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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

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

1 Background Information and Rationale

1.1 Background

Ideally, once meticulously designed, formed, and adequately used, a closed system transfer device (CSTD) should provide a protective shield from any hazardous exposures to healthcare workers during the compounding and administration of hazardous drugs (HDs). However, all CSTDs utilize a syringe, which may have a detrimental effect on the characterization of the system defined as a CSTD. An exception is a dedicated closed syringe unit that provides a closed system of its own. A regular open barrel syringe can potentially contaminate healthcare workers to various degrees depending on the drug used and its volatility, concentration, viscosity, and affinity to the syringe surface.1,2

The standard use of any HD requires filling a syringe with the drug. During the process of withdrawing the HD to the syringe, the HD comes into direct contact with the inner wall of the syringe. Hence, the syringe inner surface is directly exposed to the drug for a period of time. This may create a reaction, allowing the HD to stick to the syringe surface either by chemical affinity or by cohesive-adhesive forces of the HD. After the drug is transferred, the inner surface remains fully exposed to the environment, and potentially perilous contamination with the hazardous drug may occur by 2 possible routes: (1) by evaporation of the HD to the ambiance of the room or (2) by direct contact of the syringe plunger with the inner wall of the syringe. The latter type of contamination could be transferred via gloves of the technicians to other surfaces, resulting in spread of contamination in the working environment. Obviously, this should be prevented as much as possible and should not occur while a CSTD is used.

Different contamination results may be observed with individual HDs due to the unique physical and chemical properties of each drug.

1.2 Findings From Studies

Studies using CSTDs have shown a significant reduction in surface contamination levels, although detectable levels of hazardous substances were observed, suggesting that some systems are not entirely safe, and that healthcare workers remain at risk of exposure.3,4 A study using a surface monitoring technique further explored environmental contamination when it specifically examined the possibility of syringe plunger contamination during routine drug preparation at hospital pharmacies. Contamination by cyclophosphamide was confirmed, quantified, and localized on a standard syringe plunger.1 Results from additional studies confirmed these results with cyclophosphamide used in a CSTD that utilizes a standard syringe and revealed that drug residuals on the syringe plunger contaminate both gloves and the work environment.2,5

1.3 Study Objectives

The purpose of the study is (1) to establish evidence for HD contamination of the inner walls of regular syringes exposed to the environment and (2) to compare the intensity of contamination between commonly used HDs.

2 Protocol Overview

Three common HDs shall be evaluated in real-world conditions of use for contamination levels upon exposure to environmental surfaces of regular open barrel 50 mL syringes. A total of 50 mLs of drug will be transferred from vial to IV bag using a regular syringe and CSTD. The drugs of interest are cyclophosphamide, ifosfamide, and 5-fluorouracil. The CSTD PhaSeal will be used during each of the preparations.

ChemoGLO HD wipe kits are used for sampling the tested syringes.

3 Description of Supplies

This study used the following materials.

3-Description-of-Supplies

4 Selection of Drugs and Dosages

This study utilized 3 hazardous drugs to assess contamination.

5 Data Collection

Data was recorded on the ChemoGLO Site Map Form.

The completed ChemoGLO Site Map Form is included with the wipe samples that are sent to the lab.

6 Testing Conditions

Hospital pharmacy setting for handling and preparation of hazardous drugs (eg, cleanroom, BSC, PPE).

7 Test Procedure

  1. Remove the flip-cap from the drug vial and attach the CSTD vial adapter. Perform this and all next steps in accordance with the CSTD manufacturer’s IFU.
  2. Attach the CSTD bag adapter to the IV bag.
  3. Attach the syringe to the CSTD connector.
  4. Cyclophosphamide (CP) and ifosfamide (IF) require reconstitution; therefore, follow the instructions provided in the respective package insert and reconstitute the drugs as instructed.
  5. Connect the syringe to the vial.
  6. Invert the vial and draw 50 mL of drug.
  7. Disconnect the syringe from the vial and connect the syringe to the IV bag (at all stages using the CSTD).
  8. Inject the entire drug dose into the IV bag and disconnect.
  9. Using an adequate cutter tool, cut out a quarter from the plunger barrel knob. This step will enable controlled and easy access to the syringe barrel without interference with the tested syringe. This allows for wiping the exposed inner wall of the syringe.
  10. Pre-wet the ChemoGLO wipe in accordance with its IFU and insert the wipe into the space between the plunger and the barrel.
  11. Using a wooden rod. insert the wipe deep into the rear opening of the syringe. A single-use wooden rod is used to move the ChemoGLO wipe up and down the barrel of the syringe in the exposed syringe barrel (one quarter of the entire barrel).
  12. Push the wipe all the way down to the bottom of the syringe in 1 of the 4 spaces, thereby wiping the exposed inner wall of the syringe.
  13. The syringe plunger rod is rotated 90 degrees and the process is repeated. This occurs a total of 4 time to ensure that the entire syringe barrel is wiped. The wipe is removed.
  14. Pack and label the wipe in accordance with instructions provided in the sampling kit. The second ChemoGLO wipe is repeated on the syringe.
  15. Repeat the testing procedure a total of 15 times with the same drug (15×1=15 replicates).
  16. Repeat the previous process with each of the 3 drugs (15 x 3 = 45 replicates).
  17. Total of 45 replicates for the study

8 Study Controls

8.1 Positive Control Procedure

Perform the positive control test by inoculating the syringe barrel with the drag, and wipe sample it.

8.2 Negative Control Procedure

This step is not applicable because ChemoGLO is a validated process that does not require a negative sample to be generated for validation purposes.

The average of the positive detections from the 15 5-FU syringes is 1,327.70 ng/syringe, demonstrating significant concentrations of the drug being detected.

9 Results

5-Fluorouacil 2.5 grams Fresenius Kabi (50 mL vial)

5-FU IV bags were prepared, and the syringe barrels were tested for the presence of contamination. The following concentrations were detected by the ChemoGLO wipe kit:

9

Cyclophosphamide 1 gram Sandoz (50 mL vial)

 Cyclophosphamide IV bags were prepared, and the syringe barrels were tested for the presence of contamination. The following concentrations were detected by the ChemoGLO wipe kit:

91
An Assessment of Exposed Syringe Inner Walls as a Route of Exposure from Hazardous Drugs

The average of the positive detections from the 15 cyclophosphamide IV syringes is 1.074.75 ng/syringe, demonstrating significant concentrations of the drug being detected.

Ifosfamide 3 grams Baxter (60 mL vial)

Ifosfamide IV bags were prepared, and the syringe barrels were tested for the presence of contamination. The following concentrations were detected by the ChemoGLO wipe kit:

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

The average of the positive detections from the 15 ifosfamide syringes is 1,700.04 ng/syringe, demonstrating significant concentrations of the drug being detected.

10 Conclusions

When comparing the averages of detected concentrations of the 3 drugs (1,327.70 ng/syringe, 1,074.75 ng/syringe, and 1,700.04 ng/syringe) and in view of highest result exceeding the 4,000 ng/syringe measurement limit, these are all considered high and are of concern if they would be released into the environment or be exposed to a healthcare worker. The results of this study establish evidence for HD contamination of the inner walls of regular syringes exposed to the environment. The testing included only a single transfer of drug from vial to IV bag. Additional investigation is suggested with multiple transfers and extended duration of use that may further increase the potential for exposure. There appears to be a variation of concentrations between the different drugs (ifosfamide average is 58% higher than 5FU), indicating varying behavior of individual HDs due to tire unique physical and chemical properties of each drug. Identifying ways to reduce or contain these concentrations to eliminate this route of exposure is important for healthcare and environmental safety. 

Syringe plunger contamination by hazardous drugs: A comparative study

Introduction

Our institution administers thousands of monthly chemotherapy doses, so we were very early adopters of both USP7971 and NIOSH recommendations. 2 We had developed and implemented policies and procedures outlining safe and appropriate procedures for handling oncological agents, the utilization of cleanrooms and biological safety cabinets, personal protective equipment (PPE), and many other protective measures. Those policies and procedures included the utilization of the Phaseal Closed System Transfer Devices (CSTD) with Becton Dickinson (BD) syringes. Three years ago, we replaced the Phaseal devices with a new CSTD, Equashield. The design, simplicity, ergonomics, and the potential for decreasing our hazardous waste we felt offered an advantage over the BD Phaseal products. Favier et al.,3 in a peer-reviewed study, examined the potential for syringe plunger contamination during routine drug preparations at hospital pharmacies. This study confirmed and quantitated that considerable contamination from cyclophosphamide did occur on the BD syringe plungers. This study included wipe test sampling of syringe plungers from syringes that were purposely operated with repeated withdrawal and re-injection cycles of cyclophosphamide to simulate repeated use. The study also performed wipe test sampling of syringes collected after normal use during a pharmacy routine work day. Both groups of syringe samples were found to be contaminated. This previously undetected route of exposure poses a problem as it has identified another potential source of contamination of gloves and the work environment, which increases the risk of exposure to the pharmacy staff, nurses, patients, and their families. These findings highlight the urgent need for improved safety measures in healthcare settings. An essay on nursing should address this issue, emphasizing the importance of proper handling and disposal of hazardous substances to protect both healthcare professionals and patients. A few years later, a research laboratory specializing in antineoplastic agents and environmental contamination repeated the plunger contamination study.4 This study included Equashield syringes in addition to BD and Terumo syringes. This study confirmed the findings of the previous study3 with high contamination rates of up to 0.5 mg cyclophosphamide found on both the BD and Terumo syringe plungers. Since both manufacturers, BD and Equashield have claimed to have made enhancements in the performance of their products, we asked Equashield to sponsor a similar comparative study at our institution. Equashield agreed and a small study was developed that would test the levels of contamination of the BD syringes with Phaseal CSTD devices against those from Equashield.

Karmanos Cancer Center, Detroit, MI, USA
Corresponding author:
Stephen T Smith, Department of Pharmacy, Karmanos Cancer Center,
4100 John R. Street, Mailcode: WE01PH, Detroit, MI 48201, USA.
Email: [email protected]

Method

The study included 11 Equashield 60 mL syringe units and 12 BD PlasticTM 60 mL syringes. The Equashield syringes are a stand-alone closed system that includes factory built-in closed pressure equalization system and dry connectors. The BD syringe is a traditional single use syringe with a luer lock tip manually attached to the appropriate Phaseal dry connector (Injector). The closed pressure equalization system is built-in the Phaseal vial adapter (Protector).

