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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 – 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.

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs and Regular Syringes Using NIOSH Hazardous Drug Surrogates

1. BACKGROUND INFORMATION AND RATIONALE

1.1 Background

There are several routes of exposure to hazardous drugs (HD) throughout the drug-handling chain, from pharmaceutical compounding to patient dose administration. Closed System transfer devices (CSTD) are used to protect against such worker exposures to HDs. CSTDs should have the ability to function as a closed system that restricts drug mass (vapor or liquid) from crossing the system boundary and escaping into the surrounding environment [1,7]. However, in the absence of CSTD performance standards that currently apply to drug containment and given uncertain claims of protective performance, the protective efficiency of certain CSTDs remains in doubt for at least two of these routes of exposure.

  1. The first route of exposure occurs during the reconstitution of HDs when the diluent injection forces the venting of air saturated with drug vapor from the vial headspace to the environment. This is applicable only to vented CSTD models, the “air-cleaning systems,” designed to filter and remove aerosol or vapor contaminants from airstreams that might escape the drug transfer system [1,7]. Air-Cleaning CSTDs came to market after “barrier CSTDs,” offering significant cost savings. However, their efficacy in preventing the escape of drug vapor remains under heavy scrutiny to this date.
  2. The second route of exposure occurs in a syringe during and after injection of HDs, when a layer of the drug may remain due to adhesion on the inner walls of regular syringes used with air-cleaning and barrier-type CSTDs [12,13,14], Layers of drug compounds with vapor generating potential may evaporate into the environment and potentially contaminate the syringe plunger. This is applicable to all CSTDs that use regular open barrel off-the-shelf syringes.

In the absence of such worker protection standards, the users (e.g., health care facilities and pharmacies) have no worker-protection performance basis upon which to make their selection of a CSTD, and they may be inclined to select a product based solely upon acquisition costs and uncertain claims of protective performance [1]. Since 2015, The National Institute for Occupational Safety and Health (NIOSH) has been developing performance test protocols for CSTDs. NIOSH’s first “Vapor Containment, Performance Protocol” introduction in 2015 used IPA alcohol as the surrogate [1]. NIOSH continues to adhere to detecting escaped vapor concentrations of drug surrogates as the basic testing approach. In 2016 NIOSH introduced 9 surrogates (later extended to 1 1 surrogates) to be used in the “Performance Test Protocol for CSTDs [7].” While the testing methods and equipment have significantly changed over the years, these surrogates remain under current consideration, including alcohols for testing barrier-type CSTDs (NIOSH 2019) [8]. NIOSH’s surrogate selection strategy involved the selection of Thiotepa, the HD with the highest known vapor pressure as a worst-case scenario. To build in a safety factor, surrogates were considered with vapor pressures in the range, starting with Thiotepa and going up to approximately 100 times that [7], NIOSH also stated in its 2015 protocol that “A CSTD design that relies upon aerosol filtration to clean air that exits the drug transfer system is worker protective only if use of the CSTD is limited to compounding drugs that have no vapor generating potential. For drug compounds with either known or uncertain vapor generating potential, the protective selection of air-cleaning CSTDs requires specific test data for every’ drug type and formulation they will contact, since air-cleaning technologies can have varying efficiencies based upon the chemical and physical make-up of the contaminant.”[1] This study evaluates two out of nine NIOSH surrogates for their suitability as challenge agents for testing the aforementioned two routes of exposure. The evaluation shall determine whether CSTD efficiencies vary upon the chemical and physical make-up of surrogates to the degree that inefficient surrogates, including alcohol, shall be excluded or used only in combination with efficient surrogates.

1.2 Study Objectives

The purpose of the study in its first stage was to determine that each vented air-cleaning CSTD can have varying vapor containment efficiencies with varying contaminants since some vented CSTDs could contain vapor of one type of contaminants and absolutely fail with others.

In its second stage, the purpose of the study was to establish scientific evidence for vapor release from regular open-barrel syringes as a route of exposure and further to determine that varying contaminants can cause varying levels of vapor contamination from open-barrel syringes, ranging from high contamination to none.

This study tests four commercially available vented CSTDs using two out of nine hazardous drug surrogates selected by NIOSH for testing air-cleaning CSTDs and uses NIOSH equipment, thereby identifying ineffective surrogates and their alike that should be excluded from the NIOSH list of surrogates. Ineffective surrogates may lead users to make their selection of CSTDs that have no worker-protection performance.

