Closed System Transfer Devices Research Articles

Implementing a closed system drug transfer device to enable nurses to prepare monoclonal antibody treatment.

Efforts to increase capacity for oncology treatment in the author's Chemotherapy Day Unit, while allowing staff to treat more patients and offer more flexibility to patients, increased strain on the Aseptic Pharmacy at the author's Trust. Therefore, the possibility of nurse-led drug preparation was explored. Nurse-led monoclonal antibody (MAb) preparation was piloted to investigate whether a reduction in reliance on Aseptic Pharmacy could co-exist with maintaining optimal treatment capacity. The effectiveness of a closed system transfer device (CSTD) to protect nurses against drug exposure was also explored. A risk assessment for MAbs considered for nurse-led preparation was created, alongside a procedure for the safe handling of systemic anti-cancer therapy (SACT) with the use of a CSTD. The pilot resulted in an 89% reduction in the time patients had to wait for MAbs to be prepared. Seven oncology drugs were included in the new procedure without increasing the risk of exposure for nurses. The pilot successfully reduced demand on Aseptic Pharmacy while enabling efficient capacity use on the Chemotherapy Day Unit. The use of the CSTD minimised the risk of nurse exposure to SACT.

Impact on Quality during In-Use Preparation of an Antibody Drug Conjugate with Eight Different Closed System Transfer Device Brands.

The aim of this study was to investigate the in-use compatibility of eight commercially available closed system transfer device brands (CSTDs) with a formulated model antibody drug conjugate (ADC). Overall, in-use simulated dosing preparation applying the CSTD systems investigated raised concerns for several product quality attributes. The incompatibilities observed were mainly associated with increased visible and subvisible particles formation as well as significant changes in holdup volumes. Visible and subvisible particles contained heterogeneous mixtures of particle classes, with the majority of subvisible particles associated with silicone oil leaching from CSTD systems during simulated dose preparation upon contact with the ADC formulation. These observations demonstrate that CSTD use may adversely impact product quality and delivered dose which could potentially lead to safety and efficacy concerns during administration. Other product quality attributes measured including turbidity, color, ADC recovery, and purity by size exclusion HPLC, did not show relevant changes. It is therefore strongly recommended to test and screen the compatibility of CSTDs with the respective ADC, in a representative in-use simulated administration setting, during early CMC development, i.e., well before the start of clinical studies, to include information about compatibility and to ensure that the CSTD listed in the manuals of preparation for clinical handling has been thoroughly assessed before human use.

An assessment of exposed syringe inner walls as a route of exposure from hazardous drugs.

Maintaining safe working environments for health care personnel, especially for those who regularly handle hazardous drugs (HDs), is of utmost importance. Studies have shown that when closed system transfer devices (CSTDs) are used with standard open barrel syringes, cyclophosphamide (CP), a commonly used HD, is transferred to the syringe plunger during compounding or administration processes. This contamination can then be transferred to the work environment, endangering workers. The purpose of this study was to quantify HD contamination of the inner surface of standard open barrel syringes and to compare contamination levels between three commonly used HDs: 5-fluorouracil (5-FU), CP, and ifosfamide (IF). Each HD was transferred from a vial to an intravenous (IV) bag using a standard open barrel syringe and Becton, Dickinson and Company (BD) PhaSealTM CSTD connectors. Samples were taken from the inner surface of each of the syringe barrels to measure the amount of HD contamination. Each drug was tested 15 times and compared to a positive control. Significant amounts of each drug were transferred to the inner surfaces of the syringes. The average amounts of each drug measured were: 5-FU, 1327.7 ng (standard deviation [SD] = 873.6 ng); CP, 1074.8 ng (SD = 481.6 ng); and IF, 1700.0 ng (SD = 1098.1 ng). There was no statistically significant difference between the three drugs (p = 0.14). This study underscores the presence of HD contamination on standard open barrel syringe inner surfaces after transfer of drug from vial to syringe to IV bag. Such contamination could be spread in the working environment and expose health care workers to harm.

Evaluating drug stability and sterility in single-dose vials when accessed with a closed system transfer device.