The difference between the BD and the Equashield syringes is shown in Figures 1 and 2. The BD syringes have an open syringe barrel and a regular four ribs plunger structure. The Equashield barrel is sealed by a lid and the plunger is a small diameter metal rod that can move through the lid. A seal, seated in the center of the lid, seals the rod and ensures airtight operation of the syringe.

Four Equashield Vial Adaptors (VA-20) and four Phaseal Protectors (P-50) were attached to eight cyclophosphamide 2 g vials, respectively. Each vial was reconstituted with 100 mL of standard sodium chloride 0.9% solution to a final concentration of 20 mg/mL. There were eight syringes and adaptors utilized of each system to complete the transfer in 50 mL aliquots into the drug vials.

The syringes were divided into three equal groups for the Equashield and BD syringes, with a vial of the reconstituted cyclophosphamide designated for each group with the exception of the last group which received 2 vials each. A 50 mL aliquot of cyclophosphamide was drawn into each syringe and then injected back into the cyclophosphamide vial. This drug transfer procedure was immediately repeated twice for the syringes in group 1, four times for the syringes in group 2, and eight times for the syringes in group 3. Only 50 mL were drawn into the syringes to remain within the manufacturers’ guidelines of use and minimize the potential for a possible spill. The same withdraw and reinjection processes were applied to the syringes which were similar to those one would encounter during a routine pharmacy compounding procedure.

After the completion of the drug transfers with the Equashield and BD Phaseal syringes, the plungers were retracted back to the nominal syringe marking and a wipe test of the exposed plunger was done.

A wipe sample was taken from the biological safety cabinet work surface at the commencement of the study to rule out any possible contamination prior to the study. The size of the wiped surface was 1 ft2 (930 cm2).

The services of ChemoGloTM (Chapel Hill, North Carolina), a specialized third-party laboratory, were used to accurately quantify trace amounts of cyclophosphamide on the syringe plungers and work area sample. The ChemoGloTM assay has a low detection level of 10 ng (1 109 ) per wipe sample and is simple to use. The assay is optimized for wipe sampling of any surface area up to 1 ft2 (930 cm2), which is optimal for wiping the smaller surface of the syringe plungers. The quantification of cyclophosphamide is, therefore, the total quantity of cyclophosphamide in nanograms found on a plunger/wipe sample.

Four kits were utilized for a total of 24 wipe samples (each kit consisting of six wipes samples) which were completed in accordance to the procedures outlined by ChemoGloTM.

The wipe samples were taken using the ChemoGloTM swab with absorbed solution. The plungers were retracted back to the nominal syringe marking and the exposed plungers wiped thoroughly with the wet swabs. After the completion of the wipe sampling, the swab was placed in a dedicated labeled container. Since each wipe sample consists of two swabs and solution containers, this process was repeated for the secondary swab sampling.

All 48 containers with the wipe samples (two containers for each syringe 23 syringes, and two containers for testing the work surface) were sent overnight to ChemoGloTM laboratory for the performance of sample extraction and analysis with LC-MS/MS technology.

The test was performed in a Thermo Class II, A2 Biological Safety Cabinet by an experienced chemotherapy-certified pharmacy technician, proficient with the use of both the Equashield and Phaseal CSTDs. The working area was cleaned in accordance to our facility’s standard procedure prior to initiation of the study. To isolate the study and exclude any foreign source of contamination that may influence the results, the drug vials were cleaned with IPA pads and only materials which are required for the study were kept in the hood. Large absorbent pads were used to cover the whole work area. The pads were replaced and the gloves changed before working with each group of syringes.

Figure 1. The BDÕ syringe (left) and the EquashieldÕ syringe (right).

Syringe plunger contamination by hazardous drugs: A comparative study

Figure 2. The EquashieldÕ syringe (top) and the BDÕ syringe (bottom).

Syringe plunger contamination by hazardous drugs: A comparative study

Table 1. Amounts (ng) of cyclophosphamide on the tested syringe plungers.

Syringe plunger contamination by hazardous drugs: A comparative study

Figure 3. Contamination levels (ng) of cyclophosphamide (CP) on the tested syringe plungers.

Results

Results demonstrated significant cyclophosphamide contamination levels on 11 out of 12 BD syringes, whereas all 11 Equashield CSTDs had undetectable concentrations. The 1 ft2 (930 cm2 ) work area wipe showed minor contamination of 16.82 ng, considered to be close to the lower limits of detection level (LLQ) (Table 1).

Statistical assessment

We regard this study to be a small-scale pilot study with the intent of reviewing the two CSTDs that we were familiar with. We had little preliminary data to determine the study’s sample size; therefore, an assumption of 11 syringes was made based on previous studies.3,4 The results confirmed the assumption and show that the average contamination level for the BD plungers was ¼ 1622 ng with a variant, 2 ¼ 331 ng2 . Assuming a normal distribution, CP ~ N(µ, σ2 ), the average contamination level on the BD plunger was greater than 1228 ng, with a confidence level of 95%. That is to say, that if we used an unlimited number of syringes, we could be 95% sure that the averaged contamination level would be above 1228 ng. Since the technology is limited to detect and quantify between 10 ng and 2000 ng, for the statistical analysis of the results, we assumed that when the contamination was above the technology’s detection limit, we regarded it to be 2000 ng understanding that the true level of contamination may exceed that value several-fold. This has already been documented in previous studies 4,5 using HPLC-MS/MS analysis method (Figure 3).

The lower limits of detection (LLQ) for these assays are 10 ng. Quantities that are less than the LLQ are defined as non-detectable (ND). The upper limits of detection for these assays are 2000 ng. Quantities that are greater than 2000 ng are defined as > 2000.

Discussion

The contamination levels found on the standard BD syringe plungers confirm previous studies.3,4 This contamination highlights the potential of a significant source of low-level exposure for healthcare workers
while they prepare and handle hazardous drugs during their routine workday. It is suggested that the staff’s gloves come into contact with the syringe’s contaminated plungers then in turn, touch other surfaces such as the work area, the prepared IV bags which are distributed to patient care areas, and so forth, thus contaminating the entire work environment and increasing the potential of exposure.

Following the results of previous study,4 where contamination was also found on tested Terumo syringes, it is most likely that BD syringes generally represent standard syringes of other manufacturers as well.
Furthermore, the contamination on standard plungers is expected regardless of use of a CSTD or traditional methods when handling hazardous drugs.

Similarly, our results demonstrated no detectable level of contamination on the Equashield syringe plungers which supports previous findings3,4 as well as the NIOSH recommendations2 that endorse the use of CSTD which mechanically prohibits the escape of hazardous drug or vapor concentrations outside the system in order to minimize exposure to hazardous drugs.6

We believe that cyclophosphamide infiltrates on to the plungers of standard BD syringes by reacting and creating a layer on the inner walls of the syringe barrel.

The very minimal distance or direct contact between the plungers to the contaminated walls ‘‘allows’’ cyclophosphamide to ease its way on to the plunger. The typical squeezing of the barrel, bending or twisting of the plunger during real use conditions often creates a direct contact between plungers to the contaminated walls, thereby allowing transfer of contamination. It has been shown that the safety measures adopted through the Equashield design address the risk of plunger contamination7 by preventing contact and ensuring greater distance between the Equashield plunger rod and the syringe barrel in this contained CSTD.

Finally, the contamination levels of cyclophosphamide found on the work area sample were close to the LLQ and may therefore be considered of little consequence.

Conclusions

This study has confirmed the hazards associated with standard syringes and the importance of using appropriate closed system syringes during all preparation and handling stages of hazardous drugs, in order to significantly reduce healthcare workers’ exposure to contaminated surfaces and work environments. It is suggested that in light of this study, and the medical literature which it echoes, further investigation and consideration are required, and more rigorous regulations and policies should be established in this area in order to further minimize risks and optimize the safety of healthcare workers.

Funding

This study was partially sponsored by Equashield.

Conflict of interest

The authors have no conflict of interest to disclose.

Use of a closed system drug-transfer device eliminates surface contamination with antineoplastic agents

Background

Harmful effects from workplace exposure to antineoplastic agents were first described in the 1970s.1 Noted risks of handling these agents by nurses and other healthcare personnel include damage to DNA, infertility and a possible increased risk of cancer.2–8

The use of personal protective equipment (PPE) when handling chemotherapy has been recommended by The Occupational Safety and Health Administration (OSHA) since 1986.9 Pharmacists, pharmacy technicians and nurses risk exposure to antineoplastic agents when preparing and administering these drugs. Many studies have documented surface contamination with these agents in healthcare institutions10–14 and a recent study noted that doxorubicin can penetrate nitrile gloves.15 Additionally, hazardous drugs have been found in the urine of healthcare workers who prepare or administer chemotherapy.11,13,16 PPE is therefore used during preparation and administration in order to reduce exposure during these times. 

Prior studies have shown surface contamination outside of the biological safety cabinet.10–14 Healthcare workers are likely to come in contact with contaminated surfaces when not wearing PPE. Minimizing environmental contamination with antineoplastic agents is imperative to protect workers from the harmful effects of these agents.

Closed system drug-transfer devices (CSTD) can reduce exposure of health care workers to harmful agents. Numerous reports have been published that describe the effectiveness of CSTDs at decreasing surface contamination and exposure of healthcare personnel after implementation of the devices.13,14,16–21 The National Institute for Occupational Safety and Health (NIOSH)22 and The United States Pharmacopeia’s current USP 79723 standards recommend the use of CSTDs when preparing and administering chemotherapy in addition to the use of PPE.

Several CSTDs are marketed for use with cytotoxic agents. A recently published study of 22 United States hospitals noted that surface contamination was reduced significantly after the implementation of a well-known CSTD.14 However, the CSTD product used in this study has yet to be evaluated in the workplace setting. Testing of surfaces in the workplace for contamination after implementing the CSTD is important to validate the utility of the product.

Testing for surface contamination with cytostatic agents in the cancer center was completed for two reasons. An evaluation of the effectiveness of the standard method for preparing (Chemo Dispensing Pin, B. Braun Medical Inc.) and administering chemotherapy was necessary. The second reason was to evaluate whether the CSTD would decrease the level of surface contamination at various locations within the cancer center 1 year after implementation.

This study was conducted at an ambulatory cancer chemotherapy infusion center that is part of a large health-system in the Midwest of the United States. Within the center is a 21-chair infusion suite with a dedicated pharmacy preparing the chemotherapy products to be administered in the infusion suite. The cancer center has approximately 16,500 chemotherapy visits per year.

