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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.

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.

Evaluation of syringes used for compounding hazardous drugs and the contamination risks to healthcare personnel

Purpose

The United States Pharmacopeia (USP) recently published for comment chapter 800, standards on handling hazardous drugs which recommends for compounding the use of a Closed-System Transfer Device (CSTD) and proposes to mandate the use of CSTDs for the administration of hazardous drugs. This recommendation was proposed with consideration of risks for occupational exposures when handling hazardous drugs.

CSTDs are specifically designed to reduce this risk, however the use of commercially available syringes may re-introduce contamination risks during the compounding process. Four out of the five Food and Drug Administration (FDA) approved CSTD’s require the use of commercially available syringes. The fifth FDA approved CSTD manufactured by Equashield®, utilizes a proprietary closed-syringe designed to eliminate
plunger contamination.

This study was designed to evaluate the contamination potential of three syringes (BD ®, Covidien ®, Equashield ®) used for compounding hazardous drugs.

Methods

Simulated IV sterile compounding utilizing 2 gram vials of cyclophosphamide (CP) was performed with the three syringes; Covidien® and Becton Dickenson® 60mL syringes attached to the CSTD PhaSeal® and Equashield® 60mL syringes attached to Equashield® manufactured CSTD.

Prior to the study, multi-step decontamination procedures were used to ensure vials and experimental surfaces were uncontaminated per proposed USP 800 protocol.

A total of 72 manipulations: 24 manipulation for each syringe in a sequence of 2 manipulations for 4 syringes and 4 manipulations for 4 syringes, Figure 1.

Extreme care was taken to minimize the potential for touch contamination of the plunger during manipulations, Figure 1.

After the last manipulation, the 60mL syringe plungers were pulled back to the 50mL position for sampling.

ChemoGlo™ (Chapel Hill, NC) sampling kits were used for quantitative evaluation of CP residue on the plunger shaft to a 10ng/ft2 sensitivity.

Wipe samples were taken from the CP vials, compounder’s gloves and from each side of the plunger shaft for each of the syringes in addition to a negative control and a positive control, Figure 2. (report available)

Results

The CP vials, compounder’s gloves, and negative control samples had no CP detected while the positive CP control sample had significant CP detected (>3,500ng/ft2).

Detectable contamination occurred with all of the Covidien® syringes and 62.5% of the Becton Dickenson® syringes., Table 1

No detectable contamination was measured with Equashield® syringes.

Table 1. Syringe Plunger Contamination Results

Evaluation of syringes used for compounding hazardous drugs and the contamination risks to healthcare personnel

Figure 1. Sample Preparation Process

Figure 2. Syringe Plunger Sampling Process

Evaluation of syringes used for compounding hazardous drugs and the contamination risks to healthcare personnel

Covidien® wipe sample

Evaluation of syringes used for compounding hazardous drugs and the contamination risks to healthcare personnel

Becton Dickenson® wipe sample

Evaluation of syringes used for compounding hazardous drugs and the contamination risks to healthcare personnel

Equashield® wipe sample

Conclusion

The syringe represents the primary medical device used for transferring a drug from a manufactures’ container to patients via compounding. Several safety standards have been proposed to protect healthcare professionals handling hazardous drugs, such as the use of CSTDs. Currently, four of the five US approved CSTDs require the use of a commercially available syringe which may re-introduce occupational risks via plunger contamination during hazardous drug compounding. This study demonstrates the limitations of some commercially available syringes despite the use of appropriate CSTDs when performing multiple manipulations of hazardous drugs.

Caution must be considered when performing multiple manipulations with commercial syringes not designed for containment of hazardous drugs during the compounding process.

Disclosure: Authors of this presentation have the following to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation.

• Fouzia Berdi and Richard Gonzalez – none to disclose

• Fred Massoomi: BD Consulting/speaking/Research Grant; Covidien Consulting; Equashield: Consulting

• Study supported by Nebraska Methodist Hospital Department of Pharmacy Services, Omaha, NE

Comparative Study of Syringe Contamination by Hazardous Drugs

Since the late 1970s numerous studies have documented the potential health risks associated with exposure to hazardous drugs in healthcare settings. Evidence has indicated that exposure to these dangerous substances can lead to acute and long term health complications such as infertility, miscarriage, birth defects, leukemia and other types of cancer. It has been clearly demonstrated that workers are in danger of exposure to these drugs at all contact stages, including drug manufacture, transport, distribution, receipt, storage, preparation, administration, waste handling, and equipment repair and maintenance (ASHP, 2006).

Identifying and quantifying possible sources of contamination is of great importance, as it can contribute to a better understanding of the issues involved in the safe handling of hazardous drugs, as well as to constant improvement of drug handling methods, the development of more effective protective equipment, and the establishment of better pharmacy and bedside compounding and administration safety policies and regulations.

