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Cleaning Efficiencies of Three Cleaning Agents on Four Different Surfaces after Contamination by Gemcitabine and 5-fluorouracile a
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Antje Böhlandt , Svenja Groeneveld , Elke Fischer & Rudolf Schierl a
Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Clinical Center, Ludwig Maximilians University, Munich, Germany Accepted author version posted online: 09 Mar 2015.Published online: 13 May 2015.
Click for updates To cite this article: Antje Böhlandt, Svenja Groeneveld, Elke Fischer & Rudolf Schierl (2015) Cleaning Efficiencies of Three Cleaning Agents on Four Different Surfaces after Contamination by Gemcitabine and 5-fluorouracile, Journal of Occupational and Environmental Hygiene, 12:6, 384-392, DOI: 10.1080/15459624.2015.1009985 To link to this article: http://dx.doi.org/10.1080/15459624.2015.1009985
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Journal of Occupational and Environmental Hygiene, 12: 384–392 ISSN: 1545-9624 print / 1545-9632 online c 2015 JOEH, LLC Copyright DOI: 10.1080/15459624.2015.1009985
Cleaning Efficiencies of Three Cleaning Agents on Four Different Surfaces after Contamination by Gemcitabine and 5-fluorouracile ¨ Antje Bohlandt, Svenja Groeneveld, Elke Fischer, and Rudolf Schierl
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Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Clinical Center, Ludwig Maximilians University, Munich, Germany
Occupational exposure to antineoplastic drugs has been documented for decades showing widespread contamination in preparation and administration areas. Apart from preventive measures, efficient cleaning of surfaces is indispensable to minimize the exposure risk. The aim of this study was to evaluate the efficiency of three cleaning agents after intentional contamination by gemcitabine (GEM) and 5-fluorouracile (5-FU) on four different surface types usually installed in healthcare settings. Glass, stainless steel, polyvinylchloride (PVC), and laminated wood plates were contaminated with 20 ng/µl GEM and 2 ng/µl 5-FU solutions. Wipe samples were analyzed for drug residues after cleaning with a) distilled water, b) aqueous solution containing sodium dodecyl sulfate (10 mM) and 2propanol (SDS-2P), and c) Incides N (pre-soaked) alcoholic wipes. Quantification was performed by high-performance liquid chromatography (HPLC) for GEM and gas chromatography-tandem mass spectrometry (GCMS/MS) for 5-FU. Recovery was determined and cleaning efficiency was calculated for each scenario. Mean recoveries were 77–89% for GEM and 24–77% for 5-FU and calculated cleaning efficiencies ranged between 95 and 100% and 89 and 100%, respectively. Residual drug amounts were detected in the range nd (not detected) – 84 ng GEM/sample and nd – 6.6 ng 5-FU/sample depending on surface type and cleaning agent. Distilled water and SDS-2P had better decontamination outcomes than Incides N wipes on nearly all surface types, especially for GEM. Regarding 5-FU, the overall cleaning efficiency was lower with highest residues on laminated wood surfaces. The tested cleaning procedures are shown to clean glass, stainless steel, PVC, and laminated wood with an efficiency of 89–100% after contamination with GEM and 5-FU. Nevertheless, drug residues could be verified by wipe samples. Pure distilled water and SDS in an alcoholicaqueous solution expressed an efficient cleaning performance, especially with respect to GEM. The study results demonstrate the need to adapt cleaning procedures to the variety of drugs and surface types to develop effective decontamination strategies. Keywords
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antineoplastic drugs, cleaning, decontamination
Address correspondence to: Rudolf Schierl, Ziemssenstrasse 1, D-80336 Muenchen, Germany; e-mail: [email protected]
INTRODUCTION
H
ealth care personnel are occupationally exposed to cytotoxic substances during preparation and administration of antineoplastic agents. Biomonitoring has shown incorporation and adverse health effects in pharmacy and nurse staff despite improved technologic solutions and personal protective equipment.(1–5) Drug residues are still found on various surfaces in and around the drug preparation area of (hospital) pharmacies and oncology wards, even on assumedly “clean” surfaces (6–14) and on the outside of vials.(15–23) Dermal contact followed by transdermal absorption is suggested to be the major route of incorporation in occupational settings.(24–27) Apart from preventive measures, efficient cleaning strategies for decontamination of workstation surfaces must be consequently focused in terms of minimizing the risk of exposure to drug residues. In fact, no consistent regulation and evidence-based strategies regarding standardized cleaning protocols and effectiveness are proposed/implemented and decontamination is vaguely defined by the (American Society of Health-System Pharmacists (ASHP) as cleaning (physical removal) or deactivating (chemical degradation) following an appropriate cleaning protocol.(28) Subsequently, various studies focused on evaluating decontamination strategies including different cleaning agents, techniques, and antineoplastic substances. However, results and recommendations were inconsistent and not applicable for all antineoplastic drugs tested.(11,29–33)
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A number of studies have shown the efficiency of deactivating agents, such as sodium hypochlorite, to degrade several— if not all—investigated antineoplastic agents, but mutagenicity and other health impairing risks of the degradation products have not been excluded.(31,34–38) Mostly, investigated surfaces comprised stainless steel and glass as major components of biological safety cabinets (BSCs), while other surface materials have been less considered despite the evidence that contamination could be spread in the entire preparation and administration area. Although 5-FU is the most prescribed parenteral chemotherapy agent for cancer therapy in Germany and in many other countries and also the preparation numbers of GEM have been constantly increasing during recent years, literature data on decontamination strategies for both compounds are scarce. The aim of this study was to assess the efficiency of three routinely used cleaning agents on four different surfaces according to a standardized cleaning technique after intentional contamination by GEM and 5-FU.
Cleaning Agents The principal objective of decontamination is to remove the contaminant drug by dissolving and transferring it from the wiped surface to a disposable item (elimination) using different types of wetting solutions or prefabricated pre-soaked wipes (hydro-alcoholic, detergent, or disinfectant). Based on current decontamination practice in German pharmacy units, three different cleaning agents were evaluated in this study:
MATERIAL AND METHODS
Preparation of Compound Stock Solutions Main stock solutions of GEM and 5-FU for intentional contamination were prepared in water and acetonitrile (Merck KGaA, Darmstadt, Germany) at concentrations of 20 ng/µl (GEM) and 2 ng/µl (5-FU), respectively. As no standard analytical method for determination of GEM from wipe samples has been established in our laboratory, further dilutions of the GEM stock solution were made (10 ng/µl and 2 ng/µl) to evaluate recovery rates at different concentrations. All solutions were prepared in appropriate safety conditions under a laminar airflow hood and with personal protective equipment following the guidelines for handling of cytotoxic drugs. Preliminary test showed that the amount of 50 µl stock solution was practicable in terms of application and drying of solutions on the different surfaces.
Study Design Plates of four different materials were intentionally contaminated with defined drug amounts: 20 ng/µl (nanogram/ microliter) GEM solution and 2 ng/µl 5-FU solution. The plates were subsequently cleaned by three different cleaning agents. Residual drug contamination was collected by wipe sampling and analyzed using high-performance liquid chromatography (HPLC) for GEM and gas chromatographytandem mass spectrometry (GCMS/MS) for 5-FU. Preliminary tests on recovery rates of the newly implemented HPLC method for GEM wipe samples were conducted with dilutions of 20 ng/µl, 10 ng/µl, and 2 ng/µl. Antineoplastic Agents The study was performed using GEM (Cell Pharm, Bad Vilbel, Germany) and 5-FU (Merck KGaA, Darmstadt, Germany) for the preparation of the different stock solutions. Both substances are classified as antimetabolites. Surface Materials In pharmaceutical units the surfaces for handling cytotoxic drugs are usually composed of stainless steel (e.g., BSC, drug preparation area), glass (e.g., BSC, vials) or laminated wood (e.g., desktops, work tops, shelves, closets). Laboratory floors are frequently covered with polyvinylchloride (PVC) potentially exposed to spills during drug preparation and spreading via shoes. For evaluating cleaning results on the different surfaces, new and specifically tailored plates of 10 × 10 cm of these four materials were used as test surfaces that matched the quality of working surfaces of pharmacy preparation units and BSCs.
