USP <800>: Navigating the New Requirements for Handling Hazardous Drugs in the Community Oncology Setting

USP <800>: Navigating the New Requirements for Handling Hazardous Drugs in the Community Oncology Setting Exploratory Paper Nina K. Chavez, MBA, SPHR, FACMPE August 22, 2017 This paper is being submitted in partial fulfillment of the requirements of Fellowship in the American College of Medical Practice Executives.

Introduction The US Pharmacopeial Convention s General Chapter <800> Hazardous Drugs Handling in Healthcare Settings (USP <800>) will affect community oncology practices and freestanding cancer centers across the nation, regardless of their size or the volumes of hazardous drugs being compounded on site. Now that the chapter has been finalized, enforcement of USP <800> is scheduled to begin on July 1, 2018. The question before community oncology practices now is not if, but how will practices navigate through the daunting task of reaching compliance before the 2018 deadline? USP <800> will impact each practice in different ways, depending on how it is enforced in each state and which agency or organization chooses to enforce it. USP <800> builds on USP <795> and <797> which historically have not applied to cancer centers and oncology practices because of the individual and short-term duration of their drug compounding. Community oncology practices now find themselves in new and unfamiliar territory requiring the fast absorption of knowledge needed to meet compliance standards within the next year. Practices that are not compliant with USP <800> standards by the July 1, 2018 deadline could face a loss of market share, adverse publicity, or enforcement expenses and other obligations. The bottom line of oncology practices could be affected at the beginning of implementation to meet compliance or at the end to remediate changes, mitigate fees, and loss of revenue due to closing of infusion suite. This paper will explore the impact of meeting the new USP <800> chapter from conducting a gap analysis, setting an action plan, and implementing necessary changes to the overall financial and regulatory impacts it will have on all community oncology practices moving forward. The research methodology used in this exploratory paper combined a literature review of publication research and online articles with original research and analysis of oncology practice data samples highlighting current and historical information. 2

Impact to Community Oncology Practices The standards set forth in USP <800> will impact all oncology providers who store, prepare, compound, and/or administer hazardous drugs. The chapter will affect private community oncology practices on many levels likely changing aspects of the operations, marketing, contracting, and financial structure of oncology drug delivery in the near future. USP <800> was written to identify the safe handling of hazardous drugs (HDs) for the protection of staff and patients with a broad mandate and application to all healthcare settings. Now that USP <800> is finalized, it will apply to every relevant entity not just hospitals or compounding pharmacies as in the past and will subject all organizations to enforcement. Background According to the United States Pharmacopoeia (USP) (2014b) each year approximately 8 million American health care workers are potentially exposed to HDs. Over the years, exposure to hazardous agents in the workplace has increasingly become a concerning topic for health care workers as more and more studies document increased risks of various health problems associated with exposure. One health risk identified in health care workers with a causal relationship with exposure to antineoplastic agents is compromised reproductive health and fertility including increased risk for spontaneous abortion (Lawson et al., 2012). Aside from the documented reproductive consequences, there is a small body of literature demonstrating an increased risk for cancer in those with occupational exposure to antineoplastic agents. The Centers for Disease Control and Prevention (CDC) maintain that the literature regarding cancer risk as it relates to exposure to antineoplastic agents is limited and is composed mainly of case reports and epidemiological studies. However, it should be recognized that a risk may exist and proper studies may not have yet been published. Along with antineoplastic drugs, non-antineoplastic hazardous agents such as anti-viral drugs, hormonal agents, and bioengineered drugs have also been associated with adverse effects in 3

exposed employees including skin rashes, reproductive problems, and possibly leukemia and other cancers (Centers for Disease Control and Prevention [CDC], 2017). The National Institute for Occupational Safety and Health (NIOSH) (2004) published a safety alert that included a listing of agents that should be considered hazardous and should be handled according to specific recommendations. The list was most recently updated in 2016 to include 27 additional drugs. According to NIOSH, a hazardous drug is one that exhibits one or more of the following six characteristics in humans or animals: Carcinogenicity; Teratogenicity or other developmental toxicity; Reproductive toxicity; Organ toxicity at low doses; Genotoxicity; and/or Structure and toxicity profiles of new drugs that mimic existing drugs determined hazardous by the above criteria (NIOSH, 2014). Common national standards must be set and adopted by health systems to protect health care workers and patients from being exposed to HDs and to allow patients to experience continuity of care across the states. USP, or The US Pharmacopeial Convention, is a nonprofit organization that sets standards for various activities and areas of health care that are enforceable by the Food and Drug Administration (FDA). USP-NF General Chapters numbered below <1000> provide required guidelines and are used by the FDA and other regulatory agencies to evaluate health system compliance. In February 2017, USP published a newly finalized chapter to their publication The United States Pharmacopeia and the National Formulary (USP-NF) entitled USP General Chapter <800> Hazardous Drugs Handling in Healthcare Settings or simply USP <800> (United States Pharmacopeia [USP], 2017). 4