At the cancer center, the pharmacy technicians prepare all doses of chemotherapy under the supervision of the pharmacist. Pharmacy staffing consisted of two fulltime pharmacists and two full-time certified pharmacy technicians. An estimated 450 g of cyclophosphamide and 2600 g of 5-fluorouracil are prepared each year. The pharmacy has one biological safety cabinet for the preparation of all medication doses. The biological safety cabinet is a Class II Type A/B3 and has been in use for 10 years. 

Table 1. Cyclophosphamide (CP) and 5-fluorouracil (5FU) in wipe samples after the use of safety pins and without any prior cleaning (baseline contamination)

2A

Table 2. Cyclophosphamide (CP) and 5-fluorouracil (5FU) in wipe samples after implementation of the CSTD and after cleaning (start test period)

3

Table 3. Cyclophosphamide (CP) and 5-fluorouracil (5FU) in wipe samples one year after implementation of the CSTD.

Materials and methods

Twelve locations were chosen to be tested for environmental contamination with the cytostatic drugs cyclophosphamide and 5-fluorouracil. The twelve locations included five within the pharmacy, five in the infusion suite area and two in office spaces. The areas tested remained identical throughout the study, with the exception of the automated drug distribution station which was replaced in the first quarter of 2011. Testing sites were determined, measured and the area of each was calculated in square centimeters.

The wipe samples were taken three times. The first samples were obtained on 25 June 2010, the second samples were obtained over the period between 18 and 27 August 2010, and the third samples were obtained on 19 August 2011. All samples were collected by the lead pharmacist at the cancer center. The first samples were collected in June 2010 without prior cleaning to measure the baseline levels of contamination that was occurring with use of the containment technique being used at the time. Implementation of the CSTD occurred concurrently in the pharmacy and the infusion suite in July 2010. Time was allotted for the pharmacy technicians and the nurses to adjust to using the new devices. The pharmacy, infusion suite and offices were cleaned using wipes that contained sodium hypochlorite 0.55% solution. The cleaning was done by a pharmacist and pharmacy technician. The second samples were collected in August 2010 after the implementation of the new devices and the sodium hypochlorite cleaning technique to determine whether the contamination was fully removed. The third samples were collected in August 2011, approximately 1 year after implementation of the devices.

The EquaShieldÕ system24 uses a double membrane for drug transfers to ensure dry connections. The unique syringe is airtight and contains two chambers, the distal chamber for air and the proximal for liquid. Likewise, the connector has two needles to allow for air and liquid exchange. The air contained behind the plunger of the syringe (distal) is transferred into the drug vial when liquid drug is withdrawn into the syringe (proximal).

The wipe samples were taken using Cyto Wipe Kits (Exposure Control Sweden AB). To collect test samples, an aliquot of 0.03 M sodium hydroxide solution from the Cyto Wipe Kits was applied to each target area and wiped off twice with dry tissue paper. The tissue paper was then placed in a plastic container with a screw cap and immediately frozen and stored.

The samples were analysed on a gas chromatography-tandem mass spectrometry method system. Specificity and sensitivity are increased using gas chromatography-tandem mass spectrometry method instead of gas chromatography/mass spectroscopy.25,26

The analysis of 5-fluorouracil was performed on a high-performance liquid chromatography system with ultraviolet detection.10,11

Results

Thirty-six samples were collected throughout the study. The results of the analysis of the wipe samples are presented in the Tables 1–3. The contamination per square centimeter is calculated assuming a 100% recovery and wipe efficiency. Thus, all results are underestimates. The detection limits for the analysis of cyclophosphamide and 5-fluorouracil were 0.10 and 5 ng/mL sodium hydroxide, respectively.

The results from the first two sets show contamination with cyclophosphamide on about half of the positions in all departments during both collection periods (Tables 1 and 2). However, levels of contamination were very low and mostly just above the detection limit of the analytical method. The highest level of contamination was found on the door and handle in the pharmacy. Contamination was found in one of the office spaces upon the second collection. Contamination with 5-fluorouracil was only observed on the dispensing counter in the pharmacy during the second collection period. The results from the final collection period show no contamination with cyclophosphamide or 5-fluorouracil in the pharmacy, infusion suite or offices of the cancer center. 

Discussion and conclusion

Exposure to antineoplastic agents is harmful to healthcare workers. Surfaces that are contaminated are touched when healthcare personnel are not using PPE. Sampling of the biological safety cabinet was not done in this study. The outside of vials being used during compounding may be contaminated with cytotoxic agents.27 Our goal was not to show that contamination exists inside the biological safety cabinet but rather to determine whether common areas were more likely to cause exposure, if contaminated, of healthcare personnel.

The initial sampling results showed environmental contamination with cyclophosphamide in several departments. However, the level of contamination was very low compared with historical data.12 Contamination with 5-fluorouracil was only observed at one position. This is probably caused by a higher detection limit for the analysis of 5-fluorouracil compared to cyclophosphamide.

Sodium hypochlorite-containing wipes were used to clean surfaces prior to the second sampling. This is not ideal, as bleach is not effective at removing all antineoplastic agents and the concentration of the wipes was low. However, this is the generally accepted cleaning practice at this institution. It was essential to determine that the CSTD would reduce surface contamination given the chosen cleaning process.

Other studies have shown environmental contamination with cytostatic drugs in pharmacies and administration areas.10–12 The initial results of this study showed very low levels of contamination with cyclophosphamide and 5-fluorouracil compared to the reference data.

The final sampling results, one year after the implementation of the closed-system transfer devices, showed an environment free of contamination from cyclophosphamide and 5-fluorouracil.

At our practice site, nurses must enter the pharmacy to retrieve prepared chemotherapy products for patient administration. The door and handle are touched repeatedly by all personnel, pharmacy and nursing, while not garbed in PPE. Finding the highest level of contamination on this surface was not surprising, but it was confirmation that PPE alone cannot protect healthcare workers from antineoplastic agent exposure.

One of the samples from an office was from a desk of a physician’s support nurse. The employee did not administer chemotherapy nor did the staff member work in the infusion suite. Finding contamination with cyclophosphamide at this location demonstrated that surface contamination could spread throughout a building.

The years of experience and expertise of the pharmacy technicians (a combined 21 years of experience for two technicians) at compounding antineoplastic agents may have been a reason for the low level of contamination initially. In addition, the expertise of the infusion suite nurses (each averaging twenty years of experience) likely contributed to this observed low level of contamination.

Implementation of the closed-system transfer devices for preparing and administering chemotherapy eliminated surface contamination with cytotoxic agents at the ambulatory cancer chemotherapy infusion center.

The NIOSH22 and United States Pharmacopeia’s current USP 79723 standards only recommend the use of CSTDs when preparing and administering chemotherapy. A ‘‘safe’’ level of exposure to antineoplastic agents by healthcare workers is unknown. Based on the positive findings that CSTDs can eliminate surface contamination with antineoplastic agents, guidelines should be adapted to require their use.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of Interest

The authors have no conflict of interest to disclose.

Contamination of Syringe Plungers During the Sampling of Cyclophosphamide Solutions​

The presence of cytotoxic agents in the urine of operators and in their environment has been demonstrated. The pharmacokinetics of the urinary elimination of cyclophosphamide suggests that these drugs are absorbed cutaneously during handling. In the framework of a more general study on the contamination of hospital environment, the present study addresses the possible presence of cytotoxic agents on the plungers of syringes. The report is based on results indicating that the bacterial contamination of a plunger may result in the contamination of the solution being sampled. The study was divided into two phases. The first phase consisted in measuring the contamination of the plungers of eight syringes used for handling cyclophosphamide. Cyclophosphamide was analysed by gas chromatography – mass spectrometry with a detection limit of 0.1ng/ ml. The aim of the second phase was to localize the contamination on the plunger and thus determine the amount of drug that comes into contact with the gloves of the operators. The contamination was quantified by measuring the activity of metastable technetium. The results of the first phase showed that all the plungers were contaminated with cyclophosphamide amounts varying from 3.7 to 445.7 ng. The second phase showed that the infiltration of liquid onto the plunger depended on the solution being sampled. Almost no infiltration was seen with labelled water, but contamination appeared after the first sampling of a cyclophosphamide solution, then increased as a function of the number of times the plunger was pushed in and out. These results indicate that cyclophosphamide solutions infiltrate onto the plungers of syringes. They suggest that the general procedure for handling cytotoxic agents should be modified, and a regular replacement of syringes should be enforced. They also partly explain why the gloves of 50%/90% operators are contaminated after a single preparation. The contamination seems to depend on the type of solution sampled and the number of samplings. Initial investigations by the manufacturer of the syringes had shown that the acid pH of cyclophosphamide solutions may affect the lubricant of the joint. Our study demonstrates that the contamination of plungers is one of the sources of environmental contamination for health workers handling antineoplastic agents, even in the absence of manipulation errors. More generally, these results demonstrate that the exposure of operators cannot be clearly described unless all existing sources of contamination in their environment are identified. The implementation of suitable procedures should thus take into account all possible sources of contamination, including technical facilities such as the use of a safety cabinet or an isolator.

J Oncol Pharm
Practice (2005) 11: 1-5.

Key words: contamination; cytotoxic; exposure;
syringe plungers

Introduction

In 1979, Falck et al. suggested the possibility that health workers involved in the preparation and manipulation of anticancer drugs underwent occupational exposure to cytotoxic agents.1 The authors subsequently confirmed and quantified such exposure, mainly by measuring agents such as cyclophosphamide in urine. They obtained positive results, then extended their study to environmental contamination.2-7 They showed that the gloves and the overall working environment of these personnel were frequently contaminated by varying concentrations of cytotoxic agents.5,6 The present study, conducted within the framework of a larger study on hospital contamination, focused on the possible contamination of syringe plungers by the solution being sampled, on the basis that the bacterial contamination of syringe plungers can lead to the contamination of the solution itself.8 The presence of a cytotoxic agent on the plungers is a possible source of environmental contamination for people handling the drug whose gloves are generally contaminated, even when no manipulation error is made

MATERIALS AND METHODS

This study was conducted at the Centre Le´on Be´rard (France) with 50-ml, three-piece Becton Dickinson syringes. These syringes were chosen because of their long plungers that compel operators to touch them with their gloved hands. The study consisted of two phases.

