Recently, the number of marketed Closed System Transfer Device {CSTD) models has increased. Interest in development of a CSTD performance test protocol originated from within the healthcare industry itself, with requests for an independently-developed containment test protocol. Additionally, in view of the upcoming USP-800 mandating the use of closed systems for administration, proper evaluation of CSTD connectors is essential since vast majority of administration procedures involves exclusively the use of CSTD connectors. Several studies exist that evaluate the safety and efficacy data since the inception of Closed System Transfer Devices. Safety of CSTD is often shown by its ability to adhere to NIOSH definition of a CSTD.

NIOSH defines a CSTD as a device that mechanically prohibits the transfer of environmental contaminants into a system and the escape of hazardous drug or vapor concentrations outside the system. NIOSH definition can be summarized that a device is a CSTD if it is Leak-proof and airtight. Until November of 2015, a standard method of evaluation of the ‘Airtightness’ of a CSTD did not exist. NIOSH introduced a draft protocol titled, “A Vapor Containment Performance Protocol for Closed System Transfer Devices Used during Pharmacy Compounding and Administration of Hazardous Drugs.” This protocol will test CSTDs per this draft protocol.

Objective of this study was to test 6 different CSTD devices to assess the testing method and how the results match up with CSTD manufacturer’s claims of being able to contain alcohol and its vapor. CSTDs will be tested to the NIOSH vapor release protocol as per table below.

Table 1: CSTD Study Plan

Vapor study was performed as per NJOSH draft Protocol CDC 2015-0075-003. The study involves simulation of dose preparation as prescribed in the protocol with 8 sets of device tested per CSTD user group. Total of 48 unique data points will be generated, 8 per CSTD type, in compliance with the protocol.

4. Supplies Used

4.1 Supplies for NIOSH Vapor Study

Each section below will outline specific procedures for each of the 3 components of this protocol.

5.1 Study Procedure for NIOSH Vapor Test

Span check I calibration performed using original Miran SapphiRe field performance check kit Ref: CR014LG, with Nitrous Oxide and Sulfur Hexafluoride gases. Leak test for the test chamber was performed according to NIOSH protocol. Before the start of each task, the background concentration of IPA vapor inside the room was measured and all testing starting conditions were created in accordance to NIOSH protocol, including ventilation and zeroing. A complete CSTD brand test evaluation included four repetitions of paired sequential tasks, identified as Task 1 and Task 2. Within each paired task repetition, Task 1 procedures were conducted first, followed by Task 2.

Task 1 procedure:

Prepare 500 ml 0.9% sodium chloride IV bag with 90 ml of 70% IPA vials using 45 ml transfers
Summary Description of Task 1: To simulate reconstitution, withdraw 45 mL of 70% IPA from Viall and inject into Vial 2 (for a total volume of 95 ml in Vial 2). Swirl the 70% IPA in Vial 2 to simulate reconstitution. Withdraw 90 mL of 70% IPA from Vial 2 in 45 ml increments using the two 60 ml syringes with syringe adapters (or connectors). Inject both the syringes into the 500 mL 0.9% sodium chloride IV bag through the bag adapter. La bel the bag and place in a Ziploc bag.

Task 1 Procedures: Assemble the following supplies, and place into small supply trays for each test run:

• 2 x septum-capped vial containing 50 ml of 70% IPA, labeled 1 and 2
• 2 x 60 mL syringes, labeled 1 and 2
• 1 x 500 mL 0.9% sodium chloride IV bag
• 2 x CSTD vial adapters
• 2 x CSTD syringe adapters
• 1 x CSTD bag adapter