Impact of drug wastage is a legitimate and persistent concern. Financial impact of drug waste is borne by the hospital network, patients, and healthcare systems. Measures to reduce drug wastage may have a positive impact throughout healthcare systems. This study investigated the stability and sterility of single-dose vials when repeatedly accessed with a closed system transfer device. By evaluating the sterility and stability, these results may be used to validate the extension of vial usage and lead to potential drug wastage reduction. Sterility testing was performed in accordance with US Pharmacopeia 71. A closed system transfer device was incorporated into simulated compounding tasks, utilizing growth media. Simulated compounding tasks were performed in the clinical environment, followed by incubation to stimulate growth. Stability testing was performed in accordance with US Pharmacopeia monographs at multiple timepoints post access. Test samples were comparatively tested via high-performance liquid chromatography to freshly opened vials at each timepoint. No growth was observed in test samples. Control vials displayed growth, where appropriate. The drugs retained stability, when compared to freshly opened vials at 0, 24, 48, and 72 h, post access. This study confirms that closed system transfer devices do not contribute to microbial contamination of drug vials, following the repeated access, for up to 7 days and the tested drugs retained equivalent chemical stability for up to 72 h post access. This study may offer a manner by which a facility may assess single-dose vials' sterility and stability, following repeated access by a closed system transfer device.

Use of Closed System Transfer Devices in Oncology Clinical Trials: Establishing Processes and Overcoming Challenges

Use of Closed System Transfer Devices in Oncology Clinical Trials: Establishing Processes and Overcoming Challenges

Impact of Closed System Transfer Device (CSTD) Handling Procedure for Low-Transfer-Volume Dose Preparation of Biologic Drug Products

Many challenges have been identified for ensuring compatibility of closed system transfer devices (CSTDs) with biologic drug products. One challenge is large hold-up volumes (HUVs) of CSTD components, which can be especially problematic with early-stage biologics when low transfer volumes smaller than the nominal fill volume may be used to achieve a wide range of doses with a single drug product configuration. Here, we identified possible CSTD handling techniques during dose preparation of a drug product requiring small volume transfers during reconstitution, intermediate dilution, and dilution in an IV bag, and systematically evaluated the impact of these handling procedures on the ability to deliver an accurate dose to the next step. We show that small changes to CSTD procedures can have a major impact on dose accuracy, depending on both CSTD HUVs and drug product-specific transfer volumes. We demonstrate that it is possible to craft CSTD instructions for use to mitigate these issues, and that the dose accuracy for specific drug product/CSTD combinations can be estimated using theoretical equations. Finally, we explored potential downsides of these mitigations. Our results emphasize key factors for consideration by both drug and CSTD manufacturers when assessing compatibility and providing CSTD instructions for use with biologics requiring low transfer volumes during dose preparation.

Characterization of Silicone from Closed System Transfer Devices and its Migration into Pharmaceutical Drug Products

Closed System Transfer Devices (CSTDs) are increasingly used in healthcare settings to facilitate compounding of hazardous drugs but increasingly also therapeutic proteins. However, their use may significantly impact the quality of the sterile product. For example, contamination of the product solution may occur by leaching of silicone or particulates from the CSTDs. It was therefore the aim of the present study to identify and quantify the types of silicone oil in a panel of typically used CSTDs. Particles found after simulated CSTD compounding processes were evaluated using Light Obscuration and Micro-Flow Imaging and were confirmed to be silicone oil particles. The number of particulates shed from CTSDs was in single cases exceeding pharmacopeial limits for a final parenteral product.Using X-ray microtomography, lubrication was shown to be primarily applied at connecting parts of the CSTD. Quantitative and qualitative analysis by Fourier transform infrared spectroscopy (FTIR) revealed a total released amount between 0.8 and 16 mg per CSTD of polydimethylsiloxane or polymethyltrifluoropropylsiloxane per CSTD. While pronounced differences in total silicone content between CSTDs were observed, it did not fully correlate with particle contamination in the test solutions, potentially due to variations in CSTD design. The impact of typical surfactants in biological formulations on silicone migration into product was additionally evaluated.We conclude that CSTDs may compromise final product quality, as (different types of) silicone oil may be released from these devices and contaminate the administered product.

