An Assessment of Exposed Syringe Inner Walls as a Route of Exposure from Hazardous Drugs

Abstract Introduction:

Maintaining safe working environments for health care personnel, especially for those who regularly handle hazardous drugs (HDs), is of utmost importance. Studies have shown that when closed system transfer devices. (CSTDs) are used with standard open barrel syringes, cyclophosphamide (CP), a commonly used HD, is transferred to the syringe plunger during compounding or administration processes. This contamination can then be transferred to the work environment, endangering workers.

Purpose:

The purpose of this study was to quantify HD contamination of the inner surface of standard open barrel syringes and to compare contamination levels between three commonly used HDs: 5-fluorouracil (5-FU), CP, and ifosfamide (IF).

Methods:

Each HD was transferred from a vial to an intravenous (IV) bag using a standard open barrel syringe and Becton, Dickinson and Company (BD) PhaSealTM CSTD connectors. Samples were taken from the inner surface of each of the syringe barrels to measure the amount of HD contamination. Each drug was tested 15 times and compared to a positive control.

Results:

Significant amounts of each drug were transferred to the inner surfaces of the syringes. The average amounts of each drug measured were: 5-FU, 1327.7 ng (standard deviation [SD] =873.6 ng); CP, 1074.8 ng (SD=481.6 ng); and IF, 1700.0 ng (SD =1098.1 ng). There was no statistically significant difference between the three drugs (p=0.14).

Conclusion:

This study underscores the presence of HD contamination on standard open barrel syringe inner surfaces after transfer of drug from vial to syringe to IV bag. Such contamination could be spread in the working environment and expose health care workers to harm.

1. Introduction

Hazardous drugs (HDs), as defined by the National Institute for Occupational Safety and Health (NIOSH), are Food and Drug Administration approved medications that meet certain toxicity criteria for humans or animals. These drugs have been determined to be carcinogenic, reproductively toxic, developmentally toxic, genotoxic, and/or toxic to specific organs (e.g., heart, lungs, kidneys, liver).1,2 Common HDs include antineoplastic agents (e.g., 5-fluorouracil [5-FU], cyclophosphamide [CP], and ifosfamide [IF]), nucleosides and nucleotides (e.g., ribavirin), immunosuppressive agents (e.g., tacrolimus), disease-modifying antirheumatic agents (e.g., leflunomide), hormone-based therapies (e.g., estradiol), and other non-neoplastic agents.3

HDs pose risks not only to patients receiving them therapeutically but also to the health care personnel who compound, administer, transport, dispose, and/or otherwise handle them.1,2 Exposure to such drugs can occur through skin and mucosal membrane absorption, inhalation, incidental ingestion, or via needle stick. HD exposure may, in turn, cause adverse effects including skin rashes, infertility, and cancer.2,4–6

Thus, preventing exposure of health care workers to HDs is of utmost importance for maintaining a safe working environment. This can be achieved through the use of engineering controls, personal protective equipment (PPE), and administrative controls.2 Closed system transfer devices (CSTDs) are one type of engineering control. These needleless devices allow HD manipulations to occur within a closed system, thus protecting health care workers from undue exposure.

If a CSTD is designed well, manufactured properly, and used appropriately, it should protect health care workers from HD exposure during the compounding and administration of HD products. All CSTD syringe adapters require the use of a syringe, which depending on its design, may compromise the closed nature of a CSTD system. The open barrel of a standard syringe can potentially lead to environmental contamination, and thus danger to health care workers. The extent of contamination possible is dependent on the drug used and its volatility, concentration, viscosity, and affinity for the syringe surface.7,8

Unlike standard open barrel syringes, sealed barrel CSTD syringe units are designed to provide a completely closed system. The typical use of any HD requires filling a syringe with the drug and transferring it to an intravenous (IV) bag or IV administration line. During the process of drawing a HD from a vial into a syringe, the HD comes into direct contact with the inner wall of the syringe for a period of time. Through this exposure, the HD may adhere to the syringe surface by chemical affinity or cohesive–adhesive forces. After the drug is transferred from the syringe, the inner surface—and any residual HD adhering to the inner surface—becomes exposed to the environment.

Potential contamination of the working environment with the HD may occur by two possible routes: evaporation of the HD or direct contact with the inner wall of the syringe. The latter type of contamination could then be spread to the working environment or health care worker via gloves or direct contact with other surfaces. This method of contamination should be prevented as much as possible and ideally, should not occur during the handling of any HD. Different levels of contamination may be observed with different HDs due to the unique physical and chemical properties of each drug; however, any level of HD contamination is a reason for concern.

Studies using CSTDs in the compounding and administration of HDs have shown a significant reduction in surface contamination levels.9,10 However, detectable levels of HDs have been observed with the use of some CSTDs. This suggests that some systems are not entirely closed or if the system is closed, there are other ways people can become exposed. Ultimately, health care workers remain at risk of exposure with their use.10,11 One study using a surface monitoring technique explored environmental contamination via syringe plunger contamination during routine drug preparation in hospital pharmacies.7

Contamination by CP on a standard open barrel syringe plunger was confirmed, localized, and quantified. Result from additional studies have confirmed the transfer of CP to a standard syringe plunger.8,9 In these studies, drug residuals on the syringe plunger contaminated both gloves and the work environment.

The purpose of this study was to quantify HD contamination of the inner surface of standard open barrel syringes and to compare contamination levels between three commonly used HDs: 5-FU, CP, and IF.