The National Institute for Occupational Safety and Health (NIOSH, 2004) has recommended the use of an effective closed-system drug transfer device (CSTD) in order to facilitate safe, enclosed drug transfers and minimize the exposure to hazardous drugs and their adverse effects.

When examining surface contamination, studies using CSTDs have shown a significant reduction in contamination levels, yet detectable levels of hazardous substances were still found, suggesting that the systems are not entirely safe and that environmental contamination still places healthcare workers at risk of exposure.

In 2005, a study using a surface monitoring technique further explored environmental contamination, when it specifically examined the possibility of syringe plunger contamination during routine drug preparations at hospital pharmacies. Contamination by yclophosphamide was confirmed, quantified, and localized on a standard syringe plunger, in order to determine what quantity of the Cytotoxic agents come into contact with the operators’ gloves (Favier, Gilles, Latour, Desage and Giammarile, 2005). Thus, results revealed a previously undetected route of exposure whereby drug residuals on the syringe plunger contaminate gloves and the work environment, and most alarmingly, place unprotected hospital staff who handle the syringe outside of the safety cabinet, at great danger.

The current study was designed to provide further evidence regarding the surface contamination on standard syringe plungers and barrels during routine drug preparation, using the prevalent Cyclophosphamide. The same agent was also used to quantify drug residuals detected on the inner wall of the syringe cylinders.

As all but one currently available CSTD use standard syringes, this study is significant in establishing the efficiency of these systems in minimizing exposure to hazardous drugs. are only CSTD that has addressed this route of exposure is a new device called EQUASHIELD®.

EQUASHIELD® is a new airtight, leak-proof closed system drug transfer device that prohibits the escape of hazardous drugs and vapors into the surrounding environment through an innovative pressure equalization mechanism. EQUASHIELD® addresses the issue of contamination through the syringe:

1. EQUASHIELD’s Syringe Unit has a double jacket enclosure that seals the syringe barrel and isolates the syringe plunger’s rod. Thus, EQUASHIELD’s design ensures that contaminants remain fully contained, preventing any possibility of plunger and cylinder contact or exposure.
2. There is no direct contact between EQUASHIELD’s plunger rod and the syringe cylinder.
3. The plunger rod’s surface area in EQUASHIELD® is much smaller than that of a standard syringe plunger.
4. EQUASHIELD’s plunger rod can never be detached from the syringe, whereas in standard syringes, the plunger can be pulled out of the barrel.

In order to assess its effectiveness in reducing plunger contamination and aerosol evaporation of drug residuals compared to standard syringes used by other CSTDs, surface contamination of standard syringe plungers and inner walls (barrels) were compared with EQUASHIELD® surface contamina- tion during routine drug preparation procedures.


Method

The study examined two sources of contamination: the first test examined plunger contamination levels, whereas the second test examined the prevalence of syringe barrel residuals that can evaporate into the environment.

Plunger Contamination Test

A total of 24 syringes were used to test plunger contamination levels: 12 standard Becton Dickinson 60cc syringes, and 12 EQUASHIELD® 60cc syringes. Similarly, 24 sealable sampling cups, one for each syringe, were prepared according to the laboratory’s recommendation. All syringes and sampling cups were marked in advance with matching labels that included the following information: the syringe type (BD or ES); the number of manipulations (2M, 4M, or 8M); the serial number (1 to 12 for BD and 1-12 for ES); and an empty space to mark the CP serial number. All syringes and sampling cups were marked in advance with matching labels that included the following information: the syringe type (BD or ES); the number of manipulations (2M, 4M, or 8M); the serial number (1 to 12 for BD and 1-12 for ES); and an empty space to mark the CP serial number. Cyclophosphamide dry substance (Baxter) was admixed in original containers with sodium chlorine solution according to standard procedure, resulting in stock solutions with a concentration of 20mg/ml. pH values were measured for all solutions. All vials filled with Cyclophosphamide were marked with serial numbers. A trained person performed 2, 4 or 8 manipulations with each of the standard and EQUASHIELD® syringes. In each manipulation 50cc Cyclophosphamide were aspired from the vial into the syringe, and then emptied back into the vial. All manipulations were performed in a safety cabinet dedicated to the preparation of antineoplastic drugs, using paper sheets to cover the work area. After the completion of manipulations with each specific syringe, the paper sheet was replaced, gloves were changed and the work area was wiped with 0.1M NaOH followed by 2 Isopropanol before working with the next syringe. After the designated number of manipulations with each syringe was completed, the syringe was moved to a second safety cabinet and placed on a paper sheet. Special care was taken to prevent one syringe from touching another. A KimWipe saturated with 1ml water pH adjusted to 3.0 with HCl was applied to the plunger surfaces as illustrated in Figure 1 in order to determine the contamination level on each syringe plunger. A total of 3 wipes were taken from each plunger and stored at -18ºC until analysis. No longer than 40 minutes elapsed between the time a syringe was manipulated and the time it was wiped. After wiping was completed, syringes were placed in a closed disposal bin and the gloves and paper sheet were replaced. The pH values of the Cyclophosphamide in each vial was measured and recorded.

