, and the environment. ing sterile preparations.8 monitoring for occupational expo- Descriptions of the various classes Compounding aseptic isolator (CAI): sure to antineoplastic drugs. J Occup and types of BSCs may be found in An isolator specifically designed for Environ Hyg. 2017; 14:159-74. the CDC Biosafety in Microbiological compounding sterile, nonhazardous and Biomedical Laboratories, 5th ed., pharmaceutical ingredients or prepara- Appendix A.81 tions. The CAI is designed to maintain Appendix A—Glossary Buffer room: A type of C-SEC under nega- an aseptic compounding environment Active pharmaceutical ingredient tive pressure that meets ISO class 7 or throughout the compounding and (API): Any substance or mixture of better air quality where the C-PEC that material transfer processes.8 substances intended to be used in the generates and maintains an ISO class Compounding personnel: Individuals compounding of a drug preparation, 5 environment is physically located. who participate in the compounding thereby becoming the active ingredi- Activities that occur in this area are process.8 ent in that preparation and furnishing limited to the preparation and staging Containment primary engineering pharmacologic activity or other direct of components and supplies used when control (C-PEC): A ventilated device effect in the diagnosis, cure, mitigation, compounding HDs.8 designed and operated to minimize

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worker and environmental exposures levels, safety interlocks, and radiation Laboratory coat: A disposable or reusable to HDs by controlling emissions of shielding.6 open-front coat, usually made of cloth airborne contaminants through the Environmental Protection Agency (EPA)- or other permeable material.6 following: registered disinfectant: Antimicrobial Mutagenic: Capable of increasing the • The full or partial enclosure of a products registered with EPA for health- spontaneous mutation rate by causing potential contaminant source, care use against pathogens specified in changes in DNA.6 Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 • The use of airflow capture velocities the product labeling.8 Negative-pressure room: A room that is to trap and remove airborne contam- Externally vented: Exhausted to the maintained at a lower pressure than the inants near their point of generation, outside.8 adjacent areas; therefore, the net flow of • The use of air pressure relationships Final dosage form: Any form of a medica- air is into the room.8 that define the direction of airflow tion that requires no further manipula- Pass-through: An enclosure with into the cabinet, and tion before administration.8 interlocking doors that is positioned • The use of HEPA filtration on all Genotoxic: Capable of damaging DNA and between 2 spaces for the purpose of potentially contaminated exhaust leading to mutations.6 reducing particulate transfer while mov- streams.8 Globally Harmonized System of Classi- ing materials from 1 space to another. A Containment secondary engineering fication and Labeling of Chemicals: A pass-through serving negative-pressure control (C-SEC): The room with fixed system for standardizing and harmoniz- rooms needs to be equipped with sealed walls in which the C-PEC is placed. ing the classification and labeling of doors.8 (Note: A pass-through located It incorporates specific design and chemicals.8 before the main chamber of a com- operational parameters required to Goggles: Tight-fitting eye protection that pounding isolator is an antechamber.) contain the potential hazard within the completely covers the eyes, eye sock- Personal protective equipment (PPE): compounding room.8 ets, and facial area that immediately Items such as gloves, gowns, respirators, Containment segregated compounding surrounds the eyes. Goggles provide goggles, and face shields that protect area (C-SCA): A type of C-SEC with protection from impact, dust, and individual workers from hazardous nominal requirements for airflow and splashes. Some goggles fit over correc- physical or chemical exposures.6 room pressurization as they pertain to tive lenses.8 Positive-pressure room: A room that is HD compounding.8 Hazardous drug (HD): Any drug identified maintained at a higher pressure than Containment ventilated enclosure by at least 1 of the following 6 criteria: the adjacent areas; therefore, the net (CVE): A full or partial enclosure that carcinogenicity, teratogenicity or devel- flow of air is out of the room.8 uses ventilation principles to capture, opmental