1. Place the supplies into the environmental test chamber, close chamber, and position spring-loaded hand clamps onto environmental test chamber to create a tight chamber seal.
2. Monitor and record every change in IPA detector reading for background IPA concentrations within the test chamber.
3. Record every change in IPA detector reading for each of the following CSTD use events:
   Event 1: Attaching vial adapters
   Event 2: Mate 1st syringe with vial
   Event 3: Removing alcohol from Viall
   Event 4: Mate syringe 2 with vial 2
   Event 5: Injecting alcohol from syringe 1 into Vial 2
   Event 6: Withdrawing syringe 1 from Vial 2
   Event 7: Withdrawing syringe 2 from vial 2
   Event 8: Injecting syringe 1 into bag
   Event 9: Injecting syringe 2 into bag
4. Attach one vial adapter to each of the two vials of 70% IPA. Pause for 30 seconds or until the IPA detector stabilizes to allow the instrument to detect to any leakage.
5. Attach one IV bag adapter to the administration port of one 500 mL 0.9% sodium chloride IV bag.
6. If specific CSTD (such as PhaSeal) requires, draw 45 mL of air into the 60 mL Syringe 1.
7. Attach one syringe adapter to 60 mL Syringe 1.
8. Mate the 60 ml Syringe 1 to 70% IPA Viall using the CSTD connectors. Pause for 30 seconds or until the IPA detector stabilizes.
9. (Inject air into Vial if specific CSTD, such as PhaSeal, requires); withdraw 45 ml of 70% IPA from Vial and disconnect the syringe adapter from the vial adapter. BE SURE not to disconnect the syringe from the CSTD syringe adapter! Pause for 30 seconds or until the IPA detector stabilizes.
10. Set Viall aside; it now contains 5 ml of 70% IPA.
11. Mate Syringe 1 containing 45 ml of 70% IPA to Vial 2 using the CSTD connectors. Pause for 30 seconds or until the IPA detector stabilizes.
12. Inject 45 ml of 70% IPA into Vial 2. If specific CSTD, such as PhaSeal, requires invert the vial and withdraw 45 ml of air from Vial 2 into the Syringe 1. There should be 95 ml of 70% IPA in Vial 2. Leave Syringe 1 connected. Pause for 30 seconds or until the IPA detector stabilizes.
13. Disconnect Syringe 1 from Vial 2. Pause 30 seconds or until the IPA detector stabilizes.
14. Swirl Vial 2.
15. Reconnect Syringe 1 to Vial 2 (if specific CSTD, such as PhaSeal, requires inject the 45 ml of air into Vial 2) and withdraw 45 ml of 70% IPA; disconnect Syringe 1 with the CSTD attached. Pause for 30 seconds or until the IPA detector stabilizes.
16. Mate the syringe adapter to the IV bag adapter; inject the 45 ml of 70% IPA. Pause for 30 seconds or until the IPA detector stabilizes.
17. Disconnect at the syringe adapter from the IV bag adapter and set the syringe aside. Syringe 1 will now contain no air and no liquid, and it is closed. Pause for 30 seconds or until the IPA detector stabilizes.
18. Select 60 ml Syringe 2, (if specific CSTD, such as PhaSeal, requires draw 45 ml of air into syringe) and attach the second syringe adapter.
19. Mate Syringe 2 with Vial 2 using the CSTD connectors. Pause for 30 seconds or until the IPA detector stabilizes.
20. If specific CSTD, such as PhaSeal, requires inject air into Vial 2 and withdraw 45 ml of 70% IPA using Syringe 2. Pause for 30 seconds or until the IPA detector stabilizes.
21. Disconnect syringe adapter from the vial adapter. Pause for 30 seconds or until the IPA detector stabilizes.
22. Mate Syringe 2 with the 500 ml 0.9% sodium chloride IV bag using the CSTD connectors; inject the 45 ml of 70% IPA. IV bag now contains 90 ml of IPA and a CSTD adapter (with overfill ~640 ml ). Pause for 30 seconds or until the IPA detector stabilizes.
23. Remove Syringe 2 by disconnecting between the adapters (i.e., Syringe 2 and bag adapters). Pause for 30 seconds or until the IPA detector stabilizes.
    Task 1 is now complete. Note the stop time, then open the environmental test chamber and remove all supplies and trays. Allow the IPA detector to stabilize to background before proceeding to Task 2.
    

Task 2: Prepare 45 ml 70% IPA in 60 ml syringes for IV push andY-site administration

Summary Description of Task 2: Task 2 has two parts, simulating drug reconstitution followed by an IV push of the reconstituted drug. To simulate drug reconstitution, withdraw 45 ml of 70% IPA from Vial 3 and inject into Via l 4 (95 ml total volume in Vial 4). Swirl the 70% IPA in Vial 3 to simulate reconstitution then withdraw 90 ml of 70% IPA from Vial 4 in 45 ml increments using two 60 ml syringes with CSTD adapters. For simulating the IV push, inject each syringe dose into theY-site of the IV tubing.

Task 2 Procedures: Prepare IV setup prior to administrating the IV dose to save space inside the environmental test chamber. Insert the bag spike on the IV administration tubing into the administration port of the IV bag. Close the roller clamp on the IV tubing. Attach one non vented luer lock cap to the end of the IV tubing to prevent IPA leakage.

Assemble the following supplies and place into small supply trays for each test run:

• 2 x 50 ml vials of 70% IPA, labeled 3 and 4
• 2 x 60 ml syringes, labeled 3 and 4
• 2 x CSTD vial adapters
• 2 x CSTD syringe adapters
• 1 x CSTD IV push adapter
• 1 x CSTD bag adapter
• 1 x 500 ml 0.9% sodium chloride IV bag. Use a new bag; DO NOT use the same bag from Task 1.
• IV administration tubing with at least one needleless Y-site
• Luer lock cap