2. Methods

Three common HD products were prepared under real world compounding conditions to measure contamination levels of the inner walls of standard open barrel syringes. Using a modified NIOSH performance protocol for CSTDs,12 a total of 50 mL of drug was transferred from a vial to a 50 mL open barrel syringe, and then from the syringe to an IV bag, using the appropriate vial, syringe, and IV bag CSTD connectors. The drugs evaluated were 5-FU (50 mg/mL), CP (20 mg/mL), and IF (50 mg/mL). Becton, Dickinson and Company (BD) PhaSealTM CSTDs were used for each of the drug transfer manipulations.

The research team was comprised of a pharmacy school faculty member with extensive cleanroom experience, a pharmacy student with aseptic technique training, and a senior research associate with a doctorate in pharmacy. United States Pharmacopeia General Chapter <800> standards for protecting health care workers from HDs were adhered to throughout the testing (e.g., use of PPE, ventilated hoods, and biosafety cabinets).13

ChemoGLOTM HDClean Wipes were used for sampling the inner surfaces of the syringes, and all data were recorded on the ChemoGLOTM Site Map Form.14 Once completed, the ChemoGLOTM Site Map Forms, along with the correspondin wipe samples, were submitted to the ChemoGLOTM laboratory for analysis (Chapel Hill, North Carolina).

For each test, a CSTD vial adapter was attached to a vial containing the HD being tested, a CSTD bag adapter was attached to an IV bag, and a CSTD syringe adapter was connected to a standard open barrel syringe. The drug was then reconstituted according to the manufacturer’s instructions, if needed (i.e., CP and IF). The syringe was then attached to the vial via the CSTD adapters, and 50 mL of drug was drawn into the syringe. The 50 mL of drug was then injected into the IV bag via the CSTD IV bag adapter. Once each IV bag was prepared, the syringe barrel was tested for the presence of HD contamination.

To test the inner surface of each syringe used, a ChemoGLOTM wipe was used to wipe all four quadrants of the syringe barrel according to the following process:

  • A quarter from the plunger barrel knob was removed,
    allowing for controlled and easy access to the syringe
    barrel without interference from the syringe plunger.
    This allowed for wiping the exposed inner wall of the
    syringe.
  • A wipe was placed into the open section, and a wooden
    rod was used to move the wipe up and down.
  • The syringe plunger rod was rotated 90 degrees, and the
    process was repeated to ensure that the entire syringe
    barrel was wiped.
  • An additional ChemoGLOTM wipe was used to swab
    each syringe quadrant a second time, using the same
    method.
  • Each wipe was then packed and labeled according to the
    instructions provided in the sampling kit.

Each test was repeated 15 times for each of the three drugs, for a total of 45 tests. The sample size of 15 syringes was based on sample sizes used in similar studies.7,8 The use of a full 50 mL per injection was also based on previous studies.7,8


Positive controls for each drug were also tested by inoculating a syringe barrel with the drug, followed by wipe sampling the inner wall of the syringe using the same method described above. No negative controls were tested since the ChemoGLOTM wipe sampling procedure is a validated process that does not require a negative sample.15

The lower limit of quantitation of the ChemoGLOTM assay is 10.0 ng/ft2 (0.011 ng/cm2) per drug, and the upper limit of quantitation (ULQ) is 4000.0 ng/ft2 (4.31 ng/cm2).16 The total drug amount found on each syringe tested was determined by adding the amounts from the two wipes used for sampling (wipe 1 plus wipe 2).

Since there were three independent groups of data and the 5-FU and IF data were not normally distributed, a Kruskal–Wallis test using a 0.05 significance level was applied to the ChemoGLOTM test results to determine if there was a statistically significant difference in contamination levels between the three HDs tested. Statistical and, descriptive analyses were performed using GraphPad Prism 10.0.2 (232) software.

Results

The results of this study found the inner surfaces of all 45 syringes contaminated with the HD being tested. The average amount of 5-FU detected by the ChemoGLOTM wipe kit for the 15 syringes tested was 1327.7 ng (standard deviation [SD]=873.6 ng). The average amount of CP detected was 1074.8 ng (SD =481.6 ng), and the average concentration of IF detected was 1700.0 ng (SD=1098.1 ng). The positive controls for each drug resulted in measurements exceeding 4000.0 ng each, indicating amounts beyond the test’s ULQ. Based on previous work by Cox et al., the percent recovery of the drug on each surface is estimated to be >95%.15 See Table 1 for a complete list of the data collected.


The Kruskal–Wallis test performed on the data revealed that there was no statistically significant difference between the different drugs’ level of contamination (p=0.14).

Discussion

The results from this study found significant contamination by each of the three drugs on the inner walls of the open barrel syringes. The difference in level of contamination between the three drugs was not statistically significant, highlighting that inner surface contamination by most HDs is likely when open barrel syringes are used during compounding and administration. Any differences that would exist between different HDs would likely be due to the different chemical and physical properties of the drugs —such as their polarity, hydrogen bond donor and acceptor count, and viscosity—and their relative affinity for the syringe surface. A higher SD, as is the case of IF, indicates greater variability in contamination levels.

These findings align with results from other studies. One study that assessed the extent of CP contamination on syringe plungers showed contamination in amounts ranging from 3.7 to 445.7 ng when tested via gas chromatography/ mass spectrometry (GC/MS).7 Another study, using ChemoGLOTM wipe test sampling, found CP contamination levels greater than 2000 ng on open barrel syringe plungers and no detectable contamination on sealed barrel syringe plungers after a 50 mL aliquot of CP was drawn into each syringe and injected back into the CP vial multiple times.8 The difference in this study’s CP results from these two studies’ results is likely due to the differences in analytical tools used (GC/MS vs. ChemoGLOTM wipe tests), the number of times CP was drawn into each syringe (multiple times vs. once), and/or the sampling techniques used.