• distilled water • an aqueous solution containing 40 ml sodium dodecyl sulfate (SDS,10 mM) and 10 ml 2-propanol (SDS-2P). SDS is an organic compound and a highly effective anionic surfactant and is used in detergents for many cleaning applications. (80% 10 mM SDS and 20% 2-propanol). This formulation was selected according to the findings of Lamerie et al. who described a high global effectiveness in cleaning of 10 antineoplastic agents.(29) • commercial available alcoholic wipes (Incides N; Ecolab GmbH, Duesseldorf, Germany): containing 1-propanol and 2-propanol.
Contamination Procedure The intentional contamination of the surfaces to be investigated followed the same standardized protocol for both antineoplastic agents: Volumes of 50 µl GEM or 5-FU stock solution with different concentrations were spread in approximately 40 droplets onto the whole surface of the 10 × 10 cm plates of different materials using an adjustable volume micropipette. The contaminated plates were dried overnight under a laminar airflow hood at room temperature. All contaminations were set in triplicates for all drug concentrations and each surface. Wipe Sampling Sampling of contamination was performed according to a validated and standardized wiping procedure as described previously by Schierl et al.(12) Briefly, each contaminated/ decontaminated plate was subsequently wiped with three filters (Filter Discs 391, Sartorius Stedim GmbH, Goettingen,
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Germany) moistened with 6 drops distilled water for GEM and methanol for 5-FU. The wiping direction was changed with each filter. A new pair of gloves was taken each time before doing the next sample. All three filters were placed in a screw cap glass jar and stored at 4◦ C until analysis. The whole contamination, decontamination, and wipe sampling procedures were performed by the same person to eliminate effects of inter-individual variability. Implementation of the GEM Method As the new HPLC method for analyzing GEM wipe samples was implemented for this study, the suitability of distilled water and methanol as solvent for the wipe sample filters was evaluated in a first step prior to the decontamination experiment. Therefore, 10 × 10 cm test surfaces were contaminated in triplicates with 50 µl of stock solutions with GEM concentrations of 20 ng/µl each and dried overnight under a laminar airflow. As glass was expected to provide the most precise recovery rates due to its smooth and nonporous surface, GEM solutions in concentrations of 2 ng/µl and 10 ng/µl were additionally adopted to evaluate whether the recovery was constant over that concentration range. Wipe samples were collected as described previously, and recoveries were quantified and compared (Table I). As quantified GEM recovery values after contamination with 50 µl of the 2 ng/µl solution (containing 100 ng GEM) were comparatively low and near the limit of detection (LOD) of 10 ng/wipe sample of the analytical method, subsequent cleaning tests were performed with 20 ng/µl GEM stock solutions (containing 1000 ng GEM) to obtain reliable values. The other types of surfaces were then exposed to the 1000 ng GEM (20 ng/µl) solution and revealed recoveries between 83 and 135%. As recovery rates observed for the use of distilled water versus methanol as moisturizing solvent for the GEM wipe sampling were approximately within the same range (Table I), water was chosen as solvent for surface wipe sampling in the subsequent GEM experiments due to its lack of toxicity. Regarding 5-FU, no recovery tests were performed prior to the cleaning experiment, as a validated and very sensitive analytical method (GCMS/MS) has already been established.(14) As its limit of detection (LOD) is 50 times lower compared to GEM, intentional contamination in the cleaning experiment was performed with 5-FU stock at concentrations of 2 ng/µl. Cleaning Procedure (Decontamination) The contaminations with an equal amount of drug were set in triplicates of 50 µl each (as described previously), i.e., three plates per cleaning agent. Likewise, negative controls (plates 1–3 = blanks: no contamination, solely cleaning procedure) and positive controls (plates 13–15 = recovery: solely drug contamination, but no cleaning procedure) were taken threefold, resulting in a total number of 15 samples per surface type as shown in a schematic setup of a cleaning experiment with 20 ng/µl GEM solution as an example for any surface type (Table II). 386
TABLE I. Gemcitabine: Comparison of Distilled Water Versus Methanol as Solvent for GEM Wipe Samples after Contamination of Different Surfaces with 50 µl of 2 ng/µl (100 ng), 10 ng/µl (500 ng), and 20 ng/µl (1000 ng) GEM Stock Solution, Respectively recovery rate (mean ± standard deviation) contamination (ng)
distilled water
methanol
100 500 1000 1000 1000
71%(3.3) 85%(1.8) 75%(2.4) 109%(37.3) A 92%(3.8)B
79%(5.0) 82%(5.8) 95%(2.9) 91%(10.5)C n.a.
glass
PVC stainless steel laminated wood
1000
87%(0.9)
80%(1.2)
Note: Limit of detection = 10 ng/sample. An = 2: 83% and 135%. Bn = 2: 89% and 95%. Cn = 4.
After the contaminated plates had dried, 1 ml of the two liquid cleaning liquids agents (water vs. SDS-2P) was pipetted dropwise onto each contaminated surface and spread utilizing a whole paper towel (Kimberly Clark, Wypall Wipers, Koblenz, Germany) in circular motions. Equivalently, one alcoholic Incides N wipe per plate was used to circularly moisten the surface. Subsequently, one fresh paper towel was utilized to dry-wipe the surfaces, again performing a circular motion. The experiments were performed in a 3-day sequence. On day 1, the surfaces were contaminated with the drug solutions or pure
TABLE II. Schematic Set-up of the Cleaning Experiments: Example of the Cleaning Test with 50 µl of the 20 ng/µl (1000 ng) Gemcitabine Stock Solution No.
