Closed-system Drug Transfer Device Research Articles

Retrospective and FMECA analysis of failures in closed-system devices.

Cytotoxic drugs can be hazardous to healthcare workers involved in their preparation and/or administration. Exposure occurs during routine handling of drug vials and ampoules, preparation, administration and disposal of cytotoxic waste. The use of closed-system devices provides protection against exposure to cytotoxics, but these devices are the subject of numerous incidents. Given the nature of the drugs they contain, these incidents can be dangerous for the personnel handling them. The aim of our study is to analyze material vigilance data relating to problems frequently encountered with the various consumables of the closed system and to assess the risk of exposure of personnel to cytotoxic drugs when using these using the Failure Mode and Criticality Analysis (FMECA) method. Our study was conducted at the pharmacy of the National Institute of Oncology, the closed system drug transfer device (CSDT) used is a ChemoClave-ICU®, This device is mechanical and needleless For the materiovigilance study we carried out a retrospective study over the period from 2019 to 2022, analyzing materiovigilance data collected by National Institute of Oncology's materiovigilance and pharmacovigilance cell. Our team, trained in the FMECA method, conducted the study over a three-month period, between September and November 2022. The method was used to assess the risks incurred by staff when using the CSDT device to prepare cytotoxic drugs. Our study revealed that the most frequent incident was linked to a manufacturing defect in the device in question. According to the FMECA analysis, this incident represents a major risk, as its occurrence hampers the cytotoxic preparation process. CSDT have the advantage of being easy to use and acceptable to staff, but standards need to be developed and validated to assess the performance of these devices.

Longitudinal evaluation of environmental contamination with hazardous drugs by surface wipe sampling.

Exposure of healthcare workers to hazardous drugs can lead to adverse health effects supporting the importance of a continuous monitoring program, for example, by taking surface wipe samples. The objective was to describe the results of repeated monitoring of contamination with hazardous drugs on multiple surfaces in a hospital pharmacy and at two wards using standardized preparation techniques and cleaning procedures. Twelve surfaces in the hospital pharmacy and at two wards were sampled and analyzed for contamination with the hazardous drugs cyclophosphamide, doxorubicin, 5-fluorouracil, gemcitabine, methotrexate, and paclitaxel. The drugs were prepared with a closed-system drug transfer device (CSTD). Sampling of the drugs was performed in four trials during eight months. Liquid chromatography tandem mass spectrometry was used for the analysis of the drugs. During the four trials, contamination with five of the six hazardous drugs was found on half of the surfaces in the pharmacy and in a ward. Seventeen out of 288 possible outcomes were positive (6%), with the biological safety cabinet grate (n = 6) and scanner (n = 5) most frequently contaminated. The highest level of contamination was observed on the pass-thru window (cyclophosphamide: 2.90 ng/cm2) and the touch screen of the Diana device (5-fluorouracil: 2.38 ng/cm2). Both levels were below the action level of 10 ng/cm2. The long-term use of a CSTD in combination with appropriate cleaning has proven effective in achieving low levels of surface contamination with hazardous drugs.

A review of medical devices used for safe chemotherapy applications: Focus on ONCOERA® IV GROUP products.

The healthcare workers and the workers in the manufacturing industry of chemotherapy drugs are exposed to the "hazardous" effects of these drugs during production, transportation, distribution, administration, and disposal. In order to be protected from these harmful effects, personal protective equipment and medical devices providing safe applications are used. The aim of the present article is to review of medical devices used for safe chemotherapy applications in line with the information obtained from the literature. The international and national reliable sources, were used in the literature review for data analysis by using the keywords including chemotherapy, chemotherapy drugs, antineoplastic drugs, cytotoxic drugs, hazardous drugs, exposure to chemotherapy drugs, side effects of chemotherapy drugs, closed-system drug transfer devices, healthcare staff, needle-free devices, needle-free connectors, surface contamination, and phthalates. In order to minimize cytotoxic drug exposure, international standards were developed in the mid-1980s stating that all cytotoxic drugs should be prepared preferably in a ventilated biological safety cabinet, nurses dealing with the use of these drugs should use appropriate personal protective equipment, and in case of cytotoxic drug spillage, predefined cleaning and decontamination protocols should be followed. Although the risk of acute and long-term toxic effects in healthcare workers has decreased in recent years with these applications in the preparation and administration of cancer drugs, measurable contamination occurs in the workplace. A large number of medical devices have been developed for minimizing this type of contamination with chemotherapy drugs. In this article, these medical devices have been reviewed in detail under subtitles of closed system transfer devices, needle-free devices, and valve technology. Until the results of the evaluations to be made in new studies prove the opposite, the use of these devices with additional protection measures taken, especially during the application of dangerous drugs, is of great importance in terms of patient and employee safety.