One of the limitations of this study was that the positive controls for each drug resulted in measurements of greater than 4000 ng each. Since the ChemoGloTM assay has an ULQ of 4000.0 ng, the true amount of drug could not be determined for the controls. The amount of residual drug could have been anywhere from 4000 ng to orders of magnitude more. Therefore, even though the contamination of the syringe barrels from these three drugs can be quantified and compared via this testing method, the full clinical significance of the results cannot be determined by this
study alone.

Additionally, a full 50 mL of drug was drawn into each 50 mL syringe to maximize exposure of the syringe’s inner surface to the drug. This type of usage is not standard compounding practice and may have caused an overestimation of the amount of residual drug that would typically be left on the syringe inner wall during sterile product preparation or administration. Therefore, these results may not be fully generalizable to common compounding practices.

The difference in concentration of the CP solution versus the 5-FU and IF preparations could also have affected the relative amount of drug adhering to the syringe wall. However, the drug preparations used in this study (50 mg/mL for 5-FU, 20 mg/mL for CP, and 50 mg/mL for IF) are standard compounding concentrations, so these results reflect real-world comparisons, enhancing their generalizability.

Finally, only three HDs drugs were tested in this study, allowing for the possibility that additional HDs with different chemical and physical properties could produce different results.

Additional studies are warranted to analyze the extent of contamination after multiple transfers and with extended duration of use, both of which may increase the potential for HD exposure. Understanding the extent of contamination with such use would better reflect the risks associated with real-world compounding practices. Also, further studies examining the extent of transfer of HD from a syringe inner wall to a user’s gloves and compounding working space for these three drugs and other HDs are needed to better understand the extent of risk to health care workers with the use of open barrel syringes.

Conclusion

This study underscores the presence of HD contamination on standard open barrel syringe inner surfaces after transfer of drug from vial to syringe to IV bag. The detected amounts of each the three drugs (5-FU, CP, and IF) on the inner surface of standard open barrel syringes were high (ranging from 1074.8 to 1700.0 ng), especially given that the maximum amount measured (for one sample of IF) exceeded the ULQ set by the ChemoGLO assay at 4000.0 ng. Such levels of drug contamination are of concern since they could be transferred to the working environment and expose health care workers to harm. Identifying ways to limit contamination and exposure is important for the safety of all health care workers who regularly handle HDs.

Authors’ contribution

BTB and SFE conceived the study and were involved in protocol development and data collection. All authors researched literature and performed data analysis. LTA wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

Declaration of conflicting interests

Equashield® provided the funding and proposed the general framework of the study. SFE and LTA have also received funding support from BD, Daiwa Can Company, and Shandong Ande Healthcare Apparatus Co., Ltd. for additional CSTD-related research. SFE is a co-founder of ChemoGLOTM. The authors declare no additional conflicts of interest.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Equashield®.


ORCID iD

Lori T Armistead https://orcid.org/0000-0002-4680-0156

Assessment of Testing Method for Closed System Transfer Devices Across Vapor Release

1. Introduction

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.

2. Study Objectives

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

3. Study Design

3.1 NIOSH Vapor Study

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

Products used for testing:

5. Study Procedures

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.

Case Study: Implementing EQUASHIELD CSTDs in German Ostalb Hospitals

This account is based on interviews and written documentation provided by the hospitals, and has been approved for publication.

In an era where oncology healthcare workers face growing challenges, the implementation of Closed System Transfer Devices (CSTDs) is significantly enhancing their safety. This life saving technology has been adopted by many countries as a standard, however Germany has not yet mandated their use. Three German hospitals have pioneered the use of closed-system transfer devices (CSTDs) out of concern for their oncology team’s exposure to dangerous medications. They adopted EQUASHIELDs CSTDs to enhance their hazardous drug handling procedures, ensuring a safer and more efficient work environment. The hospitals documented the entire process and conducted in-depth interviews with the pharmacy manager to assess the efficacy of the system. This blog post explores the impact of EQUASHIELD’s Closed System Transfer Device (CSTD) on Ostalb hospitals over a 12-month period from January to December 2017, with an updated evaluation conducted in 2024. 

Understanding the Risks in Oncology

Oncology healthcare professionals face the risk of exposure to hazardous antineoplastic drugs on a daily basis. The very nature of these cytotoxic drugs which makes them so effective in combating cancer cells also makes them dangerous to healthy cells. 

Infusion therapy typically necessitates individual preparation for each patient before administration. The preparation process can lead to errors, spillages, needlestick injuries, aerosolization, and workplace contamination. Potential exposure poses significant health risks to workers throughout the entire lifecycle, from preparation through waste disposal. While patients receive concentrated doses of a limited number of Hazardous Medicinal Products (HMPs) for a defined period, workers may be exposed to small doses of a wide range of hazardous medicinal products over decades, with some experiencing daily exposure year after year.1

Exposure can occur via skin contact, ingestion, or inhalation of airborne particles. Short term health effects from minimal exposure to hazardous drugs over a long period include hair loss, taste disturbances, headaches, reproductive disorders, miscarriages, infections, and respiratory diseases. Often, the effects of exposure are long-term, not becoming evident for years or even generations of continuous exposure. Given that cancer can take decades to manifest, a diagnosis of breast cancer or leukemia in a nurse or pharmacist today might stem from workplace exposure to hazardous drugs starting in the 1980s. 2

These risks necessitate that health facilities treating cancer patients implement stringent safety precautions. Essential precautions include using personal protective equipment (PPE), following local regulations, and employing suitable solutions like CSTDs for handling chemotherapy drugs.