toxicity, reproductive toxicity Repackaging: The act of removing a prod- contain, and remove airborne con- in humans, organ toxicity at low doses uct from its original primary container taminants through HEPA filtration in humans or animals, genotoxicity, and and placing it into another primary and prevent their release into the work new drugs that mimic existing HDs in container, usually of smaller size.8 environment.8 structure or toxicity.6 Respirator: A type of PPE that prevents Cytotoxic: A pharmacologic compound Hazardous waste: Any waste that is an harmful materials from entering the that is detrimental or destructive to RCRA-listed hazardous waste (40 C.F.R. respiratory system, usually by filtering cells within the body.6 261.30-261.33) or that meets an RCRA hazardous agents from workplace air. A Deactivation: Treating a chemical agent characteristic of ignitability, corrosivity, surgical mask does not offer respiratory (such as an HD) with another chemical, reactivity, or toxicity as defined in 40 protection.6 heat, ultraviolet light, or another agent C.F.R. 261.21-.24.6 Risk assessment: Characterization of to create a less hazardous agent.6 Healthcare settings: All hospitals, medical potentially adverse health effects from Decontamination: Inactivation, neu- clinics, outpatient facilities, physi- human exposure to environmental tralization, or removal of toxic agents, cians’ offices, retail pharmacies, and or occupational hazards. Risk assess- usually by chemical means.6 Surface similar facilities dedicated to the care of ment can be divided into 5 major steps: decontamination may be accomplished patients.6 hazard identification, dose–response by the transfer of HD contamination Healthcare workers: All workers who assessment, exposure assessment, from the surface of a nondisposable are involved in the care of patients. risk characterization, and risk item to disposable ones (e.g., wipes, These include pharmacists, pharmacy communication.6 gauze, towels). technicians, nurses (registered nurses, Safety data sheet (SDS): An informational Direct compounding area (DCA): A critical licensed practical nurses, nurses’ aides, document that provides written or area within an ISO class 5 primary engi- etc.), physicians, home healthcare printed material concerning a hazard- neering control where critical sites are workers, and environmental services ous chemical (previously known as a exposed to unidirectional HEPA-filtered workers (housekeeping, laundry, and Material Safety Data Sheet). The SDS is air, also known as first air.7 waste disposal).6 prepared in accordance with the HCS.8 Disinfecting: Removal of viable organism High-efficiency particulate air (HEPA) Spill kit: A container of supplies, warning from surfaces using 70% isopropyl al- filter: Filter rated 99.97% efficient signage, and related materials used to cohol or other appropriate disinfectant in capturing particles 0.3 µm in contain the spill of an HD.8 before compounding of sterile HDs. diameter.6 Standard operating procedure (SOP): Don: To put on PPE.8 Horizontal-laminar-airflow hood Written procedures describing opera- Engineering controls: Devices designed (horizontal-laminar airflow clean tions, testing, sampling, interpretation to eliminate or reduce worker exposures bench): A device that protects the work of results, and corrective actions that to chemical, biological, radiological, er- product and the work area by supply- relate to the operations that are taking gonomic, or physical hazards. Examples ing HEPA-filtered air to the rear of the place.8 include laboratory fume hoods, glove cabinet and producing a horizontal Supplemental engineering control: An bags, retracting syringe needles, sound- flow across the work area and out adjunct control (e.g., a CSTD) that may dampening materials to reduce noise toward the worker.6 be used concurrently with primary