Identification and reduction of hazardous drug surface contamination through the use of a novel closed-system transfer device coupled with a point-of-care hazardous drug detection system.

Minimizing hazardous drug (HD) contamination is critical for protecting the health of healthcare workers (HCWs) and patients. Alarmingly, widespread HD contamination has been documented across a variety of clinical settings. Quantitative wipe sampling presents significant time and cost barriers, resulting in routine monitoring adherence rates around 25%. Closed-system drug transfer devices (CSTDs) and qualitative point-of-care tests can be implemented to overcome these barriers. In this study, we tested the effects of the BD PhaSeal Optima (Becton, Dickinson and Company), a recently introduced CSTD, on HD contamination at 2 chemotherapy infusion centers. Wipe samples were taken at 29 workstations at each location prior to and a year following CSTD implementation. Additionally, traditional liquid chromatography with mass spectrometry (LCMS/MS) analyses were compared against a novel lateral flow immunoassay HD testing device (BD HD Check; Becton, Dickinson and Company) to determine the validity of the qualitative assay. We found a 46% reduction in HD contamination after incorporating the CSTD into clinical workflows. Across time points and sites, HD contamination reported by the BD HD Check device was 91% accurate against LCMS/MS and 98% accurate within its limits of detection. Collectively, the evaluated CSTD and lateral flow immunoassay device may help to reduce HD contamination and provide real-time measures of contamination, respectively. As part of a multifaceted approach, these devices may help minimize barriers to routine monitoring, ultimately improving the safety of HCWs and patients.

Closed safety system for administration (CSSA): proposal for a new cytotoxic chemotherapy acronym.

Exposure to cytotoxic chemotherapy can result in acute and chronic conditions including nausea, headaches, rashes, miscarriages, infertility and genetic aberrations. Surface contamination can occur during drug administration, and can subsequently spread throughout the healthcare environment. Dermal contact with contaminated surfaces can lead to drug absorption. Closed system drug-transfer devices (CSTDs) were initially developed to protect pharmacists during compounding. Components include a vial adapter to prevent pressurisation leakage and a syringe connector for transferring the drug to the intravenous infusion bag. Membrane-based CSTDs require a Luer adapter for drug administration whereas Luer system-based products do not. Most European nurses are familiar with needleless connectors. Unfortunately, these devices do not provide protection from chemotherapy exposure. To decrease confusion, CytoPrevent, a multi-national, primarily European organisation has proposed the term 'closed safety system for administration' (CSSA) for Luer based CSTDs. Along with education, the new term can help promote safety for nurses administering cytotoxic chemotherapy.

Prevention of coronavirus contamination from the environment using an air-cleaning closed system drug-transfer device.

Background:Closed system drug-transfer devices (CSTD) allow the reconstitution of hazardous drugs into infusion bags, while preserving the sterility of the product and preventing the escape of liquids and aerosols into the environment. Air-cleaning technology CSTD is based on an activated carbon filter and a membrane which enable maintaining the drug sterile by filtration of air entering the vial during pressure equalization.Objective:The study aimed to investigate if an air-cleaning CSTD can prevent liquid viral contamination by human coronavirus OC43 (HCoV-OC43).Methods:Chemfort™ CSTD with (intact) or without (control) a Toxi-Guard system was used to transfer liquids between an IV bag and an empty vial (a total of 5 liquid transfers) inside a sealed glove box contaminated by HCoV-OC43 aerosols. In addition, the vial adaptor was challenged by direct spray of HCoV-OC43 solution on the septum and filter areas. HCoV-OC43 RNA was extracted from samples of the transferred liquid and compared between the devices with or without a Toxi-Guard system.Results:Use of a CSTD with the Toxi-Guard system resulted in non-detectable cycle threshold (CT) values, indicative of no detectable HCoV-OC43RNA in the transferred liquid, even when the septa and filter areas were directly sprayed with HCoV-OC43 stock solution. In contrast, use of the CSTD with no Toxi-Guard system resulted in a detectable CT value of the transferred liquid.Conclusions:Using Chemfort CSTD with integral Toxi-Guard technology can prevent the introduction of microbial and airborne contaminants into the fluid path, thus potentially protecting patients from infection.