What are CSTDs?  

According to the National Institute for Occupational Safety and Health (NIOSH), a CSTD (Closed System Transfer Device) is a drug transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drugs or vapors outside of the system. CSTDs play a crucial role in ensuring safe drug compounding and administration by protecting healthcare practitioners from exposure via leaks, spills, and vapor release.

Improving Oncology Safety at Ostalb Hospitals 

Ostalb Klinikum Mutlangen, along with two affiliated hospitals in Southwest Germany, were preparing and administering around 6,500 chemotherapy cycles and 20,000 cytostatic preparations annually. While many countries have established stricter protocols for managing hazardous drugs, Germany has not yet followed suit. Recognizing the paramount importance of staff safety, Ostalb hospitals chose to lead the way in Germany by pioneering the use of CSTDs. Before switching to EQUASHIELD, the pharmacy was not using a closed system for handling hazardous drugs.  

The pharmacy manager was eager to transition to a safer system primarily due to exposure risks. In a dedicated effort to improve safety for their oncology healthcare workers, the hospitals decided to adopt CSTDs. They identified their criteria for choosing a CSTD brand as follows: 

  • A system consisting of defined connectors, Vial Adaptors, Syringe Adaptors, and Luer Lock components for administration 
  • A leak-proof device that can manage multiple membrane access 
  • A system that will reduce occurrences of accidental disconnections and spike falloffs 
  • A system that is practical to use and will not impede workflow of busy hospital staff 
  • A system that is clinically validated to effectively protect healthcare workers 

The Decision Process 

The primary reason for selecting a closed system transfer device was to protect the oncology staff from hazardous drug contamination. The hospitals also aimed to preserve medication integrity and streamline the compounding process. The Pharmacy Manager at the time recognized the critical importance of safeguarding Pharmacy Technicians in the hazardous drugs compounding department. The high volume of daily production and the gradual decline of focus throughout the day had led to  needlestick injuries. Recognizing these hazardous incidents, she was committed to transition to a safer system for her team. She also felt a responsibility to protect the oncology nurses from exposure by residual chemicals on the outside of the prepared medications they were handling.  

The concept of a closed system remained a critical topic of discussion within the team. However, until they discovered EQUASHIELD there had been no practical closed system available on the market that could effectively meet their stringent requirements for both safety and functionality. The decision process to switch to a closed system took approximately six months and involved convincing the hospital management of its benefits, which outweigh the costs, keeping the staff safe. The Ostalb hospitals assessed various CSTD brands and chose EQUASHIELD based on their clinically proven safety and efficacy, product reliability, and user-friendly design. 

Implementing EQUASHIELD CSTDs

Staff Reactions  

It took one week for the pharmacy technicians to adapt to the EQUASHIELD system. The adoption process was seamless and intuitive, allowing them to effortlessly learn how to use the products. After the training and clinical onboarding the staff quickly adapted and learned how easy and intuitive is to use EQUASHIELD CSTDs in their workflow. After this period, they expressed high satisfaction and a preference for this system over others.  

The hospitals reported several significant improvements immediately after implementation: 

  • Improved safety for healthcare professionals 
  • Reduced risk when handling cytotoxic drugs, resulting in improved workflows and stress-free handling of patient doses 
  • Completely dry connections with no spills or drips 
  • No foaming during drug withdrawal 
  • Easier preparation when reconstituting lyophilized powders 
  • User friendly and fail proof application due to the red marked notches that indicate specifically how to apply it 
Hospitals implementing CSTD

Compatibility 

The hospitals noted smooth integration. Components they use include syringe units, spike adaptors, luer lock adaptors, female connectors, and vial adaptors. They utilized a standard tubing system.   

The hospitals have adopted EQUASHIELD for all cytotoxic preparations, including antibodies, finding it advantageous over the previous method of using specific equipment for each medication based on compatibility. 

One-Year Evaluation 

Overall Improvements 

One year after adopting EQUASHIELD’s CSTDs, all three Ostalb hospitals witnessed significant improvements in multiple areas. EQUASHIELD’s CSTD system substantially reduced contamination in the pharmacy and hospital. Reduced preparation times resulted in significant time savings in daily production. The system’s user-friendly design, with intuitive handling and clear application markings, ensures reliable and fail proof administration. Administration times have been reduced, and repetitive motion injuries have been prevented. The customer service team is responsive and ensures quick delivery, usually within 3-4 days. 

Evaluating Surface Contamination Reduction 

Wipe sampling was performed at multiple locations within the hospital system at various time points following the EQUASHIELD implementation. Of the three types of drugs used for sampling—Cisplatin, Fluorouracil, and Cyclophosphamide—all trackers pointed to lower traces of drug residue, with the vast majority being under 0.2 ng per sample detection limits. 

This reduction in contamination not only enhances the safety of pharmacists and nurses but also contributes to a clean and safe environment for support staff throughout the lifecycle of the medication. 

Time Savings

In addition to improving safety, EQUASHIELD’s CSTD have also proven to be time savers in drug preparation. When calculating the time saved while preparing top chemotherapy agents used daily, it was identified that drug preparation times could be reduced significantly by using EQUASHIELD CSTD. In some cases, the time savings were as much as 3.5 minutes per dose. Cetuximab alone saved 455 minutes annually. Similarly, other medications such as Fluorouracil, Avastin, and Herceptin achieved significant time reductions. The annual time savings in drug preparation for each staff member across 29 evaluated drugs totaled over 3,856 minutes. 

