The first American guidelines on preventing occupational exposures to antineoplastic drugs in health care settings were published in the 80s [1–5]. In Canada, the first guidelines were published in 1997 by the Canadian Society of Hospital Pharmacists . While pharmacists were quite aware of the necessity to protect health care workers from exposure to these drugs, it is the publication of 2004 Alert of the National Institute for Occupation Safety and Health (NIOSH) that rang the bell [7, 8].
In Quebec, a working group was put in place by the Association pour la santé et la sécurité au travail (ASSTSAS) in 2006 to take into account these recommendations to the local context and publish a detailed prevention guide . Further guidelines were published by the regulatory authority (e. g. Ordre des pharmaciens du Québec) to support pharmaceutical compounding [10–12].
The Centre hospitalier universitaire Sainte-Justine (CHUSJ) has been a pioneer in preventing occupational exposures to hazardous drugs. In 2005, the hospital developed locally a surveillance program for methotrexate of five sampling points (e. g. external metallic window frame of the main biological safety cabinet (BSC), back of the phone receiver, external surface of an intravenous solution bag manipulated inside the BSC during the previous hour, non-BSC working surface used for the final packaging and labeling of intravenous products and the floor of the preparation room in front of the BSC). A sixth positive control was used per series of measures. Following 238 wipe samples (excluding the 40 positive controls), five were tested positive during 2005 . This initiative demonstrated the feasibility of periodical monitoring of surface contamination in a hospital and was brought to the attention of the ASSTSAS working group. The group discussed with the Institut national de santé publique (INSPQ) to develop a broader program with more substances at a low cost. Our Unité de recherche en pratique pharmaceutique (URPP) proposed to eventually support the analysis of this national program to offer an individualized report to all participating centers. A surveillance initiative, including cyclophosphamide, methotrexate and ifosfamide, was started in 2008 with a growing number of participating centers from 2008 to 2010 (n=25) , 2012 (n=33) , 2013 (n=36) , 2014 (n=51)  and 2015 (n=48) . While these studies provide a cross-sectional portrait of surface contamination, it is interesting to explore the longitudinal profile of a single hospital to better understand the strategies implemented to minimize surface contamination.
The aim of this paper is to review the surface contamination of three hazardous drugs within a teaching hospital and comment the different strategies put in place over the years in the context of these multicenter studies.
This is a descriptive retrospective and longitudinal study. The study was conducted in a 500-bed mother-child university health center in Quebec, Canada. The hematology-oncology department was composed of an outpatient clinic (19 stretchers), two inpatient oncology units (ward #1 with 22 beds and ward #3 with 10 beds) and one inpatient bone marrow transplant (BMT) unit (ward #2 with six beds). The pharmacy satellite team prepares around 30 000 parenteral doses per year and offer a full unit dose drug distribution. No closed-system drug transfer (CSDT) devices are used but chemo-dispensing pins and appropriate aseptic techniques are used. Tubing is actually primed by pharmacy staff within BSC.
A national surveillance program
The INSPQ national program was put in place in the context of national prevention guidelines that were adopted and published in 2008 . In the guidelines, a recommendation stated that “every institution should plan regular monitoring activities with respect to both the work environment and work activities. An Environmental Monitoring Program would allow the periodic checking of contamination due to antineoplastic type hazardous drugs on work surfaces in the institution”. Also, the guidelines strongly suggest that “An evaluation should be performed prior to implementing the preventive measures proposed in the ASSTSAS guide and repeated once they are in place”. While the frequency of such surveillance was not determined by ASSTSAS, the pharmaceutical regulatory authority (Ordre des pharmaciens du Québec) suggested that such monitoring should occur twice a year (criteria 184.108.40.206)2014.02 .