1. Place the supplies into the environmental test chamber, close chamber, and position spring-loaded hand clamps onto environmental test chamber to create a tight chamber seal.
2. Monitor and record every change in IPA detector reading for background IPA concentrations within the test chamber.
3. Record every change in IPA detector reading for each of the following CSTD use events:
   Event 1: Attaching vial adapters
   Event 2: Mate 1st syringe with vial
   Event 3: Removing alcohol from Viall
   Event 4: Mate syringe 2 with vial 2
   Event 5: Injecting alcohol from syringe 1 into Vial 2
   Event 6: Withdrawing syringe 1 from Vial 2
   Event 7: Withdrawing syringe 2 from vial 2
   Event 8: Injecting syringe 1 into IV line
   Event 9: Injecting syringe 2 into IV line
4. Attach one vial adapter to each of the two vials of 70% IPA. Pause for 30 seconds or until the IPA detector. stabilizes to allow the instrument to detect to any leakage.
5. Attach one IV bag adapter to one 500 ml 0.9% sodium chloride IV bag.
6. If specific CSTD, such as PhaSeal, requires draw 45 ml of air into 60 ml Syringe 3.
7. Attach one syringe adapter to this 60 ml Syringe 3.
8. Mate the 60 ml Syringe 3 to Vial 3 using the CSTD connectors. Pause for 30 seconds or until the IPA detector stabilizes.
9. (If specific CSTD, such as PhaSeal, requires inject air into Vial 3); withdraw 45 ml of 70% IPA from Vial 3 and disconnect the syringe adapter from the vial adapter. BE SURE not to disconnect the syringe from the CSTD syringe adapter! Pause for 30 seconds or until the IPA detector stabilizes.
10. Set Vial 3 aside-it now contains 5 ml of 70% IPA.
11. Mate Syringe 3 with 45 ml of 70% IPA to Vial4 using the CSTD connectors. Pause for 30 seconds or until the IPA detector stabilizes.
12. Inject 45 ml of 70% IPA into Vial4. If specific CSTD, such as PhaSeal, requires invert the vial and withdraw 45 ml of air from Vial4 into the Syringe 3 (Syringe 3 now has 45 ml of air in it and there should be 95 ml of 70% IPA in Vial 4). Leave syringe connected. Pause for 30 seconds or until the IPA detector stabilizes.
13. Disconnect Syringe 3 from Vial4. Pause 30 seconds or until the IPA detector stabilizes.
14. Swirl Vial 4.
15. Reconnect Syringe 3 to Vial4 (If specific CSTD, such as PhaSeal, requires inject the 45 ml of air into Vial4) and
    withdraw 45 ml of 70% IPA; disconnect Syringe 3 with the CSTD attached. This syringe now contains 45 ml of 70% IPA to administer later into the IV administration set. Pause for 30 seconds or until the IPA detector stabilizes.
16. If specific CSTD, such as PhaSeal, requires draw 45 ml of air into 60 ml Syringe 4 and attach the syringe adapter.
17. Mate Syringe 4 with Vial4 using the CSTD connectors. Pause for 30 seconds or until the IPA detector stabilizes.
18. (If specific CSTD, such as PhaSeal, requires inject air into Vial 4)d withdraw 45 ml of 70% IPA using Syringe 4. Pause for 30 seconds or until t he IPA detector stabilizes.
19. Disconnect syringe adapter from the vial adapter. Syringe 4 now contains 45 ml of 70% IPA to administer later into the IV administration set. Pause for 30 seconds or until the IPA detector stabilizes.
20. Check that the roller clamps on IV administration tubing are closed, including the ones to theY-site and below.
21. Take the cover off the spike of the IV administration tubing and open the infusion port on the bag adapter of the 500 ml 0.9% sodium chloride IV bag.
22. Insert the tubing spike into the port of the bag adapter affixed to the 500 ml 0.9% sodium chloride IV bag. Pause for 30 seconds or until the IPA detector stabilizes.
23. Gently squeeze the 500 ml 0.9% sodium chloride IV bag to verify there is flow into the drip chamber.
24. Attach the IV push adapter into theY-Site. Attach Syringe 3 dose (45 ml of 70% IPA in 60 ml syringe) with syringe adapter already connected (from step 14) to the push adapter. Pause for 30 seconds or until the IPA detector stabilizes.
25. Open all IV administration tubing roller clamps below theY-site, and push the first “syringe dose” from Syringe 3 through the IV push adapter and tubing into the 500 ml 0.9% sodium chloride IV bag until the Syringe 3 is empty. Pause for 30 seconds or until the IPA detector stabilizes.
26. Remove Syringe 3 by disconnecting between the adapters (i.e., Syringe 3 and IV push adapters). Pause for 30 seconds or until the IPA detector stabilizes.
27. Select Syringe 4 for the second “syringe dose” (45 ml of 70% IPA in 60 ml syringe) with syringe adapter already connected (from step 18) and attach it to the push adapter. Pause for 30 seconds or until the IPA detector stabilizes.
28. Push the second “syringe dose” from Syringe 4 through the IV push adapter and tubing into the 500 ml 0.9% sodium chloride IV bag until the syringe is empty. Pause for 30 seconds or until the IPA detector stabilizes.
29. Remove Syringe 4 by disconnecting between the adapters (i.e., Syringe 4 and IV push adapters). Pause for 30 seconds or until the IPA detector stabilizes.
30. Close all IV administration tubing roller clamps.
    