Time savings in chemotherapy preparation with Equashield CSTDs

Evaluating EQUASHIELD 7 Years Later 

Seven years after integrating EQUASHIELD’s CSTD system into their daily operations, the hospitals continue to see improvements in staff satisfaction, time savings, and contamination reduction. The Ostalb hospital’s experience has been positive since its implementation. They are satisfied with the premium safety standards and would never consider using an alternative system. Annual wipe tests confirm that the enhanced safety levels, achieved since adoption, are consistently maintained. The system’s ease of use and safety features have significantly improved the workflow in the pharmacy department. An unexpected benefit is that the exceptional safety standards make it significantly easier to retain and recruit new staff to the oncology department. As a result, staff turnover has decreased significantly for the past seven years. 

Adopting EQUASHIELD’s closed system technology has brought significant benefits to Ostalb hospitals, enhancing safety, streamlining workflows, and boosting staff morale. 

Navigating the New EU Directives on HMPs 

The implementation of EQUASHIELD CSTDs has ensured hospital compliance with the latest EU directives on hazardous medicinal products (HMPs). The new regulations outline which medicines are considered carcinogenic, mutagenic, or reprotoxic potential. Under the new regulations, hospitals are required to use closed systems for the updated list of HMPs by April 2024. The EQUASHIELD system meets and exceeds these safety requirements, providing a safe and efficient solution for pharmacists and nurses. 

If you’re interested in learning more about how EQUASHIELD can benefit your healthcare facility, please reach out to one of our experts here.

Case Study: CSTD use in Veterinary Medicine  

Dogs get cancer at roughly the same rate as humans, with nearly half of dogs over the age of 10 developing cancer.1 Cancer is a common concern in small animals, and as our beloved companions, they deserve the highest standard of care. Recently, there has been a notable rise in the use of antineoplastic chemotherapy within small animal veterinary practice. This trend is primarily driven by a growing awareness among pet owners about tumor diseases, along with significant advancements in diagnostics and therapies for small animal oncology.  

While such therapies were initially carried out by large oncology centers, they are increasingly being offered by specialized small animal clinics.

Safety concerns  

Exposure Risks for Veterinarians and Pet Owners 

The use of cytostatic drugs poses an increased risk of exposure for veterinary staff and pet owners present during chemotherapy.  

Given that the substances involved possess mutagenic, teratogenic, and carcinogenic properties, and that it is difficult to define minimum quantities for these effects, it is crucial to minimize the risk of exposure for both veterinary personnel and pet owners. The risk of exposure on surfaces is further increased considering that most veterinary clinics do not employ primary engineering controls, such as safety cabinets or isolators. 

Research in human medicine indicates that there is no connection between the number of chemotherapy treatments administered at a facility and the degree of exposure risk.2 This means that even facilities performing a relatively small number of chemotherapy treatments must prioritize minimizing exposure risks and implementing suitable protective measures.  

The European College of Internal Medicine for Companion Animals has developed guidelines for the appropriate use of antineoplastic chemotherapeutic agents.3   

The compounding of intravenous infusion solutions for antitumor chemotherapy, along with the administration of chemotherapeutic agents, introduces distinct risks of contamination and exposure to cytostatic drugs. Veterinarians encounter significant exposure risks in these processes. 4 Key steps in the process include reconstituting the vial, accurately extracting the substance, and managing the infusion solution.  

Syringe unit with a closed syringe plunger prevents toxic aerosols from escaping.

Risks of Bacterial Contamination   

 Small animals need much less medication than humans, but the medications often come in standard-sized vials, resulting in significant waste. Traditional systems carry a high risk of microbial contamination, making multiple withdrawals unsafe, especially for immunosuppressed patients who are more vulnerable to sepsis. Additionally, many cytostatic drugs are costly, and disposing of unused substances is both expensive and harmful to the environment. 

Use of CSTDs for the Application of Cytostatic Drugs to Small Animals  

Utilizing a closed system transfer device (CSTD) mitigates both environmental and microbial contamination risks, protecting medical personnel and pet owners. 

Currently, only a limited selection of CSTDs are available on the market in small animal oncology.5 EQUASHIELD has undergone extensive testing in human oncology, clinically backed to be safe and easy to use. The use of CSTDs does not exempt the oncologist of the obligation to adhere to current legal regulations governing chemotherapy. Nonetheless, it is strongly advised for veterinarians to prioritize their own safety. 6 

Case Study: Oncology at the Kleintierzentrum Kinzigtal Small Animal Center 

This summary highlights the experiences of Kleintierzentrum Kinzigtal Small Animal Center, written by Dr. Jörg Schäffner, as they transitioned to EQUASHIELD CSTDs. For the complete article, please download here.

At the Kinzigtal Small Animal Center in Baden-WĂĽrttemberg, Germany, we regularly provide chemotherapy for various tumors, including lymphomas, mastocytomas, and epithelial tumors like prostate and anal sac carcinoma. Treatments often involve intravenous administration of cytostatic drugs such as vincristine, doxorubicin, and carboplatin, with a successful slow infusion method.  

Before the introduction of EQUASHIELD CSTDs, the conventional system left staff vulnerable to exposure. Before application, the calculated volume of a cytostatic drug was drawn from the sealed glass vial. Since multiple doses were often extracted from a single vial, this process introduced a risk of contamination for both the user and the surrounding environment. Another potential source of exposure and contamination arose when air was introduced to equalize the pressure between the vial and the syringe. Finally, there was the risk of needlestick injuries. 