Recovery rates (101% for the wiping tests and 72% for the rinsing procedure) and standard deviation of the wiping process were determined in precursory validation of the process using syringes spiked with known amounts of Cyclophosphamide.

Cylinder Contamination Test

The second test, that was designed to evaluate contamination levels on the exposed inner walls of standard syringe barrels, used a total of 21 syringes of 3 different types from 2 manufacturers: 9 standard Becton Dickinson 20cc syringes, 9 standard Becton Dickinson 60cc syringes (Manufacturer A), and 3 standard Terumo 60cc syringes (Manufacturer B).

EQUASHIELD® cylinders were not tested for contamination because their syringe units are fully enclosed, presenting no risk of vapor and aerosol evaporation.

Manipulations using Cyclophosphamide were performed in the exact same manner as in the first test (see above description). Once the designated number of manipulations with each syringe was com- pleted, 5ml of pH3 water was dripped into each of the four standard syringe quarters, and then poured into a flask that was then sealed and frozen at -18°C until analysis (see Figure 2 where colored water was used to demonstrate the actual procedure).

All samples were analyzed using a HPLC-MS/MS system consisting of an 1100 binary pump with a HTS-PAL autosampler equipped with a stack cooler for sample storage at 4°C until injection of 20µL. As previously mentioned, this step was validated using spiked syringes to determine recovery rates and standard deviation of the process (Tuerk, Kiffmeyer, Kuss, Hahn, Stuetzer, Hadtstein, Heinemann, and Eickmann, 2010).

Figure 1

Figure 2

Table 1 – Cyclophosphamide Plunger Total Contamination Levels (ng)

Table 1 – Cyclophosphamide Plunger Total Contamination Levels (ng)

Figure 3: Cyclophosphamide Plunger Contamination Levels (ng)

Figure 4: Cyclophosphamide Cylinder Contamination Levels (ng)

Results

The results of the first test indicated significant levels of contamination on standard syringe plungers; contamination levels on EQUASHIELD® syringe plungers were mostly negligible (see Table 1 and Figure 3). Contamination levels were not related to the number of manipulations performed with each syringe and could be detected as soon as after one manipulation.

Table 1 – Cyclophosphamide Plunger Total Contamination Levels (ng)

  • 2, 4 and 8 are the number of manipulations.
  • U/D-Undetectable contamination levels.

Sample analysis revealed significantly greater levels of contamination on standard syringe plungers.

Figure 3: Cyclophosphamide Plunger Contamination Levels (ng)

Plunger Contamination Levels (ng)

Standard (STD) syringes compared to EQUASHIELD® (ES) Syringe Units during routine drug preparation with Cyclophosphamide

The second test which was performed separately, revealed Cyclophosphamide contamination on all tested syringe barrels (see Table 2 and Figure 4), with greater contamination levels found on the 60cc syringes compared to the 20cc syringes.

Table 2 – Cyclophosphamide Cylinder Contamination Levels (ng)

All the tested syringe cylinders were contaminated with Cyclophosphamide. the values appearing in the table are the detected values divided by 72%, which was the recovery rate.

Figure 4: Cyclophosphamide Cylinder Contamination Levels (ng)

Discussion

Results revealed Cyclophosphamide residuals on the standard syringe plungers and barrels, supporting previous studies that suggest that syringe plunger contamination is an additional route of exposure that may contaminate gloves and work areas during hazardous drug routine preparation and administration at pharmacies and patient bedsides.

These findings may also explain surface contamination, as the contaminated plungers come into con-tact with healthcare workers’ gloves, and consequently, with work surfaces, chairs, tabletops and so forth, despite various precautions such as the use of gloves, safety cabinets and the like. Similarly, aero- sols and vapors from the syringe barrels may contribute to air contamination when evaporating into the environment or condensing upon work surfaces.

Furthermore, as standard syringe plungers are used with all but one currently available closed system drug transfer device (CSTD), it is important to alert healthcare workers to the dangers of using these systems that may present a neglected safety concern, which is particularly alarming when considering the unprotected personnel who handle the syringe outside the safety cabinet.

Finally, it is important to note that the contamination levels found on the EQUASHIELD® CSTD’s plungers is inconsequential, indicating the effectiveness of a fully enclosed syringe unit. This informa- tion may contribute to the development of more effective CSTDs and the enforcement of better poli- cies and regulations concerning the handling of hazardous drugs.

Results indicate that plunger and barrel contamination of common syringes used for drug preparation are a significant source of exposure that requires further investigation and consideration. One possible solution is the use of a fully enclosed syringe such as EQUASHIELD® that has proven to result in significantly lower contamination levels.