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)
Table 2: Contamination on the inner surface wall of two methotrexate syringes (100 mg/ml)
Table 3: Contamination on the inner surface wall often cyclophosphamide syringes (20 mg/ml)
Table 4: Contamination on the inner surface wall of ten ifosfamide syringes (40 mg/ml)
Table 5: Contamination on the inner surface wall of ten 5-fluorouracil syringes (50 mg/ml)
Table 6: Contamination on the inner surface wall of four cisplatin syringes (1 mg/ml)
Table 7: Doxorubicin results seven syringes
Table 8: Methotrexate results two syringes
Table 9: Cyclophosphamide results ten syringes
Table 10: Ifosfamide results ten syringes
Table 11: 5-Fluorouracil results ten syringes
Table 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.