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and secondary engineering controls. must be externally vented (preferred) the cabinet are significant sources of Supplemental engineering controls or have redundant HEPA filters in HD contamination transfer. offer additional levels of protection and series as an exhaust. Class I BSCs and 16. Once HD compounding is complete, may facilitate enhanced occupational CVEs are also acceptable C-PECs for wipe down the dose(s), then label and protection, especially when handling nonsterile compounding. transfer to clean transport bags, wear- HDs outside of primary and second- 5. The class II BSC (as for all C-PECs) ing noncontaminated gloves. Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 ary engineering controls (e.g., during must be located in an externally 17. Decontaminate the class II BSC after administration).8 vented, physically separate, nega- completing HD compounding. Surface decontamination: Transfer of HD tive pressure C-SEC with appropriate 18. Remove PPE according to SOPs and contamination from the surface of non- ACPH to be used for compounding policies and procedures and discard in disposable items to disposable ones (e.g., sterile and nonsterile HDs. an appropriate waste container. wipes, gauze, towels). No procedures 6. The C-SEC may be either an ISO class 19. Wash hands thoroughly with soap and have been studied for surface decontam- 7 buffer room with an ISO class 7 an- water. ination of HD-contaminated surfaces. teroom (preferred) or an unclassified The use of gauze moistened with 70% containment segregated compounding Appendix C— isopropyl alcohol, sterile water, peroxide, area (C-SCA). Recommendations for use of 7. Class II BSCs (as for all C-PECs) used or sodium hypochlorite solutions may class III BSCs and CACIs be effective. The disposable item, once in a facility that compounds both contaminated, must be contained and sterile and nonsterile HDs must be 1. Use of a class III BSC or CACI must discarded as hazardous waste. placed in separate rooms unless all be accompanied by a stringent Unclassified space: A space not required the USP chapter 800 requirements for program of work practices, includ- to meet any air cleanliness classification placement in the same room are met. ing training, demonstrated com- based on ISO.8 8. The class II BSC (as for all C-PECs) petence, contamination reduction, Ventilated cabinet: A type of engineering must run continuously if it supplies and decontamination when used for control designed for purposes of worker some or all of the negative pressure in compounding sterile and nonsterile protection (as used in these guidelines). the C-SEC or if it is used to compound HDs. These devices are designed to minimize sterile HDs. 2. A class III BSC or CACI used for ster- worker exposures by controlling emis- 9. A plastic-backed preparation mat ile HD compounding must provide sions of airborne contaminants through that does not interfere with airflow ISO cclass 5 or better air quality and (1) the full or partial enclosure of a po- to the front or back air grilles should unidirectional airflow in the main tential contaminant source, (2) the use be placed on the work surface of the work chamber and be externally of airflow capture velocities to capture class II BSC. The mat must be changed vented. and remove airborne contaminants routinely in batch compounding and 3. A class III BSC or CACI must achieve near their point of generation, and (3) immediately if a spill occurs. containment at all times during the the use of air pressure relationships that 10. Appropriate chemotherapy PPE must operation of the cabinet and during define the direction of airflow into the be worn when compounding or clean- the transfer process from the ante- cabinet. Examples of ventilated cabinets ing a class II BSC. For sterile com- chamber (compounding isolator pass- include BSCs, containment isolators, pounding, PPE must be donned per through) to the main work chamber 7 and laboratory fume hoods.6 USP chapter 797 instructions. and in reverse. 11. The class II BSC must be decontami- 4. A class III BSC or CACI used for non- Appendix B— nated and disinfected before sterile sterile compounding must meet the Recommendations for use of compounding of HDs and routinely USP chapter 800 requirements for all class II BSCs during batch compounding. C-PECs.8 It must be externally vented 1. Use of a class II BSC must be accom- 12. For sterile compounding, reduce the (preferred) or have redundant HEPA panied by a stringent program of work bioburden in the class II BSC by wip- filters in series as an exhaust. practices, including training, demon- ing down supplies with an appropriate 5. The class III BSC or CACI (as for strated competence, contamination disinfectant before placing them in the all C-PECs) must be located in an reduction, and decontamination when cabinet. externally vented, physically separate, used for compounding sterile and 13. Reduce the HD contamination burden negative-pressure C-SEC with appro- nonsterile HDs. in the class II BSC by wiping down priate ACPH to be used for compound- 2. The class II BSC has an 8–10 inch HD vials with a decontaminant such ing sterile and nonsterile HDs.