Task 2 is now complete. Note the stop time, then open the environmental test chamber and remove all supplies and trays. Allow the IPA detector to stabilize to background before proceeding with repetitions of Task 1 and Task 2 for 4 replications for each brand of CSTD. Test both Tasks for each CSTD brand.

6. Study Results

Of the 6 commonly marketed Closed System Transfer Devices that were tested only two passed the test, BD PhaSeal and Equashield, in terms of having vapor release below 0.3 ppm that is the below the detection level of the Miron analyzer. Remaining 4 CSTDs had vapor release above 1 ppm at various times in the drug manipulation process.

7. Notes

As this study was performed to evaluate the NIOSH test methodology, the Onguard/ Tevadaptor, an air-cleaning system, was also tested. This was in attempts to understand first hand why this product category was excluded from the testing protocol.

Additionally, a new source of vapor release was discovered with certain CSTDs releasing vapor when spiking the vials with respective adapters. I switched operators for each device but the result remained consistent, regardless of how vials were spiked (gently or aggressively). I discovered that slightly pressurized vials detect leaks that otherwise would remain undetected. Drugs that come in vials in liquid or powder form for reconstitution may have additional pressure within the vials based on manufacturer specifications. Pressure variances are not noted on vials, and the altitude of reconstitution may further impact pressures (i.e.,Omaha, NE, which is 1,090 feet above sea level, versus Denver, CO, which starts at 5,130 feet above sea level).

This pressure can cause the drug to spray out from around the needle and vial stopper interface. In our testing this overpressure affected the outcome for certain CSTDs (see report) during spiking their adapter into the vial. The overpressure disappeared after the initial spiking into the expansion balloons that most of the tested CSTDs had. After the spiking there was no overpressure effect observed. Only Equashield vial adaptor and Genie (ICU ChemoClave) do not have an expansion chamber to expand into. The Genie CSTD continued to leak well after the pressure was gone, at every compounding step.

Since the Genie device is severely leaky, routinely visible during the leakage test with 5-FU, the root cause analysis removed the overpressure effect as the cause of leakage. Note that temperature changes such as IPA making vials in cold clean room and executing the test in a warm conference room may contribute to pressure differentials.

Keywords

Hazardous drugs, medication compounding, National Institute for Occupational Safety and Health (US), occupational exposure, protective devices.

Date received: 9 January 2018; accepted: 28 May 2018

Introduction

Exposure to hazardous drugs in the workplace can lead to serious health risks, and these risks increase with frequency of exposure; therefore, it is crucial to limit this with the proper protective equipment. The risks associated with the compounding and administration of hazardous drugs are well known and documented.^1–9

In 1981, the Occupational Safety and Health Administration cited a northern California hospital for failure to provide protection to pharmacists preparing chemotherapy.¹⁰ This later led to the creation of a program containing recommendations for handling cytotoxic drugs in hospital¹¹ In September 2004, The National Institute for Occupational Safety and Health (NIOSH) revised the previous 1990 American Society of Health-System Pharmacists (ASHP) definition of hazardous drugs to include drugs that exhibit 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 structure and toxicity profiles of new drugs that mimic existing drugs determined hazardous by the above criteria.^12,13

The main routes of exposure are inhalation of aerosolized drug, ingestion, injection, and dermal absorption.¹³ To minimize this exposure and protect the worker, hazardous compounding takes place in a biological safety cabinet with vertical airflow hood and external exhaust. Data indicate that healthcare workers who used safe handling precautions such as gloves, gowns, and goggles were less likely to be exposed to hazardous drugs during compounding.¹⁴ However, a 1999 study that examined surface contamination with antineoplastic agents in six cancer treatment centers in Canada and the United States found measurable amounts of antineoplastic agents in 75% of pharmacy samples and 65% of the administration samples.¹⁵ Sample sites included biological safety cabinets, countertops, and floors in and adjacent to preparation areas. Widespread surface contamination increases the risk of skin contact and dermal absorption of hazardous drugs.¹³

Since the publication of the 2004 NIOSH Alert, the use of closed system transfer devices (CSTDs) for hazardous drug preparation has increased in United States hospitals. The 2011 ASHP national survey of pharmacy practice found that 41% of hospitals used CSTDs for safe handling of hazardous drugs.16 Closed systems limit the potential for generating aerosols and exposing workers to hazardous drugs, and the literature documents a decrease in drug contamination of surfaces when a CSTD is used.^17–20 Previously, the General Chapter: USP <797> Pharmaceutical Compounding – Sterile Preparations, contained minimal information for safety and handling of hazardous drugs. In February 2016, USP released a new General Chapter: USP <800> Hazardous Drugs – Handling in Healthcare Settings. The recently published General Chapter <800> guideline recommends the use of CSTDs for hazardous compounding and requires them for administration.21 Several CSTD brands exist in the marketplace, all classified as Class II medical devices, leaving multiple options for pharmacy and nursing to select. In 2012, the US Food and Drug Administration (FDA) began issuing 510(k) clearances under the product code “ONB” that was specific to CSTDs. However, there are no set performance standards for companies to follow to obtain these 510(k) clearances.22 To determine whether various CSTD products available in the market are truly closed systems, several studies have been performed that look at efficacy of connectors with drug surrogate to aid in product selection.^23–27 Thus, it is important to identify a test and process that is consistent and allows comparisons across all current and future CSTDs in their ability to be leak-proof and airtight.

