Journal of Oncology Pharmacy Practice
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Evaluation of surface contamination with cyclophosphamide following simulated hazardous drug
preparation activities using two closed-system products
Matthew D Zock, Scott Soefje and Keith Rickabaugh
J Oncol Pharm Pract published online 28 June 2010
DOI: 10.1177/1078155210374673
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J Oncol Pharm Pract OnlineFirst, published on August 12, 2010 as doi:10.1177/1078155210374673

Journal of

Oncology
Pharmacy
Practice

Research Paper

Evaluation of surface contamination withcyclophosphamide following simulated
hazardous drug preparation activities
using two closed-system products

J Oncol Pharm Practice0(0) 1–7! The Author(s) 2010
Reprints and permissions:sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1078155210374673
opp.sagepub.com

Matthew D Zock
Technical Consulting Services, RJ Lee Group, Inc., 350 Fifth Avenue, Suite 5820, New York,NY 10118, USA

Scott Soefje
Investigational Drug Section, Cancer Therapy & Research Center, The University of Texas Health
Science Center San Antonio, 7979 Wurzbach, Rm. G354, San Antonio, TX 78229, USA

Keith Rickabaugh
Materials and Analytical Services, RJ Lee Group, Inc., 350 Hochberg Road, Monroeville,
PA 15146, USA

Abstract
Purpose. A preliminary investigation was conducted to evaluate and compare the effectiveness of two closed-systemproducts in preventing contamination of typical pharmacy workplace surfaces with cyclophosphamide during simulated
hazardous drug preparation activities in a controlled laboratory setting.
Methods. Two separate trials simulating hazardous drug compounding using cyclophosphamide were performed withtwo different closed-system products. Prior to each trial, work area surfaces of the biological safety cabinet (BSC)
workbench, the BSC airfoil and front grill, and the floor below the BSC were cleaned, and wipe samples were collected and analyzed to determine, if present, levels of cyclophosphamide. Following each trial, wipe samples werecollected from the work area surfaces to determine the hazardous drug containment effectiveness of each closedsystem product.
Results. Cyclophosphamide was not detected on work area surfaces prior to each trial. Low levels were detected on
the BSC workbench surface following both trials.
Discussion. Based on the limited number of samples obtained during this preliminary study and the determination of thepresence of the chemical of interest on the drug vials, no statistical evaluation was performed to compare the relative
effectiveness of the two systems tested. Work practices and procedures regarding product operation may affect hazardous drug containment and worker safety. Further study and statistical analyses are needed.

Keywords
hazardous drug, surface contamination, effectiveness, containment, closed-system, cyclophosphamide

Introduction
Worldwide, cancer is the leading cause of death with anestimated 7.9 million deaths in 2007.1 These numbers
are expected to double before 2030.1 Given the increasein the number of patients, the increasing numbers of
new agents being developed to treat cancer and theincreasing complexity of chemotherapy combination
therapy, there will be a dramatic increase in thenumber of healthcare workers exposed to hazardous
drugs from the current estimate of 5.5 million workers
per year.2
Corresponding author:
Matthew D. Zock, Technical Consulting Services, RJ Lee Group, Inc, 350
Fifth Avenue, Suite 5820, New York, NY 10118, USA
Email: mzock@rjlg.com

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2

J Oncol Pharm Practice 0(0)Handling of chemotherapy drugs has been recognized since the 1970s as a potential health hazard toworkers. In the early 1990s, the American Society of
Health-System Pharmacists was the ﬁrst organization
to formally deﬁne ‘hazardous drugs’.3 Drugs are classiﬁed as hazardous if studies in animals or humans indicate that exposures to them have a potential for causingcancer, developmental or reproductive toxicity, or
harm to organs.3 Both the Occupational Safety and
Health Administration and the National Institute for
Occupational Safety and Health (NIOSH) haveadopted the aforementioned deﬁnition.4,5 NIOSH
expands the deﬁnition to consider a drug hazardous
if it exhibits one or more of the following six
characteristics:
1. Carcinogenicity;
2. teratogenicity;
3. reproductive toxicity;
4. organ toxicity at low doses;
5. genotoxicity; and6. structure and toxicity proﬁles of new drugs thatmimic existing drugs determined hazardous by theabove criteria.

