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. 

Monitoring Contamination On Inner Walls of Syringes Used For Preparation and Administration of Hazardous Drugs

Background

When a syringe is filled with a hazardous drug, the inner surface of the syringe is directly exposed to the drug that may react and stick to the surface. After transferring the drug to its final container or after administration, the inner wall remains fully exposed to the environment and the process of hazardous drug evaporation to the working environment may take place. Furthermore, the syringe plunger may get contaminated either by contact with the inner wall of the syringe or the drug may infiltrate onto the plunger during manipulation of the syringe if the syringe is used for multiple manipulations. Such contamination could be transferred via gloves of the operators to other surfaces resulting in spread of contamination in the working environment. Obviously, this should be prevented as much as possible.

Study design

Between 4 and 7 October 2020, forty-three 50 ml BD Plastipak luer lock syringes (actually 60 ml) were collected by the hospital pharmacy of the University Hospital Leuven in Belgium.

The syringes were collected after single use for the preparation of hazardous drugs. The drugs were transferred from the vials to the infusion bags using the ChemoClave and Spiros CSTD (ICU Medical). Drug volumes transferred varied from 36 to 60 ml. Fourteen pharmacists and technicians were involved in the preparation of the syringes (coded A- N).

The inner walls were wiped for each syringe using standard Cyto Wipe Kits for surface wipe sampling. Wiping with prewetted tissues (5 ml 0.1% formic acid solution and for cisplatin 5 ml 0.5 M HCI solution) and analysis were performed at the laboratory of Exposure Control in the Netherlands. The shape of the wipes was adapted to perform wiping on the inner walls of the syringes (Figure 1). The plunger was set at 10 ml to have sufficient access into the syringe barrel to perform the wipe sample. The wipe sample was taken by turning around the plunger to make sure the prewetted tissue contacted the total surface of the inner wall of the syringe.

Six hazardous drugs were tested because physical and chemical properties of drugs differ, and this could produce different results. Only 50 ml syringes were collected for testing to allow convenient access with the wipes. Considering the 50 ml requirement, the following drugs fitted into the study: 5-fluorouracil (50 mg/ml), cyclophosphamide (20 mg/ml), ifosfamide (40 mg/ml), methotrexate (100 mg/ml), doxorubicin (2 mg/ml), and cisplatin (1 mg/ml). Two till ten tests of each drug were performed depending on availability of the syringes during the collection period.

Touching the plunger shafts was not allowed to avoid contamination on the inner walls of the syringes caused by the gloves of the operators during preparation. Only the external knob on the end of the plunger was used for holding. To ascertain this has not happened, the wipe samples were also analysed for nine other drugs in addition to the drug handled and transferred, except for cisplatin as the sample clean up procedure and the analysis was different compared to the other five drugs tested.

Materials and methods

The syringes were collected after single use and individually packed in a plastic mini bag. The syringes were still connected to the Spiros CSTD to avoid spills with the drugs. Each syringe was provided with a unique code and details are registered in the Tables 1-6. The syringes were stored at 2-8°C until sample preparation and analysis at the laboratory performed 14,15 and 19 October 2020.

The wipe samples were taken with Cyto Wipe Kits from Exposure Control Sweden AB [1].

Before analysis, all wipe samples were extracted by adding 20 ml 0.1% formic acid solution. For cisplatin 20 ml 0.5 M HCI solution was used. Total extraction volume for the wipe samples was 25 ml.

LC-MS/MS was used for the analysis of cyclophosphamide, cytarabine, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, ifosfamide, methotrexate and paclitaxel [2]. Platinum analysis of cisplatin was performed with stripping voltametry [3]. 0.5 ml of the extract was destructed using hydrogen peroxide, hydrochloric acid and UV-light resulting in the formation of platinum (PT) ions. Finally, the platinum ions were analysed instead of cisplatin. Samples were analysed in duplicate (including destruction). Mean values are reported.

Sponsorship

The study was sponsored by Equashield Medical Ltd. and performed by Exposure Control Sweden AB.