opening in the front where drugs and as 0.5% sodium hypochlorite wipers 6. The C-SEC may be either an ISO class 76 supplies are placed into the cabinet and then with a disinfectant such as 7 buffer room with an ISO class 7 an- and whereby the compounder access- sterile 70% isopropyl alcohol before teroom (preferred) or an unclassified es the cabinet. Studies show that this placing them in the cabinet. C-SCA. opening is a source of HD contamina- 14. Consider using an FDA ONB-cleared 7. Class III BSCs or CACIs (as for all C- tion transfer to the environment. Care CSTD while compounding HDs in PECs) used in a facility that compounds must be taken to restrict unnecessary a class II BSC. Studies document a both sterile and nonsterile HDs must movements in and out of the cabinet. decrease in drug contaminants inside be placed in separate rooms unless all 3. A class II BSC used for sterile HD com- a class II BSC when some such devices the USP chapter 800 requirements for 6,8 pounding must provide ISO class 5 or are used. placement in the same room are met. better air quality and unidirectional 15. Contain supply and drug waste in the 8. The class III BSC or CACI (as for all airflow and be externally vented. class II BSC in an appropriate waste C-PECs) must run continuously if it 4. A class II BSC used for nonsterile com- bag or hard plastic container. Do not supplies some or all of the negative pounding must meet the USP chapter discard waste during operations in the pressure in the C-SEC or if it is used to 800 requirements for all C-PECs.8 It class II BSC, as entering and exiting compound sterile HDs.

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9. A plastic-backed preparation mat that such as 0.5% sodium hypochlorite gloves using a saturated wipe; never does not interfere with airflow through wipers76 and then with a disinfectant spray. the cabinet may be placed on the work such as sterile 70% isopropyl alcohol 8. Change gloves every 30 minutes dur- surface of the class III BSC or CACI. The before placing them in the cabinet ing compounding or immediately mat must be changed routinely during antechamber. when damaged or contaminated, compounding and immediately if a 18. Consider using an FDA ONB-cleared unless otherwise recommended by the Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 spill occurs. CSTD while compounding HDs in a manufacturer’s documentation. 10. A class III BSC and CACI have sleeves class III BSC or CACI. Studies docu- 9. Remove outer gloves after wiping and a fixed glove assembly or a gauntlet ment a decrease in drug contaminants down final preparation but before to access the main work chamber in the inside a C-PEC when some such labeling or removing the preparation cabinet. Always inspect the condition devices are used.6,8 from the C-PEC. of the sleeves and gauntlet as well as 19. Once HD compounding is complete, 10. Outer gloves must be placed in a con- disposable gloves to ensure they are wipe down the outer glove and the tainment bag while in the C-PEC. intact and not damaged. The sleeves dose(s), then label and transfer to 11. In a C-PEC with fixed gloves and and/or gauntlet must be decontami- the antechamber. Final doses should sleeves, these must be surface cleaned nated before and after HD compound- be placed in clean transport bags after compounding is completed to ing and disinfected before sterile in the antechamber by someone avoid spreading HD contamination to compounding. wearing clean, tested chemotherapy other surfaces. 11. The decontamination and disinfecting gloves. 12. Clean gloves (e.g., the clean inner process must be done in such a manner 20. Contain supply and drug waste in the gloves) should be used to surface that surface contamination is con- class III BSC or CACI in an appropriate decontaminate the final preparation, tained in both the main chamber and waste bag or hard plastic container. place the label onto the final prepara- antechamber (compounding isolator Remove and contain the outer glove tion, and place the preparation into pass-through). with other HD waste. Transfer the the antechamber and transport bag. 12. Gloves or gauntlets must not be re- contained waste into the antechamber 13. Wear fresh gloves to complete the final placed before completing appropriate for removal and disposal. Alternatively, check, place preparation into a clean decontamination and disinfecting of use the waste containers attached to transport bag, and remove the bag the cabinet. Use the device manufac- the cabinet, if available. from the antechamber. turer’s recommendations for chang- 21. Decontaminate the class III BSC 14. Remove gloves with care to avoid ing gloves without breaking the HD or CACI after completing HD contamination. Specific procedures containment. compounding. for