Veterinarian administering cytotoxic drug chemotherapy to small animals

Introducing EQUASHIELD

Over the past year, we have effectively mitigated these risks by utilizing the closed EQUASHIELD system. Administering treatment to restless, unsedated animals requires a safe and user-friendly approach to effectively prevent contamination of medical staff, pet owners, and the surrounding environment. It is crucial for us to have a system that can accommodate the unpredictable movements of the patient, ensuring the safe and hazard-free administration of cytostatic medications. The self-locking vial adapter, which remains firmly connected to a vial once it has been opened, and the syringe unit  connected to the double-membrane closure system thus safely reduces both hazards. The sterilized air is introduced into the drug vial from the sealed chamber in the syringe unit to equalize pressure. 

As the syringe unit is locked to the Luer Lock Adaptor of the infusion system, there is no risk of disconnection and subsequent contamination even if the patient moves. The slow application is carried out in a stress-free and controlled manner. Even when the syringe unit plunger is pulled back, the pressure equalization system reduces the risk of environmental contamination from aerosols. After administering the cytostatic drug and flushing the infusion tubing, the entire system is safely removed and disposed of in designated waste containers. Using CSTDs minimizes the risk of bacterial contamination, allowing us to make multiple withdrawals from the vial while effectively addressing the issue of waste.

 

Veterinarian using EQUASHIELD CSTD

Veterinarian using EQUASHIELD CSTD

Concluding Thoughts

In our experience, the introduction of EQUASHIELD is a significant contribution to safe chemotherapy. Our consistent positive experiences with EQUASHIELD, characterized by intuitive and safe handling, along with significant time savings compared to other systems, validate the findings of a study from North America.7 EQUASHIELD reduces the risk of microbial contamination of opened cytostatic vials.7 For medical staff and pet owners, exposure risks have been effectively reduced.  Implementing EQUASHIELD has significantly improved occupational safety in our veterinary clinic.      

The Unseen Dangers: Understanding the Occupational Risks of Chemotherapy Drugs and the Protective Role of EQUASHIELD’s CSTD

Introduction

Chemotherapy drugs, vital in cancer treatment, are not without risks for healthcare professionals, particularly nurses. Their handling poses occupational hazards due to the drugs’ potent and toxic nature. Understanding these risks and the protective measures provided by Closed System Drug-Transfer Devices (CSTDs), especially EQUASHIELD’s CSTD, is crucial for healthcare workers’ safety.

The Occupational Risks of Handling Chemotherapy Drugs

According to the CDC, healthcare workers, particularly nurses and pharmacists, face significant risks when handling chemotherapy drugs. The NIOSH (National Institute for Occupational Safety & Health) article, “Hazardous Drug Exposure in Healthcare,” states that these risks can lead to “acute and chronic health effects such as skin rashes and reproductive issues.” 

This includes “infertility, spontaneous abortions, and congenital malformations” as well as an increased risk of “leukemia and other cancers​​.” Exposure over time is associated with birth defects and miscarriages.

Doctor checking pregnant woman

Key Exposure Points For Health Professionals

Exposures occur through the compounding process and frequent handling of these drugs during administration. Healthcare workers, including nurses and pharmacists, who are in direct contact with these potent and toxic substances, are seen as the more vulnerable groups. 

According to OSHA, exposure to hazardous drugs during preparation and administration poses significant health risks, including cancer, organ toxicity, and reproductive issues. Occupational hazards are increased in the preparation phase while complying with the very low level of pharmacological compounding compared to the administration phase. The levels of risk are pretty high, and they result from processes that expose workers to substances that have the potential to cause harm. 

Therefore having proper knowledge of the harmful agents associated with this process and the safeguarding measures, such as the EQUASHIELD’s Closed System Drug Transfer Devices (CSTD), would go a long way in enhancing the work-related health and safety of the healthcare workers.

Routes of Exposure

Health worke­rs can inhale chemotherapy drug particle­s or vapors when preparing or giving treatme­nt. OncoLink, a cancer resource in Pe­nnsylvania, warns about these exposure­ risks. They state inhaling vapors is dangerous and can le­ad to other exposure through skin contact or ne­edlestick accidents. Strict safe­ty measures must be use­d to prevent these­ exposure risks.

Monitoring surface contamination of hazardous drugs is crucial, as evidenced by findings from a study conducted by the Canadian Journal of Hospital Pharmacy.

The study highlights that these hazardous drugs can settle on work surfaces and pose a risk of indirect transfer through contact, emphasizing the importance of regular environmental monitoring and rigorous cleaning protocols to safeguard healthcare workers from occupational exposure.

Threats on Healthcare Workers

A case study from the University of Michigan on the threats that affect cancer care workers found that nurses “handling hazardous drugs had twice the risk of reproductive problems.” 

The lead study author, Christopher R. Friese elaborates, “This is an invisible threat.” He further examines, “Early on we could understand that a needle stick conveyed serious health risks… This is a subtle threat, but it’s a daily threat.”

The Role of EQUASHIELD’s CSTD in Protecting Healthcare Workers

EQUASHIELD’s CSTD provides a crucial layer of protection against these occupational risks. By design, it mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapor concentrations outside the system, thus minimizing the risk of exposure during the compounding and administration of hazardous drugs​​.