Gemcitabine [ng/50 µl]
Cleaning agents
1 2 3 4 5 6 7 8 9 10 11 12
none none none 1000 1000 1000 1000 1000 1000 1000 1000 1000
Distilled water SDS-2P Incides N Distilled water Distilled water Distilled water SDS-2P SDS-2P SDS-2P Incides N Incides N Incides N
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solvent (and let dry overnight). On day 2, the contaminated surfaces were cleaned. On day 3, wipe samples were taken and the extraction was performed. Analyses were performed on day 3, day 4, or after the weekend. All experiments were performed under a laminar airflow. Analytical Procedure Gemcitabine: Extraction, sample preparation, and analysis All three filters from the wipe sampling step were collected in a screw cap glass jar. For extraction of the drug, 30 ml methanol was added and the samples were placed on a shaker for 30 min at 210 rpm. Volumes of 10 ml of the extract were filtered using a 0.2 µm filter (Sarstedt, Nuembrecht, Germany) and dried under heated nitrogen gas at 50◦ C. The samples were resuspended in 150 µl water pH 2-3 (acidified with HCl; Merck KGaA, Darmstadt, Germany). Thereof, 50 µl were diluted 1:1 with 50 µl HPLC mobile phase (see below) without phosphoric acid and transferred to a sample vial. Analysis of GEM was carried out using a HPLC system from Shimadzu GmbH (Duisburg, Germany), consisting of a SCL-10A system controller, a LC-10AD pump, a SPD-20AV UV/Vis detector, a SIL-10AD auto injector, and a CTO-10AC column oven. For separation, a LiChrospher RP18 column was used (250 mm x 4.6 mm; 5 µm; Supelco Analytical, Bellefonte, PA). As mobile phase, 470 ml deionized water (alphaQ Millipore unit, Billerica, MD) and 30 ml acetonitrile containing 1.2 g KH2 PO4 (Fluka Chemie AG, Oberhaching, Germany) and 100 µl phosphoric acid (Merck KGaA, Darmstadt, Germany) was isocratically used. Temperature was set to 30◦ C. GEM was detected at wavelength 268 nm. Flow rate was set to 1.0 ml/min and retention time was ∼5.2 min. Sample volumes of 75 µl were injected. To initially determine the retention time of GEM, an aqueous solution (0.67 ng/µl) was injected. The same GEM solution was used to monitor the stability of the analytical system. Hence, the solution was injected each day when samples were analyzed and the chromatograms were evaluated for changes in the peak area. To generate GEM calibration standards, three wipe sample filters were wetted with different volumes of a solution containing 3.8 ng/µlGEM to yield the different GEM concentrations. A standard curve was derived from measurements of five calibration standards containing 0 ng, 38 ng, 100 ng, 500 ng, and 1000 ng GEM per sample. The subsequent extraction and sample preparation was performed as described for the wipe samples (see above). The standard curve was calculated using the Shimadzu CLASS-VP 7.2.1 SP1 software (Shimadzu GmbH, Duisburg, Germany). The LOD for GEM analysis was defined as three times the signal/noise ratio and was 10 ng/sample. 5-Fluorouracile: Extraction, sample preparation, and analysis Likewise, all three filters from each 5-FU wipe sampling step were collected in a screw cap jar. For drug extraction, 30 mL methanol was added and the samples were shaken for
30 min on a shaker at 210 rpm. A volume of 10 ml of the extract was transferred into a glass tube and 20 µl of internal standard (IS: 5-chlorouracil 1.17 ng/µl; Merck KGaA, Darmstadt, Germany) was added to each sample. The samples were dried as described previously. Volumes of 100 µl acetonitrile and 50 µl of the derivatization agent N-tert-butyldimethylsilylN-methyl trifluoracetamide (TBDMS; Sigma-Aldrich Chemie GmbH, Steinheim, Germany) were added, the samples briefly vortexed and derivatized for 15 min at 70◦ C. After cooling to room temperature, the samples were vortexed for 10 sec and centrifuged for 5 min at 3000 rpm. The supernatant was then transferred to sample vials. An analytical system from Agilent Technologies (Waldbronn, Germany) was used for GC-MS analysis, composed of a 7890A GC system, a 7000 GC/MS triple quad, and a 7693 autosampler. The GC system contained a VF-5ms fused silica column (2 × 15 m with back-flush; inner diameter 0.25 mm; film thickness 0.25 µm). As carrier gas, helium 5.0 was used at a constant flow of 1.5 mL/min. The following temperature program was performed: starting temperature 70◦ C for 1 min, temperature increase (25◦ C/min) to 150◦ C, temperature increase (8◦ C/min) to 190◦ C, back-flush for 1.1 min at −11.5 ml/min. Injector temperature was set to 250◦ C and transfer line temperature to 280◦ C. The retention times of 5-FU and IS were ∼9.5 min and ∼11.2 min, respectively. Sample volumes of 1 µl were injected and pulsed splitlessly. Electron ionization (EI) was performed at an ionization energy of 70 eV. For 5-FU and the IS, the mass transitions m/z = 301→ 166.7 and 317 → 275, respectively, were employed as qualifiers and m/z = 301 → 187 and 317 → 203, respectively, were used as quantifier. The sample concentrations were determined via the ratio of the peak areas of 5-FU and IS using a previously generated standard curve. The LOD– defined as three times the signal/noise ratio– was 0.2 ng/sample for 5-FU analysis. Calculation of Mean Recovery and Cleaning Efficiency Referring to the different LODs (GEM 10 ng/sample, 5-FU 0.2 ng/sample), the cleaning test was performed by contamination with the 20 ng/µl GEM stock solution and the 2 ng/µl 5-FU stock solution. Subsequently, cleaning was applied using the three different cleaning agents (distilled water, SDS-2P, Incides N) and their efficiency was compared by determining residual contamination (recovery values) via wipe samples and subsequent HPLC (GEM) or GC-MS/MS (5-FU) analysis. The recovery values (ng) after the cleaning procedure were adjusted to the corresponding positive controls of each experiment for each surface type. Since the maximal detectable drug amount is found when no cleaning was performed at all, the mean recovery value determined from the positive control samples was set as 100% residual contamination for each surface type (RCc,mean ). Therefore, recovery values (RC) of all other wipe samples (ng) following the cleaning procedure with three different cleaning strategies were divided by the mean recovery value of the corresponding positive control samples
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TABLE III. Mean Recovery [%] of the Positive Control Samples (n = 3 each)
Glass PVC Steel Laminated wood An
GEM 1000 ng (20ng/ µl)
5FU 100 ng (2ng/µl)
85 (2.3) 81 (1.9) 77 (0.7) 89 (2.1)
66 (2.1) 77 (4.9) 24 (1.0) 50 A
= 1, no mean possible.
(RCadj = recovery adjusted to the positive control samples) and presented in percentages:
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RCadj = RC ∗ 100/RCc,mean (%) The cleaning efficiency was then calculated for each type and drug concentration and for each surface type as follows: cleaning efficiency = 100 − RCadj (%) Statistical Analysis The statistical analysis was performed using SPSS Statistics Version 21 for Windows (IBM, Armonk, NY). RESULTS Recovery of the Cleaning Tests The mean recovery values of the positive control samples (wipe samples of drug-coated plates without decontamination) of the surfaces are compiled in Table III. Cleaning Efficiency The cleaning efficiencies were calculated for each cleaning agent and for both antineoplastic drugs with respect to the mean recovery rate of the positive control samples (as described previously). The cleaning efficiencies (%) are presented in Table IV for all surface types. Gemcitabine 20 ng/µl stock solution Cleaning of the contaminated plates (n = 3 each) of all types of surfaces with distilled water or SDS-2P was found to be most effective (Table IV). No residual GEM was detected after cleaning with those two agents. In contrast, the use of Incides N alcoholic wipes lead to GEM residues on all types of surfaces after cleaning, but residual amounts were quite moderate and mostly just above the LOD of 10 ng/sample except for one sample from stainless steel (84 ng/sample) and for laminated wood (39 and 40 ng/sample, one sample n.a.). 5-FU 2 ng/µl stock solution On the glass surface, no 5-FU could be detected after cleaning with distilled water and SDS-2P (Table IV). Traces of 5-FU just at the LOD of 0.2 ng per sample were detected 388
after cleaning with the Incides N alcoholic wipes. Residual 5FU was detected on all PVC plates after cleaning with any of the three agents (range: 1.3–2.8 ng/sample) with mean contamination residues between 2.1 and 3.1% standardized to the mean positive control of 77%. Due to a low overall recovery from the stainless steel plates as indicated by the mean recovery of 24% of the positive control (Table III), the recovery values appear higher even though the detected absolute amounts of 5-FU are lower compared to those found on the other surfaces. Most residual 5FU was detected on stainless steel plates cleaned with the Incides N alcoholic wipes (1 sample < LOD, 1 sample: 1.1 ng and 1 sample 3.0 ng) as compared to cleaning with distilled water (2 samples < LOD, 1 sample 1.0 ng) and the SDS2P (0.4, 0.7, and 0.9 ng/sample). Concerning the laminated wood surfaces (range 3.4–6.6 ng/sample), evaluated cleaning efficiencies were comparatively low (mean: 89–93%), but they need to be considered very preliminarily, since only one of the positive control plates yielded a detectable amount of 5-FU (50 ng/sample). For practical reasons, this value was employed here to determine the relative recovery values after the cleaning procedure. Cleaning with the Incides N alcoholic wipes resulted in the lowest mean cleaning efficiency (89%) of the tests. The overall cleaning efficiency regarding 5-FU was lower than those for GEM. Except for the glass plates, residual 5-FU was detected on all surfaces after cleaning with all three agents. As already observed for GEM, cleaning with the Incides N alcoholic wipes was least effective, especially on laminated wood and steel, and most residual drugs tested were found in these locations.