NIOSH released a proposed protocol in 2015 to evaluate the vapor or liquid containment abilities of CSTDs.²⁸ Due to the increasing number of CSTD products since the initial NIOSH alert in 2004, the development of a performance test protocol was necessary to create standards for drug containment. In addition, developing a universal protocol will help expand validation of a CSTD beyond the current FDA 510(k) product clearance system to help healthcare systems make informed decisions. The protocol focused on simulating specific compounding and administration tasks performed by healthcare workers. Isopropyl alcohol 70% was the challenge agent used due to its safety, ease of manipulation, and detectability.²⁸ The high vapor pressure of isopropyl alcohol challenges CSTDs that claim to have a truly closed system. Unlike isopropyl alcohol, hazardous drugs are likely to settle out of the air onto surfaces if the CSTD does not contain them.

This current study followed the methodology outlined by the 2015 proposed NIOSH protocol that challenges the vapor containment abilities of CSTDs. Data were generated for the following CSTD brands: ICU Medical’s ChemoClave, ICU Medical’s ChemoLockTM, Equashield’s Equashield, B. Braun and Teva Medical’s OnGuardTM with Tevadaptor, BD Carefusion’s PhaSealTM, and BD CareFusion’s SmartSiteTM VialShield.

Table 1

Table 2

Table 3

Table 4

Methods

Study objectives and procedures

The primary objective of this study was to challenge the ability of six different CSTD brands to prevent leakage of vapor from vials during intravenous (IV) compounding and administration, determining their ability to function as closed systems. The NIOSH draft protocol (CDC-2015-0075-003) was utilized to evaluate each CSTD system during compounding (Task 1) and administration (Task 2) with 70% isopropyl alcohol as the challenge agent.²⁸

All procedures were performed in accordance with the 2015 proposed NIOSH protocol. The environmental test chamber used was constructed from a Secador Techni-dome 360 vacuum desiccator as described in the NIOSH protocol. Vapor of isopropyl alcohol that escaped during the test manipulations was measured by a Thermo Scientific^TM MIRAN SapphIRe XL Infrared Analyzer model 205B-XL.²⁸

The study involved simulation of dose preparation, as described in the protocol, with four samples for each CSTD product. In Task 1, the technician added 90 mL of isopropyl alcohol, using two 45 mL transfers from two 60 mL syringes and two 50 mL vials, to a 500 mL normal saline IV bag. The CSTD components evaluated under this task included one bag adapter, two vial adapters, and two syringe adapters. In Task 2, the technician prepared a 45 mL dose of isopropyl alcohol in each of two 60 mL syringes and injected each syringe into the Y-site of the IV tubing, simulating an IV push. The CSTD components evaluated under this task included two vial adapters, two syringe adapters, one bag adapter, and one IV port adapter.

Vapor levels were recorded for Task 1 and Task 2 after each of the following steps: attach vial adapters to two vials of 70% isopropyl alcohol (Reading 1), withdraw 45 mL of 70% isopropyl alcohol from vial 1 into syringe 1 (Reading 2), inject contents of syringe 1 into vial 2 of 70% isopropyl alcohol (Reading 3), withdraw two 45 mL syringes of 70% isopropyl alcohol from vial 2 into two separate syringes (Reading 4), and inject final two syringes into 500 mL normal saline bag for Task 1 or IV tubing for Task 2 (Reading 5). The highest detected amount of isopropyl alcohol released was recorded after five pre-specified steps during manipulations for each device, giving a total of 24 unique data points for each task, four per CSTD brand. This is summarized in Table 1.

Study evaluation and measurements

Vapor release was measured with the Thermo Scientific^TM MIRAN SapphIRe XL Infrared Analyzer, and measurements were gathered in real time after each step of the process. The highest data point recorded for each sample was used in the analysis. Readings below 0.3 parts per million (ppm) were considered below the detection limit of the equipment. Data points were adjusted for background (BG) vapor concentration and adjusted for the limit of detection of the equipment per the NIOSH protocol. BG concentrations were recorded prior to each test run over a period of 5 s. If the average BG concentration was below the limit of detection of the equipment, then no BG correction was performed. If the average BG concentrations were over the limit of detection, this value was subtracted from each data point observed. If any BG-adjusted data points were below 0 ppm, their value was adjusted to 0 ppm. The maximum data point out of the five readings recorded was the metric of interest for each test run. If this value was under the limit of detection, then it was substituted by 0.3 ppm. For Task 1 and Task 2, there were four metrics of interest corresponding with the maximum detection for each test sample. The performance threshold for successful containment of isopropyl alcohol vapor was 1.0 ppm based on the calculated limit of quantification as described in the NIOSH protocol.²⁸ Therefore, a CSTD failed to effectively contain vapor if the 95% confidence interval contained greater than or equal to 1.0 ppm. In this study, testing for individual samples was ended prematurely if a concentration significantly over 1.0 ppm was detected as there was certainty that the device had significant leakage during the set of manipulations.