The use of EQUASHIELD’s CSTD can “effectively eliminate spills and leakage during the compounding of gemcitabine” and antineoplastic drugs. According to the article “Maximizing Efficiency and Safety in Healthcare: Real Life Case Studies on Cost Savings with Closed System Drug Transfer Devices (CTSDs),” it can significantly reduce the risk of surface contamination and exposure. Therefore providing a safe working environment for anyone in the space. 

Pharmacist using EQUASHIELD CSTD

Highlighting EQUASHIELD’s CSTD studies, the National Library of Medicine inscribes the effectiveness of “Reducing Leakage during Antineoplastic Drugs Compounding,” EQUASHIELD discovered that gemcitabine (GEM) was not detected in samples when using the EQUASHIELD® II system, indicating its effectiveness in preventing contamination. 

Moreover, a significant reduction in detectable levels of antineoplastic drugs “in surface sampling wipes after the implementation of the EQUASHIELD’s CSTD.” Notably, the design of EQUASHIELD with a metal rod as a syringe plunger prevents contamination of the plunger itself, a common contamination site in other CSTDs​​.

Comparative Analysis with Other CSTDs

EQUASHIELD has been compared with other CSTDs in terms of containment of liquids and vapors – demonstrating its effectiveness in reducing operator exposure to hazardous drugs reinforces the critical role of CSTDs like EQUASHIELD in protecting healthcare workers​​.

When addressing the issue of hazardous drug exposure and the transfer of environmental contaminants, NIOSH employs a CSTD successfully. It create­s “an airtight seal betwee­n drug vials, syringes, and IV bags.” This mechanical approach “preve­nts the release­ of harmful aerosols and vapors.” It greatly reduce­s risks from direct contact, skin exposure, and inhalation.

Conclusion

The­ occupational hazards of handling chemotherapy drugs are significant and can se­riously impact healthcare workers’ he­alth. Using CSTDs, especially EQUASHIELD’s CSTD, effe­ctively reduces the­se risks by preventing drug le­aks and surface contamination. Healthcare facilitie­s must adopt such protective measure­s to ensure staff safety and we­ll-being.

Application of the 2015 proposed NIOSH vapor containment performance protocol for closed system transfer devices used during pharmacy compounding and administration of hazardous drugs

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 ScientificTM 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 ScientificTM 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

Evaluation of Vial Transfer Devices for Containment of Hazardous Drug Vapors

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

Evaluation of Vial Transfer Devices for Containment of Hazardous Drug Vapors

PhaSeal® by Carmel Pharma

Chemo Mini-Spike Plus™ Dispensing Pin

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

Spiro Male Connector and Clave

Vial Adapter and Clave® by ICU Medical Inc.

Vial Adapter and Clave® by ICU Medical Inc.

B. Braun OnGuard™ System by Teva Medical Ltd.

Evaluation of Vial Transfer Devices for Containment of Hazardous Drug Vapors

Alaris’ Smart Site® by Cardinal Health

Alaris’ Smart Site® by Cardinal Health

CyTwo-Fer by Baxa

CyTwo-Fer by Baxa

CHEMO-AIDE by Baxter

CHEMO-AIDE by Baxter

Chemoprotect Spike® by Codan US Corporation

Chemoprotect Spike® by Codan US Corporation

Containment Testing to Assess the Efficacy of Closed System Transfer Devices

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

Comparative Study of Vapor Containment Efficiency of Hazardous Drug Transfer Devices

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.

Efficiency of Closed System Transfer Devices (CSTDs). Comparative Study 

Introduction

Some of tire drugs used in medical care (e.g., in cancer treatments) are extremely hazardous. Some of these compounds are volatile and might escape to the air in medical facilities. Long term exposine to such compounds, even at low concentrations, can lead to serious health risks to healthcare workers [1,2]. Therefore, it is important to reduce exposine by containing hazardous drug and its vapor releases using proper protective equipment. This can be achieved using specially designed CSTD systems. Some CSTDs that are venting air from drug vial headspace are equipped with air filtration technologies, that should prevent the escape of hazardous substances to the environment. Such systems are supposed to protect the operators from exposure. 

Unfortunately, no performance standard for CSTDs has been published and it is not clear that the performance of all CSTD systems are adequate [3]. In this study, the vapor emission diuing CSTD-assisted transfer of water from a syringe to a vial containing drug surrogate was measured. Three filter CSTD systems were tested for preventing the leakage of vapors of three surrogates. Tire tests were carried out under conditions representing real usage of dings by healthcare workers, in an experimental setup that allows monitoring of the escaped vapors.

Experimental

Experimental

Three CSDT systems were compared: ChernoClave/Spiros (Type A, in the following), SmartSite/Texium (Type B) and OnGuard/Tevadaptor (type C). All units comprise two parts (adapters): one is fixed on tire syringe and the other is on the ding vial. Both Type A and Type B vial adapters contain a hydrophobic micronic filter; Type C vial adapters use a double-filter technology with a combination of micronic filter and an active carbon filter. Liquid can then be transferred from, or to the syringe, and the air pressure in the vial is equalized by air moving in or out of the system to environment through the filtered port.

Chemicals

The CSTDs were tested with three surrogates for hazardous dings from the list of nine agents proposed by NIOSH [4]: Tetramethylurea, Alfa Aesar, Thermo Fisher Scientific (United Kingdom), Tefraethylurea, Tokyo Chemical Industry Co. LTD (Japan), Propylene glycol (1,2-Propanediol), Chen Shmuel Chemicals LTD (Israel). All reagents were used as received. Ultrapure water (18.2 MfUcm. Direct-Q* 3) was used in all the experimental procedures.