Use of Closed System Transfer Devices (CSTDs) with Protein-Based Therapeutic Drugs—A Non-Solution for a Non-Problem?

Use of Closed System Transfer Devices (CSTDs) with Protein-Based Therapeutic Drugs—A Non-Solution for a Non-Problem?

Cost-effectiveness study of closed system transfer devices for the preparation of antineoplastic agents

Most cytostatic drugs cannot be administered directly to patients in their marketed presentation, but require previous reconstitution conducted in the Pharmacy Unit areas for cytostatic preparation.There are systems that allow drug reconstitution and transfer once it has been diluted, in order to protect staff from any potential contamination during handling. These are commonly known as Closed Systems, and generally have a piece for vial attachment and a syringe adapter with a built-in filter, that replace the traditional needles. Closed systems feature different characteristics and costs which is necessary to analyze in order to determine the most efficient one.

Cost-effectiveness study of closed system transfer devices for the preparation of antineoplastic agents

Most cytostatic drugs cannot be administered directly to patients in their marketed presentation, but require previous reconstitution conducted in the Pharmacy Unit areas for cytostatic preparation.There are systems that allow drug reconstitution and transfer once it has been diluted, in order to protect staff from any potential contamination during handling. These are commonly known as Closed Systems, and generally have a piece for vial attachment and a syringe adapter with a built-in filter, that replace the traditional needles. Closed systems feature different characteristics and costs which is necessary to analyze in order to determine the most efficient one.

Best Practices for Microbial Challenge In-use Studies to Evaluate the Microbial Growth Potential of Parenteral Biological Products; Industry and Regulatory Considerations.

Microbial challenge in-use studies are performed to evaluate the potential for microbial proliferation in preservative-free single dose biological products after first puncture and potential accidental contamination during dose preparation (e.g. reconstitution, dilution) and storage. These studies, in addition to physicochemical in-use stability assessments, are used as part of product registration to define in-use hold times in Prescribing Information and in the pharmacy manual in the case of clinical products. There are no formal guidance documents describing regulator expectations on how to conduct microbial challenge in-use studies and interpret microbial data to assign in-use storage hold-times. In lieu of guidance, US Food and Drug Administration (FDA) regulators have authored publications and presentations describing regulator expectations. Insufficient or unavailable microbial challenge data can result in shortened in-use hold times, thus microbial challenge data enables flexibility for health care providers (HCPs) and patients, while ensuring patient safety. A cross-industry/FDA in-use microbial working group was formed through the Innovation & Quality (IQ) Consortium to gain alignment among industry practice and regulator expectations. The working group assessed regulatory guidance, current industry practice via a blinded survey of IQ Consortium member companies, and scientific rationale to align on recommendations for experimental design, execution of microbial challenge in-use studies, and a decision tree for microbial data interpretation to assign in-use hold times. Besides the study execution and data interpretation, additional considerations are discussed including use of platform data for clinical stage products, closed system transfer devices (CSTDs), transport of dose solutions, long infusion times, and the use of USP <797> by HCPs for preparing sterile drugs for administration. The recommendations provided in this manuscript will help streamline biological product development, ensure consistency on assignment of in-use hold times in biological product labels across industry, and provide maximum allowable flexibility to HCPs and patients, while ensuring patient safety.

A Survey on Handling and Administration of Therapeutic Protein Products in German and Swiss Hospitals

Protein products in hospitals often have to be compounded before administration to the patient. This may comprise reconstitution of lyophilizates, dilution, storage, and transport. However, the operations for compounding and administration in the hospital may lead to changes in product quality and possibly even impact patient safety. We surveyed healthcare practitioners from three clinical units using a questionnaire and open dialogue to document common procedures and their justification and to document differences in handling procedures. The survey covered dose compounding, transportation, storage and administration. One key observation was that drug vial optimization procedures were used for some products, e.g., use of one single-use vial for several patients. This included the use of spikes and needles or closed system transfer devices (CSTDs). Filters or light protection aids were used only when specified by the manufacturer. A further observation was a different handling of the overfill in pre-filled infusion containers, possibly impacting total dose. Lastly, we documented the complexity of infusion administration setups for administration of multiple drugs. In this case, flushing procedures or the placement and use of filters in the setup vary. Our study has revealed important differences in handling and administration practice. We propose that drug developers and hospitals should collaborate to establish unified handling procedures.