Phase 1
In order to study the actual contamination of syringe plungers employed for the preparation of cyclophosphamide solutions, eight syringes were used for about 8 h (9:00 – 17:00), then samples were taken throughout the day when the syringes were needed to fill prescriptions. The number of times the plunger was pushed in and out was recorded. At the end of the day, a half compress (20*20, Tetra Medical) impregnated with 5 mL of water for injectable preparations was applied onto the polypropylene plunger after it had been pulled out to its fullest extension. The compress was then stored in a glass flask at -20oC until analysis.

Sample treatment. The compress was placed in a silanized glass tube with 0.1 mL of a solution of 250 ng/mL trofosfamide (internal control) and 0.5 mL Tris buffer, pH 8. The cyclophosphamide was extracted with 15 mL of unstabilized diethyl ether. The sample was shaken mechanically for 10 min, then the organic phase was removed, centrifuged at 3000 rpm for 6 min, then placed in a silanized glass tube. The aqueous solution was extracted again as before. The entire organic phase was dried with anhydrous sodium sulfate, then evaporated under a light stream of nitrogen at 35oC until a volume of 2 mL was obtained. The diethyl ether residue was transferred to a 3-mL glass flask, then evaporated to dryness under a light stream of nitrogen at 35oC.

Derivatization. The dried residue was treated with 100 mL of ethyl acetate and 100 mL of trifluoroacetic anhydride (derivatization agent). The solution was shaken for a few seconds, then heated at 708C for 15 min. After the solution had been returned to room temperature, it was evaporated to dryness under a light stream of nitrogen, then 100 mL of toluene were added. After 5 min mechanical shaking, 1 mL of the solution was injected into the chromatograph.

In these conditions, the mean recovery rate (9/SD) of cyclophosphamide with the sampling method described above was 859/10%.

Analytical conditions. Cyclophosphamide was analysed by gas chromatography-mass spectrometry (GC-MS) with a detection limit of 0.1 ng/mL. We used a Hewlett-Packard 5 MS capillary chromatographic column with an internal diameter of 0.25 mm, a film thickness of 0.25 mm, and a length of 30 m. The carrier gas was helium 5.5, the pressure at the head of the column was 17 kPa, the gas flow was 50 mL/min, and the column flow was about 1 mL/min. The splitless injection mode was used.

Gas chromatographic conditions. The initial oven temperature was 1108C. After 1 min, it was progressively increased by 158C/min to 2808C. After 0.5 min, it was increased by 258C/min to 3108C. After 3.57 min, the oven temperature was decreased to 1108C for 0.2 min before the next injection.

Mass spectrometry. The interface and source temperatures were 2808C and 2008C, respectively. The energy of the ionizing electrons was 70 eV, and the trap current was 150 mA.

Characteristics of selected ion monitoring. Two entry windows were used: the first one from 9.00 to 11.20 min, during which the mass filter was adjusted to ions 307, 309 and 212 of cyclophosphamide, and the second one from 11.20 to 13.00 min, during which the mass filter was adjusted to ions 273, 275 and 182 of the internal standard. Under these conditions, cyclophosphamide trifluoroacetate and trofosfamide were eluted at retention times of 10.308 and 12.080 min, respectively.

Phase 2
The objective of the second phase was to localize the contamination on the plunger with solutions of technetium-99m, in order to determine what quantity of cytotoxic agent could come into contact with the gloves of operators. Two solutions were prepared:

  • 50 mL of a solution of 99mTc, with an activity of 1 GBq;
  • 50 ml of a solution of 20 mg/mL cyclophosphamide in water with 1 GBq of 99mTc.

Both were placed in 50-mL polyvinyl chloride bags. Three tests were performed.

  • In the first and second tests, 1, 3, 5 and 10 samples of the solution of 99mTc and of the solution of cyclophosphamide and 99mTc were drawn up by an operator who avoided touching the plunger with his gloves during sampling. The axis of the plunger was unchanged.
  • In the third test, 1, 3, 5 and 10 samples of the solution of cyclophosphamide and 99mTc were drawn up by an operator who touched the plunger with his gloves during sampling. The axis of the plunger was thus modified, which corresponds to the actual situation in normal use. After each in-and-out movement of the plunger, the gloves were removed and the contaminating activity measured with an external Canberra probe. The data points reported correspond to the mean of activities measured on four different syringes.

Sampling on plungers. Three samples were taken from the plunger of each syringe with swabs impregnated with double-distilled water (Figure 1). Samples corresponded to the surface of the upper half of the plunger (E1), the surface of the plunger adjacent to the joint (E2) and the surface of the joint itself (E3), respectively

Analytical method. Activity was measured using a Packard Cobra counter with five measurement wells. Both the background activity and the rate of decay of 99mTc were taken into account in the measurements.

Contamination-of-syringe-plungers-during-the-sampling-1-jpg

Figure 1. Location of samples from syringe plungers.

RESULTS

Phase 1
The plungers of the eight syringes tested were contaminated with cyclophosphamide (Table 1) (mean value, 71.5 ng; range, 3.7-445.7 ng). Cyclophosphamide concentration in the solution was 20 mg/mL, which corresponds to a mean volume of 3.6 nL (0.2-22.3 nL). 

Contamination reached 50 ng or more in one of three syringes, and about 5 ng in two of three syringes. No relationship was found between the number of in-and-out movements of the plunger and the quantity of cyclophosphamide on the plunger.

Phase 2
The results of the second phase are shown in Tables 2 and 3. Almost no contamination was found when labelled water was used (A). Contamination remained under 1 nL, even after 10 in-and-out pushes, although a slight increase was noted when the number of plunges increased. The contamination of the plungers was consistently greater with the solution of radiolabelled cyclophosphamide than with the pure radiolabelled solution, regardless of the test or the number of in-and-out pushes. This difference became obvious after the first use of the syringe, whether the operator touched the plunger with gloves or not; however, the total contamination of the plungers was more important after the operator had touched the plunger than otherwise, but this difference disappeared after 10 plunges.

Upper and lower surfaces of the plungers (E1 and E2). The contamination of the upper and lower surfaces of the plungers corresponds to the amount of contaminant that could come into contact with the gloves of operators.

  • Almost none (90 pL, Table 2) was found with radiolabelled water, regardless of the number of inand-out plunges.
  • Contamination increased after only five in-and-out plunges in the test with no contact with the plunger. Little contamination was seen after the first in-and-out plunge, but the amount increased rapidly as a function of the number of plunges; a 50-fold increase was noted between one and 10 plunges (from 0.08 to 3.99 nL).

DISCUSSION

Our results show that cyclophosphamide infiltrates onto the plungers of syringes, suggesting that the general procedure for the manipulation of cytotoxic agents should be modified. Syringes should not be used throughout the day, but should often be replaced with new ones. Systematic replacement after each manipulation is not justified, as we have shown that leakage onto the plunger occurs only after a syringe has been used several times.

These results also call into question the use of twopiece syringes for reconstituting antineoplastic drugs, as these syringes are less watertight than three-part syringes. This study may lead, as was the case for gloves, to establishing recommendations for the use of certain syringes for the manipulation of cytotoxic agents.

The infiltration onto the plunger is higher with the cyclophosphamide solution than with labelled water, and the quantity increases with the number of uses of the syringe. We suppose that the cyclophosphamide solution itself reacts with the joint or the syringe to ease its way onto the plunger. Initial investigations have shown that the acid pH of the cyclophosphamide solution may affect the silicone used to lubricate the syringe.

The finding that cyclophosphamide infiltrates onto the plungers of syringes further accounts for the contamination of gloves, as well as flasks, during drug manipulation,5,6 even when no handling error is made. The different amounts deposited on the upper and lower surfaces of the plunger in the various tests (either when operators touched the plunger on sampling cyclophosphamide or when they did not) indicate that up to 10.2-53.4 ng of the drug may contaminate the gloves of operators after 5-10 in-and-out plunges (Table 3). This contamination, when repeated all day and going unrecognized, or when not efficiently dealt with, might contribute to the occupational exposure of operators.

Table 1. Amounts and volumes of cyclophosphamide on the plungers of the eight syringes

Contamination of syringe plungers during the sampling 2

Table 2. Volumes (nL) of contaminating agents on the plungers of syringes; results of three tests

aE1, upper surface; E2, lower surface; E3, joint.
bA, sampling of 99mTc solution without touching plunger; bB, sampling of a
solution of cyclophosphamide and 99mTc without touching plunger; bC,
sampling of a solution of cyclophosphamide and 99mTc when touching
plunger.

  • No such trend was found in the third test, when the operator touched the plunger (C). The contamination remained relatively stable, with volumes on upper and lower surfaces varying between 0.52 and 1.32 nL (Table 2). However, the contamination after one and three plunges was, respectively, 13.5 and 3.2 times greater in this test than when the operator did not touch the plunger (B). On the opposite, it was, respectively, 2.0 and 3.0 times lower than in B after 5 and 10 plunges.

Surface of the joint (E3). As for upper and lower parts of the plunger, the contamination of the joint was negligible in the test with 99mTc only, although it slightly increased with the number of in-and-out plunges. A linear progression of the joint contamination was seen in the test with cyclophosphamide when the manipulator did not touch the plunger (B). This was not the case when the plunger was touched (C): wide variations were found in the amount of contamination (0.24-6.67 nL), regardless of the number of in-and-out plunges. Changing the axis of the plunger therefore appears to play a critical role in the contamination of the joint.

Table 3. Amounts (ng) of cyclophosphamide present on plungers; results of two tests

Contamination of syringe plungers during the sampling of cyclophosphamide solutions

aE1 upper surface; E2, lower surface; E3, joint. bB, sampling of a solution of cyclophosphamide and 99mTc without touching plunger; bC, sampling of a solution of cyclophosphamide and 99mTc when touching plunger.

Assessment of Closed System Transfer Devices 5-FU Drug Leakage

1 Introduction

Recently, the number of marketed Closed System Transfer Device (CSTD) models has increased. Interest in development of a CSTD performance test protocol originated from within the healthcare industry itself, with requests for an independently-developed containment test protocol. Additionally, with the approval of USP chapter 800 mandating the use ofclosed systems for administration_ proper evaluation ofCSTD connectors is essential since vast majority ofadministration procedures involves exclusively the use ofCSTD connectors. To date, several leakage studies have been performed to show whether or not different brands of CSTDs are free ofleaks, drips, microbeads and drug residuals. However, most of these studies are performed on drug surrogates via a litmus paper, UV light, etc. This protocol will test CSTDs with actual antineoplastic agent Fluorouracil (5-FU}.