Analyzer

The air samples were analyzed using the Gasmet DX4040 FTIR analyzer which is also used by NIOSH [5], The calibration earner gas used was nitrogen, 99.999% purity. The volume of its measurement chamber is 400 ml and the effective optical pass is 9.8 m. The analyzer was properly calibrated (by manufacturer) prior to the experiments and retested in our lab, using a standard mixture of gases.

The spectra of the tested surrogates and the relevant spectral range used for their analysis, are shown in Fig. 2.

Setup

A vial connected to a syringe through CSTD, was positioned at a 45-degree angle, as depicted in Fig. 1. It was placed between a glass funnel and a Buchner funnel, equipped with sintered glass filter. The air passed through the sinter glass filter, forming quasi-laminar flow. The air, together with the emitted contaminants were partially collected by the upper glass funnel and conducted to the analyzer via teflon tube. The air was circulated along this pass during the analyzer’s measurement time.

The following points were taken into consideration in the design of the experimental setup:

(a) The testing system is an opened one. Using a large chamber closed system, that mimics a room, would dilute the released chemicals below the instrumental detection limit. On the other hand, using a small volume chamber, would not properly represent real conditions, due to development of pressure differentials and due to large surface-to-volume ratio (chamber walls adsorb molecules). The chosen configuration avoids these dr awbacks since it is external to CSTD and doesn’t interfere with any known aspect of CSTD performance, but at a price: some molecules escaping the CSTD system may not reach the analyzer. This is not very important, since our task is to compare the performance of various CSTD systems and not to measure the absolute amount of chemicals released.

(b) Tire commonly used by healthcare workers inclined configuration (45-degree) was selected after testing many different angles and proper optimization. Horizontal air flow, migirt cause losing too much of the emitted molecules, which are either heavier or lighter than air. Vertical air flow is physically not possible and is not in use.

Table 1. CSTD containment performance data.

CSTD containment performance data

Fig. 1. The experimental setup, including placement of the syringe, vial with the test surrogate, CSTD system and the gas flow (black arrows)

Efficiency of Closed System Transfer Devices (CSTDs). Comparative study

Fig. 2 The spectra of the tested substances. The wavelengths used for analysis are indicated.

The spectra of the tested substances

Analysis area: 958-1300 cm-1

The spectra of the tested substances 2

Analysis area: 925-1304 cm-1, 2640-3180 cm-1

Analysis area: 895-1300 cm1

Procedures

Tire task of the procedure was to reproduce normal operation of tire CSTD system, as routinely done in hospitals. First, 100 ml glass vial containing 3 ml of a surrogate was prepared. To comply with real powder drugs that have drug coated inner walls, and in order to have standard conditions for the compar ison, the vial was rolled on its side, to achieve surface wetting, which does not depend on the dynamic conditions of the injection. However, care was taken not to allow surrogate contact with the vial’s rubber stopper. Then 60 ml of deionized water was injected to tire vial, using CSTD. The injection was carried out manually, and tire injection time was 16-18 s.

Concentrations were measured at sampling times of 20 s, (plus one second for writing and saving the data). At 20 s sampling time, water injection was started at the tenth second of the first measuring cycle. A new measurement began after the concentration reached zero. The highest data point of concentration was recorded for each surrogate.

All measurements were carried out at room temperature of 23 â€“ 24.5 °C, while avoiding air turbulences.

Additional Study Procedures

Study development and optimization involved additional testing with significant variations of study parameters and surrogates. The additional testing included testing with sampling time of 1 s and 5 s in addition to 20 s. The concentrations recorded at 20 s sampling time are lower than those obtained at 5 s and tire highest values are recorded at 1 s sampling time. However, the better repeatability was obtained at 20 s sampling time. The reason is that longer sampling averages over high and low concentration values in the measurement chamber, while short sampling time can indicate high actual concentrations reached at certain time. Nevertheless, for the same reasons, the standard deviations are lower at longer sampling times. The results indicate that dining the injection, there might be moments of high release of the chemicals.

Results and discussion

The results for average maximum concentrations detected with Gasmet DX4040 FTIR analyzer for the three CSTDs and three drug surrogates, are shown in Table 1. The standard deviations of these averages, calculated from repeating die measurements 10 times, are also indicated.

Table 1. CSTD containment performance data.

The interpretation of these data is related to the experimental setup used and the measurement procedure. First, note that these concentrations are not room concentrations, but concentrations recorded in the analyzer’s measurement chamber. The concentrations start at zero, increase during the injection (due to emission of the compounds from the CSTD systems), and then decrease and return to zero. Quantification with this open system setup is limited to the highest value cited and absolute quantification is not possible. These values provide evidence for the escape of vapor from the tested CSTDs and can be used for comparing the performance of the examined systems. 

In general, all three systems are leaking. However, there are differences between the tested systems. Type A and Type B CSTDs showed a relatively high level of leakage. Type C demonstr ated better filtration properties than the other two CSTDs.

There are also differences in the leakage of the 3 tested surrogates, up to a factor of 45. It means that tire CSTD’s performance strongly depends on the surrogate. Propylene Glycol was hardly or not detectable with Type C, but both other surrogates Tetramethyhuea and Tetraethylurea were clearly leaking from same Type C. Tire results indicate that perhaps Propylene Glycol is not a suitable testing agent for these safety devices. Tetramethylurea demonstr ated the highest concentration values and stability throughout the study with all three tested CSTDs.

Further research is needed for the CSTD performance protocol, with other NIOSH surrogates and testing methods.