Frequency and component analysis of contaminants generated in preparation of anticancer agents using closed system drug transfer devices (CSTDs)

Occupational exposure of anticancer agents during their preparation has been recognized as a serious hazard. Closed system drug transfer devices (CSTDs) enable “safe” preparation of agents for medical personnel and ensure a safe hospital environment. However, artificial particles of infusion materials have been reported during CSTD use. Here, the incidence of insoluble fine particles during preparation of anticancer agents using CSTDs was examined. Visible insoluble fine particles were found in 465 (9.4%) of 4948 treatment cases at Ehime University Hospital with CSTD use. Contaminants occurred more frequently during preparation of monoclonal antibodies than cytotoxic anticancer agents (19.4% vs. 4.1%, respectively, P < 0.01). A similar survey was conducted at nine hospitals to investigate the incidence of insoluble fine particles with or without CSTDs. Insoluble fine particles were detected in 113 (15.4%) of 732 treatment cases during preparation of monoclonal antibodies with CSTD use. In contrast, the occurrence of insoluble fine particles without CSTDs was found in only 3 (0.073%) of 4113 treatment cases. Contamination with CSTDs might cause harmful effects on patients during cancer therapy. We strongly recommend the use of in-line filters combined with infusion routes after CSTD use to avoid contamination-associated adverse events.

Evaluation of propylene glycol methyl ether as a potential challenge agent for leak detection of liquid and headspace from closed system drug transfer devices using Fourier transform infrared spectroscopy.

Choosing an appropriate surrogate of hazardous drugs for use in testing Closed System Drug-Transfer Devices (CSTDs) is a challenging endeavor with many factors that must be considered. It was suggested that the compound propylene glycol methyl ether (PGME) may meet many of the criteria we considered important in a suitable surrogate. Criteria included sufficient volatility to evaporate from aqueous liquid leaks efficiently, a Henry's constant which produced sufficient vapor phase concentrations to make headspace leaks detectable, and suitability for detection using a low-cost detection system. We evaluated the measurement of vapors from solutions containing PGME released inside a closed chamber. We present data used to quantify limits of detection, limits of quantification, bias, precision, and accuracy of Fourier Transform Infrared Spectroscopy (FTIR) measurements of vapors from 2.5 M PGME solutions. The effects of ethanol as a component of the PGME solution were also evaluated. Liquid drops of PGME solutions and headspace vapors above PGME solutions were released to simulate leaks from CSTDs. Using a calibration apparatus, an instrumental limit of detection (LOD) of 0.25 ppmv and a limit of quantitation (LOQ) of 0.8 ppmv were determined for PGME vapor. A LOD of 1.1 μL and a LOQ of 3.5 μL were determined for liquid aliquots of 2.5 M PGME solution released in a closed chamber. Accurate quantitation of liquid leaks required complete evaporation of droplets. With the upper end of the useable quantitation range limited by slow evaporation of relatively large droplets and the lower end defined by the method LOQ, the method evaluated in this research had a narrow quantitative range for liquid droplets. Displacement of 45 mL of vial headspace containing PGME vapor is the largest amount expected when using the draft NIOSH testing protocol. Release of an unfiltered 45 mL headspace aliquot within the NIOSH chamber was calculated to produce a concentration of 0.8 ppmv based on the Henry's constant, which is right at the instrumental LOQ. Therefore, the sensitivity of the method was not adequate to determine leaks of PGME vapor from a headspace release through an air filtering CSTD when using the draft NIOSH testing protocols with an FTIR analyzer.