1.3 Introduction

This was a three stages study:

  1. In the first stage, air was sampled by an FTIR analyzer directly in front of the vent opening of a CSTD. The analyzer detects and quantifies in real-time the vapor concentrations that are vented out of the CSTD during the injection of 50ml of water into a vial containing 3ml of surrogate. This process is identical to reconstitution.
  2. In the second stage, 50ml of the surrogate/water solution from the first stage was transferred to an IV bag using the same CSTD and syringe. Air was sampled by the analyzer from the open back of the syringe during the injection of the surrogate solution into the IV bag. This process is identical to standard hazardous drug transfer from vial to bag using CSTD.
  3. In the third stage, surrogate incompatibilities with CSTDs were excluded. All tested devices were stored for at least 72 hours, and their mechanical integrity and functionality were examined.

The first stage complies with recent NIOSH’s approach to separately test the air-cleaning feature. In its 2019 update [8], NIOSH suggested a two-stage approach to testing Air Cleaning CSTDs: “Stage 1-Air Filter Test: The CSTD via! adapter of an air-cleaning CSTD was first to he evaluated” [8];

NIOSH also suggested in its 2019 update, the use of Gasmet DX4040 FTIR analyzer for testing barrier type CSTDs with Ethanol (see test layout in Fig. 1) [8];

However, the universal DX4040 analyzer is designed to detect hundreds of various gases with very low limits of detection, including five of the nine NIOSH surrogates. This analyzer is ideal for this study as it allows for straightforward testing in real-time for vapor containment efficacy of both the Air-Cleaning feature of vented CSTDs and vapor that may be generated by regular open barrel syringes used with CSTDs for compounding and administration of hazardous drugs. This study is based on characteristics of handling Cyclophosphamide, Ifosfamide, Cytarabine and similar drugs using the same reconstitution and transfer procedures and range of dosages or concentrations [Package Inserts 9, 10, 11]. NIOSH selected its surrogates to represent undiluted Active Pharmaceutical Ingredients (API) [7], which Ifosfamide is an example. Ifosfamide is a common hazardous antineoplastic drug listed on the NIOSH List of Hazardous Drugs. Each vial contains 3 grams of Ifosfamide which is free of any excipients. Injection of diluent (e.g., SWFI) into Ifosfamide vial is required for reconstitution [Package Insert 9]. In all terms, the testing represents the actual usage of drugs and CSTDs. This study doesn’t aim to provide absolute vapor quantities, but the performance metric of interest as the maximum concentration value (in ppm) observed during each test run. 1

1.4 Methods

The methods of testing are illustrated in Figures 2 and 3, which are based upon the NIOSH approach (Fig. 1) but simplified. Figure 4 illustrates the first stage, the “Air Filter Test: The CSTD vial adapter of an air-cleaning CSTD was to first be evaluated” (NIOSH 2019) [8].

The Gasmet FTIR analyzer has a flexible air sampling tube with a 60mm diameter glass funnel attached on its end. The funnel allows for efficient air sample suction since vented gases from CSTDs may spread in all directions.

Similar to the NIOSH test layout (Fig. 1), the analyzer has attached to its air-outlet another flexible tube with a 50mm glass funnel on its end to create a loop and significantly increase sample collection efficiency. The openings of both funnels are brought in proximity and face each other. A stand with clamps is used to fixate the assembly in position.

Figure 3 illustrates the second stage: The Gasmet FTIR analyzer has a flexible tube to allow air sampling from the open syringe barrel. For simplicity, the air-outlet is not looped.

Testing methods for the first stage (filter test) are as follows:

  1. 100mL vials are filled with 3mL of NIOSH surrogate
  2. CSTD adapters are attached to an IV bag containing sterile water for injection (SWFI)
  3. CSTD syringe adapters are connected to regular syringes and then are connected to IV bag. The syringes are filled with 50mL of SWFI in accordance to the individual manufacturer IFU.
  4. CSTD vial adapter is attached to the surrogate vial, and the CSTD syringe is attached to said vial adapter.
  5. The vent opening of the vial adapter is placed between the two funnels, and 50mL of SWFI is injected within 12 seconds into the vial, thereby monitoring the real-time analysis data on screen.
  6. The analyzer runs on continuous mode and collects the vented air from CSTDs. The results are displayed every second in ppm and indicate whether or not the Air-Cleaning system is able to filter out the surrogate gas and vapor component from the vented air.
  7. The above steps were repeated with each of the four CSTD brands 10 times and with each of the two surrogates (4 x 10 x 2 = 80 replicates).