In general, USP <800> builds on the standards and recommendations set forth by both USP <795> Pharmaceutical Compounding Nonsterile Preparations and USP <797> Pharmaceutical Compounding Sterile Preparations. USP <800> further emphasizes protecting personnel by containment of hazardous drug exposure to as low a level as reasonably achievable, or ALARA, a standard used to measure radiation exposure of employees. The chapter covers the process of handling hazardous drugs including receiving and unpacking, preparing, compounding, dispensing, and administering. Health care organizations must proactively think about how to implement the changes outlined in USP <800> in order for their facilities to be in compliance. Opposition to the application of USP <800> to community oncology practices was led by independent oncology practices in cooperation with organizations including the Association of Community Cancer Centers (ACCC), American Society of Clinical Oncology (ASCO), and Oncology Nursing Society (ONS) through debate forums and public comments requesting the consideration of reasonable changes and recommendations. Despite this fierce opposition, the chapter is now final and published and enforcement set to begin in less than one year. Documentation and Standard Operating Procedures Written policies and procedures provide the framework for the entire operations of a company by outlining clear directions for employees as well as detailed insight into the philosophies, values, and ethical standards that govern the company. In light of USP <800>, the creation and maintenance of a standard operating procedure (SOP) manual for every practice infusion mixing room and pharmacy is an essential step in creating a culture of compliance and workplace safety. Every organization should designate a compounding supervisor responsible for ensuring that compliance is met with respect to all areas of USP <800>, environmental controls are appropriate and in good working condition, and personnel are adequately trained in handling of hazardous drugs. 5

Most community oncology practices are QOPI (Quality Oncology Practice Initiative) certified with ASCO; this certification requires safe practices for both the compounding and administration of chemotherapy. When developing a USP <800> compliance strategy taking those policies into consideration during the gap analysis will be beneficial. Unlike stand-alone pharmacies, oncology practices need to review the entire infusion process including the infusion mixing room/pharmacy, infusion suite/administration area, shipping and receiving, and anywhere else HDs may be handled within a practice. Including all aspects of HD handling in this review is one of the fundamental steps for ensuring USP <800> compliance throughout a community oncology practice. A practice can easily go about this by establishing a team and designating an aforementioned compounding supervisor who will construct a gap analysis to determine where a practice is versus where they need to be to meet compliance standards. Educating the USP <800> team, explaining relevant sections of USP <800> and the NIOSH regulations related to HDs, and establishing a pharmacy organizational strategy for the handling, storage, and disposal of HDs all foster the creation of an environment of compliance and starts the culture change that needs to happen for success. In the process of developing an HD strategy, gaining buy-in and soliciting leadership support from nursing and other clinical services is just as important as garnering support from the physicians and practice management team. Many community oncology practices do not employ a pharmacist or pharmacy staff, and smaller practices still use OCN certified Oncology Nurses to mix chemotherapy. While maintaining these staffing choices is still possible in adherence with USP <800>, practices will face greater difficulty. If nursing continues to mix, they must follow the same rules that pharmacy staff adhere to and all SOPs created; therefore, it is important for the USP <800> team to include nursing staff who mix. While management will drive the initiative to make the necessary changes, it is the staff pharmacists, nurses, and pharmacy technicians handing HDs who will be instrumental in identifying areas requiring compliance assistance. A practice will find greater and faster success in the task of complying 6

with the USP <800> standards if it employs a team effort. Although nurses are not overseen by the state board of pharmacy, under USP<800> the mixing room and process of compounding are governed and enforced by USP (USP, 2014a). Therefore, compounding and mixing processes will change in order to meet USP compliance. Practices that still use OCN nurses to mix chemotherapy will need to consider having only one nurse mix all day, because once a nurse is garbed and in the clean room or C-SCA they should remain in the clean room mixing chemotherapy for all patients. The old preparation method that allowed each individual nurse to mix their own chemotherapy is not permissible under USP <800> as it breaks the negative pressure seal and leaves the clean room open to contamination of the sterile environment (USP, 2014a). This regulatory change could affect nursing job satisfaction as nurses are patient oriented and did not necessarily choose to act as mixing technicians. Pharmacy technicians will be, if they are not already, part of the mixing team. Another issue that may arise is that in many states nursing cannot oversee pharmacy technicians: only a registered pharmacist can oversee technicians. Small oncology practices must recognize the potential added costs of hiring a pharmacy technician and a pharmacist, which may create a substantial burden that could prove reason enough for the closure of smaller infusion suites in practices nationwide. Some of the activities that must be documented in a SOP include, but are not limited to: The acquisition, preparation, and dispensing of an HD; Personnel training and the use of PPE; and Maintenance of equipment and supplies. All of these activities and records must be available for review. Personnel who transport, compound, or administer HDs must document their training according to OSHA standards and other applicable laws and regulations. 1 Practices must maintain SOPs for the safe handling of HDs for all situations in which these HDs are used throughout a facility. SOPs for handling of 7