A Systematic Approach to Evaluating Closed System Drug-Transfer Devices During Drug Product Development

The use of Closed System Drug-Transfer Devices (CSTDs) has increased significantly in recent years due to NIOSH and USP recommendations to use them during preparation of hazardous drugs. Mechanistic and material differences between CSTDs and traditional in-use components warrant an assessment of their impact on product quality and dosing accuracy. Using a combination of prevalent CSTDs with biologic molecules, we performed an extensive assessment of the effect of using CSTDs for dose preparation and observed no negative impact on product quality attributes. Additionally, we found that the CSTD hold-up volume is 2 to 4-fold higher than conventional in-use components and exhibited a strong dependence on the CSTD brand used. We also found that the CSTD brand and dosing volume have a major influence on dosing accuracy with suboptimal protein recovery at very low dosing volumes. We identified entrapment of product in the CSTD spike as the root cause for this sub-optimal recovery and found that flushing the CSTD spike with a brand-new syringe and not the dosing syringe aided in complete protein recovery. Taken together we present a systematic approach to evaluate the risks and impact of CSTD to drug product quality, dose preparation, and dosing accuracy.

Source apportionment and quantification of liquid and headspace leaks from closed system drug-transfer devices via Selected Ion Flow Tube Mass Spectrometry (SIFT-MS).

A system to differentiate and quantify liquid and headspace vapor leaks from closed system drug-transfer devices (CSTDs) is presented. CSTDs are designed to reduce or eliminate hazardous drug (HD) exposure risk when compounding and administering HDs. CSTDs may leak liquid, headspace, or a mixture of the two. The amount of HD contained in liquid and headspace leaks may be substantially different. Use of a test solution containing two VOCs with differences in ratios of VOC concentrations in the headspace and liquid enables source apportionment of leaked material. SIFT-MS was used to detect VOCs from liquid and headspace leaks in the vapor phase. Included in this report is a novel method to determine the origin and magnitude of leaks from CSTDs. A limit of leak detection of 24 μL of headspace vapor and 0.14 μL of test liquid were found using Selected Ion Flow Tube Mass Spectrometry (SIFT-MS).

Establishing a protocol for the compatibilities of closed-system transfer devices with multiple chemotherapy drugs under simulated clinical conditions.

Closed-system drug transfer devices (CSTDs) are used to prevent occupational exposure to hazardous drugs in health care providers. They are considered Class II medical devices by the US FDA and are cleared but not approved before marketing. While compatibility tests are conducted by CSTD manufacturers, the procuring institution needs to consider performing its own studies before buying these devices. Herein we tested the compatibility of the components of the Needleless® DualGuard CSTD system (vial access clips, vial access spikes, and administration adaptors) with 10 antineoplastic drugs, under simulated clinical conditions, including compounding and administration, and examined drug potency maintenance, plasticizer migration, and device functionality. All drugs maintained potency within 5%. Diisononyl phthalate leakage was observed from the administration adaptors for paclitaxel and concentrated etoposide solution. In addition, white particles were discovered in CSTDs storing busulfan solution and small cracks were observed on devices which stored melphalan. Thus, it was concluded that even in simulated clinical conditions, instead of extreme conditions, there are still concerns regarding the efficacy and safety of CSTD components. The methodology may be used to implement and detect possible interactions between antineoplastic agents and CSTD components before procurement.

Questionnaire Survey for Multiple Occupations on the Usability of Closed-system Drug-transfer Devices and Evaluation of the Economy and the Impact on Operational Efficiency

Questionnaire Survey for Multiple Occupations on the Usability of Closed-system Drug-transfer Devices and Evaluation of the Economy and the Impact on Operational Efficiency

Effectiveness of Closed System Drug Transfer Devices in Reducing Leakage during Antineoplastic Drugs Compounding.

This study, conducted in a centralized cytotoxic drug preparation unit, analyzes the effectiveness of two closed system drug transfer devices (CSTDs) in reducing leakage during antineoplastic drug compounding. Wipe/pad samplings inside and outside the preparation area were taken during surveillance programs from 2016 to 2021. All samples were analyzed for gemcitabine (GEM) contamination. In 2016, the presence of GEM in some samples and the contamination of the operators’ gloves in the absence of apparent drug spilling suggested unsealed preparation systems. In subsequent monitoring, GEM was also evaluated in the vial access device and in the access port system to the intravenous therapy bag of TexiumTM/SmartSiteTM and Equashield® II devices after the reconstitution and preparation steps of the drug. The next checks highlighted GEM dispersion after compounding using TexiumTM/SmartSiteTM, with positive samples ranging from 9 to 23%. In contrast, gemcitabine was not present at detectable levels in the Equashield® II system in all of the evaluated samples. The Equashield® II closed system seems effectively able to eliminate spills and leakage during gemcitabine compounding. Since drugs with different viscosities can have different effects on CSTDs, Equashield® II needs to be considered with other antineoplastic drugs during a structured surveillance program.

