Shaun W. Phillips, PharmD, MBA

	The increasing cost of health care is a major concern for health systems, patients, and insurance providers nationwide. The Centers for Medicare & Medicaid Services projects that health spending will grow an average of 5.8% per year over the next 20 years.

 Prescription expenses in 2015 alone rose overall by 11.7%, with the greatest increase being in health maintenance organizations, at 25.3%.

 There is a constant balancing act for health care systems to provide the newest and most up-to-date care for patients while being financially responsible. The results of a recent study show that for the top 20 cancer drugs, up to 37% of the leftover drug in the vial is discarded.

 Wasting even a small portion of expensive antineoplastic drugs can translate to significantly increased costs. 

	For many years, the United States Pharmacopoeial Convention (USP) Chapter <797> has directed pharmacies on safe compounding techniques to minimize microbial growth. USP <797> states that a single-dose sterile product must be used within 6 hours of being breached if opened and stored in an International Standards Organization (ISO) Class 5 environment and within 1 hour if opened and stored in worse than an ISO 5 environment. The 6-hour rule is based on very specific and strict testing described in USP <71>.

 This rule, while in place to protect patients from infection, can lead to pharmacies wasting significant amounts of expensive medications that might still be stable, safe, and active for several days or weeks. 

	USP recently published a new chapter, USP <800>, which will require hospitals to implement new processes to help protect patients, health care providers, and the environment from hazardous drugs (HDs). Anyone compounding substances that are listed on the National Institute for Occupational Safety and Health (NIOSH) HD list will have to adhere to the strict regulations laid out by USP <800>.

 For hospitals, this means implementation of additional protection levels, including closed-system transfer devices (CSTDs). These devices are designed to contain HD drips, sprays, and vapors that occur during compounding and administration.

 There are several CSTDs available for HD compounding and administration. The most common brands are PhaSeal, Spiros, ChemoClave, and OnGuard.

	The FDA recently gave approval to a CSTD to extend the beyond-use dating (BUD) of opened vials from 6 hours to 7 days, with up to 10 reconnections of components.

 Equashield has been found to prevent the release of vapors into the environment and has fewer leakage issues than other CSTDs.

 Some also consider Equashield easier to use than other available products. A study conducted by The University of New Mexico Hospital found that both pharmacy departments and nursing staff preferred Equashield over 2 other products tested. The study was a 4-step process that included a survey of the health care personnel who would be using the CSTDs. At the end of study, the consensus was that the Equashield components simplified the entire drug compounding and administration processes.

	Nelson Laboratories performed a test with extreme-use conditions to assess the ability of Equashield to prevent the transfer of microbial contaminants into drug vials. The double-membrane design of Equashield is thought to prevent the ingress of bacteria by protecting the coring-free needles from contamination by environmental microbes. Nelson Laboratories used 4 groups of vials that contained growth media. These groups were accessed by 770 Equashield syringes, for 5, 7, or 10 times—depending on the group&mdash;over a 7-day period. The surfaces of the access membranes were inoculated with either gram-positive or gram-negative bacteria for 30 minutes and then disinfected with a 70% isopropyl alcohol pad before media was withdrawn from the vial. To replicate standard hospital compounding, ISO 5 environmental conditions were used throughout. As an additional extreme measure, one-third of the Equashield syringes and vial adapters were products that had expired. After 7 days of being accessed, the vials were incubated for 2 days at 30° C to 35°C, for a total of 9 days of testing. There was no growth in any of the media-filled vials at the end of the study. Nelson concluded that the double-membrane needleless design of the device is essential for the prevention of the ingress of environmental contaminants into the vial and HD substances from egressing.

The results of the Nelson Laboratories study were validated by a similar study done by the University of Toronto. This study included a control group of vials that were not accessed during the study, as well as control groups that contained microbial contamination. There were 32 vials per study group, for a total of 288 vials. The vials were incubated for 14 days, after which none that had been accessed using Equashield had microbial growth. All positive controls demonstrated growth within 48 hours of inoculation and all negative controls showed no growth for the duration of the study. This study concluded that Equashield can maintain the sterility of single-use vials in ISO Class 5 environments and conditions poorer than ISO 5.

	With FDA approval to extend the microbial stability of the drugs by 7 days, there are theoretical cost savings available to organizations that use CSTDs with this change in practice. Some of the savings may cover the cost of implementing a CSTD. Mount Sinai Hospital recently assessed the cost savings realized through the Equashield system for 1 month, when it used the CSTD to extend the BUD of expensive chemotherapy and biotherapy agents. The hospital did a prospective economic analysis for 28 of the agents in single-dose vials it uses by documenting wasted amounts of the agents on a daily basis and estimating the potential waste if the vials had been thrown out on the same day rather than 7 days later. Although the researchers found a cost savings for just 6 agents, the sum of these 6 was enough to offset the cost of using Equashield to be compliant with USP <800> and extend the BUD by 7 days.

	Despite several CSTDs being FDA-approved for extended BUD, The Joint Commission (TJC) and the USP do not universally recognize the extended BUD results from published studies. TJC states that in order to take advantage of prolonged BUD, each facility must conduct, at a minimum, its own sterility testing for each agent not simply use data from other studies.