2 Study Objectives

Objective of this study was to test 6 different CSTD devices to assess how it matches up with their claims of being leak-proof. CSTDs were tested for 5-FU leakage detection.

Administration phase simulation:

3 Study Design

The Litmus test was performed per protocol. There were 6 brands of CSTDs evaluated in this study. 10 unique devices from each brand of CSTD were tested. 3 connector membrane or /uer activations were made per device with 5 Fluorouracil and drug was transferred back and forth between activations. Following the activations connector surfaces were tested for drug residue. 

All devices were allowed to go through 1′1 membrane activation without any litmus detection. The litmus test was executed on 2nd and 3’d membrane activation.

Note that 5-FU was chosen due to its wide usage in oncology, low cost and good visibility on litmus paper. While 5- FU is in the pH range of 10, if desired the test is expandable with same materials and methodology to test additional drugs in same pH range or in the acidic pH range (preferably pH 2-4). Also, handling and cutting of litmus paper was done with nitrile gloves.

Additionally, only pharmacists or pharmacy technicians skilled in use of the tested CSTDs performed this test in accordance to protocoland manufacturers’ directions for use.

4 Supplies Needed

For assessment of Litmus Testing with 5-FU the following supplies were used:

5 Study Procedures

 5.1 Negative and positive controls

For the negative control procedural steps are followed:

  1. A 5-FiourauracillOml vial was capped with a CSTD Vial Adapter
  2. A lOml syringe was attached to a mating CSTD Syringe Adapter (if needed)
  3. One piece of litmus paper was dipped at least half of it into sterile water for Irrigation. The wet litmus paper was padded on an absorbing pad to remove excess water droplet.
  4. This padded litmus paper was backed with a slight finger press on each membrane of the two mating components of the CSTD system. Sufficient distance was kept on the litmus paper between the t wo tested membranes. The purpose of rubbing with wet litmus stripe and the two twist motions is to simulate a membrane disinfection procedure with an IPA pad, a quarter turn left and quarter turn right.
  5. Immediately a photograph of the negative sample was taken and denote ‘–‘ if no color change was determined and ‘y’ if color change was determined.
  6. Pass criteria for the negative test is if no color change was determined.
  7. One negative control test was performed for each brand of CSTD tested.
  8. If no color change was determined the negative control vial, syringe and CSTD were deemed appropriate to be used for the litmus drug test.

For the positive control procedural steps are followed:

  1. A 5-Fiourauracil10ml vial was accessed and a small amount of the drug was placed on the litmus paper.
  2. Pass criteria for the positive test is if color change was determined.

5.2 Study Procedurefor Litmus Drug Test

The following procedural steps were followed:

  1. A 5-Fiourauracil10ml vial was capped with a brand of CSTD Vial Adapter
  2. A 10ml syringe was attached to a mating CSTD Syringe Adapter (if needed)
  3. The syringe was attached to the vial.
  4. A 7ml of total volume of drug was pulled by the process of Pull-Push-Pull to simulate bubbles removal: pull 4ml, push back 4ml and pull 7ml
  5. The vial was inverted upright to reinject 5ml back into the vial (2mlleft in the syringe).
  6. The two mating systems were disconnected
  7. The syringe was attached to the vial and the remaining 2ml was injected from the syringe into the vial.
  8. Steps 4 to 6 were repeated.
  9. One piece of litmus paper was dipped at least half of it into sterile water for irrigat ion, t hen patted dry onto an absorbing pad to remove excess water droplet.
  10. The wet litmus paper was backed with a slight finger press on each membrane of the two mating components of the CSTD system. Sufficient distance on the litmus stripe was kept between the two tested membranes. The purpose of rubbing with wet litmus stripe and the two twist motions is to simulate a membrane disinfection procedure with an IPA pad, a quarter turn left and quarter turn right.
  11. Immediately photograph of each sample was taken and denote ‘-‘ if no color change was determined and ‘y’ if color change was determined
  12. Process steps 7 to 11 were repeated with the same CSTD (for a total of 3 activations)
  13. Test were repeated for 9 additional devices within the CSTD category with 9 additional vialsof 5-FU
  14. Test were completed for 5 additional CSTD brands and results recorded into data collection sheet with image capture

6 Results

The test has been performed without any adverse occurrences. No product or procedure failures were noted. The results are clear and consistent throughout testing of the same CSTD system. The test sensitivity allows clear differentiation between performances of various CSTD systems. Of all the CSTDs brands tested, Equashield brand of CSTD was able to withstand membrane activations and showed 0 leaks. Our expectations that the test is easily replicable by any hospital pharmacy were met.

Table 1: CSTD Study Plan

Summary data is presented below:

7 Appendices

Appendix I: Data Summary Table for Drug Litmus Test

Appendix II: Onguard/Tevadaptor Data Collection

SheetAppendix Ill: PhaSeal Data Collection Sheet

Appendix IV: ViaiShield Data Collection Sheet

Appendix V: Equashield Data Collection Sheet

Appendix VI: ChemoCiave Data Collection Sheet

Appendix VII: Chemolock Data Collection Sheet

Effectiveness of Closed System Drug Transfer Devices

1 Introduction

Antineoplastic drugs, also known as cytotoxic or cytostatic drugs, are medications designed to destroy cells that grow rapidly and uncontrollably, preventing them from replicating or growing. Unfortunately, they are non-selective and do not differentiate between malignant and normal cells; it is therefore likely that they can damage healthy tissues, resulting in adverse health effects [1].
Essential for cancer treatment, they also play an important role in hematology. Addi- tionally, they are used to treat rheumatologic diseases, multiple sclerosis, psoriasis, and lupus erythematosus [2]. These drugs are therefore widely used, and the number of prepa- rations and administrations has increased significantly over the years, highlighting the risk associated with occupational exposure [3,4].
The U.S. National Institute for Occupational Safety and Health (NIOSH) has included antineoplastic drugs in their definition of hazardous drugs because they are dangerous chemical agents that are known or suspected to cause adverse effects from exposure in the workplace. It is well known that healthcare workers who are continuously exposed to low doses of antineoplastic drugs may experience acute symptoms such as allergic reactions, headache, nausea, and vomiting or long-term effects including genotoxicity, infertility, and fetal abnormalities [5]. To minimize exposure, the guidelines for the safe handling of antineoplastic drugs and for protecting workers recommend using biological safety cabinets (BSCs) with a laminar vertical airflow hood and external exhaust in preparation areas as well as wearing adequate personal protective equipment (PPE) and undergoing staff education [6]. Wipe sampling for antineoplastic drug surface residue of is considered the method of choice to assess the risk of occupational exposure and to determine the effectiveness of safe handling procedures in healthcare settings [7].
The exposure to antineoplastic drugs can occur via direct and indirect contacts. The main routes of direct exposure are the inhalation of aerosolized drugs, ingestion, and injection through accidental needle sticks. Spills, leaks, and aerosols are often caused by needles or by Luer lock-based needleless connectors. Indirect exposure from dermal absorption is caused by aerosolized antineoplastic drugs that can settle on work surfaces. A possible contamination source is the open barrel of a standard syringe plunger when it comes into contact with the cytotoxic agent during aspiration and remains exposed to the environment once the drug is discharged from the syringe [8].
Many strategies have been deployed to reduce the risk of occupational exposure to dangerous drugs for healthcare professionals, including control devices designed to act as closed systems and preventing exposure through liquid or vapor leakage. These devices, known as closed system drug transfer devices (CSTDs), are defined by NIOSH as transfer devices that mechanically prohibit the escape of hazardous drugs or vapor concentrations from the system and the entry of environmental contaminants into the system. Closed systems, equipped with a mechanism to regulate the differential pressure inside and outside the vial, limit the potential for aerosol generation and, consequently, the exposure of workers.
Since the publication of the NIOSH Alert in 2004 [9], the use of CSTDs for the prepara- tion of hazardous drugs has been encouraged in United States hospitals, and the European Biosafety Network has also began to promote these prevention devices [10]. However, the interest in and the usage of CSTDs significantly increased after the publication of the United States Pharmacopeia (USP) General Chapter (800), “Hazardous Drugs-Handling in Healthcare Settings” [11].
Today, several CSTDs are available on the market. They are designed differently from each other, and they should act to maintain a closed connection between the vial and the syringe or transfer device. There are two primary CSTD device-to-device interface designs that are available today: the needle-free common fluid pathway and the membrane-to- membrane needle pathway [12]. CSTDs with a needle-free common fluid pathway use mating membranes or plastic components that, when they are connected, open a common channel for transferring drugs and vapors, and when they are disconnected, the system is closed and sealed. Membrane-to-membrane needle pathway CSTDs use two adjacent membranes that are engaged by one or more needles for the removal of drugs and vapors and for equalizing pressure. As the system is disengaged, the needles are scrubbed of drug residue by the membranes and is stored securely within the system.
PhaSealTM from BD Medical (Franklin Lakes, NJ, USA) was the first CSTD approved
by the U.S. Food and Drug Administration (FDA) in 1998. Since then, a range of CSTDs have been approved as closed system transfer devices, including ChemoLockTM/ChemoClaveTM (ICU Medical, San Clemente, CA, USA), Equashield® (Plastmed, Ltd., Tefen, Israel), Equashield® II (Equashield, Port Washington, NY, USA), TexiumTM (BD Carefusion, San Diego, CA, USA), OnGuard®/Tevadaptor® (B. Braun Medical, Bethlehem, PA, USA), Genie® with Spiros® (ICU Medical, San Clemente, CA, USA), Halo® (Corvida Medical, Eagan, MN, USA), Arisure® (Yukon Medical, Durhan, NC, USA) [13].
Since the introduction of CSTDs in early 2000, numerous studies have demonstrated their effectiveness at decreasing surface contaminations and occupational exposure of healthcare personnel [14–19].
The primary purpose of this study was to evaluate the effectiveness of two closed system transfer devices (TexiumTM/SmartSiteTM and Equashield® II) in reducing leakage during antineoplastic drug compounding, which was achieved by surface wipe sampling. The antineoplastic drug gemcitabine (GEM) was measured using surface wipe sampling in the work area, in the vial access device, and in the access port system to an intravenous therapy bag (IV bag) after the reconstitution and drug preparation steps. The performance of different CSTDs was also assessed by comparing the most recent literature data.

Table 1.