Testing methods for the second stage (syringe test) are as follows:

  1. 50mL of the surrogate solution is withdrawn into a syringe from the vial that was tested in the first stage, and the syringe is then connected to the IV bag for injection.
  2. The end of the sampling tube is placed in the syringe barrel’s back opening, and 50mL of the surrogate solution is injected into the IV bag, thereby monitoring the real-time analysis data on the screen.
  3. The analyzer runs on continuous mode and collects the vapor generated from the syringe. The results are displayed every second in ppm and indicate whether or not surrogates stick to the syringe inner walls exposed to the environment and generate vapor.
  4. The above steps are repeated with each of the CSTD syringes from the first stage (80 replicates).
  • Positive and negative controls are performed for both first stages.
  1. 50mL of the surrogate solution is withdrawn into a syringe from the vial that was tested in the first stage, and the syringe is then connected to the IV bag for injection.
  2. The end of the sampling tube is placed in the syringe barrel’s back opening, and 50mL of the surrogate solution is injected into the IV bag, thereby monitoring the real-time analysis data on the screen.
  3. The analyzer runs on continuous mode and collects the vapor generated from the syringe. The results are displayed every second in ppm and indicate whether or not surrogates stick to the syringe inner walls exposed to the environment and generate vapor.
  4. The above steps are repeated with each of the CSTD syringes from the first stage (80 replicates).
  • Positive and negative controls are performed for both first stages.

Testing methods for the third stage (surrogate compatibility validation) are as follows

  1. All tested devices after the first and second stage are collected and stored at room temperature for the duration of 72 hours.
  2. After 72 hours, the CSTD devices are checked for mechanical and visual integrity, leaks, functionality and filter blockage.

2 Description of Investigational Products

2.1 Devices

This study includes the testing of four commercially available CSTD products and a commonly used regular syringe:

2.2 Surrogates

Two surrogates for hazardous drugs were utilized to assess vapor containment. The surrogates were chosen based on preliminary testing and study development:

3 Data Collection

For purposes of the Vapor Containment Efficacy protocol, the performance metric of interest is the maximum value observed during each test run. In order to create Background (BG) adjusted test data, the maximal BG concentration must be subtracted from the maximum concentration data point (value) collected during the test run. Maximum BG concentration data shall be observed and recorded for at least five seconds prior to the start of each test. As part of the data analysis, the maximum observed BG concentration shall be then subtracted from the maximum concentration value observed during the test run to create BG adjusted test data. The final test result equals the BG adjusted maximum concentration [1]“Within the environmental sciences, where environmental data are evaluated to estimate true exposures, the rules for handling below LOD data can he complex and labor intensive. For purposes of the CSTD evaluation protocol, the performance metric of interest is the maximum value observed during the test run.”[1]

4 Testing Conditions

  1. No direct airflow or turbulences on testing site
  2. Ambient temperature 72°F – 77°F
  3. Keeping all materials and equipment at ambient temperature
  4. Regularly refreshing the room air
  5. Keeping undiluted vials upright to avoid contact to vial stopper

5 Study Setup

  1. Analyzer and laptop were wired to operate in cable mode and powered. The CalcmetPro software that operates the analyzer is specified by Gasmet and was used with the laptop.
  2. Following at least 45 minutes of analyzer warm-up, the zero calibration for the background was performed at the beginning of every day of testing using a nitrogen gas of 99.999% purity in accordance with the analyzer manufacturer’s instructions.
  3. After the calibration, the “analysis time” in Calcmet software was set to “continuous” mode, “1 second measuring time” and “pump enabled.” This setup allows for continuous air sampling (suction) with recurring 1-second-long cycles of analysis (updated results shown every second).
  4. The sampling tube was connected to the “sample in” port and the return air tube connected to the “sample out” port. Glass funnels were attached to the ends of the tubes and clamped to the testing stand inclined at a 45° angle (see configuration in Fig. 2),
  5. Empty 100mL vials were filled with 3ml of Propylene Glycol using a pipettor and were sealed with a rubber stopper and aluminum cap using the crimper device. Vials were labeled.
  6. The same fill process was repeated with Tetramethylurea using a new pipette.
  7. CSTD bag spike adapters were attached to SWFI bags, and the respective CSTD syringe connectors were attached to syringes. All syringes with the respective four types of CSTDs attached were accurately filled with 50mL of SWFI in accordance with the CSTD manufacturer’s instructions for use.