Validation of chemotherapy drug vapor containment of an air cleaning closed-system drug transfer device.

PurposeThe purpose of this study was to test the efficacy of ChemfortTM, an air filtration closed-system drug transfer device to prevent release of chemotherapy drug vapors and aerosols under extreme conditions. The air cleaning system is based on the adsorption of drug vapors by an activated carbon filter in the Vial Adaptor before the air is released out of the drug vial. The functionality of the carbon filter was also tested at the end of device’s shelf life, and after a contact period with drug vapors for 7 days. Cyclophosphamide and 5-fluorouracil were the chemotherapy drugs tested.MethodsThe Vial Adaptor was attached to a drug vial and both were placed in a glass vessel. A needle was punctured through the vessel stopper and the Vial Adaptor septum to allow nitrogen gas to flow into the vial and to exit the vial via the air filter into the glass vessel which was connected to a cold trap. Potential contaminated surfaces in the trap system were wiped or rinsed to collect the escaped drug. Samples were analyzed using liquid chromatography tandem mass spectrometry.ResultsCyclophosphamide and 5-fluorouracil were detected on most surfaces inside the trap system for all Vial Adaptors without an activated carbon filter. Contamination did not differ between the Vial Adaptors with and without membrane filter indicating no effect of the membrane filter. The results show no release of either drug for the Vial Adaptors with an activated carbon filter even after 3 years of simulated aging and 7 days of exposure to drug vapors.ConclusionsValidation of air cleaning CSTDs is important to secure vapor and aerosol containment of chemotherapy and other hazardous drugs. The presented test method has proven to be appropriate for the validation of ChemfortTM Vial Adaptors. No release of cyclophosphamide and 5- fluorouracil was found even for Vial Adaptors after 3 years of simulated aging and 7 days of exposure to drug vapors.

Pressure Compatibility Test of Closed System Drug Transfer Devices for 71 Anticancer Drugs

Occupational exposure to anticancer drugs may increase the risk of cancer and the risk of miscarriage and stillbirth, and cause other adverse events such as hypersensitivity reactions, skin/mucous reactions, and digestive symptoms. Several studies have investigated the use of closed-system drug-transfer devices (CSTDs) to reduce the environmental pollution by hazardous drugs. However, few reports have verified whether CSTDs contain the hazardous drugs within the vials. The BD PhaSealTM System is a CSTD that is frequently used in Japan. However, the fit of each anti-cancer drug vial has not been investigated. We investigated the fit of 71 major anti-cancer drug vials and protectors released and frequently used in Japan by means of a pressure compatibility test that we developed. The pressure compatibility test involved attaching a three-way stopcock to a Luer lock syringe and attaching an injector in line with the syringe. The pressure tubing was connected to the other side of the three-way stopcock and connected to the pressure inlet of the pressure gauge. The pressure in the anti-cancer drug vial was raised to 100 kPa and connected/disconnected repeatedly. If the pressure fluctuation during the 10th connection was within 6%, it was defined as "no change", and the compatibility of the protector and the vial was evaluated. The median pressure reduction rates at the 10th connection ranged from -1.98% to -4.95%. All drugs surveyed had an error rate within 6%. The BD PhaSealTM Protector was shown to be compatible with the 71 anti-cancer drugs we surveyed.

An Industry Perspective on Compatibility Assessment of Closed System Drug-Transfer Devices for Biologics.