DISCUSSION
C
leaning protocols for drug preparation surfaces have to be practicable and must therefore include decontamination management of a multitude of handled antineoplastic drugs. Nevertheless, due to the different drug characteristics, investigations on single marker drugs are helpful to develop a comprehensive and appropriate cleaning strategy. Data on decontamination of GEM and 5-FU residues are rare and are now focused in the present study. The efficacy of three cleaning agents on GEM and 5-FU on four different surfaces was evaluated by environmental monitoring. Glass and stainless steel are the most frequently used materials for surfaces inside BSCs and isolators. However, since environmental monitoring studies(6,7,9–13) indicated drug residues on surfaces in the whole preparation and administration area, other materials used for carts, administration desks, storage shelves, floors and so on are just as important. In this study, also, plates of laboratory PVC and laminated wood that is used for work and administration desks were investigated.
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TABLE IV.
Schematic Set-up of All Tests and Cleaning Efficiencies (%) of All Substances and Surfaces
Recovery During implementation of the HPLC method for GEM, recovery rates of GEM were satisfying and constantly in similar order of magnitude for all GEM solutions and all types of surfaces, namely glass, stainless steel, PVC, and laminated wood. In fact, recoveries on steel, PVC, and laminated wood were even higher than on glass comparing results after contamination with 20 ng/µl GEM solution. Nevertheless, one has to bear in mind the small number of wipe samples for determining recovery rates. Especially for PVC and stainless steel, these observations should not be overestimated because one out of three samples each has not been available for analysis. Cleaning Procedure The choice of the cleaning agents was based on current decontamination practice in German pharmacy units and comprises both alcoholic agents and detergents. Water is the most widely used solvent in cleaning solutions and is a good parameter for comparison with other cleaning solutions. SDS is an effective anionic surfactant which promotes the desorption of antineoplastic substances and reinforces their solubility and is easily available in pharmacy units. Its effectiveness has been proven on both stainless steel and glass surfaces.(29) The mixture of SDS and isopropyl alcohol is often used in current
pharmacies as the properties of alcohol help to reduce residual (detergent) film from surfaces. The efficiency of distilled water, SDS-2P, and alcoholic wipes is based on the elimination of the drug. SDS was expected to improve the decontamination of most hydrophobic components compared to pure aqueous solutions. Sodium hypochlorite, which chemically degrades antineoplastic drugs, is restricted for use at stainless steel surfaces due to its oxidizing effects and its environmental toxicity and health impairing degradation products, i.e., other chemically active metabolites with potential mutagenic risks.(35,37,38) There is also the risk of deterioration of cleaned surfaces, which requires rinsing the surfaces with water after use to avoid corrosion phenomena.(29,39) None of the cleaning agents tested led to residual contaminations markedly exceeding 10% of the original contamination of both drugs tested. On the other hand, none of the cleaning agents removed the drug contamination with 100% efficiency from all surfaces tested. In general, cleaning of GEM and 5-FU was most efficient using pure water or SDS-2P as compared to cleaning with Incides N alcoholic wipes, which is most likely due to the hydrophilic properties of both cleaning solutions. This is in accordance with findings of Lamerie et al.(29) who also indicate that surfactants as cleaning agents appear to be
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promising as they are an ideal compromise between their relative harmlessness and detergent capacities. However, in that study, effectiveness of ultrapure water on contaminated stainless steel was shown to be satisfying for only few drugs including GEM, but obviously insufficient to remove all ten investigated antineoplastic agents, especially on hydrophobic compounds (5-FU was not tested). In our study, only the cleaning scenario of removing 5-FU from laboratory PVC appeared to have—as an exception—a cleaning efficiency of Incides N wipes as high as those of distilled water. This exception might indicate that the cleaning efficiency depends on the combination of both cleaning agent and surface to be cleaned and also the method of application could affect the cleaning outcome, as indicated by Le et al.(39) who described that spraying of the cleaning liquid on the surface compared to wiping enables better recovery of platinum-drugs. However, Hon et al.(30) found that the method of previous cleaning agent application (directly onto surface or indirectly onto a wipe) seemed to have a minimal effect while using an isopropyl alcohol wipe additionally after cleaning effectively reduced the drug residuals (cyclophosphamide, methotrexate) on the surfaces. Surprisingly, both GEM and 5-FU recovery values from laboratory PVC after cleaning with different agents were comparable with those from glass. However, regarding practical considerations about cleaning laboratory PVC surfaces such as floors, one needs to take into account that the sampled plates used in the experiments were cut from new and unruffled PVC. In contrast, laboratory floors are constantly exposed to walking, standing, and moving of personnel and equipment and, as a consequence, the surface roughens over time and pores develop, impairing the surface cleaning by allowing persistent deposit of substances. PVC and laminated wood exhibit small pores in their surfaces which are likely to hide small residues of contamination, especially after long use (“drug memory”). They are supposed to express higher residual drug concentrations than the samples from brand new materials without any “drug memory.” Only one out of three control samples from 5-FU-contaminated laminated wood plate without any cleaning (positive control) had 5-FU concentration >LOD (50 ng), which might be due to a problem in handling the wipe samples. Unexpected low 5-FU amounts were recovered (positive controls) on the stainless steel surface (24%) after contamination with the 5-FU solution compared to other surfaces (glass 66%, PVC 77%). One possible hypothesis might be the occurrence of specific interactions between 5-FU and the stainless steel surface. Another reason might be an ineffective performing of the wipe samples. As the stainless steel surfaces were very slippery, it was difficult to build up enough force during the wiping. As assumed by Lamerie et al.,(29) the variations observed between glass and stainless steel surfaces can also be accounted for by their physicochemical characteristics. Glass as a more hydrophilic surface has a higher wettability, and stainless steel as metal has a higher hydrophobicity and a lower wettability. 390
Several studies have been published to evaluate cleaning procedures using eliminating or deactivating agents to remove cytotoxic contamination on workplace surfaces,(11,29–33,39,40) but comparison is restricted due to variability and differences in methodologies, antineoplastic drugs tested, cleaning agents, and performance tested, detection limits, and so on. LIMITATIONS
S
ome study limitations have to be addressed and include the small number of samples and the fact that only two antineoplastic drugs were examined under experimental conditions. We are aware that we could not exactly imitate real contamination scenarios and all cleaning schemes in pharmacy preparation and administration units where additional parameters of the daily working routine have to be taken into account. Moreover, sizes of sampled surfaces (100 cm2) and amounts of applied drug contamination (50 µl) and decontamination agents (1 ml) are not necessarily representative. Hydroalcoholic solutions, however, are commonly used in German hospital pharmacies, often in combination with a detergent due to their low cost and their good compatibility with surfaces. In this study, no further combinations of cleaning agents were tested as we only intended to verify wipe samples as a reliable control tool for evaluating cleaning efficacy. To avoid interindividual variability regarding sampling performance, the same individual was tasked to conduct all the intentional contamination, the cleaning, and the wipe sampling. Nevertheless, differences in the practical performance cannot be ruled out. CONCLUSION
T
he results of this study demonstrate that current cleaning procedures can reduce the exposure risk of antineoplastic drugs to the operator and the environment, but they cannot completely eliminate it. Materials commonly used for BSCs/isolators were tested, but also floor covering (PVC) and benchtop materials that are present in the whole area of the drug preparation and administration units. Drug residues of GEM and 5-FU could be verified by wipe samples and quantified by the analytical methods. The mixture of SDS and isopropyl alcohol but also pure distilled water demonstrated good results for actual cleaning procedures for the two tested hydrophilic antineoplastic drugs (especially GEM) which does well in meeting current practice in a large number of pharmacies. Cleaning efficiency was lowest when using pre-soaked alcoholic towels. Regarding5-FU, the overall cleaning efficiency was lower and surface types and cleaning agents are supposed to have more influence at recovery rates and cleaning efficiencies. These results indicate the potential need to adapt cleaning procedures to the variety of drug compounds used and the specific surface types to develop adequate and effective decontamination strategies.
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ACKNOWLEDGMENT
T
he tailored plates of the four materials were kindly provided by Helmut Ober, Department for Chemistry and Pharmacy, Ludwig Maximilians University, Munich, Germany.