Two closed-system products which appeared to becommonly used in health care settings were evaluated.
Both products include vial and intravenous (IV)bag adaptors and connectors that were designed toprevent hazardous drug release. The ﬁrst was
Oncology
Preparation
andChemoCLAVETM
Delivery System (ICU Medical, Inc.) which include
the GenieTM Closed Vial Access Device (REF CH-77),
the SpirosTM Closed Male Connector (REF CH2000);(Figure 1), and the Access Device, IV Bag, Clave
Connector (REF CH-10). Once the Spiros was attached
to a syringe and the Genie was attached to a vial, threeuser steps were required for ﬂuid transfer. The needlefree Spiros was connected to the Genie Closed Vial
Access Device by inserting the male end of the Spiros
into the female end of the Genie, pressing, and twisting.
Disconnection required twisting in the opposite direction and withdrawing from the Genie. Access to the IV
Access Device was identical.
The second product was PhaSealÕ (Carmel Pharma),
which included the ProtectorTM vial access device (REF

NIOSH and The United States Pharmacopeia’s
General Chapter 797 (USP 797) recommend using aclosed-system transfer device to minimize occupational
exposures to antineoplastic and other hazardous
drugs.5,6 The NIOSH deﬁnition of a closed system is
one that mechanically prevents the transfer of environmental contaminants into the system and the escape ofdrug or vapor out of the system. Some studies haveshown the beneﬁts of a closed system in reducing hazardous drug surface contamination when compared to
traditional preparation techniques in the clinicalsetting.7–9
This study was conducted to evaluate and compare
two closed-system products during simulated hazardous drug preparation activities using a known amountof cyclophosphamide in a laboratory setting. Attempts
were made to control, minimize, and evaluate otherknown sources of environmental contamination which
may be found in clinical settings to help focus on theclosed-system products’ eﬃciencies in minimizing contamination of typical pharmacy workplace surfaces.

Methods
The study site was an experimental laboratory setting.
A Class 100 clean room and a Class II Biological Safety
Cabinet (BSC) vented to the outdoors were utilized.
There was no knowledge of prior use or handling of
cyclophosphamide in the clean room or BSC at the
study site.

Figure 1. ChemoCLAVETM System: Genie Closed Vial Access
Device with internal balloon and Spiros Closed Male Connector.

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Zock et al.

3P50), the InjectorTM Luer Lock male connector (REF
N31); Figure 2), and the Infusion Adaptor (REF
C100). Once the Injector Luer Lock was attached to asyringe and the (Protector was attached to a vial, ﬁve
user steps were required for ﬂuid transfer. The Injector,
with a contained needle, was connected to the Protector
by inserting the male end of the Injector into the female
end of the Protector, pressing, twisting, lifting a leveron the Injector (to release a needle cap), and pushing
the needle into the vial. Disconnection was achieved bypulling the needle out of the vial, twisting in the opposite direction, and withdrawing from the Protector.
Access to the Infusion Adaptor was identical.
A certiﬁed pharmacy technician specializing inoncology preparations performed all simulated compounding duties using standard aseptic and hazardous
drug preparation techniques and personal protective
equipment. The technician had approximately 1 year

Figure 2. PhaSealÕ Protector 50 vial access device withexternal balloon and Injector Luer Lock male connector.