HDs should include: Hazard communication program (HCP) Occupational safety program Labeling of HDs Procurement of HDs Use of proper engineering controls (e.g. C-PECs, C-SECs) Use of personal protective equipment based on activity (e.g. receipt, transport, compounding, administration, spill, and disposal) Receiving and storage of HDs Decontamination/deactivation, cleaning, and disinfection Transport Environmental monitoring Spill control Medical surveillance Types of Exposures Practices will need to develop a HD strategy along with their compliance team to help meet the goal of limiting the types of exposures. This can be done by performing a gap analysis, reviewing the HCP and SOPs, and considering all points of contact during the processing of HDs. Clinical and nonclinical staff can be unintentionally exposed to HDs through various means of contact including ingestion, inhalation, injection, and mucosal absorption. Staff can experience unintentional exposure when touching contaminated surfaces, when cleaning dust or spills, or when involved in the disposal of these substances. All areas with unintentional exposure risks should be considered when developing new or updating existing policies. All areas with unintentional exposure risks should be considered when 8

developing new or updating existing policies. Handling HDs at any level of preparation, dispensing, and administration poses risk of this exposure. Access to areas where HDs are stored and prepared must be limited to authorized staff to avoid unintentional exposure to HDs. Table 1 Partial List of Potential Areas of Unintentional Exposure Risk Receiving or unpacking orders Counting doses from bulk containers Crushing tablets or opening capsules to mix in food or compound an oral liquid Weighting, mixing, diluting or reconstituting HDs Touching work surfaces that have HD residue present Handling body fluids with HDs as well as contaminated clothing, linens, and other materials Pouring liquids into a different container (may be oral or topical products) Expelling air from a syringe containing an HD or expelling the HD from a syringe Inhaling aerosolized HDs (patient or visitor sharing room with another patient) Maintaining equipment and devices (e.g. by work control/engineers) Tables 2 and 3 highlight the growth in number and type of supplies and PPE used by one medium-sized community oncology practice prior to USP <797> and USP <800> and the current mix of supplies and PPE required to meet compliance standards (USP, 2014a). As expected, there is a significant increase to the list of required supplies needed when compounding the same drug before and after USP <800> implementation. This is an additional cost burden to community oncology practices that they are currently unable to recoup. Hospitals and outpatient centers have the ability to bill payers for both facility fees and supply costs in order to recoup compliance losses. However, in the physician fee schedule environment the cost has to be absorbed from the current reimbursement rate. Cost versus reimbursement will be reviewed later in the financial impact section. 9

Table 2 Rituximab Supplies/PPE Compliance Comparison Current compliance with USP <800> Prior to USP <797> and USP <800> One 16g needle Graduated cylinder to minus Normal Saline out of bag Secondary tubing needle free valve tubing One 16g needle Graduated cylinder to minus Normal Saline out of bag Secondary tubing needle free valve tubing 1000ml bag of NS 0.9% 1000ml bag of NS 0.9% Gallon size zip lock bag Red Sharps container for waste Sterile alcohol wipes Two-60cc syringes Gallon size zip lock bag Red Sharps container for waste Sterile alcohol wipe Two-60cc syringes Disposable white lab jacket Double shoe covers Hair cover Face mask Antibacterial medicated soap Sterile glove 1 pair Lint free towel to dry hands Gamma irradiated Sterile alcohol 1 mini spike Fluid resistant gown Chemo gloves 1 pair 10

Table 3 Cisplatin Supplies/PPE Compliance Comparison Current compliance with USP <800> Prior to USP <797> and USP <800> Sterile alcohol wipe Sterile alcohol wipe 2 texium 60ml needle free syringes 60ml syringes 500ml bag of NS 0.9% 500ml bag of NS 0.9% Secondary set smart site needle free valve tubing Large plastic chemo labeled zip lock 2 gallon size bag Yellow sharps container/ Black sharps container for waste Secondary tubing needle free valve tubing Large plastic chemo labeled zip lock 2 gallon size bag Yellow sharps container/ Black sharps container for waste Disposable white lab jacket Disposable blue plastic Chemo Jacket Hair Cover Double shoe covers Two Face mask or N95 mask Antibacterial medicated soap 2 pairs sterile gloves Lint free towels to dry hands Gamma irradiated sterile alcohol Care fusion smart site vial shield to spike vial Needle free valve Sterile lint free wipes with 2% bleach to wipe bag off Medium 1 gallon chemo zip lock bag for chemo waste Chemo gloves 1 pair 11

Current compliance with USP <800> Prior to USP <797> and USP <800> Fluid resistant gown One 16g needle Hazard Communication Program The Occupational Safety and Health Administration (OSHA) requires a written work plan that describes how HDs are identified and defines the process of supplying safety data sheets (SDS) for each HD available within a center. Community oncology practices and freestanding cancer centers are also required to address how it will ensure that all employees are trained before any initial exposure or work assignment, and how they will respond to questions or concerns regarding potential or actual exposures. Robust training and competency assessments must include verification and documentation with specific testing of proper techniques, and these must be reassessed at least annually or more frequently if changes occur or if new products have become available for use. Other considerations for training should include: Safety when transporting HDs; Compounding different HD dosage forms; Protection when administering HDs; Decontamination, disinfection, disposal, and cleaning; Spill control; and Staff training and competency assessments. Personal Protective Equipment The American Journal of Health-System Pharmacists published an article by Connor et al. (2005) that evaluated three studies looking at vial contamination of chemotherapeutic agents. 12