removal must be established and 13. Sterile gloves must be donned over 22. Remove PPE according to SOPs and followed. the gauntlet or fixed glove before policies and procedures and discard in 15. Outer gloves should be removed and compounding sterile HDs (see glove appropriate waste container. contained inside the C-PEC. section for additional details). In a 23. Wash hands thoroughly with soap and 16. Change gloves after administering an negative pressure cabinet, the addi- water. HD dose or when leaving the immedi- tional glove may require being taped to ate administration area. the fixed glove to avoid risking it being Appendix D— 17. Dispose of contaminated gloves as dislodged. Recommendations for use of contaminated waste. 14. Appropriate chemotherapy PPE must gloves 18. Wash hands with soap and water after be worn when compounding or clean- removing gloves. ing a class III BSC or CACI. There is no 1. Two pairs of ASTM D6978-tested exemption from the requirement for gloves are required for compounding Appendix E— wearing a chemotherapy gown when sterile and nonsterile HDs, for the ad- Recommendations for use of compounding in a class III BSC or ministration of HDs, and for cleanup CACI. For sterile compounding, don of HD spills. gowns PPE per USP chapter 797 instructions.7 2. Chemotherapy gloves should be worn 1. Gowns should be worn during com- Sterile gloves tested to ASTM Standard for handling all HDs, including non- pounding, during administration, D-6978 for chemotherapy gloves antineoplastics, and for reproductive when handling waste from patients must be available near the cabinet to risk–only HDs. recently treated with HDs, and when allow placement of the gloves into the 3. Double gloves should be worn during cleaning up spills of HDs. antechamber to affix to the fixed glove any handling of HD shipping cartons 2. Select disposable gowns of material assembly. or drug vials and handling of HD waste tested to be protective against the HDs 15. The class III BSC or CACI must be or waste from patients recently treated to be used. decontaminated and disinfected be- with HDs. 3. Gowns must be changed per the man- fore sterile compounding of HDs and 4. Select powder-free, high-quality gloves ufacturer’s information for perme- routinely during batch compounding. made of latex, nitrile, polyurethane, ation of the gown. If no permeation 16. For sterile compounding, reduce neoprene, or other materials that meet information is available for the gowns the bio-burden in the class III BSC ASTM D6978 for chemotherapy gloves. used, change them every 2–3 hours or or CACI by wiping down supplies 5. Inspect gloves for visible defects. immediately after a spill or splash. with an appropriate disinfectant 6. For sterile HD compounding, the outer 4. Remove gowns with care to avoid before placing them in the cabinet glove must be sterile. spreading contamination. Specific antechamber. 7. Sanitize gloves with sterile 70% iso- procedures for removal must be estab- 17. Reduce the HD contamination burden propyl alcohol or other appropriate lished and followed.7,8 in the class III BSC or CACI by wiping disinfectant before performing any 5. To avoid spreading HD contamination down HD vials with a decontaminant aseptic compounding activity. Wipe and exposing other healthcare work-

2028 AM J HEALTH-SYST PHARM | VOLUME 75 | NUMBER 24 | DECEMBER 15, 2018 HANDLING HAZARDOUS DRUGS ASHP REPORTS

ers, gowns worn in HD handling areas 12. Reduce the HD contamination burden 4. Counting and pouring of HDs should must not be worn to other areas. in the C-PEC by wiping down HD vials be done carefully, and clean equip- 6. Dispose of gowns immediately upon before placing them in the C-PEC. ment should be dedicated for use with removal. 13. To avoid inadvertent contamination these drugs. 7. Contain and dispose of contaminated of the outside surface, transport bags 5. Contaminated equipment should be gowns as trace chemotherapy waste. must never be placed in the C-PEC cleaned initially with gauze saturated Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 8. Wash hands after removing and dis- work area during compounding. with sterile water; further cleaned posing of gowns. 