experience working with ChemoCLAVE and approximately 7 years experience working with PhaSeal.
Cyclophosphamide was selected as a hazardous drug
marker for its common use in the clinical setting andthe availability of a sensitive analytical method todetect trace levels of the chemical. The analytical limit
of detection for cyclophosphamide was 15.7 ng per
sample. Wipe samples were collected from strategic
locations and items to sample for cyclophosphamide
on surfaces. All wipe samples were collected using
Cyto Wipe Kits (Exposure Control B.V.).
At each sampling location(s), the surfaces were measured to determine the surface area that was to be sampled. A new pair of nitrile gloves was donned prior tothe collection of each sample. Using a medicine dropper, 17 ml of solution was applied to each surface. A
paper tissue was used to spread the solution over theentire pre-measured area and the area was sampled bywiping in multiple directions using moderate hand pressure. During the sampling, emphasis was placed on
sampling the surfaces in a manner as to not wipe outside of the measured surface area and to not damage
the tissue. The tissue was placed in a plastic 175-ml
sample bottle. A second tissue was used to completely
dry the surface using unidirectional wiping techniques
and was also placed in the same sample bottle.
For items that would not permit the solution to beplaced on the surface, approximately one-half of thesolution from the medicine dropper was placed directlyon the ﬁrst paper tissue. The surfaces were sampled ateach location as described above, the remaining solution was placed on the second paper tissue, and thesurface was wiped a second time as describedabove, carefully folding the tissue and completely
drying the surface.
The study was performed over a 2-day period. On
Day 1 of the study, the site was prepared by measuring
and demarcating the surfaces to be sampled on the BSC
workbench (4400 cm2), the BSC airfoil and front grill(2000 cm2), and the ﬂoor directly below and in front of
the BSC (4400 cm2). All of the surfaces that wereselected to be sampled were cleaned using SurfaceSafeÕ (Hospira). Surface Safe is a product that was
designed to inactivate cytotoxic drug substances including cyclophosphamide, and remove them from surfaces
using a two-step application process. Following Surface
Safe application, the surfaces were further cleaned
using ﬁltered water and lint-free towels and allowed
to dry.
In a separate area of the clean room, 40 vials containing 1g of lyophilized cyclophosphamide powder(Baxter) were removed from their individual outer
cardboard box packaging materials and randomly
divided into two groups of 20 vials each designated as
Vial Group 1 and Vial Group 2. Composite wipe

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4

J Oncol Pharm Practice 0(0)samples were collected from the exterior surfaces of thevials to determine if contamination was present on thecontainers in their as-received conditions from the manufacturer. All vials used during the study were sampled.
Five vials were wiped for each composite wipe sample.
The wipes were folded after each vial was sampled tominimize spreading possible contamination between
vials during sampling.
On Day 2 of the study, the product trials were conducted. The ChemoCLAVE trial was conducted ﬁrst
using Vial Group 1, followed by the PhaSeal trial
using Vial Group 2. Prior to each trial and after cleaning with Surface Safe, a wipe sample was collected fromthe demarcated surface areas of the BSC workbench,
BSC airfoil/grill, and the ﬂoor to determine if
the surfaces were free from cyclophosphamide
contamination.
Vials were placed on protective/absorbent pads oneither side of the demarcated area within the BSC tominimize possible exterior vial contamination fromcontacting the sampling surfaces. For each trial, thepharmacy technician donned a new pair of gloves andperformed compounding activities inside the BSC overthe demarcated areas. Each of the 20 cyclophosphamide vials were reconstituted using 50 ml of 0.9%
sodium chloride for injection, then three individual volumes of 5 ml each were removed from each of the 20
vials and transferred to 10 IV bags (six transfers to eachbag) containing closed-system connectors (totals foreach trial: 60 transfers; 300 ml solution; 6 g cyclophosphamide.) The pharmacy technician was observed while
performing duties during the trials. The duration ofeach trial was 1h. Following each trial, wipe samples
were collected from the demarcated areas of the BSC
workbench, BSC airfoil/grill, and the ﬂoor, and fromthe pharmacy technician’s gloves. A composite sample
of both gloves used during the trial was collected utilizing one tissue media for each glove. All exterior surfaces of the gloves were wiped. Concentrations werereported in ng cyclophosphamide per cm2 of surface
area, or for gloves, reported as total ng cyclophosphamide per pair.
A total of ﬁve ﬁeld blank samples were collectedduring the study for quality control purposes. The
ﬁeld blank samples were handled similarly to environmental wipe samples, only no surfaces were wiped.
Approximately one-half of the solution was placed oneach tissue media, and the tissues were folded andplaced in the sample bottles.
All of the wipe samples obtained were contained insample bottles as soon as possible after collection andwere stored in an insulated container with dry ice. At
the completion of the study, all samples were packaged
with dry ice and shipped to Exposure Control in The
Netherlands for analysis.