Results

Data were collected over a two-day period. A total of eight samples were tested for each of the six CSTD brands, with four samples tested per task. Each sample had a total of five readings recorded, which corresponded with specific steps in the manipulation process. The data point of interest for each sample was the maximum reading of isopropyl alcohol from the detector after adjustments for BG concentrations and zero corrections, shown in Tables 2 and 3. The mean and 95% confidence interval of the mean were calculated for the maximum adjusted concentrations of isopropyl alcohol (ppm) observed for each CSTD product during Task 1 and Task 2, shown in Table 4.

Average values less than 1.0 ppm indicated that the CSTD successfully contained isopropyl alcohol vapor per the NIOSH protocol. For Task 1, two CSTDs successfully contained isopropyl alcohol vapor per NIOSH protocol, and for Task 2, three CSTDs successfully contained the isopropyl alcohol vapor.

Discussion

In this study, only two CSTDs performed as truly closed systems during both compounding and administration manipulations, measured by the release of isopropyl alcohol vapor using the Thermo ScientificTM MIRAN SapphIRe XL Infrared Analyzer. The 2015 NIOSH draft protocol proposed the use of the Thermo ScientificTM MIRAN SapphIRe XL Infrared Analyzer to quantitatively measure isopropyl alcohol that escaped during the test manipulations because the instrument is capable of providing a specific response to isopropyl alcohol, has a moderately low detection limit of 0.3 ppm, and is commonly available in the industry. A BG0max concentration of 0 ppm would indicate a truly closed system; however, a substitute zero of 0.3 ppm was utilized based on the limit of detection of the equipment.

From the limit of detection, the limit of quantification at which analytes can be definitively quantified was calculated to be 1.0 ppm. NIOSH claims that the false negative rate above the limit of quantification is negligible, ensuring that leakage measured during this study does indeed represent true leakage from the CSTD’s manipulations.²⁸ If a CSTD product reached a concentration significantly over 1.0 ppm, the testing for that particular manipulation was ended prematurely because there was significant leakage. For this reason, data presented in this study should be used to determine if a CSTD product is truly a closed system, but cannot be used to rank the CSTD products in their ability to maintain a closed system.

This protocol tested two types of CSTDs: physical arrier and air filtration devices. However, the 2015 IOSH protocol draft only claims to be applicable or CSTDs of the physical barrier type and did not ake into consideration the air filtration devices.²⁸ Air-cleaning or filtration technology CSTD systems re only worker protective if they are used to compound drugs with no vapor generating potential. sopropyl alcohol has a higher vapor pressure than hazardous drugs currently used therapeutically, which ould result in a falsely high detection of vapor that ould not be representative of vapor release when compounding with actual drug. This needs to be considered hen evaluating the results of air-cleaning or filtration technology CSTDs. The reason these were introduced into the test is that the initial idea by NIOSH was that this performance test would cover all device types and that these devices are marketed and sold against the physical barrier CSTDs. The 2016 NIOSH draft protocol addresses the limitations of the 2015 protocol by developing an additional test protocol for air-cleaning systems that includes a definitive surrogate agent that more closely resembles the actual vapor pressures of a hazardous drug. Potential surrogate compounds that are considered better based on criteria including high vapor pressure, solubility of at least 0.10%, liquid at room temperature, and low toxicity. The surrogate compounds under review for incorporation into the protocol include dimethyl sulfoxide, trimethyl phosphate, tetramethylurea, triacetin, propylene glycol, tetraethylurea, triethyl phosphate, 2-phenoxyethanol, and tripropyl phosphate.29 However, neither protocol has been finalized as NIOSH continues to investigate. Sites that utilize air-cleaning technology CSTDs could routinely conduct wipes to detect contamination on the surfaces where hazardous drugs are compounded and administered, a recommendation within USP <800>. This could help evaluate the effectiveness of containing hazardous drugs.

Conclusion

To improve employee safety in chemotherapy preparation, CSTDs that demonstrate no leakage should be the preferred choices. In this study, both PhaSealTM and Equashield products proved to be adequately closed in both Task 1 and Task 2, while ChemoLockTM showed to be closed only in Task 2. All other products failed both tasks when measuring for isopropyl alcohol vapor release.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Stephen F Eckel is a founder of ChemoGLO, LLC

Background

Medical personnel have been examining the issues of exposure to hazardous medications and prevention. Malformations, spontaneous abortions, and stillbirths have been associated with exposures to cytostatic agents. Closed-system drug transfer devices are recommended by the National Institute for Occupational Safety and Health (NIOSH) for the containment of hazardous drugs. The purpose
of this study is to examine available products utilized for drug-transfer to determine which device prevents the escape of vapor meeting the NIOSH definition of closed.