Results

The results of the contamination measured on the inner surface walls of the syringes are presented in the Tables 1-6. In addition, nine other drugs were measured to check for potential transfer of contamination by the gloves of the operators to the prepared syringes (except for cisplatin). The detection limit based on the extraction volume of 25 ml is 0.25 ng for cyclophosphamide (CP), cytarabine (CYT), gemcitabine (GEM), ifosfamide (IFO) and methotrexate (MTX), 5 ng for docetaxel(DOC), doxorubicin (DOX) and paclitaxel (PAC), 12.5 ng for etoposide (ETO) and 5-fluorouracil (5FU). Due to background levels of platinum (PT), the limit of quantification is set at 2.5 ng. This corresponds to 3.9 ng cisplatin.

Contamination was found for doxorubicin,methotrexate, cyclophosphamide and ifosfamide on the inner walls of all syringes (Tables 1-4). Contamination with 5-fluorouracil was detected on four out of ten syringes (Table 5). Contamination with platinum, representing cisplatin, was not detected on the four syringes tested (Table 6).

Mean levels of contamination differ between the drugs showing the highest contamination for ifosfamide (486 ng) and cyclophosphamide (298 ng), followed by 5-fluorouracil (52 ng) and doxorubicin (45 ng). The lowest level of contamination was found for methotrexate (6 ng), and cisplatin was not detected at all (< 3.9 ng). However, this does not correspond to the concentrations of the drugs prepared as the highest drug concentration was found for methotrexate (100 mg/ml), followed by 5-fluorouracil (50 mg/ml), ifosfamide (40 mg/ml), cyclophosphamide (20 mg/ml), and finally doxorubicin (2 mg/ml) and cisplatin (1 mg/ml).

It should be noticed that the results were not statistically evaluated for a potential effect of the concentrations of the drugs, the volumes transferred and the operators involved (worker s effect). A potential effect of the volumes transferred is not expected as the means are about the same.

Contamination with the nine other drugs, to check for potential contamination by the gloves of the operators on the prepared syringes, was not found. This indicates that it is very unlikely that the measured contamination is caused by other (previous) activities than the handling itself.

Discussion and Conclusion

Contamination was found for doxorubicin, methotrexate, cyclophosphamide and ifosfamide on the inner walls of all syringes. 5-fluorouracil was detected on a few syringes and cisplatin was not detected at all. In addition, differences in the levels of contamination were found between the drugs but it seems they are not correlated to the concentration of the drugs handled. This indicates that some drugs stick more to the inner walls of syringes than others especially doxorubicin followed by cyclophosphamide and ifosfamide. The sticking effect is about ten times lower for 5-fluorouracil, cisplatin and methotrexate. The differences can be explained by different product characteristics such as physical and chemical properties of the drugs.

Although the focus was to wipe the inner walls of the syringes, it cannot be excluded that the contamination measured also includes potential contamination on the plunger rods. Each syringe (except for cisplatin) was also checked for contamination with nine other drugs to measure contamination from the gloves of the operators that could be transferred to the plunger by handling the syringes. However, no other drugs were found except the ones tested indicating that the syringes were properly collected and the wipe testing at the laboratory was performed without contamination.

Appendix

Validation of wipe testing

As a separate study supplement, the remaining contamination on the inner walls of the syringes was measured after wiping to verify the effectiveness of the wiping procedure. Thereto, the syringes were placed upright with the plunger still at 10 ml, and 50 ml 0.1% formic acid solution was poured in the space between barrel and plunger. For the cisplatin syringes, 50 ml 0.5 M HCI solution was used. The liquid was removed after 60-90 min and analysed separately from the wipe samples.

The detection limit based on the extraction volume of 50 ml is 0.5 ng for cyclophosphamide (CP), cytarabine (CYT), gemcitabine (GEM), ifosfamide (IFO) and methotrexate (MTX), 10 ng for docetaxel (DOC), doxorubicin (DOX), and paclitaxel (PAC), 25 ng for etoposide (ETO) and 5-fluorouracil (5FU). Due to background levels of platinum (PT), the limit of quantification is set at 5 ng platinum corresponding to 7.8 ng cisplatin.