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs 3
Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs
Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs 2

Figure 3:

Evaluation-of-Vapor-Containment-Efficacies-of-Air-Cleaning-CSTDs-4-jpg

2.1 Device

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs 5

2.2 Surrogates

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs 6

13 Results

13.1 Final Test Results

1. OnGuard/Tevadaptor CSTD / Gasmet analyzer# 1

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs and Regular Syringes Using NIOSH Hazardous Drug Surrogates

 2. OnGuard/Tevadaptor CSTD / Gasmet analyzer# 2

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs and Regular Syringes Using NIOSH Hazardous Drug Surrogates

3. Chemfort CSr “D / Gasmet analyzer# 1

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs and Regular Syringes Using NIOSH Hazardous Drug Surrogates

4. SmartSite/Texium CSTD / Gasmet analyzer# 1

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs and Regular Syringes Using NIOSH Hazardous Drug Surrogates

5. ChemoLock CSTD / Gasmet analyzer# 1

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs and Regular Syringes Using NIOSH Hazardous Drug Surrogates

6. Positive Control / Gasmet analyzer# 1

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs 12

7. Negative Control / Gasmet analyzer# 1

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs 13

8. 5 seconds Measuring Time Setup / OnGuard/Tevadaptor CSTD / Gasmet analyzer# 1

Evaluation of Vapor Containment Efficacies of Air-Cleaning CSTDs and Regular Syringes Using NIOSH Hazardous Drug Surrogates

6 Test Procedure First Stage

  1. Each vial was laid on its side and rolled slowly on the table surface to coat the inner glass walls with the surrogate; this simulates the drug powder that is typically distributed all over the inner walls of the drug vial. The vial was partially inverted while rolling to coat the inner vial neck, thereby avoiding contact between the surrogate and the rubber stopper.
  2. The CSTD vial adapter was attached to the vial in accordance with the CSTD manufacturer’s instructions for use. For OnGuard/Tevadaptor and Chemfort CSTDs only, the side of the hidden vent opening was visually identified and marked. The syringe previously filled with 50mL SWFI (with its CSTD connector) was connected to the surrogate vial CSTD adapter.
  3. The connected syringe and vial were clamped in the testing stand with a 45° angle and the vent opening facing up (see Fig. 2). The upper sampling funnel was brought in the closest position to the vent opening of the CSTD vial adapter. The lower funnel was brought in the opposite position at the vial adapter’s underside while facing the upper funnel head-on. The lower funnel was preferred to be a Buchner type because of its better laminar air distribution.
  4. While preparing for injecting SWFI, all sampled vapor and gases concentrations (also called background concentrations) are displayed on the laptop monitor in ppm every second. Prior to the start of each test run (injection), these background (BG) concentrations were observed for at least five seconds and the maximum BG concentration value was recorded in the data collection form.Note, when analyzing the final test results, the recorded maximum BG concentration must be subtracted from the maximum concentration value (data point) collected during the test run to create BG-adjusted test data. If BG was zero, then there is no need for BG adjustment.
  5. The SWFI was injected into the vial within 12 seconds by pushing the plunger at a steady pace while observing the laptop monitor for surrogate concentration values to change. After waiting a while for the highest concentration value, it was recorded in the data collection form. Typically, after reaching the highest value, the vapor dissolves in the ambiance and the values begin to decrease until reaching BG levels or zero. In case no vapor was detected, the values remain at BG levels or zero. To accelerate the air cleaning and refreshment in the analyzer for the next test run, one of the funnels was moved aside until the analyzer reading drops to BG levels or zero before starting the next test.
  6. The ambient temperature and the analyzer’s cell temperature were recorded during the testing.
  7. In addition to manual recording in data collection forms, the Calcmet software automatically saves all analysis data and spectra. These study files were saved.
  8. The syringe and vial were unclamped from the stand, disconnected from each other and stored for use in the second stage of the study. Vials were kept upright.
  9. This testing procedure was repeated for a total of 10 times with the same CSTD type and same surrogate and further repeated with four CSTDs and two surrogates, generating a total of 80 replicates for the first stage of the study.