14. Final preparations should be surface with detergent, sodium hypochlorite decontaminated within the C-PEC solution, and neutralizer; and then Appendix F— and placed into the transport bags, rinsed. The gauze and rinse should be Recommendations for working wearing clean gloves, taking care not contained and disposed of as contami- in any C-PEC to contaminate the outside of the nated waste. transport bag. 6. Crushing tablets or opening capsules 1. The C-PEC must be appropriately 15. Decontaminate the work surface of the should be avoided; liquid formulations vented to the outside. Check all gauges C-PEC before and after compounding should be used whenever possible. and alarms before using a C-PEC for per the manufacturer’s recommen- 7. During the compounding of HDs compounding HDs. dations or with detergent, sodium (e.g., crushing, dissolving, or pre- 2. Select the appropriate C-PEC for the hypochlorite solution, and neutralizer, paring a solution or an ointment), type of HD compounding (sterile or or another tested decontaminating workers should wear nonpermeable nonsterile). cleaner. gowns and double gloves. Com- 3. PPE appropriate to the C-PEC must 16. Decontaminate all surfaces of the pounding should take place in a be worn when compounding HDs in a C-PEC at the end of the batch, day, or ventilated cabinet. C-PEC. shift, as appropriate to the workflow 8. Compounding nonsterile forms of 4. The use of a C-PEC must be accom- according to facility policy. Typically, HDs in equipment designated for ster- panied by a stringent program of a C-PEC in use 24 hours a day would ile products must be undertaken with work practices, including operator require decontamination 2 or 3 times care. Appropriate containment, deac- training and demonstrated compe- daily. Disinfect the C-PEC before tivation, and disinfection techniques tence, contamination reduction, and compounding a dose or batch of must be utilized. decontamination. sterile HDs with sterile 70% isopropyl 9. HDs should be dispensed in the final 5. Decontaminate the C-PEC before be- alcohol. dose and form whenever possible. ginning HD compounding at the begin- 17. Wipe down the outside of the class Unit-of-use containers for oral liquids ning of the day and per the established II BSC front opening and the floor have not been tested for containment decontamination schedule. If rinsing is in front of the BSC with detergent, properties. Most exhibit some spillage required, use sterile water for irrigation sodium hypochlorite solution, and during preparation or use. Caution to remove the cleaning agent. neutralizer, or another tested decon- must be exercised when using these 6. Disinfect the C-PEC with sterile 70% taminating cleaner, at least daily. devices. isopropyl alcohol before begin- 18. Wipe down the inside and outside 10. Bulk containers of liquid HDs, as well ning sterile HD compounding and of the antechamber door of the class as specially packaged commercial routinely during batch compounding. III BSC or CACI at least daily and the HDs, must be handled carefully to Use sterile wipers to apply the disin- handle of the antechamber frequently avoid spills. These containers should fectant. Do not spray anything into a with detergent, sodium hypochlorite be dispensed and maintained in C-PEC used for HD compounding to solution, and neutralizer, or another sealable plastic bags to contain any avoid aerosolizing or transferring HD tested decontaminating cleaner. inadvertent contamination. residue. 19. Seal and then decontaminate surfaces 11. Disposal of unused or unusable non- 7. Do not place unnecessary items in of waste and sharps containers before injectable dosage forms of HDs should the work area of the C-PEC, where HD removing from the C-PEC. be performed in the same manner as contamination from compounding for hazardous injectable dosage forms may settle on them. Appendix G— and waste. 8. Do not crowd the C-PEC. 9. Gather all needed supplies before Recommendations for Appendix H— beginning compounding. Avoid exiting compounding and handling Recommendations for reducing and reentering the work area of the nonsterile HD dosage forms exposure to HDs during C-PEC. 1. HDs should be labeled or otherwise administration in all practice 10. A plastic-backed preparation mat that identified as such to prevent improper settings110,120 does not interfere with airflow through handling. the C-PEC may be placed on the work 2. Tablet and capsule forms of HDs Intravenous administration surface of the direct compound- should not be placed in automated 1. Only trained and certified staff may ing area. The mat must be changed counting machines, which subject administer HDs. routinely during compounding and them to stress and may introduce 2. Appropriate PPE must be worn when 8,55 immediately if a spill occurs. powdered contaminants into the work administering HDs. 11. Appropriate handling of the area. 3. The use of gloves, gown, and face preparation in the C-PEC, including 3. During routine handling of non- shield (as needed for splashing) is wiping with sterile 70% isopropyl sterile HDs and contaminated required. alcohol or another appropriate equipment, workers should wear 4. Gloves for handling HDs must be disinfectant, is necessary for sterile 2 pairs of gloves that meet ASTM tested to and meet ASTM D6978 for 8,100 compounding. D6978 requirements.100 chemotherapy gloves.