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Cleaning Efficiencies of Three Cleaning Agents on Four Different Surfaces after Contamination by Gemcitabine and 5-fluorouracile a
a
a
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Antje Böhlandt , Svenja Groeneveld , Elke Fischer & Rudolf Schierl a
Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Clinical Center, Ludwig Maximilians University, Munich, Germany Accepted author version posted online: 09 Mar 2015.Published online: 13 May 2015.
Click for updates To cite this article: Antje Böhlandt, Svenja Groeneveld, Elke Fischer & Rudolf Schierl (2015) Cleaning Efficiencies of Three Cleaning Agents on Four Different Surfaces after Contamination by Gemcitabine and 5-fluorouracile, Journal of Occupational and Environmental Hygiene, 12:6, 384-392, DOI: 10.1080/15459624.2015.1009985 To link to this article: http://dx.doi.org/10.1080/15459624.2015.1009985
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Journal of Occupational and Environmental Hygiene, 12: 384–392 ISSN: 1545-9624 print / 1545-9632 online c 2015 JOEH, LLC Copyright DOI: 10.1080/15459624.2015.1009985
Cleaning Efficiencies of Three Cleaning Agents on Four Different Surfaces after Contamination by Gemcitabine and 5-fluorouracile ¨ Antje Bohlandt, Svenja Groeneveld, Elke Fischer, and Rudolf Schierl
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Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Clinical Center, Ludwig Maximilians University, Munich, Germany
Occupational exposure to antineoplastic drugs has been documented for decades showing widespread contamination in preparation and administration areas. Apart from preventive measures, efficient cleaning of surfaces is indispensable to minimize the exposure risk. The aim of this study was to evaluate the efficiency of three cleaning agents after intentional contamination by gemcitabine (GEM) and 5-fluorouracile (5-FU) on four different surface types usually installed in healthcare settings. Glass, stainless steel, polyvinylchloride (PVC), and laminated wood plates were contaminated with 20 ng/µl GEM and 2 ng/µl 5-FU solutions. Wipe samples were analyzed for drug residues after cleaning with a) distilled water, b) aqueous solution containing sodium dodecyl sulfate (10 mM) and 2propanol (SDS-2P), and c) Incides N (pre-soaked) alcoholic wipes. Quantification was performed by high-performance liquid chromatography (HPLC) for GEM and gas chromatography-tandem mass spectrometry (GCMS/MS) for 5-FU. Recovery was determined and cleaning efficiency was calculated for each scenario. Mean recoveries were 77–89% for GEM and 24–77% for 5-FU and calculated cleaning efficiencies ranged between 95 and 100% and 89 and 100%, respectively. Residual drug amounts were detected in the range nd (not detected) – 84 ng GEM/sample and nd – 6.6 ng 5-FU/sample depending on surface type and cleaning agent. Distilled water and SDS-2P had better decontamination outcomes than Incides N wipes on nearly all surface types, especially for GEM. Regarding 5-FU, the overall cleaning efficiency was lower with highest residues on laminated wood surfaces. The tested cleaning procedures are shown to clean glass, stainless steel, PVC, and laminated wood with an efficiency of 89–100% after contamination with GEM and 5-FU. Nevertheless, drug residues could be verified by wipe samples. Pure distilled water and SDS in an alcoholicaqueous solution expressed an efficient cleaning performance, especially with respect to GEM. The study results demonstrate the need to adapt cleaning procedures to the variety of drugs and surface types to develop effective decontamination strategies. Keywords
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antineoplastic drugs, cleaning, decontamination
Address correspondence to: Rudolf Schierl, Ziemssenstrasse 1, D-80336 Muenchen, Germany; e-mail: [email protected]
INTRODUCTION
H
ealth care personnel are occupationally exposed to cytotoxic substances during preparation and administration of antineoplastic agents. Biomonitoring has shown incorporation and adverse health effects in pharmacy and nurse staff despite improved technologic solutions and personal protective equipment.(1–5) Drug residues are still found on various surfaces in and around the drug preparation area of (hospital) pharmacies and oncology wards, even on assumedly “clean” surfaces (6–14) and on the outside of vials.(15–23) Dermal contact followed by transdermal absorption is suggested to be the major route of incorporation in occupational settings.(24–27) Apart from preventive measures, efficient cleaning strategies for decontamination of workstation surfaces must be consequently focused in terms of minimizing the risk of exposure to drug residues. In fact, no consistent regulation and evidence-based strategies regarding standardized cleaning protocols and effectiveness are proposed/implemented and decontamination is vaguely defined by the (American Society of Health-System Pharmacists (ASHP) as cleaning (physical removal) or deactivating (chemical degradation) following an appropriate cleaning protocol.(28) Subsequently, various studies focused on evaluating decontamination strategies including different cleaning agents, techniques, and antineoplastic substances. However, results and recommendations were inconsistent and not applicable for all antineoplastic drugs tested.(11,29–33)
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A number of studies have shown the efficiency of deactivating agents, such as sodium hypochlorite, to degrade several— if not all—investigated antineoplastic agents, but mutagenicity and other health impairing risks of the degradation products have not been excluded.(31,34–38) Mostly, investigated surfaces comprised stainless steel and glass as major components of biological safety cabinets (BSCs), while other surface materials have been less considered despite the evidence that contamination could be spread in the entire preparation and administration area. Although 5-FU is the most prescribed parenteral chemotherapy agent for cancer therapy in Germany and in many other countries and also the preparation numbers of GEM have been constantly increasing during recent years, literature data on decontamination strategies for both compounds are scarce. The aim of this study was to assess the efficiency of three routinely used cleaning agents on four different surfaces according to a standardized cleaning technique after intentional contamination by GEM and 5-FU.
Cleaning Agents The principal objective of decontamination is to remove the contaminant drug by dissolving and transferring it from the wiped surface to a disposable item (elimination) using different types of wetting solutions or prefabricated pre-soaked wipes (hydro-alcoholic, detergent, or disinfectant). Based on current decontamination practice in German pharmacy units, three different cleaning agents were evaluated in this study:
MATERIAL AND METHODS
Preparation of Compound Stock Solutions Main stock solutions of GEM and 5-FU for intentional contamination were prepared in water and acetonitrile (Merck KGaA, Darmstadt, Germany) at concentrations of 20 ng/µl (GEM) and 2 ng/µl (5-FU), respectively. As no standard analytical method for determination of GEM from wipe samples has been established in our laboratory, further dilutions of the GEM stock solution were made (10 ng/µl and 2 ng/µl) to evaluate recovery rates at different concentrations. All solutions were prepared in appropriate safety conditions under a laminar airflow hood and with personal protective equipment following the guidelines for handling of cytotoxic drugs. Preliminary test showed that the amount of 50 µl stock solution was practicable in terms of application and drying of solutions on the different surfaces.
Study Design Plates of four different materials were intentionally contaminated with defined drug amounts: 20 ng/µl (nanogram/ microliter) GEM solution and 2 ng/µl 5-FU solution. The plates were subsequently cleaned by three different cleaning agents. Residual drug contamination was collected by wipe sampling and analyzed using high-performance liquid chromatography (HPLC) for GEM and gas chromatographytandem mass spectrometry (GCMS/MS) for 5-FU. Preliminary tests on recovery rates of the newly implemented HPLC method for GEM wipe samples were conducted with dilutions of 20 ng/µl, 10 ng/µl, and 2 ng/µl. Antineoplastic Agents The study was performed using GEM (Cell Pharm, Bad Vilbel, Germany) and 5-FU (Merck KGaA, Darmstadt, Germany) for the preparation of the different stock solutions. Both substances are classified as antimetabolites. Surface Materials In pharmaceutical units the surfaces for handling cytotoxic drugs are usually composed of stainless steel (e.g., BSC, drug preparation area), glass (e.g., BSC, vials) or laminated wood (e.g., desktops, work tops, shelves, closets). Laboratory floors are frequently covered with polyvinylchloride (PVC) potentially exposed to spills during drug preparation and spreading via shoes. For evaluating cleaning results on the different surfaces, new and specifically tailored plates of 10 × 10 cm of these four materials were used as test surfaces that matched the quality of working surfaces of pharmacy preparation units and BSCs.