All three studies found surface contamination of vials of cyclophosphamide, ifosfamide, fluorouracil, and cisplatin obtained from commercial manufacturers in both the United States and Europe. These studies stress the importance of proper handling through the entire hazardous drug process. It is expected that, in addition to those employees preparing and administering hazardous drugs, Personal Protective Equipment (PPE) will also be worn by employees that are involved in receiving, transporting and stocking hazardous drugs such as the pharmacy technicians, nurses, shipping and receiving clerks and transportation staff as well as those employees involved in disposing of patient waste and cleaning spills such custodial technicians. PPE as defined by USP <800> includes the wearing of two pairs of ASTM-tested chemotherapy gloves that have been evaluated for permeability; impervious gowns that close in the back; and head, hair, shoe, and sleeve covers when compounding hazardous drugs. Special care must be taken when compounding sterile products as the outside glove must always be sterile (USP, 2014). When nurses are administering hazardous drugs, they need only wear ASTM-tested chemotherapy gloves and an impervious gown, but they may require additional eye and face protection if splashing or aerosolization of the dosage form is possible. For further information regarding PPE use, USP <800> provides a table of various activities included in the hazardous drug handling process and the PPE required to be worn during those activities. As a guideline, all personnel involved in any step of the hazardous drug handling process should wear PPE. Wearing PPE should not be limited to those personnel who are directly involved in compounding, preparing, or administering hazardous drugs such as pharmacists, pharmacy technicians, and nurses (USP, 2014). 13

Table 4 Summary of Required Personal Protective Equipment (PPE) (USP, 2014) PPE Item Receiving Damaged or Broken Compounding (Sterile and Non-sterile) Cleanup (Routine) Gloves X X X X Collection & Disposal of Waste/Spills Gown X X X X Hair, face, beard, and shoe covers Eye and face protection X X X X X X Respiratory protection X X Note. Adapted from General chapter <800> hazardous drugs handling in healthcare settings, by United States Pharmacopoeia, retrieved from http://www.usp.org/sites/default/files/usp_pdf/en/m7808.pdf Copyright 2014 by United States Pharmacopoeia. Engineering Controls Three types of containment engineering controls are outlined in the chapter and should be present when compounding hazardous drugs: primary, secondary and supplemental. A containment primary engineering control (C-PEC) is the hood or work surface in which hazardous drugs are being prepared, a containment secondary engineering control (C-SEC) is the room in which the hazardous drugs are being prepared and the supplemental engineering control refers to items such as closed-system drug-transfer devices (CSTDs). As a general rule, regardless of the type of compounding, the C-PEC is required to be externally vented. Therefore, a laminar airflow workbench (LAFW) or compounding aseptic isolator (CAI) must not be used to compound hazardous drugs. In addition, the C-SEC should be a segregated room dedicated to hazardous drug compounding. The C-SEC should be 14

maintained at negative pressure relative to adjacent spaces and have the appropriate number of air exchanges based on the type of compounding taking place. Hazardous drugs should never be manipulated in an area that is of positive pressure in relation to adjacent spaces, as this would allow for contamination of adjacent spaces by outward airflow. Sterile HD Compounding Community oncology practices and cancer centers compound sterile HDs and non-hds obligating them to follow the sterile compounding processes set forth in USP <797> for all mixing they perform. According to USP <800>, sterile HD compounding must take place in a Class II BSC (biological safety cabinet or hood) or a Compounding Aseptic Containment Isolator (CACI). USP <800> allows for the hood to be placed in an ISO Class 7 environment; this is the most sterile means of compounding (cleanroom). However, USP recognizes that an ISO Class 7 environment may not always be available, particularly in oncology clinics where compounding is taking place or smaller institutions without dedicated cleanrooms. Considering this, USP made allowances for HD compounding to alternatively take place in a containment segregated compounding area (C-SCA) that does not contain ISO Class 7 air with the expectation that one of the following conditions is met (see Table 5): A CACI is present (USP <797> beyond use dating may be applied in this situation); or A BSC is present, all compounding meets low- or medium-risk compounding definitions, and finished products are given a maximum beyond use date (BUD) of 12 hours (2014a). Regardless of the lack of ISO Class 7 air, the C-SCA must meet all the requirements for a C-SEC (i.e., segregated room, negative pressure, appropriate air exchanges, etc.). This differs from the standard previously published in USP <797> that allowed facilities that compounded a 15

small volume of hazardous drugs to only have a BSC or CACI for HD compounding in a nonnegative pressure room. Table 5 Acceptable Configurations for Hazardous Drug Compounding Compounding Function C-PEC C-SEC Air Changes Per Hour (ACPH) Maximum BUD Compounding Sterile HD in a Cleanroom Class II BSC CACI ISO 7 Classified 30 ACPH (HEPA supply) As listed in <797> Compounding Sterile HD in a CACI Not in a Cleanroom CACI C-SCA 12 ACPH (exhaust) As listed in <797> Compounding Low- or Medium- Risk Sterile HDs in a BSC Not in a Cleanroom BSC C-SCA 12 ACPH (exhaust) 12 hours Note. Adapted from General chapter <800> hazardous drugs handling in healthcare settings, by United States Pharmacopoeia, retrieved from http://www.usp.org/sites/default/files/usp_pdf/en/m7808.pdf Copyright 2014 by United States Pharmacopoeia. USP <797> and USP <800> provide a practical solution in that they do not require a cleanroom for medical practices if the practice can limit itself to starting the infusion of its compounded sterile products within 12 hours of completing the compound. If a practice or cancer center can meet this stipulation, the practice can be compliant by limiting compounding to C-SCA. This can be an isolated, restricted-traffic room just large enough to house a containment primary engineering control and an operator wearing adequate gowning, garb, and personal protective equipment. USP <800> stipulates that a C-SCA must meet criteria specific to ventilation and airflow. However, if a clinic cannot adhere to a 12-hour beyond-use date the only way to achieve compliance will be to construct or gain the use of a fully functional cleanroom (USP, 2014a). 16