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5. Two pairs of tested chemotherapy 24. Do not push or force materials con- 5. Designate a workplace for handling gloves are required for administering taminated with HDs into the waste HDs. injectable antineoplastic HDs.8 container. 6. Have a spill kit and HD waste contain- 6. Gather all necessary equipment and 25. Carefully remove, contain, and dis- er readily available. supplies, including PPE. card gloves. 7. Procedure for gloving: wash hands 7. CSTDs are required when the dosage 26. Wash hands thoroughly after remov- and don double gloves. Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 form allows. ing gloves. 8. Always work below eye level. 8. Use needleless systems whenever 9. Visually examine HD dose while it is possible. Intramuscular or subcutaneous still contained in transport bag. 9. Use Luer-Lok fittings for all needleless administration 10. If HD dose appears intact, remove it systems, syringes, needles, ancillary 1. The use of double gloves and gown is from the transport bag. devices, infusion tubing, and pumps. If required. 11. Place a plastic-backed absorbent a CSTD cannot be used, position gauze 2. Gather all necessary equipment and pad on the work area, if necessary, to pads to catch leaks from needleless supplies, including PPE. contain any spills. and other devices that may leak at con- 3. Use Luer-Lok safety needles or re- 12. After administration, wearing double nection points. tracting needles or shields. gloves, contain and dispose of materi- 10. Designate a workplace for handling 4. Syringes should have Luer-Lok als contaminated with HDs into the HDs. connections and be less than three- HD waste container. 11. Have a spill kit and HD waste container fourths full. 13. Do not push or force materials readily available. 5. Designate a workplace for handling contaminated with HDs into the HD 12. Procedure for gowning and gloving: HDs. waste container. Wash hands, don first pair of gloves, 6. Have a spill kit and HD waste contain- 14. Carefully remove, contain, and dis- don gown and face shield, and then er readily available. card gloves. don second pair of gloves. Gloves 7. Procedure for gloving: wash hands 15. Wash hands thoroughly after remov- should extend beyond the elastic or and then don double gloves (1 pair ing gloves. knit cuff of the gown. Double gloving under gown, 1 over). 8. Always work below eye level. requires 1 glove to be worn under the Appendix I—Recommended cuff of the gown and the second glove 9. Visually examine HD dose while still over the cuff. contained in transport bag. contents of HD spill kit 13. Always work below eye level. 10. If HD dose appears intact, remove it 1. Sufficient supplies to absorb a spill of 14. Visually examine HD dose while it is from the transport bag. about 1,000 mL (volume of 1 i.v. bag still contained in the transport bag. 11. Remove the syringe cap and connect or bottle). 15. If HD dose appears intact, remove it appropriate safety needle. 2. Appropriate PPE to protect the work- from the transport bag while wearing 12. Do not expel air from syringe or er during cleanup, including 2 pairs gloves. prime the safety needle. of disposable gloves (1 outer pair of 16. Place a plastic-backed absorbent pad 13. After administration, discard HD heavy utility gloves and 1 pair of in- under the administration site to absorb syringes (with the safety needle at- ner gloves tested to ASTM D6978). leaks and prevent drug contact with tached) directly into an HD waste 3. Disposable HD-resistant gown the patient’s skin. container. or coverall tested against HD 17. If priming occurs at the administra- 14. Wearing gloves, contain and dispose permeability. tion site, prime i.v. tubing with an i.v. of materials contaminated with HDs. 4. Disposable HD-resistant shoe covers. solution that does not contain HDs or 15. Do not push or force materials 5. Chemical splash goggles. prime using the backflow method. contaminated with HDs into the HD 6. Protective face shield to be used 18. Use the transport bag as a containment waste container. with goggles (for full range of splash bag for HD containers and i.v. sets and 16. Carefully remove, contain, and dis- protection). all materials contaminated with HDs. card gloves. 7. NIOSH-approved disposable 19. Discard HD i.v. containers with the 17. Wash hands thoroughly after remov- respirator.a administration sets attached; do not ing gloves. 8. Absorbent, plastic-backed sheets or remove the set. spill pads. 20. Wash surfaces that come into contact Oral administration 9. Disposable toweling. with HDs with detergent, sodium 1. Double gloves are required, as is a 10. At least 2 sealable, thick plastic hypochlorite solution, and neutralizer, face shield if there is a potential for hazardous waste disposal bags (prela- if appropriate. spraying, aerosolization, or splashing. beled with an appropriate warning 21. Wearing gloves, contain and dispose of 2. Workers should be aware that tablets label). materials contaminated with HDs. or capsules may be coated with a dust 11. One disposable scoop for collecting 22. To remove PPE, carefully begin with of residual HD that could be inhaled, glass fragments. outer gloves. Still wearing the inner absorbed through the skin, ingested, 12. One puncture-resistant container for gloves, remove remaining PPE from or spread to other locations and that glass fragments. least to most contaminated and dis- liquid formulations may be aerosol- 13. An approved cartridge respirator for card as trace waste. ized or spilled. use with contents of spill kit.a 23. HD waste containers must be suf- 3. No crushing or compounding of oral ficiently large to hold all discarded HDs may be done in an unprotected aRespirators may only be used by workers material, including PPE. environment. who have been trained and fit-tested to the 4. Gather all necessary equipment and appropriate respirator. supplies, including PPE.