7 Test Procedure Second Stage

  1. The clamps, stand, and funnels used in the first stage of the study were removed from the analyzer.
  2. Only the assembly, as illustrated in Fig. 3 was kept for the second stage of the study.
  3. The syringe with its CSTD connector was attached to the original vial containing the surrogate solution from the first stage of the study. The vial was inverted, and 50mL of the surrogate solution was drawn into the syringe. The syringe was disconnected from the vial and connected to the original IV bag from the first stage of the study. All steps were performed in accordance with the CSTD manufacturer’s instructions for use.
  4. The bag and syringe were brought into position as illustrated in Fig. 3 and the sampling tube of the analyzer was placed inside the syringe opening, as shown in Fig. 3.
  5. Before injecting the surrogate solution into the bag, BG concentrations were observed for at least five seconds and the maximum BG concentration value was recorded in the data collection form.
  6. The surrogate solution was injected into the bag by pushing the plunger at a normal pace and the sampling tube was allowed to follow the plunger into the syringe barrel.
  7. After waiting a while for the highest concentration value, it was recorded in the data collection form. In case no vapor was detected the values remain at BG levels or zero. The tube was removed, and the concentration values decrease down to BG levels or zero.
  8. The syringe with its CSTD connector was disconnected from the bag CSTD adapter.
  9. This testing procedure was repeated for all 80 replicates from the first stage of the study.

8 Test Procedure Third Stage (Compatibility Validation)

  1. All test replicates from the first and second stages (syringe, bag, vial, CSTDs) were stored at room
  2. temperature for the duration of at least 72 hours. Vials were kept in an upright position.
  3. After 72 hours of storage, the syringes and vials were connected. The plunger was pulled to draw 50ml of air and pushed to reinject. The syringe was disconnected from the vial and connected to the bag. The solution was pulled and pushed from and into the bag. The devices were observed for leaks, functionality and mechanical integrity.
  4. Visual inspection for damages was performed for all devices, followed by visual inspection for the vent filters of the CSTDs. ChemoClave and SmartSite filters are clearly visible. For accessing the OnGuard and Chemfort filters, the snap-fitted covers were removed. Removing the covers causes absolutely no damage and exposes both filters (hydrophobic and activated charcoal).
  5. The inspection results were recorded.

9 Study Controls

9.1 Negative Control Procedure

  1. A negative control test was performed with one CSTD prior to testing with surrogates.
  2. The negative control is identical to the test procedure with sunogates but with water only.
  3. An additional negative control is provided by the analyzer during each test run of the study. The analyzer is set to detect both surrogates simultaneously (can detect 25 gases at the same time) and during the injection of one surrogate, the concentration values of the second surrogate remain unaffected, which is a negative control indication.

9.2 Positive Control Procedure

The positive control test was performed by bypassing the CSTD vent filter.

  1. A representative CSTD with a visible filter was chosen, and using a needle, and a hole was punctured in the middle, through the vent hole, to bypass the filter.
  2. Regular test procedures with both surrogates were performed and the results of the unfiltered stream of vapor were recorded.

10 Additional Study Procedures

10.1 Second Gasmet analyzer

A second Gasmet DX4040 analyzer was rented to reconfirm the key study results. This added 10 OnGuard/Tevadaptor replicates to the study that were tested with TMU surrogate. The testing with analyzer# 2 was identical to testing performed with analyzer# 1.
Late delivery of Gasmet analyzer# 2 and shortage in test products towards the end of the study limited the scale of testing with analyzer# 2.

Analyzer# 2 was also used to monitor BG levels to reconfirm BG levels of analyzer# 1.

10.2 5 Seconds “Measuring Time”

Additional 10 OnGuard/Tevadaptor replicates were tested with a different, a 5 seconds measuring time cycle. In this study, the analyzer’s “measuring time” (analysis time) is set to 1 second (the analyzer allows only 1, 5, 20 and 60 seconds measuring times). This is necessary as the vapor release during injection is just a few seconds long and dissolves very fast in the ambiance. Measuring with longer intervals misses the peak data points and analyzed concentration values appear lower. This additional testing session was performed to reconfirm that vapor escape from CSTDs is detected even with 5 seconds measuring time; and, reconfirm that 1 second setup is the right choice for this study.

1 1 Changes from Planned Study Procedures

The study protocol planed two injections of 50ml in the first and second stage into the same vial and same bag (mimicking 2g cyclophosphamide reconstitution with 100ml of diluent). This was changed at the beginning of the study after initial tests showed very high concentration values of vapor escape from CSTDs right on the first injection.