Twelve standardized sampling sites, six in pharmacy areas and six in outpatient patient care areas, were selected. Samples were collected by one research assistant. Photographs of the standardized sampling sites were taken. For each sample, a standardized surface of about 600 cm2 (20 cm×30 cm) was sampled with one 6 cm×8 cm Wypall X60 wipe (Kimberly Clark Professional, Newton Square, Pennsylvania). The wipe was moistened with 1 mL of sampling solution (10 % methanol and 90 % 5 mmol/L ammonium acetate). Each side of each wipe was used twice to sample a surface: once horizontally and once vertically. Sites were sampled at the end of a workday or in the morning, before surfaces were washed. The sampling technique, an adaptation of the technique described by Larson et al., was developed by the Institut national de santé publique du Québec .
Moreover, 12 additional standardized sampling sites were identified to characterize two inpatient care wards. These sites were a preparation shelf in the pharmacy storage room, a refrigerator door handle in the pharmacy storage room, a pharmacy storage door handle, a nursing trolley, a nurse counter, a biohazardous waste disposal container cover, a patient room door handle, a patient room counter, a smart pump touchpad screen, a patient room floor, a patient room toilet seat and a patient bathroom sink. The analytical procedure has been described previously .
CHU Sainte-Justine profile
In order to describe the historical profile of contamination of hazardous drugs in our hospital, we extracted from the multicenter study our results per year (2010 , 2012 , 2013 , 2014 , 2015 , 2016 (yet unpublished results). As a complementary study to the national multicenter study, 12 new points of measure were identified for inpatient care ward and two patient care wards were sampled in May 2016 for a total of 24 points of measure.
Results were expressed in ng/mL and converted to pg/cm2. The limits of detection and quantification varied overtime according the analytic method in place and are described in the results. The limit of detection was used as the reporting limit. The ratio of positive samples was calculated. A sample was considered positive for a particular drug if the value was above the limit of detection and if the quantifier peak was within the maximum tolerance of mean calibrator for confirmatory criteria (signal/noise ratio > 3, retention time ±0.02 min, quantifier/qualifier ion ratio±20 %). Descriptive statistical analyses (CHUSJ value per sampling points and 75th percentile per multicenter study) were carried out with PASW Statistics 24.0 (SPSS Inc., Quarry Bay, Hong Kong). For calculations, concentrations that fell between the limit of detection and the limit of quantification were assigned a value corresponding to the limit of quantification divided by 2 and concentrations that fell below the limit of detection were assigned a value corresponding to the limit of detection divided by 2.
A total of 72 samples (e. g. 36 in the pharmacy and 36 in outpatient care area) were obtained between 2010 and 2016 for a total of 216 analyses (three drugs/samples tested). The proportion of positive samples was 50 % (36/72) for cyclophosphamide, 32 % (23/72) for ifosfamide and 19 % (14/72) for methotrexate. The cyclophosphamide concentrations measured varied from undetectable to 400 pg/cm2. The ifosfamide concentrations measured varied from undetectable to 830 pg/cm2. The concentrations of methotrexate measured varied from undetectable to 660 pg/cm2. The ratio of positive samples per year varied between 0 and 9/12. The ratio of positive samples above the 75th percentile per year varied between 0 and 9/12. There were a similar proportion of positive results in the pharmacy (35 % (38/108)) than in the outpatient care areas (32 % (35/108)).
The antineoplastic use of each drug was respectively 632 g in 2012, 529 g in 2013, 514 g in 2014, 453 g in 2015 and 475 g in 2016 for cyclophosphamide, 933 g in 2012, 465 g in 2013, 510 g in 2014, 540 g in 2015 and 660 g in 2016 for ifosfamide and 1,350 g in 2012, 311 g in 2013, 541 g in 2014, 550 g in 2015 and 600 g in 2016 for methotrexate.
Moreover a total of 24 samples were obtained in 2016 in two oncology inpatient care wards. There were no positive samples to cyclophosphamide, ifosfamide and methotrexate.
Table 1 shows the profile of local surface contamination of cyclophosphamide, ifosfamide and methotrexate per year extracted from the multicenter studies. In order to benchmark local contamination to multicenter results, we calculated the ratio of local samples above the 75th percentile of the multicenter results.