Methods

Nine drug-transfer devices were tested:

• Spiros™ Male Connector and Clave® (ICU Medical Inc.)
• Vial Adapter and Clave® (ICU Medical Inc.)
• B. Braun OnGuard™ System (Teva Medical Ltd.)
• Chemo Mini-Spike Plus™ Dispensing Pin (B. Braun Medical Inc.)
• Alaris’ Smart Site® (Cardinal Health)
• CyTwo-Fer (Baxa)
• CHEMO-AIDE (Baxter)
• Chemoprotect Spike® (Codan US Corporation)
• PhaSeal® Protector 50 & Injector Luer Lock (Carmel Pharma)

Titanium tetrachloride (TiCl4) was used to simulate gas-containing active drug. Titanium tetrachloride generates very visible smoke when it comes into contact with moisture in the air. It was placed into glass vials attached to the above transfer devices to determine which system prevents the escape of vapor.

Results / Conclusions

Only the PhaSeal® System prevented the release of titanium smoke out of the closed-system drug transfer device. Only the PhaSeal® System met the NIOSH definition of a closed-system drug transfer device.

PhaSeal® by Carmel Pharma

PhaSeal® by Carmel Pharma

Spiros™ Male Connector and Clave® by ICU Medical Inc.

Vial Adapter and Clave® by ICU Medical Inc.

B. Braun OnGuard™ System by Teva Medical Ltd.

Alaris’ Smart Site® by Cardinal Health

CyTwo-Fer by Baxa

CHEMO-AIDE by Baxter

Chemoprotect Spike® by Codan US Corporation

OBJECTIVE

The primary objective was to compare the contamination between barrier and filterbased closed-system transfer devices

METHODS

• Two barrier-based (Equashield^® and PhaSeal^™) and two filter-based (Tevadapter^® and ChemoClave^®) CSTDs were used to manipulate ten samples each of ifosfamide, methotrexate, and etoposide
• Three manipulations performed at approximately 0, 4-6, and s24 hours for each drug-device combination
• After each manipulation, the vial/vial adapter was disconnected from the syringe/syringeadapter and the membranes were wiped with a ChemoGLO^™ wipe
• Once all three manipulations had been completed, each bag was opened and wiped using ChemoGLO^™ wipes
• Before opening a new drug-device combination, the laminar flow hood was wiped using ChemoGLO^™ HDCIean wipes
• Completed ChemoGLO^™ Wipe Kits were sent to ChemoGLO^™ to be analyzed using LC-MS technology
• Student’s t-test was used for two-way comparisons and two-way ANOVA for comparison of average contamination among devices

CONCLUSIONS

• Barrier-based devices are associated with significantly less HD contamination than filterbased devices
• There was significant contamination when using PhaSeal™ with ifosfamide manipulations
• Potentially, there are unstudied chemical characteristics of HDs that affect the performance of CSTDs
• Compared to all other CSTDs, Equashield®
• had significantly lower contamination than all other CSTDs tested
• The smoke test and 70% isopropyl alcohol vapor test do not adequately assess the effectiveness in controlling HD contamination
• Further studies are needed to fully elucidate the effects of various HDs on CSTD performance

DISCLOSURE

The authors of this presentation have the following disclosures concerning possible financial or personal relationships with commercial entities:

• Joseph Arminger, BS, PharmD- No Disclosures
• Alyson Leonard, PharmD, BCPS- No Disclosures
• Adam Peele, PharmD. MHA, BCPS. BCOPNo Disclosures
• Crystal Peyton, BS, CPhT- No Disclosures Funding provided by Equashield, LLC

RESULTS

Table 1: Average contamination stratified by device and HD

Table 2: Summary of primary and secondary outcome results

As the risks associated with occupational exposure to hazardous drugs become increasingly evident, growing awareness is given to the methods, procedures and means involved in the preparation and administration of such drugs. All aim to provide healthcare workers with maximum protection, by minimizing the contact of hazardous drugs with
their immediate environment. Various reputable
publications such as NIOSH Alert (2004)1 and ASHP Guidelines on Handling Hazardous Drugs (2006)2, highlight the effectiveness of implementing appropriate working practices and using adequate protective equipment. Both NIOSH1 and ISOPP7 have recommended the u se o f clo sed sy s tem transfer devices (CSTD), prohibiting the escape of contaminants into the environment, as a vital part
of any protective equipment. Similarly, the effectiveness of CSTD has been well documented in numerous studies.

The effcacy and necessity of CSTD is unanimous and well established among relevant safety organizations. The compliance of available equipment with the deffnition of a CSTD as “a closed system drug transfer device [that] mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drugs and vapor concentrations into the environment ” is still
ambiguous and contradictory.