The Formulation Workstream of the BioPhorum Development Group (BPDG), an industry-wide consortium, has identified the increased use of closed system drug-transfer devices (CSTDs) with biologics, without an associated compatibility assessment, to be of significant concern. The use of CSTDs has increased significantly in recent years due to the recommendations by NIOSH and USP that they be used during preparation and administration of hazardous drugs. While CSTDs are valuable in the healthcare setting to reduce occupational exposure to hazardous compounds, these devices may present particular risks that must be adequately assessed prior to use to ensure their compatibility with specific types of drug products, such as biologic drugs, which may be sensitive. The responsibility of ensuring quality of biologic products through preparation and administration to the patient lies with the drug product sponsor. Due to the significant number of marketed CSTD systems, and the large variety of components offered for each system, a strategic, risk-based approach to assessing compatibility is recommended herein. In addition to traditional material compatibility, assessment of CSTD compatibility with biologics should consider additional parameters to address specific CSTD-related risks. The BPDG Formulation Workstream has proposed a systematic risk-based evaluation approach as well as a mitigation strategy for establishing suitability of CSTDs for use.

Development of a simple compatibility inspection method using pressure in a BD PhaSeal™ system and hazardous drug vials.

Many reports support the use of closed system drug transfer devices (CSTDs) to protect against exposure to hazardous drugs during their preparation. However, leakage may occur if the CSTD fails to maintain hermeticity when fitted into the vial. Our aims were to devise a measure to prevent HD exposure and to develop a test method to verify CSTD function when a BD PhaSeal™ protector is used in HD preparation. We selected the BD PhaSeal™ System, which is the most commonly used CSTD device in Japan. The sealability of the BD PhaSeal™ protector and vial is considered to be due to the hermeticity of the protector and the rubber stopper of the vial. We constructed a protector with a damaged sealing rim and monitored the pressure fluctuation 10 times when the BD PhaSeal™ injector was connected to the pressurized vial. The reduction in pressure of the protector in the group without a damaged sealing rim was 5%, while that in the group with the damaged sealing rim was 84.9%. It was suggested that leakage occurred through the gap between the protector and the rubber stopper when using a vial that was not in close contact with the sealing rim. In this study, we developed a test that can be easily used to verify the compatibility of the BD PhaSeal™ protector and a vial in the clinical setting. Thus, when new hazardous drugs are being prepared, these measures can be taken to ensure that the risk of exposure is reduced or eliminated.

What are the effects of closed-system drug-transfer devices for reducing exposure of healthcare staff to hazardous drugs?

What are the effects of closed-system drug-transfer devices for reducing exposure of healthcare staff to hazardous drugs?

Evaluating Six Commercially Available Closed-System Drug-Transfer Devices Against NIOSH's 2015 Draft Vapor Protocol.

Purpose: In 2015, the National Institute for Occupational Safety and Health (NIOSH) published a draft vapor containment protocol to quantitatively evaluate combined liquid, aerosol, and vapor containment performance of commercially available closed-system drug-transfer devices (CSTDs) that claim to be effective for gas/vapor containment within a controlled test environment. Until the release of this proposed protocol, no standard method for evaluating airtightness of CSTDs existed. The aim of this study was to evaluate six commercially available CSTDs utilizing NIOSH draft protocol methodology to evaluate vapor containment under a robust vapor challenge. Methods: In this study, six commercially available CSTDs were tested utilizing draft NIOSH vapor containment protocol methodology to simulate drug compounding and administration using 70% isopropyl alcohol (IPA) as the challenge agent. All device manipulations were carried out in an enclosed test chamber. A Miran sapphIRe gas analyzer was used to detect IPA vapor levels that escaped the device. Study test included the two tasks designated by the NIOSH protocol, with additional steps added to the evaluation. Tasks were repeated 10 times for each device. Results: Only three of the six tested CSTDs (Equashield®, HALO®, and PhaSealTM) had an average IPA vapor release below the quantifiable performance threshold (1.0 ppm) for all tasks performed. This value was selected by NIOSH to represent the performance threshold for successful containment. The remaining three CSTDs had vapor release above 1 ppm at various times during the IPA manipulation process. Conclusion: Equashield®, HALO®, and PhaSealTM devices tested met the 2015 NIOSH protocol quantifiable performance threshold, functioning as a truly closed system. Quantifiable effective data may be useful in product selection.

Review of studies examining microbial contamination of vials used for preparations done with closed-system drug transfer devices

ObjectivesThe main objective was to identify all studies that present data regarding microbial contamination of vials used for preparation with closed-system drug transfer devices (CSTDs). Our secondary objective was to...