Profile of surface contamination of cyclophosphamide, ifosfamide and methotrexate per year extracted from the multicenter studies.
|Years||Shipment reception Counter||Storage Shelf or bin||Front grille Inside the hood||Floor In front of the hood||Service hatch or counter for post-preparation validation||Tray used for drug delivery||Storage Shelf or bin||Counter used for priming or validation or counter near the administration area||Arm rest||Patient room counter||Outpatient clinic counter||Exterior surface of antineoplastic drug container||Local ratio of positive samples||Local ratio of samples above 75th percentile of the multicenter study||LOD from multicenter study||LOQ from multicenter study||Global 75th percentile of multicenter study|
Note: LOD: limit of detection, LOQ: limit of quantification, NA: not available.
This is a longitudinal study that describes the profile of surface contamination of a single teaching mother-child hospital that participated to a Canadian annual multicenter study. These results show the presence of traces of hazardous drugs in the pharmacy and the outpatient care clinic throughout the years from 2010 until 2016 while no traces were measured in two inpatient care areas in 2016. While the proportion of positive samples per targeted hazardous drug has varied overtime with ups and downs, the average percentage of positive samples is lower or equal to 50 % (e. g. 50 % (36/72) for cyclophosphamide, 32 % (23/72) for ifosfamide and 18 % (13/72) for methotrexate).
Percentage of positive samples
Regarding the proportion of positive samples, our results are better or similar than other published studies considering no CSDT are being used. For example, Sessink et al. reported a reduction in surface contamination with cyclophosphamide in 30 US Hospital pharmacies following implementation of a CSDT in 2013 . From 143 samples collected, 80 % of the wipe samples of the 4 surfaces tested positive for cyclophosphamide contamination (77 % for the BSC surfaces, 87 % for the BSC airfoils, 89 % for the floors in front of the BSCs, and 67 % for the countertops). Simon et al. evaluated the effectiveness of a CSDT in reducing surface contamination in a new antineoplastic drug compounding unit . From 686 surface samples measured, the proportion of positive samples went, for instance from 50.7 % to 38.5 % for cyclophosphamide (p=0,037), from 38.9 % to 8.4 % for ifosfamide (p < 0.0001) and from 49.3 % to 43.4 % for gemcitabine (NS). Hon et al. described the contamination of frequently contacted surfaces by health care workers in six area health care facilities . From a total of 438 surface wipes, 159 (36 %) had concentrations above the limit of detection for cyclophosphamide without the use of CSDT. Connor et al. examined environmental samples from pharmacy and nursing areas for five drugs at three University-based US Cancer Centers . Eighty-one wipe samples were collected in the pharmacy areas and 62 wipe samples were collected in the nursing/patient areas. From 143 wipe samples (representing 715 separate analyses for five drugs e. g. cyclophosphamide, ifosfamide, paclitaxel, 5-fluorouracil and cytarabine), at least one of the five drugs was present above the limit of detection (LOD) in 60 % of the wipe samples and 32 % of the samples had more than one drug present. Sugiura et al. investigated environmental contamination with cyclophosphamide at six hospitals . Samples were collected at 12 sites within two divisions of each facility. A contamination with cyclophosphamide was identified in half of the sampling sites. Viegas et al. analyzed 327 samples from two Portuguese hospitals and showed 37 % of positive samples with at least one hazardous drug (e. g. cyclophosphamide, 5-FU, paclitaxel) . In our hospital, the proportion of positive samples between 2008 and 2016 were 50 % for cyclophosphamide, using a very sensitive analytical technique (e. g. LOD 0.36 pg/cm2).