Under normal working conditions, drugs tend to evaporate in gaseous form into the preparation site ambient air. Their condensation may contaminate: work surfaces, biological safety cabinets (BSC), preparation rooms, equipment, gloves and gowns, as well as the prepared IV bags and syringes in the BSC, that are ready to be sent to the administration area (Kifmeyer, Kube, Opiolka, Schmidt, Schöppe, Diplom Volkswirt, and Sessink, 20024 ; Vandenbroucke and Robays, 20015).

Furthermore, inhalation of toxic vapor evaporating during preparation is suspected to be one of the main routes of exposure.

Studies by Thekla K.Kiffmeyer and Kube et al.4, Vandenbroucke and Robays5, and Connor, Shultsb and
Fraserc6 , demonstrate the behavior of hazardous drug vapors and the ineffciency of fflters in protecting against exposure to such vapor. These findings must be considered when designing safety measures.

Furthermore, although CSTD is only one essential aspect in an overall set of measures that must be applied, it is clear that setting definite criteria for CSTD is required in order to ensure that only safe, completely leak-proof and airtight devices capable of providing genuine protection are accepted and
used as a CSTD. Using a genuine CSTD can signiffcantly improve the safety of healthcare workers.

In the current test, a replication of a test performed by Jorgenson & Cam Au et al.3 at the University of Utah Health Care, air injected by a syringe sweeps the Titanium tetrachloride vapor from the vial. In the case of filter venting based systems, the swept vapor passes unhindered through the filter into the environment. Titanium rapidly reacts with atmospheric moisture: TiCl4 + 2H2 O > TiO 2 + 4HCl. The hydrogen chloride absorbs water to form tiny droplets of
hydrochloric acid, which may absorb more water to produce large droplets that effciently scatter light. In addition, the intensely white titanium dioxide is also an effcient agent for scattering light. The smoke generating at the filter’s exterior is clearly visible, demonstrating the vapor’s behavior. Another portion of smoke is generated inside the vial, through the reaction with the moisture in the air coming from the
syringe. Some smoke particles that are too large to pass through the filter remain in the vial.

Objective

Thee purpose of this study was to evaluate the vapor containment effciency of several commercially available devices, mainly by grouping them into two main categories: filter venting based systems vs. pressure equalization based systems, in order to evaluate the airtight sealing properties of each category and to determine which devices can prevent the escape of vapor during the preparation and administration of
hazardous drugs.

Method

The following drug transfer devices were tested for vapor containment effectiveness, using vials with Titanium tetrachloride as a drug substitute. Titanium tetrachloride acts as a vapor simulator, generating clearly visible smoke when reacting with atmospheric moisture. Each device was observed during its operation for any release of Titanium into the environment. 27ml and 7ml glass vials were filled with 3ml and 1.5ml Titanium tetrachloride TiCl4 (purum ≥99.0%), respectively. 

A 20mm crimper was used to seal the vials with vial stoppers and 20mm aluminum crimp seals with flip-off caps. Tge filling and sealing procedures were performed in an ultra dry environment in an airtight glove box. The sealed vials were taken out of the glove box and the remaining procedure was conducted under ambient conditions. Each system was tested separately, beginning with assembly according to the manufacturer’s instructions, and attachment of a 20ml luer-lock Becton & Dickinson syringe, filled with 20ml of environmental air. Each system is equipped with a vial access adaptor, which was attached to the vial. The syringe with each system’s dedicated connector was connected to the vial adaptor and 20ml of air was injected manually during 5 seconds at a constant speed. Each system was tested with 27ml and 7ml vials.

Results

Only the closed systems with full pressure equalization, i.e. Equashield™ and Phaseal® prevented the release of Titanium tetrachloride into the environment and complied with the NIOSH deffnition for a Closed System Drug Transfer Device (see Figures 1 and 2).

Filter venting systems, i.e. Tevadaptor®/Onguard™ and Chemoprotect® spike, were consistently releasing similar and clearly visible smoke during all tests, with both vial sizes (see Figures 3 and 4). There were negligible differences in Titanium release severity between the vial sizes. The filter of Chemoprotect® spike is clearly visible on one side of the device and the release of Titanium was deff- nitely observed only through the filter. The two filter layers (particle filter and activated charcoal) of Tevadaptor®/Onguard™ are invisible from the outside and are covered by an easily removable housing, which does not affect the device performance. The Titanium test was performed on an additional 5 exposed devices, confirming that the Titanium release occurs only through the filters.

After testing, filters of Tevadaptor®/Onguard™ and Chemoprotect®, were carefully inspected by an x8 magnifying glass, for any evidence of leaks and damages which could have contributed to the escape of the Titanium. As in previous tests performed by Jorgenson & Cam Au et al.3 at the University of Utah, and by the SP National Testing and Research Institute in Borås, Sweden3, where filters were gold coated and viewed under electron microscopy, no evidence of such damage was found.