Characterization of education, technical practices and attitudes of Portuguese pharmacy technicians towards manipulation of cytotoxic drugs.

Pharmacy professionals that manipulate cytotoxic drugs need to undergo educational programs, adopt the most convenient practices, and use appropriate equipment to avoid, as far as possible, occupational exposure to cytotoxic drugs. The main goal of this work is to characterize the education, technical practices, and attitudes towards cytotoxic drugs, of Portuguese pharmacy technicians. A questionnaire comprising eleven questions deemed pertinent was elaborated and subsequently validated by a pilot test. The anonymous, web-based survey was conducted between December 2022 and January 2023, by graduated pharmacy technicians that had manipulated cytotoxic drugs between 2017 and 2022. A total of 77 pharmacy technicians responded to the survey. Although sixty-six pharmacy technicians (86%) had been trained before beginning to manipulate cytotoxic drugs, the promotion of regular post-admission training by the institutions is sparse - only assumed by 53% of the pharmacy technicians (n = 41). All participants reported using gloves and gown during manipulation and the use of double gloves was common (99%; n = 76). Compliances with the recommended limit time for uninterrupted manipulation activity (82%; n = 63) and systematic double-checking (86%; n = 66) were high, but the regular use of sterile gauze around syringe connection sites 58% (n = 45), was less frequent. None of the surveyed pharmacy technicians used closed-system transfer devices (CSTD) and 41 (53%) of those who used spikes did not thoughtfully use these devices. The implementation of regular training programs in manipulating cytotoxic drugs should be fostered, to promote the more judicious use of engineering controls and transversal adoption of the safest technical practices.

116 A Performance Testing Protocol for Closed System Transfer Devices Used During Pharmacy Compounding and Administration of Hazardous Drugs

Abstract Cytotoxic and other hazardous drugs, whilst potentially therapeutic to patients, pose an occupational exposure hazard to healthcare workers during compounding and administration. However, occupational exposure to these drug compounds can be reduced with the use of closed system transfer devices (CSTDs) designed to prevent the escape of aerosol, liquid or vapour from a hazardous drug vial. In 2015 NIOSH developed a test procedure to assess the containment performance of CSTDs using an isopropanol-water challenge agent and infra-red detection. However, this protocol could not be used to assess devices using air filtration technology. HSE and BSTL therefore developed a modified procedure, using less volatile challenge agents and measurement using thermal desorption (TD) and gas chromatography-mass spectrometry (GC-MS), which could be used to assess all CSTD types. Unlike the NIOSH procedure this approach does not give a ‘real-time’ result but shows significantly greater sensitivity with the challenge agents used; typically being able to detect an airborne concentration of less than 1 part per billion (ppb). Testing carried out using a solution of 2-phenoxyethanol as the challenge agent showed no evidence of release with three of the four CSTDs tested; two barrier devices and one using air filtration. The tests also showed limits of detection to be dependent not only on the analytical procedure but on the effectiveness of the cleaning regime used to decontaminate the exposure chamber between tests.

Closed System Transfer Devices (CSTDs): Understanding Potential Over- and Under- Dosing of Liquid Vial Drug Products and How to Generally Mitigate

Closed system transfer devices (CSTDs) are a major challenge for drug manufacturers to assess and assure drug compatibility and acceptable dosing accuracy for a range of clinical administration strategies. In this article, we systematically investigate parameters affecting the loss of product during transfer by CSTDs from vials to infusion bags. We show that liquid volume loss increases with vial size, vial neck diameter, and solution viscosity - while dependent on stopper design. We further compared CSTDs’ performance with a traditional syringe transfer and learned that loss is larger for CSTDs than for syringe transfer. Based on experimental data, a statistical model was developed to predict drug loss upon transfer by CSTDs. The model predicted that, for single dose vials with USP<1151> conforming overfill, a complete extraction and transfer of the full dose can be assured for a broad range of CSTDs, product viscosities, and vial types (2R, 6R, 10R, 20R) if a flush (of syringe, syringe adaptor, bag spike) is performed. The model also predicted that complete transfer cannot be achieved for fill volumes ≤ 2.0 mL. For multi-dose vials and pooling of several vials, respectively, the effective dose transfer (i.e., ≥ 95%) for all CSTDs tested was predicted to be achieved if a minimum of 5.0 mL is transferred.