Level of contamination
Regarding the level of contamination measured and reported, our results are again better or similar to other published studies considering no CSTD are being used. For instance, in Sessink’s study, the median values for surface contamination with cyclophosphamide were reduced from 220 to 30 pg/cm2 with CSDT . In Simon’s study, the median values of cyclophosphamide before cleaning were respectively 351 pg/cm2 and 123 pg/cm2, without and with CSDT while they were respectively 34 pg/cm2 and 46 pg/cm2 after cleaning . In Hon’s study, the arithmetic mean of cyclophosphamide was 201 pg/cm2 and the geometric mean concentration was 19 pg/cm2 . In Connor’s study, cyclophosphamide mean concentrations was respectively 710, 16,000 and 470 pg/cm2 in pharmacy areas and 1, 120 and 70 pg/cm2 in patient area for location 1, 2 and 3 . In Sugiura’s study, the contamination level of cyclophosphamide varied between non detectable and 6,100 pg/cm2 . In our hospital, the median value for cyclophosphamide is 0.85 pg/cm2 over the years, a value well below other reported values and without the use of CSDT.
Contributing factors to low contamination
Numerous factors can explain such relatively low surface contamination in our hospital. This is a mother-child hospital with pediatric oncology and its specificities (e. g. cancer types, pediatric dosages). The number of grams of each hazardous drug used may differ in our hospital from other published studies but these numbers are often not reported and it is not clear about what period of drug use consumption should be collected and used as relevant predictor of potential contamination. Following the implementation of the ASSTSAS prevention guide and almost all recommendations (except washing the vials at reception before storage), pharmacy staff started to prime intravenous tubing for nurses in 2011, contributing to limit potential surface contamination in outpatient and inpatient environments. Training sessions and visual reminders were also repeated periodically and posted to ensure optimal training of pharmacy and nursing staff. Our facility was audited by the regulatory authority in 2014. Additional cleaning with water for final compounded products was also introduced in 2014. Parents and patients were also taught the optimal management of biological fluids throughout their stay. Finally, a urinary surveillance study was conducted in 2015 in 102 exposed healthcare workers (e. g. 74 nurses, 9 pharmacy technicians, 11 pharmacists and 7 physicians). No detectable urinary traces of cyclophosphamide, ifosfamide, methotrexate and 5-FU metabolite (F-BAL) were found .
This study shows a longitudinal perspective of the surface contamination of hazardous drugs in a teaching mother-child hospital without the use of CSTD. While the proportion of positive samples varies, contamination is very low. We believe every hospital should review its annual scorecard of contamination with a longitudinal perspective. All stakeholders should not forget that these measures are usually performed once a year. A punctual rise of contamination may not necessarily reflect increasing trend, therefore a look at the historical data should be done.
A bi-annual surface contamination study at a national level cost a marginal fraction of CSTD use and this should certainly be implemented to optimize public fund before systematic use of CSTD. Addition of 5-FU, gemcitabine and hopefully other hazardous drugs would also increase the robustness of the national program. Finally, the opportunity to measure urinary contamination of healthcare workers should also be considered as a national level, taking into human resources, practical and legal issues. All these elements will certainly be considered through the revision of our national prevention guide, which is planned in 2017.
This study has limitations. It is a retrospective study with annual measures of surface contamination of hazardous drugs. Repeated measures within a shorter period of time would allow a better description of the contamination. Considering more children are hospitalized as inpatients to receive their chemotherapy, we conducted a complementary set of measures to cover both inpatient care units. The proportion of inpatients and outpatients should be taken into account when measuring the risk at the bedside in different healthcare settings. Finally, the recovery from surfaces was good for most surfaces but lower for linoleum (37–82 %, coefficient of variation of 7–22 %), which could underestimate the contamination on the floor of some hospitals.
This study shows a longitudinal perspective of the surface contamination of hazardous drugs in a teaching mother-child hospital. Every hospital should review its annual scorecard of contamination with a longitudinal perspective to minimize drug contamination. It is possible to contain surface contamination with hazardous drugs with different strategies.
Conflicts of interest statement: The authors state no conflict of interest. They have read the journal’s publication ethics and publication malpractice statement available at the journal’s website and hereby confirm that they comply with all its parts applicable to the present scientific work.
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