• distilled water • an aqueous solution containing 40 ml sodium dodecyl sulfate (SDS,10 mM) and 10 ml 2-propanol (SDS-2P). SDS is an organic compound and a highly effective anionic surfactant and is used in detergents for many cleaning applications. (80% 10 mM SDS and 20% 2-propanol). This formulation was selected according to the findings of Lamerie et al. who described a high global effectiveness in cleaning of 10 antineoplastic agents.(29) • commercial available alcoholic wipes (Incides N; Ecolab GmbH, Duesseldorf, Germany): containing 1-propanol and 2-propanol.
Contamination Procedure The intentional contamination of the surfaces to be investigated followed the same standardized protocol for both antineoplastic agents: Volumes of 50 µl GEM or 5-FU stock solution with different concentrations were spread in approximately 40 droplets onto the whole surface of the 10 × 10 cm plates of different materials using an adjustable volume micropipette. The contaminated plates were dried overnight under a laminar airflow hood at room temperature. All contaminations were set in triplicates for all drug concentrations and each surface. Wipe Sampling Sampling of contamination was performed according to a validated and standardized wiping procedure as described previously by Schierl et al.(12) Briefly, each contaminated/ decontaminated plate was subsequently wiped with three filters (Filter Discs 391, Sartorius Stedim GmbH, Goettingen,
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Germany) moistened with 6 drops distilled water for GEM and methanol for 5-FU. The wiping direction was changed with each filter. A new pair of gloves was taken each time before doing the next sample. All three filters were placed in a screw cap glass jar and stored at 4◦ C until analysis. The whole contamination, decontamination, and wipe sampling procedures were performed by the same person to eliminate effects of inter-individual variability. Implementation of the GEM Method As the new HPLC method for analyzing GEM wipe samples was implemented for this study, the suitability of distilled water and methanol as solvent for the wipe sample filters was evaluated in a first step prior to the decontamination experiment. Therefore, 10 × 10 cm test surfaces were contaminated in triplicates with 50 µl of stock solutions with GEM concentrations of 20 ng/µl each and dried overnight under a laminar airflow. As glass was expected to provide the most precise recovery rates due to its smooth and nonporous surface, GEM solutions in concentrations of 2 ng/µl and 10 ng/µl were additionally adopted to evaluate whether the recovery was constant over that concentration range. Wipe samples were collected as described previously, and recoveries were quantified and compared (Table I). As quantified GEM recovery values after contamination with 50 µl of the 2 ng/µl solution (containing 100 ng GEM) were comparatively low and near the limit of detection (LOD) of 10 ng/wipe sample of the analytical method, subsequent cleaning tests were performed with 20 ng/µl GEM stock solutions (containing 1000 ng GEM) to obtain reliable values. The other types of surfaces were then exposed to the 1000 ng GEM (20 ng/µl) solution and revealed recoveries between 83 and 135%. As recovery rates observed for the use of distilled water versus methanol as moisturizing solvent for the GEM wipe sampling were approximately within the same range (Table I), water was chosen as solvent for surface wipe sampling in the subsequent GEM experiments due to its lack of toxicity. Regarding 5-FU, no recovery tests were performed prior to the cleaning experiment, as a validated and very sensitive analytical method (GCMS/MS) has already been established.(14) As its limit of detection (LOD) is 50 times lower compared to GEM, intentional contamination in the cleaning experiment was performed with 5-FU stock at concentrations of 2 ng/µl. Cleaning Procedure (Decontamination) The contaminations with an equal amount of drug were set in triplicates of 50 µl each (as described previously), i.e., three plates per cleaning agent. Likewise, negative controls (plates 1–3 = blanks: no contamination, solely cleaning procedure) and positive controls (plates 13–15 = recovery: solely drug contamination, but no cleaning procedure) were taken threefold, resulting in a total number of 15 samples per surface type as shown in a schematic setup of a cleaning experiment with 20 ng/µl GEM solution as an example for any surface type (Table II). 386
TABLE I. Gemcitabine: Comparison of Distilled Water Versus Methanol as Solvent for GEM Wipe Samples after Contamination of Different Surfaces with 50 µl of 2 ng/µl (100 ng), 10 ng/µl (500 ng), and 20 ng/µl (1000 ng) GEM Stock Solution, Respectively recovery rate (mean ± standard deviation) contamination (ng)
distilled water
methanol
100 500 1000 1000 1000
71%(3.3) 85%(1.8) 75%(2.4) 109%(37.3) A 92%(3.8)B
79%(5.0) 82%(5.8) 95%(2.9) 91%(10.5)C n.a.
glass
PVC stainless steel laminated wood
1000
87%(0.9)
80%(1.2)
Note: Limit of detection = 10 ng/sample. An = 2: 83% and 135%. Bn = 2: 89% and 95%. Cn = 4.
After the contaminated plates had dried, 1 ml of the two liquid cleaning liquids agents (water vs. SDS-2P) was pipetted dropwise onto each contaminated surface and spread utilizing a whole paper towel (Kimberly Clark, Wypall Wipers, Koblenz, Germany) in circular motions. Equivalently, one alcoholic Incides N wipe per plate was used to circularly moisten the surface. Subsequently, one fresh paper towel was utilized to dry-wipe the surfaces, again performing a circular motion. The experiments were performed in a 3-day sequence. On day 1, the surfaces were contaminated with the drug solutions or pure
TABLE II. Schematic Set-up of the Cleaning Experiments: Example of the Cleaning Test with 50 µl of the 20 ng/µl (1000 ng) Gemcitabine Stock Solution No.