The wipe samples were prepared by adding 140 ml of
a 0.03 M NaOH solution. After extraction, a part of theextract was subjected to laboratory ‘clean up’ operations.10,11 Samples were analyzed using a gas chromatograph that was equipped with dual mass spectrometers(GC-MSMS), which is an enhancement to the original
method developed for GC-MS.12 Speciﬁcity andsensitivity are increased using GC-MSMS in place of
GC-MS.13

Results
Vial wipe sampling results
Cyclophosphamide was detected on the exterior ofsome vials in Vial Group 1 (used for the
ChemoCLAVE trial.) Of the four composite wipe samples collected from Vial Group 1, two samples showed
detectable levels and two samples showed no cyclophosphamide contamination. No cyclophosphamide
was detected on the exterior of vials intended for the
PhaSeal trial (Vial Group 2). Table 1 summarizes thecomposite vial sample results.

Pre-trial wipe sampling results
No cyclophosphamide was detected on the BSC or
ﬂoor surfaces following cleaning with Surface Safe
and prior to both trials. Table 2 summarizes the pretrial sample results.

Post-trial wipe sampling results
Following the ChemoCLAVETM trial, no cyclophosphamide was detected on the BSC airfoil/grill or the
ﬂoor. Cyclophosphamide was detected on the BSC
workbench and the pharmacy technician’s pair ofgloves. Following the PhaSealÕ trial, cyclophosphamide was detected on the BSC workbench, but not on

Table 1. Summary of vial sample results
Vial group
1(Used for ChemoCLAVETM
trial)
2(Used for PhaSealÕ trial)aComposite
samplesa

Cyclophosphamide(ng)

Sample 1
Sample 2
Sample 3
Sample 4
Sample 1
Sample 2
Sample 3
Sample 4

ndb
nd
2694
17
nd
nd
nd
nd

Each composite sample was taken from five 1g vials.
nd ¼ not detected (cyclophosphamide < 15.7 ng).

b

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Zock et al.

5

the BSC airfoil/grill, the ﬂoor, or the pharmacy technician’s gloves. Table 3 summarizes the post-trial
sample results.

Quality control sample results
No cyclophosphamide was detected on the ﬁeld blanksamples.

Discussion
Surface contamination in pharmacies and treatmentareas has been a major concern. BSCs, countertops,
ﬂoors in and adjacent to preparation areas, tabletops,
chairs, and ﬂoors in treatment areas may have contamination with hazardous drugs when a closed-system is
not used. A study examining the contamination in six
sites in the US and Canada found that measurable
amounts of the antineoplastic agents (cyclophosphamide, ifosfamide, ﬂuorouracil) were detected in 75%
of pharmacy samples and 65% of administration
samples.14
Many factors may contribute to surface contamination in the clinical setting. Some studies have also
shown contamination on the exterior of vials asreceived from manufacturers.15,16 Unreported or inadequately cleaned spills, transport and placement of contaminated objects, patient body ﬂuids, and spreadingby hand or foot contact may contribute to surface
contamination.

This study was conducted in a controlled laboratory
setting, using known amounts of cyclophosphamide,
while taking measures to minimize other known sourcesof surface levels common in the clinical setting. Thisapproach was used to help focus on the closed-systemproducts’ eﬃciencies in minimizing contamination of
typical pharmacy workplace surfaces.
The results from the analyses of the wipe samples
collected from the BSC workbench, airfoil/grill, andthe ﬂoor following cleaning with Surface Safe
showed that the surfaces were free from detectablelevels of cyclophosphamide prior to each trial.
Cyclophosphamide was detected in low concentrations
on the BSC workbench surfaces but not on the airfoil/
grill or ﬂoor following both trials.
It was postulated that vial contamination may contribute to levels of cyclophosphamide on the work area
surfaces following the product trials. To determine ifvial contamination could have contributed to surface
levels, wipe samples were collected from the vials andthe technician’s gloves. To help minimize possible vial
contamination from contributing to surface levels, vials
were placed on protective pads on either side of thedemarcated area of the BSC workbench and the technician was careful not to touch or place vials on the
workbench.
Although many of the vials used in the study
had no detectable cyclophosphamide contamination,
the results showed that some vials used for the
ChemoCLAVE trial had detectable levels. The presence