Environmental Quality and Control Environment quality is another area of cost that community oncology practices will need to bare. It has not been a standard operating practice to take consistent, regular surface samples of infusion suites. USP <800> states that regular environmental sampling should take place so as to ensure complete containment of hazardous drugs within drug preparation areas. The work surface of the hood, countertops where hazardous items are placed, areas surrounding hoods (including floor below work area) and patient administration areas should undergo surface wipe sampling. Samples should then be assayed for presence of hazardous drug residue and if measurable contamination is present action such as evaluation of employee work practices, retraining, cleaning and evaluation of engineering controls must be taken. Ideally, sampling should occur at baseline and at least every six months thereafter (USP, 2014a). Closed-system drug-transfer devices should be considered highly recommended during compounding of hazardous drugs by pharmacy staff and should be considered required during administration of hazardous drugs by nursing personnel when the dosage form allows. It is recognized that some dosage forms such as intrathecals, irrigations, ophthalmic preparations and topical agents may not allow for a CSTD to be used. Wick, Slawson, Jorgenson, and Tyler (2003) published a study evaluating employee exposure prior to and after implementing a CSTD. Wick et al. found that prior to CSTD use, six out of eight employees (nurses, pharmacists, pharmacy technicians and a control) were found to have cyclophosphamide present in their urine and two out of those eight were found to have ifosfamide present in their urine. After implementation of a CSTD, the urine of all eight employees was found to be free of both agents (2003). The FDA has approved various closed-system drug transfer devices and practices should take care to evaluate each device for appropriateness within their clinics. Medical Surveillance A medical surveillance program is also a new requirement included in USP <800>. The 17

program is intended to monitor employees in such a manner as to minimize harmful effects in those who may be exposed to hazardous drugs. All employees involved in any aspect of the hazardous drug handling process should be screened at baseline and on a regular basis thereafter for health status changes as they may relate to hazardous drug exposure. The regulation mandates written policies and procedures for medical surveillance and recommends testing and monitoring of staff for HD exposure through medical history, physical examination, laboratory studies, and biological monitoring (USP, 2014a). Massoomi outlined one example of a surveillance program as a four-tier program (as cited in Bennett, Felt, & Granko, 2015, p. 18): Tier 1: self-surveillance (education efforts, notification of health changes) Tier 2: employer/supervisor surveillance (tier one activities plus trending sick call types for high-risk employees, etc.) Tier 3: comprehensive medical surveillance (tier one and two activities plus medical and laboratory tests) Tier 4: post-exposure surveillance (medical tests, documentation of known exposure, continual monitoring A medical surveillance program should ideally include all of the following: Establishment of a monitoring strategy (typically a questionnaire) for identifying employee exposure to hazardous drugs (drugs handled, hours spent handling drugs, number of preparations or administrations per week, etc.); A means for monitoring employee health at baseline (general health history, reproductive history, etc.) and periodically thereafter (typically this is accomplished via an annual questionnaire); Development of a program to obtain baseline clinical evaluations (laboratory values, physical examinations, etc.) and subsequent evaluations on a scheduled 18

basis dictated by employee exposure and risk; and A plan for addressing health status changes that have been identified through the medical surveillance program (Bennett et al., 2015). Regardless of the medical surveillance program design, if health changes are identified in exposed employees, practices should take action by examining all engineering controls for containment efficiency, performing environmental sampling within engineering controls and evaluating the employee s compliance with PPE and knowledge of the organization s policies and procedures related to hazardous drug handling. If deficiencies in equipment functionality or employee knowledge are noted, a plan of action should be developed to prevent future employee exposure. Various organizations such as the American Society of Health-System Pharmacists (ASHP), NIOSH, and ONS provide additional information regarding development of a proper medical surveillance program (American Society of Health-System Pharmacists [ASHP], 2006; NIOSH, 2012; Polovich, 2011). Financial Impact for Compliance in Community Oncology Settings As noted in the June 9, 2015 publication ASCO Urges Evidence-based, Flexible Drug Handling Requirements in Comments on USP <800>, ASCO urged the USP organization to reevaluate the proposed USP <800> changes. 2 ASCO noted the potential negative impact on access to cancer care because resources needed to implement the proposed changes were not available in many oncology practice settings and represented prohibitive financial and administrative burdens on oncology practices and clinics. In addition to the investment in new space and equipment, the ongoing staff training, environmental monitoring, and cleaning standards will add substantial time commitments and expenses to meet USP <800> compliance. Cleaning procedures alone can be prohibitively costly. The costs of having a cleanroom certified twice a year can be in the thousands of 19

dollars. Just having a surface contamination study can cost between $2000 to $3000, and these studies alone are recommended to be done on a regular basis. The ongoing maintenance costs are significant as well. Tables 6 and 7 below present the average cost for equipment, software, construction, and supplies. Although many items are one-time costs to practices, the nearly $100,000 required for the physical plant changes is a significant burden to community oncology practices. USP <800>-compliance maintenance comes with a long list of ongoing costs including PPE, surface sampling, certification of BSC and cleanrooms, and CTSD systems (USP, 2014a). Tables 6 and 7 also detail the ongoing annual costs of upward of $90,000 practices can expect to spend depending on patient volume and number of employees. Table 6 Average Equipment, Software, Construction, and Supply Cost Equipment, Software or Supplies Frequency Average Cost CSTD Annually $60,000.00 Incubator One time cost $1,000.00 Pharmacy log software (this can be done manually) Annually $24,000.00 Air sampling Annually $1,500.00 Surface sampling Annually $2,280.00 Media fill test Annually $1,700.00 Hepa filters Annually $4,000.00 Medical surveillance (Upon new hire, exposure, and By employee $1,750.00 termination - based on 5 employees) BSC One time cost $8,000.00 General-Use Pass Through Chamber One time cost $8,000.00 Cleanroom or CSC-A construction cost One time cost $25,000.00 HVAC systems upgrade One time cost $10,000.00 Exhaust fans for external venting of BSC One time cost $2,000.00 20