Gemcitabine [ng/50 µl]
Cleaning agents
1 2 3 4 5 6 7 8 9 10 11 12
none none none 1000 1000 1000 1000 1000 1000 1000 1000 1000
Distilled water SDS-2P Incides N Distilled water Distilled water Distilled water SDS-2P SDS-2P SDS-2P Incides N Incides N Incides N
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solvent (and let dry overnight). On day 2, the contaminated surfaces were cleaned. On day 3, wipe samples were taken and the extraction was performed. Analyses were performed on day 3, day 4, or after the weekend. All experiments were performed under a laminar airflow. Analytical Procedure Gemcitabine: Extraction, sample preparation, and analysis All three filters from the wipe sampling step were collected in a screw cap glass jar. For extraction of the drug, 30 ml methanol was added and the samples were placed on a shaker for 30 min at 210 rpm. Volumes of 10 ml of the extract were filtered using a 0.2 µm filter (Sarstedt, Nuembrecht, Germany) and dried under heated nitrogen gas at 50◦ C. The samples were resuspended in 150 µl water pH 2-3 (acidified with HCl; Merck KGaA, Darmstadt, Germany). Thereof, 50 µl were diluted 1:1 with 50 µl HPLC mobile phase (see below) without phosphoric acid and transferred to a sample vial. Analysis of GEM was carried out using a HPLC system from Shimadzu GmbH (Duisburg, Germany), consisting of a SCL-10A system controller, a LC-10AD pump, a SPD-20AV UV/Vis detector, a SIL-10AD auto injector, and a CTO-10AC column oven. For separation, a LiChrospher RP18 column was used (250 mm x 4.6 mm; 5 µm; Supelco Analytical, Bellefonte, PA). As mobile phase, 470 ml deionized water (alphaQ Millipore unit, Billerica, MD) and 30 ml acetonitrile containing 1.2 g KH2 PO4 (Fluka Chemie AG, Oberhaching, Germany) and 100 µl phosphoric acid (Merck KGaA, Darmstadt, Germany) was isocratically used. Temperature was set to 30◦ C. GEM was detected at wavelength 268 nm. Flow rate was set to 1.0 ml/min and retention time was ∼5.2 min. Sample volumes of 75 µl were injected. To initially determine the retention time of GEM, an aqueous solution (0.67 ng/µl) was injected. The same GEM solution was used to monitor the stability of the analytical system. Hence, the solution was injected each day when samples were analyzed and the chromatograms were evaluated for changes in the peak area. To generate GEM calibration standards, three wipe sample filters were wetted with different volumes of a solution containing 3.8 ng/µlGEM to yield the different GEM concentrations. A standard curve was derived from measurements of five calibration standards containing 0 ng, 38 ng, 100 ng, 500 ng, and 1000 ng GEM per sample. The subsequent extraction and sample preparation was performed as described for the wipe samples (see above). The standard curve was calculated using the Shimadzu CLASS-VP 7.2.1 SP1 software (Shimadzu GmbH, Duisburg, Germany). The LOD for GEM analysis was defined as three times the signal/noise ratio and was 10 ng/sample. 5-Fluorouracile: Extraction, sample preparation, and analysis Likewise, all three filters from each 5-FU wipe sampling step were collected in a screw cap jar. For drug extraction, 30 mL methanol was added and the samples were shaken for
30 min on a shaker at 210 rpm. A volume of 10 ml of the extract was transferred into a glass tube and 20 µl of internal standard (IS: 5-chlorouracil 1.17 ng/µl; Merck KGaA, Darmstadt, Germany) was added to each sample. The samples were dried as described previously. Volumes of 100 µl acetonitrile and 50 µl of the derivatization agent N-tert-butyldimethylsilylN-methyl trifluoracetamide (TBDMS; Sigma-Aldrich Chemie GmbH, Steinheim, Germany) were added, the samples briefly vortexed and derivatized for 15 min at 70◦ C. After cooling to room temperature, the samples were vortexed for 10 sec and centrifuged for 5 min at 3000 rpm. The supernatant was then transferred to sample vials. An analytical system from Agilent Technologies (Waldbronn, Germany) was used for GC-MS analysis, composed of a 7890A GC system, a 7000 GC/MS triple quad, and a 7693 autosampler. The GC system contained a VF-5ms fused silica column (2 × 15 m with back-flush; inner diameter 0.25 mm; film thickness 0.25 µm). As carrier gas, helium 5.0 was used at a constant flow of 1.5 mL/min. The following temperature program was performed: starting temperature 70◦ C for 1 min, temperature increase (25◦ C/min) to 150◦ C, temperature increase (8◦ C/min) to 190◦ C, back-flush for 1.1 min at −11.5 ml/min. Injector temperature was set to 250◦ C and transfer line temperature to 280◦ C. The retention times of 5-FU and IS were ∼9.5 min and ∼11.2 min, respectively. Sample volumes of 1 µl were injected and pulsed splitlessly. Electron ionization (EI) was performed at an ionization energy of 70 eV. For 5-FU and the IS, the mass transitions m/z = 301→ 166.7 and 317 → 275, respectively, were employed as qualifiers and m/z = 301 → 187 and 317 → 203, respectively, were used as quantifier. The sample concentrations were determined via the ratio of the peak areas of 5-FU and IS using a previously generated standard curve. The LOD– defined as three times the signal/noise ratio– was 0.2 ng/sample for 5-FU analysis. Calculation of Mean Recovery and Cleaning Efficiency Referring to the different LODs (GEM 10 ng/sample, 5-FU 0.2 ng/sample), the cleaning test was performed by contamination with the 20 ng/µl GEM stock solution and the 2 ng/µl 5-FU stock solution. Subsequently, cleaning was applied using the three different cleaning agents (distilled water, SDS-2P, Incides N) and their efficiency was compared by determining residual contamination (recovery values) via wipe samples and subsequent HPLC (GEM) or GC-MS/MS (5-FU) analysis. The recovery values (ng) after the cleaning procedure were adjusted to the corresponding positive controls of each experiment for each surface type. Since the maximal detectable drug amount is found when no cleaning was performed at all, the mean recovery value determined from the positive control samples was set as 100% residual contamination for each surface type (RCc,mean ). Therefore, recovery values (RC) of all other wipe samples (ng) following the cleaning procedure with three different cleaning strategies were divided by the mean recovery value of the corresponding positive control samples
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TABLE III. Mean Recovery [%] of the Positive Control Samples (n = 3 each)
Glass PVC Steel Laminated wood An
GEM 1000 ng (20ng/ µl)
5FU 100 ng (2ng/µl)
85 (2.3) 81 (1.9) 77 (0.7) 89 (2.1)
66 (2.1) 77 (4.9) 24 (1.0) 50 A
= 1, no mean possible.
(RCadj = recovery adjusted to the positive control samples) and presented in percentages:
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RCadj = RC ∗ 100/RCc,mean (%) The cleaning efficiency was then calculated for each type and drug concentration and for each surface type as follows: cleaning efficiency = 100 − RCadj (%) Statistical Analysis The statistical analysis was performed using SPSS Statistics Version 21 for Windows (IBM, Armonk, NY). RESULTS Recovery of the Cleaning Tests The mean recovery values of the positive control samples (wipe samples of drug-coated plates without decontamination) of the surfaces are compiled in Table III. Cleaning Efficiency The cleaning efficiencies were calculated for each cleaning agent and for both antineoplastic drugs with respect to the mean recovery rate of the positive control samples (as described previously). The cleaning efficiencies (%) are presented in Table IV for all surface types. Gemcitabine 20 ng/µl stock solution Cleaning of the contaminated plates (n = 3 each) of all types of surfaces with distilled water or SDS-2P was found to be most effective (Table IV). No residual GEM was detected after cleaning with those two agents. In contrast, the use of Incides N alcoholic wipes lead to GEM residues on all types of surfaces after cleaning, but residual amounts were quite moderate and mostly just above the LOD of 10 ng/sample except for one sample from stainless steel (84 ng/sample) and for laminated wood (39 and 40 ng/sample, one sample n.a.). 5-FU 2 ng/µl stock solution On the glass surface, no 5-FU could be detected after cleaning with distilled water and SDS-2P (Table IV). Traces of 5-FU just at the LOD of 0.2 ng per sample were detected 388
after cleaning with the Incides N alcoholic wipes. Residual 5FU was detected on all PVC plates after cleaning with any of the three agents (range: 1.3–2.8 ng/sample) with mean contamination residues between 2.1 and 3.1% standardized to the mean positive control of 77%. Due to a low overall recovery from the stainless steel plates as indicated by the mean recovery of 24% of the positive control (Table III), the recovery values appear higher even though the detected absolute amounts of 5-FU are lower compared to those found on the other surfaces. Most residual 5FU was detected on stainless steel plates cleaned with the Incides N alcoholic wipes (1 sample < LOD, 1 sample: 1.1 ng and 1 sample 3.0 ng) as compared to cleaning with distilled water (2 samples < LOD, 1 sample 1.0 ng) and the SDS2P (0.4, 0.7, and 0.9 ng/sample). Concerning the laminated wood surfaces (range 3.4–6.6 ng/sample), evaluated cleaning efficiencies were comparatively low (mean: 89–93%), but they need to be considered very preliminarily, since only one of the positive control plates yielded a detectable amount of 5-FU (50 ng/sample). For practical reasons, this value was employed here to determine the relative recovery values after the cleaning procedure. Cleaning with the Incides N alcoholic wipes resulted in the lowest mean cleaning efficiency (89%) of the tests. The overall cleaning efficiency regarding 5-FU was lower than those for GEM. Except for the glass plates, residual 5-FU was detected on all surfaces after cleaning with all three agents. As already observed for GEM, cleaning with the Incides N alcoholic wipes was least effective, especially on laminated wood and steel, and most residual drugs tested were found in these locations.