2 Materials and Design

2.1 Study Design and Sample Collection

This study was conducted in the centralized cytotoxic drug preparation unit of a Genova hospital pharmacy department.
The sterile doses of parental cytotoxic drugs were prepared every day through manual compounding in two class II BSCs with a return air system, located in a negative pressure clean room. The return air was filtered through a high efficiency particulate air (HEPA) filter and a carbon filter. The cytotoxic drugs were distributed to the oncology wards of three hospitals.
Every day four nursing operators prepared the cytotoxic drugs, alternating their work of preparing drugs in the BSC (the first operator) and supporting the work of the preparer (the second operator).
Wipe and pad samples were taken during the surveillance programs from 2016 to 2021. Double monitoring was performed in 2018.
In order to assess the antineoplastic drug exposure assessment of the healthcare workers, 5-fluorouracile, gemcitabine, paclitaxel, and platinum compounds were used as markers.
Beginning in 2017, wipe samplings of the spike adaptor and the access port to the IV bag were performed during gemcitabine preparation. Therefore, the comparison results obtained from gemcitabine monitoring are reported in this study are for the CSTDs only.
Until the end of 2019, the CSTDs used for antineoplastic drug compounding included the system solutions TexiumTM/SmartSiteTM (BD), which were afterwards replaced with the Equashield® II (Equashield).

2.2 Standard Practices

According to the national guidelines [20,21], cytotoxic drugs were prepared in a BSC using sterile latex rubber chemoprotective gloves and replacing them every 30 min. According to procedure, disposable gowns, overshoes, and head coverings were required. Antineoplastic drugs and infusion solution followed this path: from the warehouse, where they were stored, they were transferred to the filter area, and from there they were carried to the clean room through the pass-box. Transport cases were used for all handling. The BSC work surfaces, side walls, and glass barrier were cleaned with 70% ethanol solution (Farmecol 70, Nuova Farmec) before the workday began. Before starting antineo- plastic preparation, absorbent sheets with plastic backing were placed on the shelf of the BSC to contain the dispersion of the drugs in case of accidental spillage. Before dilution, each preparation was wiped at the insert point of the drug with a gauze pad moistened with Farmecol 70.

At the end of the compounding process, each drug was sealed in a plastic bag labeled with the identification of the receiver patient. The plastic bags were placed in a rigid plastic container, and they were transferred out of the clean room through the pass-box. From the antineoplastic drug preparation unit, the drugs were transported directly to the patient-treatment department in a closed bag.

The working surfaces were wiped with Farmecol 70 at the end of the work shift and during the day if necessary. A deep cleaning of the clean room floor and walls was conducted with a cleaner containing chlorex at the end of the workday.

2.3. Wipe Sampling and Personal Pad

Wipe sampling allowed the verification of possible drug dispersion on the sur- faces while the personal pad enabled assessment of the efficiency of the BSC during working hours activity.

A predetermined wipe/pad sampling scheme for selected surface areas inside and outside the preparation area was studied and repeated over time. Inside the clean room, sampling locations included work surfaces, airfoils, countertops, and BSC power buttons. Moreover, in the active work area, we also took samples from the worktable, the pen used by the second operator, the floor, the intercom, and various handles. Sampling points outside of the clean room included the worktable, handles, case, the office desk, and the phone. The forearm and chest of the operators were sampled using pads. The gloves were also sampled using wipes.

Wipe samplings were conducted using a paper filter (Whatman ashless, grade 41) wetted with 0.2 mL of Milli-Q deionized water. The sample collection was conducted by wiping in two different directions, from up to down and from left to right [22–24].

Similar to the wipe samples, the pads were paper filter (Whatman ashless, grade 41). The nursing staff involved in preparing the drugs wore three pads on the outer surfaces of disposable gowns: on the right and left forearm and on the front of the chest [25].

2.4. Sample Extraction
After the wipe and pad samplings, each filter was transferred into a 50 mL polypropy- lene container to be transported to the laboratory, where it was immediately processed. Each filter was wetted with 4.8 mL of deionized water and extracted by ultrasound for 5 min. The extracted samples were filtered with Millex-GP 0.22 µm (Millipore, Burlington, MA, USA) filters and analyzed using a high-performance liquid chromatography system. All of the operations were performed under a chemical hood.

2.5. HPLC Analysis
A total of 100 µl of the sample was injected into the HPLC system 1260 Infinity II (Agilent Technologies, Santa Clara, CA, USA), which was equipped with a variable wave- length UV detector and the software OpenLAB CDS ChemStation (Agilent Technologies, Santa Clara, CA, USA). Separation and quantification of gemcitabine were performed at the wavelength λ: 266 nm using a Raptor FluoroPhenyl column 100 mm × 2.1 mm ID and a particle size of 2.7 µm, equipped with a Raptor FluoroPhenyl EXP guard column cartridge with a 5 mm × 2.1 mm ID and a particle size of 2.7 µm and a mobile phase of methanol/water buffered with 0.02 M ammonium acetate at pH 4.7 (2:98, v/v) at a flow of 0.5 mL min−1. All HPLC-grade solvents were purchased from Merck. Gemcitabine (Accord) 100 mg/mL was used as the calibration standard.
2.6. Quality Controls
For each monitoring, blank wipes/pads were extracted and analyzed according to the sample procedure to determine the limit of detection (LOD) and to set the zero concentra- tion for each analytical run. The LOD for GEM, calculated as the average value of the field blanks plus 3 times the standard deviation, was 5 ng/wipe. The limit of quantification (LOQ), defined as 3 × LOD, was 15 ng/wipe. Analyzed blanks were always at background signal levels. The precision level obtained from the triplicate standards of the GEM was 0.6%. Recoveries were performed using 6 wet filters wetted with 10 µL of gemcitabine standard, creating 3 filters at 0.05 µg/wipe and 3 filters at 5 µg/wipe as final concentrations. The recovery filters were extracted and analyzed according to sample procedure, resulted in a level of 98 ± 4%.

2.7. Statistical Analysis
The statistical significance of the difference between the data obtained using the TexiumTM/SmartSiteTM in 2016–2018 (n = 74) and those obtained using the Equashield® in 2020–2021 (n = 38) was tested through a non-parametric Mann–Whitney U test using the software Statview (SAS Institute, Cary, NC, USA).

3 Results

Table 1 shows the GEM concentration in wipe/pad samples during the antineoplastic drug monitoring programs from 2016 to 2021.

Table 1. Results of GEM concentrations (ng/wipe) in wipe/pad samples during the monitoring programs from 2016 to 2021.

In 2016, the presence of GEM was found in six of the 35 samples. Contamination was present on the grid and the external border of the BSC with 25 and 22 ng/wipe, respectively, and on the worktable with 43 ng/wipe. High concentrations of GEM (3.8 µg/wipe) were found on the left glove of the first operator in the absence of apparent accidental spillage of drug. The second operator’s forearm and right glove were also slightly contaminated (19 and 15 ng/wipe, respectively). From these results, it was assumed that gemcitabine could derive from unsealed preparation systems.

In successive checks from 2017 to 2021, the spike/vial adaptor access and valve IV bag access port of the closed system devices were monitored during gemcitabine compounding. High levels of GEM were evidenced in wipes of devices in the 2017 and 2018 sampling campaigns, but the drug was below the detection limit (LOD) of 5 ng/wipe in 2020 and 2021 checks.
In 2017, the GEM concentrations were 27.0 and 14.4 µg/wipe in the spike and ac- cess port, respectively. The results were also confirmed in two 2018 checks. During the
first sampling, 2018(I), GEM concentrations in the spike and the IV bag access port were
206.4 and 3.4 µg/wipe, respectively, while during the second check, 2018(II), GEM concen- trations were 431.8 and 17.5 µg/wipe. In 2017, a trace of GEM was found on the right forearm of the first operator (20 ng/wipe). In 2018(I), the right and left gloves of the first operator were strongly GEM contaminated (2.6 and 16.4 µg/wipe, respectively), as was the left glove of the second operator (113 ng/wipe). In the 2018(I) monitoring program, the center and the grid of the cabinet were found to be contaminated by GEM (670 and 184 ng/wipe, respectively) as was the handle of the pass-box (286 ng/wipe), evident signs of a widespread dispersion of the drug. In 2018(II), GEM concentrations were also found in the BSC grid (11.4 µg/wipe) and in its external border (409 ng/wipe). In 2020 and 2021, gemcitabine was not present at detectable levels in any wipe/pad samples. Mann– Whitney U test analysis indicated that the difference between the recorded values for the TexiumTM/SmartSiteTM and Equashield® was significantly different, with a U value of 1159 and a p value = 0.0064.
With these results, the study intends to encourage the use of CSTDs, and if prop- erly designed and used, they offer healthcare professionals advanced protection against potentially hazardous drug exposures.

5 Discussion

Environmental monitoring has played an important role in protecting workers from exposure to antineoplastic drugs because it has allowed the identification of the weak points in the working procedures. GEM was detected in all spikes and bag access ports of the closed system solution TexiumTM/SmartSiteTM, often producing the drug contamination of the gloves of both preparer and support operator, with consequent dispersion outside the BSC. When using the TexiumTM/SmartSiteTM solution, the percentages of GEM-positive samples ranged from 9 to 23%.

In contrast, GEM was not present at detectable levels in any sample when compound- ing using the Equashield® II system. As a result, the Equashield® II closed system seemed able to effectively eliminate spills and leakage during antineoplastic drug compounding and, consequently, the surface contaminations in the antineoplastic drug unit.

These results are supported by studies focused on the containment function of CSTDs. TexiumTM male Luer and SmartSiteTM vented vial access were examined by Jorgenson et al. [26] for their airtightness and leak-proof capacity in both preparation and administration practices. They performed two tests using titanium tetrachloride and fluo- rescein sodium to simulate the escape of vapor and the contamination of the connections between the vial and the syringe and the between syringe and the access port. The visi- ble presence of titanium smoke in the first test highlighted that the system was not able to prevent vapor escape. In the second test, the presence of fluorescein leaking outside the connections during preparation and administration manipulations demonstrated the potential drug release into the work environment. A successive study, with fluorescein also chosen as the tracer to measure contamination during the preparation of a solution using the TexiumTM and SmartSiteTM systems, confirmed the same results for the same critical points [27].