Equipment, Software or Supplies Frequency Average Cost (Camera Verification System) Remote Rx Checking of admixtures (needed in order to not break negative pressure seal) One time cost $37,000.00 Total one time cost $91,000.00 Total annual cost $93,480.00 Estimated cost for medical surveillance $5,250.00 Table 7 PPE Cost to Infusion Suite for Compounding and Administration Nursing Preparation and Administration of Premedication Drugs per patient (See Appendix A) Nursing Preparation of Chemotherapy Treatment and Administration of Chemotherapy Drugs per patient (See Appendix B) Infusion Mixing Pharmacy Preparation of Chemotherapy Drugs per patient (See Appendix C) Infusion Mixing Pharmacy Preparation of Non-Chemotherapy Drugs per patient (See Appendix D) $29.09 $35.39 $52.66 $40.89 Total Cost per Patient per Day $158.03 Total Cost for 100 Patients / Day $15,803.00 Conclusion Pharmacy regulations can and will affect community oncology practices under the new USP <800> chapter. Community oncology practices and cancer centers that typically operate under state medical boards will find state pharmacy boards visiting their sites to monitor compliance as of July 1, 2018. Even if a practice has not registered within a state as a registered pharmacy, that pharmacy is subject to pharmacy board regulations. Depending on the enforcement agency, mixing rooms could be shut down until compliance is met. This could 21

bankrupt most practices or cause them to sell to larger organizations with a capital budget to meet compliance. Planning ahead is the best chance for a practice to roll out smoothly and implement new regulations; community oncology practices can find one of several USP savvy consulting services to prepare smartly for enforcement. For practices that may still be waiting to comply and/or are considering waiting to see how enforcement will be rolled out should consider the following. Legislative action. The local state legislature may take action related to the standards set forth in USP 800 and make them law with enforceable deadlines. The current deadline is July 1, 2018 as set by USP. The court of public opinion. The USP <800> standards have been written to protect staff and patients; it would be difficult to argue that they should not be followed in any setting. Enforceability. USP chapters numbered below <1000> are considered enforceable, and those with higher numbers are considered guidelines. The USP <800> regulation is national in scope and applies to all healthcare providers regardless of type or size private or hospital-based, pharmacy or physician. Enforcement. This varies, because the USP does not have its own enforcement body giving enforcement responsibilities to the FDA, the Joint Commission, OSHA, and individual state pharmacy boards. Many small and medium-sized community oncology practices have a long way to go in meeting the standards of USP <800>. Practices are now starting to scramble as they attempt to implement changes needed for compliance, and some are not confident that they will meet the deadline. It is estimated that 20% of practices are not going to be prepared in time. Many larger practices will be ready but only due to significant cost, tweaking processes, rewriting 22

policies, and generating different operating procedures to better meet the chapter. Crucial among all the preparations is the creation of an action plan that includes a gap analysis to begin evaluating current operating procedures and space/infrastructure needs to reach full USP <800> compliance. A pharmacy evaluation will also identify if waivers need to be requested from a state board of pharmacy if a facility is not currently in compliance. The proactive step of performing a pharmacy evaluation could avoid any potential shut down of the drug compounding processing activities until full compliance can be achieved. The pharmacy evaluation may require the services of design professionals to identify the potential space modifications or building infrastructure modifications needed for compliance. However, state boards of pharmacy will be more amenable if a practice demonstrates progress made toward achieving USP <800> compliance. It is very clear that compliance is expected no matter the cost to community oncology practices due to the main goal of USP <800> being to protect employees from hazardous drug exposures. 23

References American Society of Health-System Pharmacists. (2006). ASHP guidelines on handling hazardous drugs. American Journal of Health-System Pharmacists, 63, 1172-1193. Retrieved from http://forums.pharmacyonesource.com/phos/attachments/phos/pharmacy_ops/471/1/haz_ AJHP.pdf Bennett, S. C., Felt, K. C., & Granko, R. P. (2015, July). Prepare pharmacy and nursing for USP <800>. Pharmacy Purchasing & Products, 1507, 14-18. https://www.pppmag.com/documents/v12n7/pdfs/ppp_1507_usp800.pdf Centers for Disease Control and Prevention. (2017, March 31). Hazardous drug exposures in health care. Retrieved from https://www.cdc.gov/niosh/topics/hazdrug/ Connor, T. H., Sessink, P. J., Harrison, B. R., Pretty, J. R., Peters, B. G., Alfaro, R. M., Dechristoforo, R. (2005, March 1). Surface contamination of chemotherapy drug vials and evaluation of new vial-cleaning techniques: Results of three studies. American Journal of Health-System Pharmacy, 62(5), 475-484. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15745910 National Institute for Occupational Safety and Health. (2012, November). Medical surveillance for healthcare workers exposed to hazardous drugs (DHHS (NIOSH) Publication No. 2013-103). Cincinnati, OH: NIOSH Publications Dissemination. Retrieved from https://www.cdc.gov/niosh/docs/wp-solutions/2013-103/pdfs/2013-103.pdf National Institute for Occupational Safety and Health. (2004a, September). NIOSH alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in health care settings (DHHS (NIOSH) Publication No. 2004-165). Cincinnati, OH: NIOSH Publications Dissemination. Retrieved from https://www.cdc.gov/niosh/docs/2004-165/pdfs/2004-165.pdf National Institute for Occupational Safety and Health. (2014b, September). NIOSH list of 24