Table 2. Summary of pre-trial sample results
Prior to ChemoCLAVETM trial

Prior to PhaSealÕ trial

Surface
description

Surfacearea (cm2)

Cyclophosphamide(ng)

Cyclophosphamide
concentration (ng/cm2)

Cyclophosphamide(ng)

Cyclophosphamide
concentration (ng/cm2)

Floor
Airfoil/grill
Workbench

4400
2000
4400

nda
nd
nd

<0.004<0.008<0.004nd
nd
nd<0.004<0.008<0.004and ¼ not detected (cyclophosphamide < 15.7 ng).

Table 3. Summary of post-trial sample results
Following ChemoCLAVETM trial

Following PhaSealÕ trial

Surface
description

Surfacearea (cm2)

Cyclophosphamide(ng)

Cyclophosphamide
concentration (ng/cm2)

Cyclophosphamide(ng)

Cyclophosphamide
concentration (ng/cm2)

Floor
Airfoil/grill
Workbench
Gloves

4400
2000
4400
2 gloves

nda
nd
468
377

<0.004<0.008
0.11
nab

nd
nd
622
nd

<0.004<0.0080.14
naa

nd ¼ not detected (cyclophosphamide < 15.7 ng).
na ¼ not applicable.

b

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6

J Oncol Pharm Practice 0(0)of the chemical on the vials may have contributed to the
low level detected on the BSC workbench. It wasobserved that on two occasions during the
ChemoCLAVE trial, a vial was inadvertently placedon the BSC workbench by the technician performing
the simulated compounding duties. The presence of contamination on some vials and on the technician’s gloves
suggests that the chemical was transferred to the gloves.
It is possible that contamination was spread to the workbench by contact with syringes and/or IV bags that werehandled by the technician’s gloves. It is assumed that vial
contamination was reduced due to vial wipe sampling,and higher levels would be expected on the pharmacy
technician’s gloves and on surfaces if the vial wipe sampling had not been conducted.
The surface transfer of the chemical as postulated
above with the ChemoCLAVE trial is an unlikely
factor in the PhaSeal trial. This is because, although
there was a low level of cyclophosphamide detectedon the BSC workbench following the PhaSeal trial,no contamination was detected on the vials or on thepharmacy technician’s gloves. It is possible that work
practices and procedures regarding product operation
could have contributed to surface contamination
during the PhaSeal trial. On two occurrences the
Injector Luer Lock protective needle caps were notretracted when withdrawn from the drug vials exposing
the needle. Small droplets that normally would otherwise be contained could have possibly reached the BSC
workbench. These occurrences also posed needlestickhazards.
The concentrations reported in these results were
calculated with no determination of analyte recoveries
and wipe eﬃciencies. Therefore, all results reported are
estimates of the concentrations present on the surfaces
sampled.
Vial contamination may have contributed to the lowlevel of cyclophosphamide observed on the BSC workbench following the ChemoCLAVE trial. Work practices and procedures regarding product operation may
have contributed to the low level of cyclophosphamide
observed on the BSC workbench following the PhaSeal
trial. Work practices and procedures regarding productoperation appeared to be an important factor in hazardous drug containment and needle safety when using
PhaSeal, but not when using ChemoCLAVE, which
requires fewer user steps and it is needle free. The
PhaSeal Injector Luer Lock model (REF N31) thatwas used for this study has been replaced by a more
recent model (REF N35).
Based on the limited number of samples obtained
during this preliminary study and the determinationof the presence of the chemical of interest on the drug
vials, no statistical evaluation was performed to compare the relative eﬀectiveness of the two systems tested.

Further study and statistical analyses are needed toinvestigate the containment eﬀectiveness of the products in a controlled setting.
Acknowledgments
We would like to thank pharmacy personnel from Maine
Center for Cancer Medicine for their contributions to thisstudy. This work was supported by ICU Medical, Inc.

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