In contrast, some studies have shown a percentage decrease of antineoplastic drug detectable levels in surface sampling wipes after the implementation of the Equashield® CSTD. Clark and Sessink [28] demonstrated that when using the Equashield® to prepare and administer chemotherapy drugs, the surface contamination for the evaluated cyto-toxic agents, cyclophosphamide and 5-fluorouracile, were eliminated. The Equashield® design with a metal rod as a syringe plunger prevents plunger contamination, as shown by Smith and Szlaczky [29]. The authors evaluated the plungers of BD syringes with the PhaSealTM CSTD against those of the Equashield® using wipe test sampling after repeated withdrawal and re-injection cycles of cyclophosphamide in order to simulate their repeated use. They found significant cyclophosphamide contamination levels on most PhaSealTM BD syringes, while the Equashield® syringes remained uncontaminated at undetectable levels. Wilkinson et al. [30] proved that Equashield® was qualified to handle hazardous drugs by using 2-phenoxyethanol as the surrogate for cytotoxic drugs when testing the vapor containment performance of different CSTDs according to the NIOSH protocol [31]. The same authors highlighted that OnGuard®/Tevadaptor® and PhaSealTM also met the acceptance criteria for significantly reducing operator exposure, while ChemoClaveTM did not meet these requirements. Forshay et al. [6] evaluated the vapor containment abilities of Equashield® II and five other CSTDs (ChemoClaveTM, ChemoLockTM, OnGuard®/Tevadaptor®, PhaSealTM, and SmartSiteTM/VialShield®) dur- ing the tasks of compounding and administration. The performances were assessed by measuring the vapor release for 70% isopropyl alcohol according to the NIOSH proto- col [32]. Among the considered CSTDs, only the Equashield® and PhaSealTM proved to be adequately close in both tasks. Another recent study compared three different CSTDs (PhaSealTM, ChemoLockTM, and Equashield® II) for their adoption into the daily practice of compounding and administration [18]. No statistically significant difference in the compounding efficiency was observed among the three different devices, while in terms of ease of use, PhaSealTM required more steps than the ChemoLockTM and Equashield® II. In terms of ease of use, it also has been shown in a previous study that the Equashield® system is more readily accepted by operators than the PhaSealTM [33].
From the abovementioned studies, we can deduce the effectiveness of the Equashield® at ensuring the containment of liquid and/or vapor, but this does not preclude that other CSTDs may be equally effective. The differences among the devices as well as the lack of standard quantitative methods for assessing CSTD performances, as underlined by USP (800), do not facilitate a choice for which the currently available CSTDs would be best suited to the daily practices of hazardous drug compounding and administration. A recent study by Besheer et al. [34] highlighted the need to evaluate the performance aspects of CSTDs to select the best system for their intended use. In this study, four commercially available, but not identified, CSTDs were evaluated for different suppliers in combination with different container-closure systems, different vial sizes and vial types, and different caps. The tests assessed the integrity of the systems by using the helium leak test to measure the force required to assemble the vial adaptor, the presence of particles after pushing the CSTD through the rubber stopper, and the hold-up volume that was not extracted from the vial. The helium container-closure integrity test proved a significant variability among the same CSTDs from a single vendor and among different CSTDs, leading the authors to conclude that CSTDs may not be fully sealed and that there may be leaks.
The other performances evaluated by Besheer et al. [34] could affect drug administra- tion and, even if they do not directly affect the compounding steps covered by our study, they are fundamental for the choice of device. The penetration force seems to depend on the CSTD type, including the rubber stopper puncture force. The presence of significant visible particles contaminating the final product due to stopper coring and shedding depends on the CSTD type that is used as well as the presence of subvisible particles, in particular, silicone oil. The hold-up volume or the volume that cannot be extracted from the vial or that remains in the CSTD components could depend on the vial size, the viscosity of the solution, or the CSTD design—in particular, the spike or needle length and the opening position. The authors concluded by asserting that all of these factors may affect drug administration, causing contamination or leading to a systematic underdosing, therefore affecting the drug efficacy.

In another recent paper, Kulju et al. also examined the hold-up volume, comparing the performances of the PhaSealTM, TexiumTM/SmartSiteTM, OnGuard®/Tevadaptor®, Equashield®, ChemoClaveTM, and ChemoLockTM [35]. The authors established that the different CSTDs contribute to volume loss by using sterile water during simulated pro- cesses of drug preparation and subcutaneous administration in different measures. Before testing, the authors assumed that the Luer lock adapter, a component required in all membrane-to-membrane needle pathway CSTDs, could be a potential source of volume loss in 0.5–3.0 mL subcutaneous/intramuscular administrations, due to the presence of a dead space of about 0.1 mL. This hypothesis was not confirmed. In fact, two CSTDs of different design, ChemoClaveTM, a needle-free closed-fluid pathway, and PhaSealTM, a membrane-to-membrane needle pathway, had the lowest volume losses. All of the other CSTDs had more than twice the mean volume loss of the ChemoClaveTM and PhaSealTM.
Solutions with different viscosities might behave differently in a CSTD; therefore, had the authors used hazardous drugs instead of sterile water, the results might have been different. The study also highlighted that the volume loss was independent of the prepared volume. Therefore, volume loss can be significant for administrations below a 3 mL threshold, but it becomes less important as the administration volume increases. During the trials, it was also observed that after the connection between the TexiumTM closed male Luer and the needle, multiple drops of fluid escaped from the system and collected inside the needle cap. This confirmed that TexiumTM is not suitable for intramuscular and subcutaneous administration, and it is probably for this reason that the operative instructions do not include this use.
Considering the above, we confirmed that the choice of CSTD for hazardous drug compounding and administration is not easy to make. It is possible that different devices must be used depending on the drug type, but these assumptions must be validated.
Limitations of our study include its retrospective nature and the relatively small number of cases.

6 Conclusions

CSTDs are important supplemental engineering controls for containing the exposure of healthcare professionals involved in the handling of hazardous drugs.
GEM dispersion was found after compounding with the TexiumTM/SmartSiteTM, while the Equashield® appeared to be completely tight and able to eliminate exposure to
GEM. However, to understand why drugs with different viscosities may have different effects on the device, it will be important to evaluate the performance of the Equashield® with other antineoplastic drugs during a structured surveillance program.
The high interest in this topic has led to many studies that have mainly focused on the containment features of CSTDs; however, it will be important to also verify the functionality attributes of CSTDs as well as their impact on final product quality. It is commonly acknowledged that an important goal is to harmonize testing procedures to undertake real comparisons among studies.

Author Contributions: Conceptualization, M.T.P.; methodology, A.F.; validation, M.T.P. and A.I.; formal analysis, M.T.P.; investigation, M.T.P.; resources, M.T.P.; data curation, M.T.P. and A.F.; writing—original draft preparation, M.T.P.; writing—review and editing, M.T.P.; visualization, A.I.; supervision, A.I.; funding acquisition, M.T.P. All authors have read and agreed to the published version of the manuscript.

Funding: This work was supported by grants from the Italian Ministry of Health (Ricerca Corrente no. C708A).

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement: All data are contained within this manuscript.

Conflicts of Interest: The authors declare no conflict of interest.

PPC 2016 Poster Abstract

À un article synthèse sur le sujet, puis ils étaient invités à signer un CBPPL. Quatre semaines après la signature du code, les étudiants pouvaient répondre à sept questions relatives à leurs perceptions sur le sujet. Une échelle Likert et une échelle dichotomique (oui/non) ont été utilisées selon les questions.

Résultats : Au total, 198 étudiants (taux de réponse : 100%) ont signé le CBPPL en août 2015 et 197 étudiants ont répondu aux questions quatre semaine plus tard. Dans l’ensemble, 99% étaient en accord avec le fait que la lecture de l’article synthèse les a sensibilisés aux risques des comportements en ligne en exerçant la pharmacie. La majorité (94%) était d’avis que cet article les a exposés aux opportunités des médias
sociaux et autres outils en ligne en pharmacie. Un total de 96% a confirmé que la lecture du CBPPL les a fait réfléchir et a remis en question certaines pratiques. Un total de 73% ont modifié certains paramètres d’accès de leurs comptes en ligne et 28% ont abandonné certaines plates-formes. De plus, 89% se sont dits intéressés à un atelier structuré sur l’utilisation responsable des médias sociaux.

Conclusion : La signature d’un code de CBPPL est faisable et contribue à la sensibilisation et à des changements de comportements d’étudiants en pharmacie de 1er cycle.

Chambre des erreurs : une simulation afin de sensibiliser le personnel soignant aux risques du circuit du médicament

Daupin J¹, Pelchat V², Atkinson S1, Bussières JF¹,³
¹Unité de recherche en pratique pharmaceutique, Département de pharmacie, CHU Sainte-Justine, Montréal, QC
²Direction des soins infirmiers, CHU Sainte-Justine, Montréal, QC
³Faculté de pharmacie, Université de Montréal, Montréal, QC

Contexte : Agrément Canada détermine ses exigences en ce qui concerne le circuit du médicament à partir de la norme sur la gestion des médicaments.

Objectifs : Évaluer la capacité du personnel soignant à identifier des erreurs reliées au circuit du médicament dans le cadre d’une simulation et évaluer la satisfaction du personnel exposé à cette activité.

Méthodologie : Il s’agit d’une étude descriptive transversale. En préparation à la visite d’agrément, nous avons scénarisé 30 vignettes relatives au circuit du médicament de la prescription à l’administration de doses de médicaments. Ving-quatre erreurs (pratiques non conformes) étaient dissimulées. Un aménagement représentant une pharmacie d’étage et une chambre de patient a permis de scénariser de façon réaliste le circuit (p.ex. lit, comptoirs, pompe, ordonnances, étiquettes, seringues, chariots). Des plages horaires de jour-soir-nuit ont été offertes avec publicité afin d’inciter la participation. Chaque participant avait en main une grille afin d’indiquer la présence ou l’absence d’erreur par vignette ainsi qu’un questionnaire de satisfaction (13 questions).

Résultats : Au total, 175 personnes (moyenne 12,1±10,5 années d’expérience) se sont présentées à l’activité (70,4%-infirmières, 8,3%- pharmaciens, 6,5%-médecins/résidents, 4,7%-assistant-technique, 10,7%-autres) durant 9 plages horaires pour 75 heures. Le taux moyen d’exactitude des participants était de 65,9%±13,1%. Sept vignettes comportaient un taux d’exactitude <50% pour les thèmes suivants :
seringue, lavage des mains, identification du patient, port de gants, relevé de température, abréviation et incompatibilité. Parmi les énoncés, les participants ont considété la simulation comme étant très pertinente (96%), très efficace (97%) et lui accordait en moyenne une note de 8,9±1,2. Une majorité de répondants (84%) envisageait d’apporter des changements à sa pratique.