antineoplastic and other hazardous drugs in healthcare settings, 2014 (DHHS (NIOSH) Publication No. 2014-138). Cincinnati, OH: NIOSH Publications Dissemination. Retrieved from https://www.cdc.gov/niosh/docs/2014-138/pdfs/2014-138.pdf Lawson, C. C., Rocheleau, C. M., Whelan, E. A., Lividoti Hibbert, E. N., Grajewski, B., Spiegelman, D., & Rich-Edwards, J. W. (2012). Occupational exposures among nurses and risk of spontaneous abortion. American Journal of Obstetrics & Gynecology, 206(4), 327.e1 327.e8. http://dx.doi.org/10.1016/j.ajog.2011.12.030 Polovich, M. (Ed.). (2011). Safe handling of hazardous drugs (2nd ed.). Oncology Nursing Society Pittsburgh, PA: Oncology Nursing Society. Tocco, A. (2015). The future impact of USP 800 in the health care setting. Retrieved from http://www.michiganpharmacists.org/portals/0/education/cearticles/usp800012015.pdf United States Pharmacopoeia. (2014a). General chapter <800> hazardous drugs handling in healthcare settings. Retrieved from http://www.usp.org/sites/default/files/usp_pdf/en/m7808.pdf United States Pharmacopoeia. (2014b). USP-NF notices: General chapter <800> hazardous drugs handling in healthcare settings. Retrieved from www.usp.org/uspnf/notices/compounding-notice United States Pharmacopoeia. (2017). FAQs: <800> hazardous drugs handling in healthcare settings. Retrieved from http://www.usp.org/frequently-asked-questions/hazardous-drugshandling-healthcare-settings) Wick, C., Slawson, M. H., Jorgenson, J. A., & Tyler, L. S. (2003). Using a closed-system protective device to reduce personnel exposure to antineoplastic agents. American Journal of Health-System Pharmacists, 60, 2314-2320. Retrieved from http://www.oncosystems.com.tr/dosyalar/wick-slavson-jorgenson%20- Using%20a%20closedsystem%20protective%20device%20to%20reduce%20personnel%20exposure.pdf 25

Tables Table 1 - Partial List of Potential Areas of Unintentional Exposure Risk... 9 Table 2 - Rituxan Supplies/PPE Compliance Comparison... 10 Table 3 - Cisplatin Supplies/PPE Compliance Comparison... 10 Table 4 - Summary of Required Personal Protective Equipment (PPE)... 14 Table 5 - Acceptable Configurations for Hazardous Drug Compounding... 16 Table 6 - Average Equipment, Software, Construction, and Supply Cost... 20 Table 7 - PPE Cost to Infusion Suite for Compounding and Administration... 21 26

Appendices Appendix A Nursing - Preparation and Administration of Premedication Drugs Prep the Patient Port Supplies Amount Price Cost Purple Gloves 1 0.08 $0.08 White Gloves 1 0.09 $0.09 Alcohol Prep 2 0.01 $0.02 Huber needle set 1 4.78 $4.78 Luer-lok access device 1 0.83 $0.83 Central line dressing change kit 1 5.20 $5.20 Ethyl Chloride Spray 1 0.54 $0.54 Monject.9% Sodium Chloride - Flush Syringe 1 0.54 $0.54 Clave Connector 1 1.28 $1.28 Print Patient lab labels 1 1.20 $1.20 Premedication Drug Supplies Amount Price Cost Purple Gloves 1 0.08 $0.08 Tempo Tape 1 0.73 $0.73 Non-DEPH Y Type Catheter Extension Set 1 3.20 $3.20 Tegaderm Film 1 0.36 $0.36 Alcohol Prep 2 0.01 $0.02 Smallbore Extension Set 1 1.37 $1.37.9% Sodium Chloride Injection USP 100ml 1 1.91 $1.91 Clave Connector 1 1.28 $1.28 Tourniquet 2 0.19 $0.38 IV Tubing 1 4.73 $4.73 3M Transpore - Tape or Paper Tape 1 0.48 $0.48 Total Cost for 1 Patient / Day $29.09 Total Cost for 100 Patients / Day $2,909.00 27