Remainingcontamination was foundfor all doxorubicin, methotrexate, cyclophosphamide and ifosfamide syringes (Tables 7-10), for seven out of ten 5-fluorouracil syringes (Table 11), and for none of the cisplatin syringes (Table 12).

The results show higher amounts of drugs in the liquid than in the wipe samples, except for thecisplatin syringes where nocontamination was found.This indicates that the wiping is less effective than the use of the liquid or the contamination was also present on other parts especially the plunger. If the plunger would have been contaminated, drug amounts can be higher in the liquid than in the wipe sample as the plunger was not wiped.

The liquids were also analysed for nine other drugs in addition to the drug handled and transferred, except for cisplatin as the sample clean up procedure and the analysis was different compared to the other five drugs tested. Contamination withthe nine other drugs was not found.

Figure 1: Tissue for wiping and syringe (left) and tissue inside syringe barrel (right)

Table 1: Contamination on the inner surface wall of seven doxorubicin syringes (2 mg/ml)

Contamination on the inner surface wall of seven doxorubicin syringes

Table 2: Contamination on the inner surface wall of two methotrexate syringes (100 mg/ml)

Contamination on the inner surface wall of two methotrexate syringes

Table 3: Contamination on the inner surface wall often cyclophosphamide syringes (20 mg/ml)

Contamination on the inner surface wall often cyclophosphamide syringes

Table 4: Contamination on the inner surface wall of ten ifosfamide syringes (40 mg/ml)

Contamination on the inner surface wall of ten ifosfamide syringes

Table 5: Contamination on the inner surface wall of ten 5-fluorouracil syringes (50 mg/ml)

Contamination on the inner surface wall of ten 5-fluorouracil syringes

Table 6: Contamination on the inner surface wall of four cisplatin syringes (1 mg/ml)

6 Contamination on the inner surface wall of four cisplatin syringes

Table 7: Doxorubicin results seven syringes

7 Doxorubicin results seven syringes

Table 8: Methotrexate results two syringes

8 Methotrexate results two syringes

Table 9: Cyclophosphamide results ten syringes

9 Cyclophosphamide results ten syringes

Table 10: Ifosfamide results ten syringes

10 Ifosfamide results ten syringes

Table 11: 5-Fluorouracil results ten syringes

11 5-Fluorouracil results ten syringes

Table 12: Cisplatin results four syringes

12 Cisplatin results four syringes

Recovery

Two positive control samples for each drug (inner walls of syringes spiked with drug solutions) and two negative control samples (inner walls of syringes spiked with solutions not containing drugs) were also included in the study. These samples were obtained by dripping the solutions on the inner walls of the syringes. One hour after spiking, the samples were collected. The spiked amount was 1000 ng for doxorubicin, cyclophosphamide, ifosfamide, methotrexate and 5-fluorouracil, and 10 ng for cisplatin.

Two positive control samples for each drug (inner walls of syringes spiked with drug solutions) and two negative control samples (inner walls of syringes spiked with solutions not containing drugs) were also included in the study. These samples were obtained by dripping the solutions on the inner walls of the syringes. One hour after spiking, the samples were collected. The spiked amount was 1000 ng for doxorubicin, cyclophosphamide, ifosfamide, methotrexate and 5-fluorouracil, and 10 ng for cisplatin.

The recovery is based on the total contamination (tissue and liquid). However, the recovery is higher in the tissues than in the liquids for doxorubicin, 5-fluorouracil, methotrexate, and cisplatin and comparable for cyclophosphamide and ifosfamide (Tables 7-12). The results are contradictory compared to the results of the syringe samples and could be explained by a shorter time for the drugs to stick on the inner surface of the syringes after spiking compared to normal practice. In addition, the added liquid containing the drugs is easily absorbed by the tissues before the liquid is added. Consequently, drug amount can be higher in the wipe samples. 

The results show good recoveries for cyclophosphamide and ifosfamide, moderate recoveries for cisplatin, methotrexate and 5-fluorouracil, and a low recovery for doxorubicin indicating an underestimation of the measured contamination. The duplicates show little variation.

As expected, none of the ten drugs was detected in the negative control samples.