DISCUSSION
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leaning protocols for drug preparation surfaces have to be practicable and must therefore include decontamination management of a multitude of handled antineoplastic drugs. Nevertheless, due to the different drug characteristics, investigations on single marker drugs are helpful to develop a comprehensive and appropriate cleaning strategy. Data on decontamination of GEM and 5-FU residues are rare and are now focused in the present study. The efficacy of three cleaning agents on GEM and 5-FU on four different surfaces was evaluated by environmental monitoring. Glass and stainless steel are the most frequently used materials for surfaces inside BSCs and isolators. However, since environmental monitoring studies(6,7,9–13) indicated drug residues on surfaces in the whole preparation and administration area, other materials used for carts, administration desks, storage shelves, floors and so on are just as important. In this study, also, plates of laboratory PVC and laminated wood that is used for work and administration desks were investigated.
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TABLE IV.
Schematic Set-up of All Tests and Cleaning Efficiencies (%) of All Substances and Surfaces
Recovery During implementation of the HPLC method for GEM, recovery rates of GEM were satisfying and constantly in similar order of magnitude for all GEM solutions and all types of surfaces, namely glass, stainless steel, PVC, and laminated wood. In fact, recoveries on steel, PVC, and laminated wood were even higher than on glass comparing results after contamination with 20 ng/µl GEM solution. Nevertheless, one has to bear in mind the small number of wipe samples for determining recovery rates. Especially for PVC and stainless steel, these observations should not be overestimated because one out of three samples each has not been available for analysis. Cleaning Procedure The choice of the cleaning agents was based on current decontamination practice in German pharmacy units and comprises both alcoholic agents and detergents. Water is the most widely used solvent in cleaning solutions and is a good parameter for comparison with other cleaning solutions. SDS is an effective anionic surfactant which promotes the desorption of antineoplastic substances and reinforces their solubility and is easily available in pharmacy units. Its effectiveness has been proven on both stainless steel and glass surfaces.(29) The mixture of SDS and isopropyl alcohol is often used in current
pharmacies as the properties of alcohol help to reduce residual (detergent) film from surfaces. The efficiency of distilled water, SDS-2P, and alcoholic wipes is based on the elimination of the drug. SDS was expected to improve the decontamination of most hydrophobic components compared to pure aqueous solutions. Sodium hypochlorite, which chemically degrades antineoplastic drugs, is restricted for use at stainless steel surfaces due to its oxidizing effects and its environmental toxicity and health impairing degradation products, i.e., other chemically active metabolites with potential mutagenic risks.(35,37,38) There is also the risk of deterioration of cleaned surfaces, which requires rinsing the surfaces with water after use to avoid corrosion phenomena.(29,39) None of the cleaning agents tested led to residual contaminations markedly exceeding 10% of the original contamination of both drugs tested. On the other hand, none of the cleaning agents removed the drug contamination with 100% efficiency from all surfaces tested. In general, cleaning of GEM and 5-FU was most efficient using pure water or SDS-2P as compared to cleaning with Incides N alcoholic wipes, which is most likely due to the hydrophilic properties of both cleaning solutions. This is in accordance with findings of Lamerie et al.(29) who also indicate that surfactants as cleaning agents appear to be
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promising as they are an ideal compromise between their relative harmlessness and detergent capacities. However, in that study, effectiveness of ultrapure water on contaminated stainless steel was shown to be satisfying for only few drugs including GEM, but obviously insufficient to remove all ten investigated antineoplastic agents, especially on hydrophobic compounds (5-FU was not tested). In our study, only the cleaning scenario of removing 5-FU from laboratory PVC appeared to have—as an exception—a cleaning efficiency of Incides N wipes as high as those of distilled water. This exception might indicate that the cleaning efficiency depends on the combination of both cleaning agent and surface to be cleaned and also the method of application could affect the cleaning outcome, as indicated by Le et al.(39) who described that spraying of the cleaning liquid on the surface compared to wiping enables better recovery of platinum-drugs. However, Hon et al.(30) found that the method of previous cleaning agent application (directly onto surface or indirectly onto a wipe) seemed to have a minimal effect while using an isopropyl alcohol wipe additionally after cleaning effectively reduced the drug residuals (cyclophosphamide, methotrexate) on the surfaces. Surprisingly, both GEM and 5-FU recovery values from laboratory PVC after cleaning with different agents were comparable with those from glass. However, regarding practical considerations about cleaning laboratory PVC surfaces such as floors, one needs to take into account that the sampled plates used in the experiments were cut from new and unruffled PVC. In contrast, laboratory floors are constantly exposed to walking, standing, and moving of personnel and equipment and, as a consequence, the surface roughens over time and pores develop, impairing the surface cleaning by allowing persistent deposit of substances. PVC and laminated wood exhibit small pores in their surfaces which are likely to hide small residues of contamination, especially after long use (“drug memory”). They are supposed to express higher residual drug concentrations than the samples from brand new materials without any “drug memory.” Only one out of three control samples from 5-FU-contaminated laminated wood plate without any cleaning (positive control) had 5-FU concentration >LOD (50 ng), which might be due to a problem in handling the wipe samples. Unexpected low 5-FU amounts were recovered (positive controls) on the stainless steel surface (24%) after contamination with the 5-FU solution compared to other surfaces (glass 66%, PVC 77%). One possible hypothesis might be the occurrence of specific interactions between 5-FU and the stainless steel surface. Another reason might be an ineffective performing of the wipe samples. As the stainless steel surfaces were very slippery, it was difficult to build up enough force during the wiping. As assumed by Lamerie et al.,(29) the variations observed between glass and stainless steel surfaces can also be accounted for by their physicochemical characteristics. Glass as a more hydrophilic surface has a higher wettability, and stainless steel as metal has a higher hydrophobicity and a lower wettability. 390
Several studies have been published to evaluate cleaning procedures using eliminating or deactivating agents to remove cytotoxic contamination on workplace surfaces,(11,29–33,39,40) but comparison is restricted due to variability and differences in methodologies, antineoplastic drugs tested, cleaning agents, and performance tested, detection limits, and so on. LIMITATIONS
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ome study limitations have to be addressed and include the small number of samples and the fact that only two antineoplastic drugs were examined under experimental conditions. We are aware that we could not exactly imitate real contamination scenarios and all cleaning schemes in pharmacy preparation and administration units where additional parameters of the daily working routine have to be taken into account. Moreover, sizes of sampled surfaces (100 cm2) and amounts of applied drug contamination (50 µl) and decontamination agents (1 ml) are not necessarily representative. Hydroalcoholic solutions, however, are commonly used in German hospital pharmacies, often in combination with a detergent due to their low cost and their good compatibility with surfaces. In this study, no further combinations of cleaning agents were tested as we only intended to verify wipe samples as a reliable control tool for evaluating cleaning efficacy. To avoid interindividual variability regarding sampling performance, the same individual was tasked to conduct all the intentional contamination, the cleaning, and the wipe sampling. Nevertheless, differences in the practical performance cannot be ruled out. CONCLUSION
T
he results of this study demonstrate that current cleaning procedures can reduce the exposure risk of antineoplastic drugs to the operator and the environment, but they cannot completely eliminate it. Materials commonly used for BSCs/isolators were tested, but also floor covering (PVC) and benchtop materials that are present in the whole area of the drug preparation and administration units. Drug residues of GEM and 5-FU could be verified by wipe samples and quantified by the analytical methods. The mixture of SDS and isopropyl alcohol but also pure distilled water demonstrated good results for actual cleaning procedures for the two tested hydrophilic antineoplastic drugs (especially GEM) which does well in meeting current practice in a large number of pharmacies. Cleaning efficiency was lowest when using pre-soaked alcoholic towels. Regarding5-FU, the overall cleaning efficiency was lower and surface types and cleaning agents are supposed to have more influence at recovery rates and cleaning efficiencies. These results indicate the potential need to adapt cleaning procedures to the variety of drug compounds used and the specific surface types to develop adequate and effective decontamination strategies.
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ACKNOWLEDGMENT
T
he tailored plates of the four materials were kindly provided by Helmut Ober, Department for Chemistry and Pharmacy, Ludwig Maximilians University, Munich, Germany.
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