Conclusion : Cette étude démontre la pertinence et l’efficacité d’une simulation de type « chambre des erreurs » afin de sensibiliser le personnel d’un établissement de santé aux risques du circuit du médicament.

Evaluation of the Sterility of Single-Use Vials Undergoing Multiple Access Following Application of a Closed System Transfer Device

Perks W, Carating H, Iazzetta J, Charbonneau LF, Walker SE
Department of Pharmacy, Sunnybrook Health Sciences Centre, Toronto, ON Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON

Background: Closed system transfer devices (CSTD) are designed for safe handling of hazardous drugs from preparation to administration.
According to NIOSH, these devices are airtight and leak-proof. While these devices protect staff, as a closed system they could also minimize microbial contamination.

Objective: To test whether attaching a CSTD (Equashield®) to singleuse vials can minimize microbial contamination and extend the “use-by” date following multiple withdrawals under extreme-use-conditions.

Methods: An Equashield® vial adapter was attached to three 20 mL vials (A, B, C) containing sterile TSB growth medium and placed in each of 6 biological safety cabinets weekly for 16 weeks. Vial A (control) had no medium removed during the week. One mL of medium was removed once daily x5 days from vial B, and twice daily x5 days from vial C. At day 5, vials were collected, incubated at 37o C for 14 days and inspected visually every 2 days for microbial growth. As a positive control, TSB vials were inoculated with less than 102 of S. epidermidis ATC 12228. As a negative control, an unopened vial of TSB was incubated for the duration of the study.

Results: All positive control vials demonstrated growth within 48 hours. All negative control vials showed no growth throughout the study. During the 16-week study all accessed vials remained sterile following storage at
room temperature for 5 days and subsequent incubation for 14 days. None of the 192 vials accessed 1440 times or the 96 vials that had the CSTD attached but had no broth removed demonstrated contamination. The 95% confidence interval of the contamination rate is 0.000 to
0.035%.

Conclusions: Attachment of a CSTD adapter to single-use vials within an ISO-5 environment has the ability to maintain sterility following multiple withdrawals during 5 days and stored in worse than ISO-5 conditions.

Evaluation of a Critical Incident: Simulating Hydromorphone Concentrations Using Population-Based Pharmacokinetic Parameters

Zheng H², Wong L², Bailey C³, Sawyer J4, Wu T4, Zhou L4,Van Der Vyver M4, Belo S4, Walker SE¹,²
¹Department of Pharmacy, Sunnybrook Health Sciences Centre, Toronto, ON
²Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON
³Quality & Patient Safety, Sunnybrook Health Sciences Centre, Toronto, ON
4Acute Pain Service, Sunnybrook Health Sciences Centre, Toronto, ON

Background: Opioids are commonly used for pain management in a postoperative setting but use can be associated with life-threatening respiratory depression. Naloxone administration is used to rescue patients suffering from respiratory depression. An unexpected death of a patient after the hydromorphone dose was increased triggered an investigation into the safety of opioids in pain management.

Development of an On-Going Sterility Monitoring Program for Single-Use Vials Undergoing Multiple Access Following Application of a Closed System Transfer Device

Methods: On study day 0, ICG solutions of 2.5mg/mL were prepared in 5mL PP syringes, reconstituted with SWFI. Three syringes were stored at 25°C, 4°C, -20°C or -67°C. ICG concentrations were determined 8 times over each study period at each temperature using a validated
stability indicating analytical method. Chemical stability was based on the intersection of the lower limit of the 95% confidence interval of the observed degradation rate and the time to achieve 90% of the initial
concentration (T-90).

Results: The analytical method separated degradation products from ICG such that the concentration was measured specifically, accurately and reproducibly (1.73% (CV(%)). Analysis of variance revealed significant differences in percent remaining due to study day (p=0.009) and temperature (p=0.035). The calculated T-90, with 95% confidence, exceeded the 28-day study period for syringes stored in the freezer at
either -20°C or -67°C. The calculated T-90, with 95% confidence, was 34.11 hours at 25°C and 37.38 hours at 4°C.

Conclusions: We conclude that 2.5mg/mL solutions of ICG may be stored frozen at -20°C or -67°C for up to 28 days, but at 4°C or 25°C, solutions should be stored for only 36-hours. Syringes stored in the freezer for up 28-days can be withdrawn from the freezer, allowed to thaw, but should be used within 24-hours of withdrawal from the freezer. Under these conditions more than 92.5% of the initial ICG concentration will remain at 24 hours.

Development of an On-Going Sterility Monitoring Program for Single-Use Vials Undergoing Multiple Access Following Application of a Closed System Transfer Device

Charbonneau LF¹, Carating H², Mascioli M¹, Iazzetta J¹, Perks W¹, Stinson J¹, Nedzka-Rajwans I¹, Walker SE²
¹Department of Pharmacy Sunnybrook Health Sciences Centre, Toronto, ON
²Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON

Background: Closed system transfer devices (CSTD) are designed to protect healthcare workers from exposure to hazardous drugs. These devices have also been shown to minimize microbial contamination of single use vials (SUV). However, NAPRA has suggested that annual testing of the CSTD is necessary to assure continued sterility. Since validation requires more than 3000 transfers, the feasibility of an on-going monitoring program was investigated.

Objective: To test whether attaching a CSTD (Equashield®) to SUVs can minimize microbial contamination and extend the “use-by” date following multiple withdrawals under extreme-use-conditions.

Methods: An Equashield® vial adapter was attached to one 20-mL vial containing sterile TSB growth medium and placed in each of 4 biological safety cabinets weekly. 1-mL samples were drawn from each vial at immediately following application of the CSTD and at 48 and 168 hours. Prior to sample withdrawal vials were visually inspected for turbidity. After 1 week, vials were collected, incubated at 37oC for 14-days and inspected visually every 2 days for evidence of contamination
(turbitidy). 

For positive controls, three TSB vials were inoculated with less than 102 of S.epidermidis ATC12228. As a negative control, three unopened vials of TSB were incubated for 14 days. Stopping rules included growth in 2 CSTD vials in fewer than 100 consecutive vials (contamination rate using lower limit of 80%-Confidence Interval (CI) is greater than 0.20%).

Results: All positive control vials demonstrated growth within 48-hours. All negative control vials showed no growth. During the first 20-weeks of monitoring, all CSTD vials (80 vials – 240 transfers) remained sterile following storage at room temperature for 7 days and subsequent
incubation for 14-days. The 95%-CI of the contamination rate is 0.000 to 0.021%.

Conclusions: Attachment of a CSTD to single-use-vials within an ISO-5 environment has the ability to maintain sterility following multiple withdrawals over 7-days.

Stability of 0.04, 0.1, and 0.2 mg/mL Vitamin K (Phytonadione) in 5% Dextrose in Water Solutions Stored in Polyvinyl Chloride Bags at 4°C over 9 Days

Plaetzer WJ¹, Facca N², Smith N³
¹Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON
²Department of Pharmacy, London Health Sciences Centre, London, ON
³Department of Pathology and Laboratory Medicine, 3London Health Sciences Centre, London, ON

Background: To our knowledge, no stability data exist for 0.04, 0.1 and 0.2 mg/ml intravenous vitamin K (phytonadione) solutions in 5% dextrose in water (D5W) in polyvinyl chloride (PVC) bags.

Objectives: To test the physical and chemical stability of the 0.04- 0.2 mg/ml vitamin K solutions in D5W over 9 days at 4°C.

Methods: Prepared solutions were stored at 4°C for 9 days, with samples taken daily and frozen pending analysis. Samples from selected days throughout the study were analysed in quintuplicate by gas chromatography/mass spectrometry, with vitamin K-d7 as the internal standard
(ISTD). Vitamin K/ISTD peak area ratios (PARs) were calculated for and compared to those of Day 0 by calculating them as a percentage of the Day 0 value. Mass spectra of Day 9 drug peaks were compared to those of Day 0 peaks to confirm purity. Physical stability was assessed visually daily.

Results: The vitamin K concentration in the preparation of 0.04 mg/ml vitamin K in D5W declined, with the lower 95% confidence limit falling below 90% of the Day 0 value within 45 hours. The lower limits of the 95% confidence intervals of the 0.1 & 0.2 mg/ml vitamin K solutions always remained above 90% of the day 0 values. Day 9 mass spectra of
all solutions were identical to those of Day 0. All solutions remained visually consistent over the 9 days.

Conclusions: These data support 0.1 & 0.2 mg/ml vitamin K solutions in D5W as physically and chemically stable for 9 days, but 0.04 mg/ml vitamin K in D5W was chemically stable for less than 2 days.

Leakproof Connection Integrity Test For Devices Intended for Handling Hazardous Drugs

Objective

To determine if the ICU Medical System, B. Braun OnGuardTM System, Cardinal Health/Alaris System or PhaSeal® System connections are leak proof or have the potential to allow drugs to escape into the environment during the preparation and administration phases of hazardous drug handling.

Methods

Four transfer devices were tested:

  • The ICU Medical System (SpirosTM Male Connector & Clave® Connector)
  • The B. Braun OnGuardTM System (Vial Adaptor & Syringe Adaptor) by Teva Medical Ltd.
  • The Alaris System (SmartSite® Vented Vial Access Device & TexiumTM Male Luer) by Cardinal Health
  • The PhaSeal® System (Protector & Injector Luer Lock) by Carmel Pharma

A liquid with low pH was used as a substitute for active drug. Litmus paper was used as a pH indicator. Blue litmus paper turns red under acidic conditions.

Syringes were filled with fluid and injected into vials attached to the above transfer devices. After aspirating back and disconnecting, the connections of each device were pressed against litmus paper to detect the presence of any fluid.

Every component of each device was tested for 10 manipulations.

Results

Visible leakage occurred outside of the components on the ICU Medical System SpirosTM and Clave® connections, the B. Braun OnGuardTM System and the Cardinal Health/Alaris System during all manipulations.

No leakage was observed in any of the manipulations with the PhaSeal® System by Carmel Pharma.

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

B. Braun OnGuard™ Vial Adaptor & Syringe Adaptor by Teva Medical Ltd.

Alaris SmartSite® Vented Vial Access Device & Texium™ Male Luer by Cardinal Health

Alaris SmartSite® Vented Vial Access Device & Texium™ Male Luer by Cardinal Health