14 Conclusions

All four tested vented air-cleaning CSTDs and the syringes failed to contain vapor, and significant concentrations were released to the environment.

14.1 Tetramethylurea (TMU) surrogate:

The released vapor concentrations mean values of OnGuard/Tevadaptor and Chemfort, which share the same filtration, were 1.22ppm, 0.95ppm, 1.4ppm and the maximum values were 2.32ppm, 2.34ppm and 2.45ppm (by groups as tested with both Gasmet analyzers# 1 and 2).

SmartSite mean values were 11.85ppm and the ChemoLock CSTD with 26.13ppm mean value released the highest vapor concentrations.

The mean vapor concentrations released from the open barrel of the syringes were relatively constant at 0.45ppm, 0.33ppm, 0.43ppm, 0.41ppm and 0.48ppm.

14.2 Propylene Glycol (PG) surrogate:

OnGuard/Tevadaptor and Chemfort, which share the same filtration, did not release PG vapor concentrations; their mean values were at 0.1Ippm and 0.02ppm, which are low close to background levels.

SmartSite and ChemoLock released vapor concentrations with mean values of 1.34ppm and 4.5ppm, respectively.

The mean vapor concentrations measured on the open barrel of the syringes were very low at 0.20ppm, 0.12ppm, 0.15ppm and 0.23ppm, very close to background levels.

14.3 Compatibility:

After 72 hours of storage at room temperature, all tested devices and vent filters maintained their functionality, mechanical integrity and didn’t leak.

14.4 Supplemental Testing

Although with slightly lower values, the second Gasmet analyzer# 2 reconfirmed the results of analyzer# 1 and reconfirmed the vapor escape from the tested CSTDs and syringes. Supplemental testing with larger analysis intervals (5 seconds) reconfirmed the correctness of this study setup.

14.5 Detailed Conclusions

  1. It can be concluded that TMU surrogate vapor was released in significant quantities from all CSTDs and syringes tested. TMU was compatible with the CSTDs and syringes under the study testing conditions. TMU is a suitable surrogate for testing CSTDs and syringes.
  2. It can also be concluded that PG surrogate vapor was not released from two of the CSTD brands tested and from syringes, although the same CSTDs and syringes did release vapor concentrations with the TMU surrogate. PG vapor was released from the other two CSTD brands but in significantly lower concentrations than with TMU. PG is not a suitable surrogate for testing CSTDs and syringes.
  3. It can be determined that vented air-cleaning CSTD can have varying vapor containment efficiencies with varying contaminants, and the same vented CSTD can contain vapor of one type of contaminants and absolutely fail to contain with others.
  4. It can also be determined that scientific evidence is established herewith for vapor release from regular open-barrel syringes as a route of exposure.
  5. It can be further determined that varying contaminants can cause varying levels of vapor contamination from open-barrel syringes, ranging from high contamination to none.
  6. It can be concluded that given the established fact of vapor release from regular open-barrel syringes as a route of exposure, the testing of syringes with 1PA alcohols alone is not suitable for performance protocol (NIOSH) because alcohol doesn’t adhere to syringe walls and alcohol is factually not detectable with any draft NIOSH protocol. Without the addition of a suitable surrogate for testing CSTDs and syringes, alcohol alone should not be used.
  7. It is appropriate to note that ineffective surrogates may lead users to make their selection of CSTDs that have no worker-protection performance.

Further research and testing are necessary. There are at least further nine surrogates on the NIOSH list of surrogates that should be evaluated. After years of research done by NIOSH, finding adequate surrogates that would cover all routes of exposure is the only acceptable solution.

What is a Closed System Transfer Device (CSTD)?

According to the National Institute for Occupational Safety and Health (NIOSH), a CSTD 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 system1. These devices serve as a critical tool to prevent exposure to hazardous drugs, which can cause serious health effects in healthcare workers. The use of CSTDs has been mandated in several countries, including the United States, due to the high incidence of hazardous drug exposure among healthcare workers. In this article, we will explore the key features and regulatory requirements of CSTDs, and why they are essential in protecting healthcare workers from hazardous drug exposure.

Why are CSTDs so important?

Hazardous drugs, such as chemotherapy agents, antiviral medications, and immunosuppressive drugs pose significant health risks to medical personnel who handle them. These risks include skin irritation, allergic reactions, reproductive issues, and even the development of cancer2. To minimize exposure to hazardous drugs and ensure the long-term health and safety of medical personnel, it is essential to implement best practices and safety measures. 