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Appendix J— final container for disposal as RCRA II BSC or similarly equipped class III Recommendations for spill hazardous waste. BSC or CACI. 14. Carefully remove all PPE using the 7. If the spill results in liquid being cleanup procedure inner gloves. Place all disposable introduced onto the HEPA filter or if General PPE into disposal bags. Seal bags and powdered aerosol contaminates the 1. Assess the size and scope of the spill. place them into the hazardous waste “clean side” of the HEPA filter, use of Downloaded from https://academic.oup.com/ajhp/article-abstract/75/24/1996/5248544 by BIBLIOSAN Remote CILEA CLAS user on 12 March 2020 Call for trained help, if necessary. container (not trace-contaminated the C-PEC should be suspended until 2. Spills that cannot be contained waste). the equipment has been decontami- by 2 spill kits may require outside 15. Remove inner gloves; contain in a nated and the HEPA filter replaced. assistance. small, sealable bag; and then place 3. Post signs to limit access to spill area. into the appropriate final container for Appendix K—OSHA- 4. Obtain spill kit and respirator. disposal as hazardous waste. recommended steps for 5. Don appropriate PPE, including inner 16. Wash hands thoroughly with soap and immediate treatment of and outer gloves and respirator. water. 6. Once fully garbed, contain spill using 17. Once a spill has been initially decon- workers with direct skin or eye spill kit. taminated, have the area cleaned contact with HDs133 7. Carefully remove any broken glass by housekeeping, janitorial staff, or 1. Call for help, if needed. fragments and place them in a environmental services. 2. Immediately remove contaminated puncture-resistant container. clothing. 8. Absorb liquids with spill pads. Spills in a C-PEC 3. Flood affected eye with water or iso- 9. Absorb powder with damp disposable 1. Spills occurring in a C-PEC should be tonic eyewash for at least 15 minutes. pads or soft toweling. cleaned up immediately. 4. Clean affected skin with soap (not a 10. Spill cleanup should proceed progres- 2. Obtain a spill kit if the volume of the disinfectant cleanser) and water; rinse sively from areas of lesser to greater spill exceeds 30 mL or the contents of 1 thoroughly. contamination. drug vial or ampule. 5. Obtain medical attention. 11. Completely remove and place all 3. Utility gloves (from spill kit) should 6. Document exposure in employee’s contaminated material in the disposal be worn to remove broken glass in the medical record and medical surveil- bags. C-PEC. Take care not to damage the lance log. 12. Rinse the area with water and then sleeve or fixed-glove assembly in the 7. Supplies for emergency treatment clean with detergent, sodium hypo- class III BSC or CACI. (e.g., soap, eyewash, sterile saline for chlorite solution, and neutralizer or 4. Place glass fragments in the puncture- irrigation) should be immediately other validated decontamination resistant HD waste container located located in any area where HDs are solution. in the C-PEC. stored, compounded, or administered. 13. Rinse the area several times and place 5. Thoroughly clean and decontaminate all materials used for containment and the C-PEC. cleanup in disposal bags. Seal bags 6. Clean and decontaminate the drain and place them in the appropriate spillage trough located under the class

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