Appendix B Nursing Preparation of Chemotherapy Treatment and Administration of Chemotherapy Drugs Cost to handle Chemo Drugs and Non Chemo Drugs Amount Price Cost Purple Gloves 1 0.08 $0.08 Blue Gown 1 2.71 $2.71 Chemo Drug/Non Chemo Drug Supplies to Prep Patient Amount Price Cost Purple Gloves 1 0.08 $0.08 Monject.9% Sodium Chloride - Flush Syringe 1 0.54 $0.54 Alcohol Prep 2 0.01 $0.02 Clean up from starting the Chemo Drug Amount Price Cost Disposing of products in yellow bio-hazard container 1 5.52 $5.52 Chemo Drug Supplies to Prep Patient for second Chemo drug using Dextrose Amount Price Cost Purple Gloves 1 0.08 $0.08 Dextrose 5% 50mL 1 1.77 $1.77 Dextrose 5% 250mL 1 5.75 $5.75 Dextrose 5% 500mL 1 5.75 $5.75 Monject.9% Sodium Chloride - Flush Syringe 1 0.54 $0.54 Alcohol Prep 2 0.01 $0.02 Tubing 1 4.73 $4.73 Clean up from starting the Chemo Drug Amount Price Cost Disposing of products in yellow bio-hazard container 1 5.52 $5.52 Supplies to prepare Patient to go home Amount Price Cost Purple Gloves 1 0.08 $0.08 Alcohol Prep 2 0.01 $0.02 Heparin IV Flush syringe 12mL 1 0.39 $0.39 Disposing of Chemo Drug/Non Chemo Drug bags Amount Price Cost Special bag used to place the chemo drug bags 1 0.15 $0.15 Disposing of products in yellow bio-hazard container 1 1.38 $1.38 Supplies to clean up site Amount Price Cost 28

Purple Gloves 1 0.08 $0.08 Sani-Cloths or Sani-Wipes 4 0.04 $0.18 Total Cost for 1 Patient / Day $35.39 Total Cost for 100 Patients / Day $3,539.00 29

Appendix C Infusion Mixing Pharmacy Preparation of Chemotherapy Drugs Infusion Pharmacy Supplies Amount Price Cost Gown 1 2.70 $2.70 Bonnet 1 0.05 $0.05 Gloves 1 0.90 $0.90 Chemo Drug Supplies Amount Price Cost 250ml D5W 1 5.75 $5.75 secondary set tubing 1 6.02 $6.02 Chemo (CTSD) vial access device 1 2.60 $2.60 CTSD 20mL syringe 1 2.12 $2.12 CTSD 60mL syringe 1 2.60 $2.60 Alcohol pad 3 0.21 $0.62 chemo mixing pad 1 1.09 $1.09 chemo bag 1 0.56 $0.56 chemo auxiliary label 1 2.50 $2.50 250mL sodium chloride 1 2.68 $2.68 Chemo Drug Transport Bag Cleaning Supplies Amount Price Cost Bleach Spray 1 16.50 $2.06 Sterile alcohol spray 1 13.92 $1.74 Sani-Cloths 1 7.37 $0.61 Disinfection Spray 1 2.12 $2.12 Clean up from preparing the Chemo drugs Amount Price Cost Disposing of all products in yellow bio-hazard container 1 13.80 $13.80 Infusion Pharmacy Time Amount Price Cost Chemo Gloves 1 0.67 $0.67 Glove Nitrile 1 0.10 $0.10 Clean up Supplies Amount Price Cost Surface Safe 1 1.96 $0.25 Sani-Cloths 1 7.37 $0.61 Quick lean mop 2 1.39 $0.23 Lint free wipes 2 0.14 $0.28 Total Cost for 1 Patient / Day $52.66 Total Cost for 100 Patients / Day $5,266.00 30

Appendix D Infusion Mixing Pharmacy Preparation of Non-Chemotherapy Drugs Infusion Pharmacy Supplies Amount Price Cost Gown 1 2.70 $2.70 Bonnet 1 0.05 $0.05 Gloves 1 0.90 $0.90 Mask 1 0.05 $0.05 Gloves 1 0.90 $0.90 Non-Chemo Drug Supplies Amount Price Cost 5mL syringe 1 0.10 $0.10 Sodium chloride 150mL 1 5.60 $5.60 Sterile water 20mL 1 1.02 $1.02 Alcohol pad 3 0.21 $0.62 BD 16 gauge needle 1 0.20 $0.20 250mL sodium chloride 1 2.68 $2.68 100mL sodium chloride 1 1.80 $1.80 BD 5mL syringe 1 0.10 $0.10 Empty Glass Container 250ml 1 5.16 $5.16 Empty Glass Container 500ml 1 5.37 $5.37 Clean up from preparing the Chemo drugs Amount Price Cost Disposing of products in red bio-hazard container 1 12.17 $12.17 Infusion Pharmacy Time Amount Price Cost Glove Nitrile 1 0.10 $0.10 Clean up Supplies Amount Price Cost Surface Safe 1 1.96 $0.25 Sani-Cloths 1 7.37 $0.61 Quick lean mop 2 1.39 $0.23 Lint free wipes 2 0.14 $0.28 Total Cost for 1 Patient / Day $40.89 Total Cost for 100 Patients / Day $4,089.00 31

Endnotes 1 See OSHA Standard 1910.120 Hazardous Waste Operations and Emergency Response. https://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=standards&p_id=9 765 2 See ASCO Urges Evidence-based, Flexible Drug Handling Requirements in Comments on USP <800>. https://www.asco.org/advocacy-policy/asco-in-action/asco-urges-evidencebased-flexible-drug-handling-requirements 32