What is the regulation status in the USA? 

Specific requirements mandated by USP 800 guidelines include: 

USP 800 is a set of guidelines3 developed by the United States Pharmacopeia (USP) and mandated by the Occupational Safety and Health Administration (OSHA) to prevent occupational exposure to hazardous drugs for healthcare workers. USP 800 aims to protect healthcare personnel, patients, and the environment by outlining safety standards for the handling and disposal of hazardous drugs in healthcare settings. 

  1. Proper use of personal protective equipment (PPE), such as gloves, gowns, masks, and eye protection. 
  1. Establishment of designated areas for receiving, storing, compounding, and administering hazardous drugs. 
  1. Implementation of engineering controls, including biological safety cabinets and compounding aseptic containment isolators. 
  1. Proper handling, decontamination, and disposal procedures for hazardous drugs and contaminated materials. 

Specific requirements mandated by USP 797 guidelines include:   

USP 7974 is a comprehensive set of standards designed to ensure safe compounding practices for sterile preparations. These regulatory requirements address critical aspects, including personnel qualifications, training, and hygiene; environmental quality and control; facilities and equipment; standard operating procedures (SOPs); and quality assurance and documentation. Personnel involved in sterile compounding must undergo proper training and demonstrate competency through written and practical assessments while adhering to strict hygiene protocols.  

  1. Personnel Qualifications and Training: Ensure that all staff involved in sterile compounding have appropriate training, demonstrate competency through assessments, and follow strict hygiene protocols. 
  1. Environmental Quality and Control: Maintain defined air quality standards using primary engineering controls, and regularly monitor the compounding environment to minimize contamination risks. 
  1. Facilities and Equipment: Design compounding areas that are segregated from other activities, with proper equipment such as laminar airflow workbenches or biological safety cabinets, and adhere to controlled temperature and humidity conditions. 
  1. Standard Operating Procedures (SOPs) and Quality Assurance: Develop and implement SOPs for all compounding activities, including preparation, labeling, storage, and disposal of compounded sterile preparations, and perform quality control measures such as sterility testing, endotoxin testing, and beyond-use dating. 

Closed System Transfer Devices (CSTDs), such as EQUASHIELD’s CSTD product line, play a crucial role in reducing the risk of exposure and contamination while complying with USP 800 and USP 797 guidelines. EQUASHIELD CSTDs provide a physical barrier between the clinician and the hazardous drug, preventing the escape of hazardous drugs or vapors into the environment during compounding and administration processes. 

When does exposure to hazardous drugs occur? 

Exposure to hazardous drugs and their vapors occurs throughout the whole chain of drug handling, from receiving at the hospital warehouse until disposal. Compounding and administration constitute the major portion of the drug handling chain as more people are exposed, thereby increasing the risk of exposure.

Contamination with hazardous drugs can occur via several routes: 

  • Oral – through ingestion 
  • Inhalation – breathing in vapors 
  • Dermal – contact

Different roles in handling hazardous drugs require specific recommendations: 

Pharmacists and Pharmacy Technicians

1. Use closed-system transfer devices (CSTDs) during drug compounding to prevent the escape of hazardous drugs or vapors. 

2. Work in a designated area with proper ventilation, such as a biological safety cabinet or compounding aseptic containment isolator. 

3. Wear appropriate personal protective equipment (PPE), including gloves, gowns, masks, and eye protection. 

4. Dispose of contaminated materials properly, following the facility’s hazardous waste disposal guidelines.

Nurses and Healthcare Providers 

  1. Utilize CSTDs during drug administration to minimize the risk of spills or leaks.  
  1. Wear PPE, such as gloves and gowns, while administering hazardous drugs and handling contaminated equipment. 
  1. Follow proper procedures for handling and disposing of hazardous drugs, including using puncture-resistant sharps containers for needles and syringes. 
  1. Educate patients and their families about the safe handling of hazardous drugs at home, including proper storage, administration, and disposal. 

Environmental Services and Waste Management Staff

  1. Wear appropriate PPE when cleaning areas where hazardous drugs are prepared or administered. 
  1. Follow facility-specific protocols for decontamination and cleaning procedures. 
  1. Dispose of hazardous drug waste according to local, state, and federal regulations. 