	Bronson Battle Creek (BBC) is a community hospital with an integrated comprehensive cancer center. The infusion area of the BBC Cancer Care Center (CCC) has its own dedicated chemotherapy compounding area that is fully compliant with the current USP regulations for mixing HDs; it compounds nearly 300 HD preparations per month. The annual drug spend for the hospital is about $15 million, with approximately $11 million coming from the CCC. Any cost saving in the CCC would be beneficial to the hospital. 

	The main purpose of this study was to determine whether the BUD extension with the use of a CSTD had a financial benefit from decreasing waste that would offset the cost of implementation of the CSTD at a comprehensive CCC. Secondary objectives included a count of the number of parenteral antineoplastic and biologic agents compounded in the CCC, measured employee exposure to HDs, determined cost savings from being able to use larger bulk vials of products, and a survey of the use of CSTDs in other Michigan hospitals.

	All of the antineoplastic agents and biologic agents were prepared in the BBC outpatient care center area, which uses a Class 2, Type A2 biological safety cabinet with an ISO Class 5 environment. Personnel trained in the CCC compounding area observe current USP <800> rules and regulations for preparation and handling of HDs in anticipation of the July 2018 enactment. The stability of medications used in the CCC was gathered from manufacturer recommendations (Table 1

). For billing and insurance purposes, the current protocol at BBC for opened vials is to discard them after each patient. BBC is a qualified 340B facility and is able to purchase appropriate outpatient medications, such as those used in the CCC at 340B pricing; however, for the purposes of this study, the group purchasing organization cost was used as the basis for the calculations. 

	The 20 most commonly used antineoplastic and biologic agents administered in the BBC CCC from June 2015 to June 2016 were included in this study. All patients older than 18 years who received their antineoplastic or biologic agent in the CCC were included. Methotrexate doses compounded in the CCC for use in the obstetric unit were excluded from the study. For the primary outcome, a Microsoft Excel spreadsheet was used to record the data and perform the calculations. The calculation performed was:

	[(The price of the drug saved by using extended BUD + the price of the CSTDs not used on the vials that were saved with extended BUD) — The price of the CSTDs that would have been used = The cost of implementing a CSTD]. 

	A wipe study by ChemoGLO was done as directed by USP <800> pre-implementation of a CSTD to assess for employee &ensp;» exposure to HDs in the pharmacy, nursing, and patient areas. Six areas were tested for 5 HDs. Of these 5 HDs, 4 were commonly compounded in the CCC. One HD that was tested acted as a control because it was not dispensed in the CCC. The site tested was considered contaminated if there was more than 10 ng/ft2 of drug present. 

In addition to the above tests, a survey was developed to assess CSTD use in Michigan hospitals. To increase the likelihood of a response, it was designed to not take more than 5 minutes. There were 9 questions; 7 were single-response only and 2 allowed multiple answers. The survey was sent to 25 Michigan institutions via email. Institutions were included if the contact information of the pharmacy manager was known.

	With extended BUD of the drug vials in the CCC, there are significant projected annual cost savings (

), with the greatest cost savings seen with expensive medications (high cost per mL) and the least with inexpensive medications (low cost per mL). 

	For secondary objectives, the potential for cost savings with the use of larger-dose vials was realized for 10 of the 20 medications assessed. This included medications that already had cost savings with extended BUD, as well as those that did not have cost savings in the original analysis. Outside of the top 3 medications dispensed by quantity (fluorouracil, paclitaxel, and carboplatin), overall there was the potential for significant annual cost savings (

	The wipe study that assessed employee exposure showed detectable drug levels in 2 locations (sites 4 and 6) for paclitaxel or fluorouracil (

). The area with the most contamination was the ledge of the pass-through window between the chemotherapy IV room and the pharmacy area. Ifosfamide acted as our control because it is not compounded in the CCC and was found to be negative. 

	Fifteen hospitals responded to the survey (60% response rate). Of this group, 60% had between 100 and 500 beds. When asked whether they had a dedicated CCC, 93% responded yes. In addition, all responded that they already used a CSTD, despite 7% not having a dedicated CCC. The most commonly used CSTD was Equashield (33%), followed by CareFusion and PhaSeal (20% each). All of the respondents also reported implementing the CSTD to compound chemotherapy as their primary reason for use. Additional reported reasons for the use of the CSTD included batching products (13%), extending BUD (6%), and improving cost savings (6%). The most common perceived expense per month of the CSTD was between $1000 and $5000. Eighty-seven percent of respondents reported staff indifference to implementation of the CSTD at their facility. 

	BBC implemented a CSTD to improve the safety of its workplace environment. Based on this study’s findings, there is potential for cost savings through extending the BUD of single-dose vials, especially for smaller community hospitals. These savings are not limited to larger university hospitals. BBC will be conducting the required sterility testing to pursue extended BUD for the items that showed the greatest cost benefit. 

	When choosing a CSTD, it is important for an organization to evaluate the ability of the product to properly protect employees from HD contamination. To date, there are no strict guidelines by any regulatory organization that dictate the testing of CSTDs to determine their ability to meet USP <800> requirements. This can lead to confusion about what CSTDs meet requirements when an organization is deciding which device to implement. In an attempt to standardize the testing and compliance of CSTDs, NIOSH recently published a protocol that gave some guidance on standardizing CSTD testing; however, it does not have the authority to enforce its recommendations. As USP <800> comes into effect, it will be important for manufacturers to continue to do studies and for government agencies to standardize the CSTD testing process to help organizations make informed decisions when implementing them.

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Articles

There is a constant balancing act for health care systems to provide the newest and most up-to-date care for patients while being financially responsible.