Clinical Oncology Society of Australia Position Statement: 2022 update to the safe handling of monoclonal antibodies in healthcare settings.

The aims were to (a) review the scientific literature on occupational risk, including exposure mechanisms and risk assessment, with regards to handling monoclonal antibodies (mABs) in healthcare settings; and (b) update the recommendations in the Clinical Oncology Society of Australia (COSA) safe handling of monoclonal antibodies in healthcare settings position statement, published in 2013. A literature search was conducted between April 24, 2022, and July 3, 2022, to identify evidence relating to occupational exposure and handling of mABs in healthcare settings. Evidence in the literature was compared to the Position Statement published in 2013, and any potential additions, deletions, or revisions were discussed by the authors, and then agreed changes were made. Thirty-nine references were included in this update, comprising of the 2013 Position Statement itself and 10 of its references, as well as 28 new references. The risks to healthcare workers in the preparation and administration of mABs arise from four distinct exposure mechanisms: dermal, mucosal, inhalation, and oral. Updates included recommendations on using protective eyewear during the preparation and administration of mABs, developing a local institutional risk assessment tool and handling recommendations, considerations for using closed system transfer devices, and to have awareness of the nomenclature change from 2021 for new mABs. Practitioners should follow the 14 recommendations to lower occupational risk when handling mABs. Another Position Statement update should occur in 5-10 years to ensure the currency of recommendations.

Container closure integrity testing and process validation of closed system transfer devices for aseptic reconstitution of drug vials connected to fluid bags

ObjectivesThe closure integrity and process validation of closed system transfer devices (CSTDs) should be confirmed before implementation in clinical settings. We aimed to investigate the closure integrity and validate the...

The impact on central line-associated bloodstream infection rates following the introduction of a closed system transfer device in oncology wards

Prevention of hazardous drug exposure is essential in averting unnecessary health risks to health care workers (HCW). To address the risk to HCWs when handling hazardous drugs, engineering controls can be utilized to reduce the exposure. A closed system transfer device (CSTD) was introduced for hazardous drugs administration in 6 oncology wards; this new CSTD was associated with a significant increase in CLABSI rates.

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.

Part II: Matrix based scaffold lyophilization facilitates processing as a prerequisite for an innovative packaging system

On large manufacturing lines, the fill finish process of drugs is generally accomplished by filling vials and syringes with their respective deliverable doses. Glass as a final container provides excellent protection of the drug product because of its chemical inertia, gas impermeability and relative robustness. However, due to potential needle stitch issues, diluent mix ups, or the required use of complex closed system transfer devices, lyophilizate vials present a significant challenge for healthcare professionals during the correct preparation of intravenous (IV) infusions. A more suitable container could potentially minimize such shortfalls during the preparation of IV infusions. Our investigations aimed at assessing if a novel medication system, consisting of an infusion bag separated into individual dry product and liquid diluent chambers, could facilitate the storage of a lyophilized product equivalently to the current standard, a vial. By incorporating an intermediate process container into two different dual chamber bags (DCB), the stability of a model monoclonal antibody formulation (mAb) was studied. The DCBs were evaluated over a 24-week period against their liquid and lyophilized dosage form equivalents in glass vials. Their stability was assessed through investigations into protein stability, residual moisture uptake of the dry products and permeability of the foil and film materials. It could be demonstrated that the stability of the incorporated drug is highly dependent on the container configuration. Ultimately it could be shown that the storage of lyophilizates is equally possible in DCBs as it is in vials, while being stored next to the diluent within the administration device.