Medical facilities and employers play a critical role in supporting these safety measures by providing adequate resources, including: 

  1. Regular training and education for all staff handling hazardous drugs, ensuring they are well-versed in safety protocols and procedures. 
  2. Supplying the necessary PPE and CSTDs for all personnel who handle hazardous drugs. 
  3. Implementing specialized ventilation systems and designated areas for drug preparation and administration. 
  4. Establishing clear guidelines and procedures for decontamination, cleaning, and waste disposal. 

How can EQUASHIELD CSTDs help?  

Pharmacists can protect themselves from hazardous drug exposure by implementing various safety measures, including the use of EQUASHIELD® Closed System Transfer Devices (CSTD). These devices are designed to create a physical barrier between the clinician and the hazardous drug, minimizing the risk of exposure during the compounding and administration process. 

EQUASHIELD® CSTDs are unique in their ability to cover more routes of exposure than other solutions. Extensive clinical evaluation and studies4 have shown that standard syringes can become contaminated with hazardous drugs on surfaces exposed to the environment, potentially leading to vapor escape and plunger contamination. EQUASHIELD® addresses this issue with its closed-back syringe design, providing superior protection compared to alternative systems. 

In conclusion, minimizing exposure to hazardous drugs is crucial for the long-term health and safety of medical personnel. By implementing best practices, using CTDS, appropriate PPE and equipment, and providing ongoing training and support, medical facilities can create a safer work environment for all staff members involved in handling hazardous drugs. 

Vapor Containment Efficacy of Air-Cleaning CSTDs with 3 NIOSH Surrogates

Purpose:

The primary objective o f this study was to determine the effectiveness of three hazardous drug surrogates suggested by NIOSH with 5 vented CSTDs and thereby help to exclude ineffective surrogates from the NIOSH surrogates list, as ineffective surrogates m ay lead to a false sense o f security from the use o f CSTDs, thereby putting the w ell-being o f healthcare workers at risk

Methods:

The continuously updated NIOSH list of hazardous drugs contains a large variety of molecules and compounds. NIOSH states that “… air-cleaning technologies can have varying efficiencies based upon the chemical and physical make-up of the contaminant.” The current study was intended to assess the varying efficiencies of air-cleaning CSTDS and the appropriateness of 3 out of 9 HD surrogates (tetramethylurea, tetraethylurea, and propylene glycol) suggested by NIOSH for use in testing o f aircleaning CSTDs. This study was designed to evaluate straightforward the vapor containment efficacy o f the air-cleaning technology (air filter test) in 5 commercially available air-cleaning CSTDs during simulated hazardous drug reconstitution using 3 of the 9 NIOSH-proposed surrogates and the Gasmet DX4040 FU R analyzer which is also utilized by NIOSH for the development o f its CSTD performance protocols. The DX4040 analyzer is designed to detect over 300 various gases at low concentrations, including 5 of the 9 NIOSH surrogates. The analyzer’s air sampling funnel was placed externally next to the vent opening o f an air-cleaning CSTD vial adapter during the injection o f 60ml of diluent (water) into a vial containing 3ml of undiluted surrogate.

The analyzer was run on continuous mode to collect the vented air from the CSTDs and any escaped surrogate vapor concentrations were detected, quantified and displayed in real-time. The surrogate concentration selected for this study was intended to correspond to the real-world condition of a 3-gram dose of ifosfamide free of excipients (eg, 3mL surrogate) and the required injection of 60ml of diluent (water) during the reconstitution process. In this study, 10 replications of testing for each of the CSTDs was conducted with each surrogate, yielding a total of 150 measurements. 72-hours after testing, a compatibility assessment was performed to exclude CSTD incompatibility with the surrogates. The compatibility study assessed whether the functionality and integrity of the
tested CSTDs are affected.

Conclusions:

The tested air-cleaning CSTDs failed to contain vapor, and significant concentrations were released into the environment, which were detected and quantified; Tetramethylurea concentrations were the highest, followed by Tetraethylurea. Propylene Glycol was proven to be an inappropriate and
ineffective surrogate since minimal detectable concentrations of Propylene Glycol were released into the environment from CSTDs that utilize carbon filters with additional hydrophobic filters. The study provided evidence and data to confirm that air-cleaning technologies can have varying efficiencies
based upon the chemical and physical make-up of the contaminant. The tested surrogates were found compatible under the tested conditions with the tested CSTDs.