PEER REVIEWEDOTH E R

Evaluation of Closed-system Transfer Devices in
Reducing Potential Risk for Surface Contamination
Following Simulated Hazardous-drug Preparation
and Compounding
Abstract

Closed-system transfer devices mitigate occupational exposure risks
associated with hazardous-drug handling. This study was conducted in acontrolled laboratory to evaluate theeffectiveness of a needle-free and aneedle-based closed-system transfer
device in minimizing surface contamination during simulated compounding, preparation, and administration.
A needle-based and a needle-freeclosed-system transfer device underwent three trials per system. Each trial
included reconstituting cyclophosphamide in a vial, withdrawing cyclophosphamide from the vial, andpushing cyclophosphamide into an
intravenous bag. After every trial,
wipe samples were collected from fivesources: biological safety cabinet
workbench (left and right sides), biological safety cabinet grill, biologicalsafety cabinet airfoil, and technicians’
gloves. Wipe samples were then analyzed using high-performance liquid
chromatography with dual-mass
spectrometry to measure cyclophosphamide concentrations. Surface contamination levels from 30 post-trial
tests (15 per device) are reported,
representing five different surface
wipe samples from three trials foreach device. Pre-trial samples of precleaned vials and work surfaces were80

S

STA B I L I TY

P P E N E T R AT I O NFF O R M U LAT I V ECScott Soefje, PharmD, MBA, BCOP, 		
FCCP, FHOPA
Keith Rickabaugh, CIH
Rahul Rajkumar, MD, MPH
Kathryn P. Wall, PhD
obtained to ensure no cyclophosphamide contamination. Field blank samples were analyzed
for quality-control purposes. Post-trial wipe
sample analyses following each of the three needle-free trials did not detect cyclophosphamide
on the biological safety cabinet workbench (bothleft/right), biological safety cabinet grill, biological safety cabinet airfoil, or the technician’s
gloves. For the needle-based closed-systemtransfer device, the wipe sample analyses after
the first trial showed no contamination; however,
cyclophosphamide was detected on the rightbiological safety cabinet workbench at concentrations of 0.223 ng/cm 2 and 0.021 ng/cm 2,
respectively, following the second and third
trials. No cyclophosphamide was found on thetechnician’s gloves after any of the three needle-based closed-system transfer device trials.
Based on surface contamination analyses, thisstudy verified the ability of a needle-freeclosed-system transfer device in preventing theescape of cyclophosphamide during simulated
compounding and preparation. Needle-freeclosed-system transfer devices warrant consideration for the handling of hazardous drugs.

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CLINICAL STUDYO OTHERThe authors’ affiliations are: Scott Soefje,
Director, Pharmacy
Cancer Care, AssistantProfessor of Pharmacy,
Mayo Clinic, Rochester, Minnesota; Keith
Rickabaugh, Technical Director, Materials& Analytical Services,
RJ Lee Group, Monroeville, Pennsylvania;
Rahul Rajkumar,
Healthcare Consultant,
Boston Strategic Partners, Inc., Boston, Massachusetts; Kathryn P.
Wall, Senior Medical
Communications
Consultant, Boston
Strategic Partners, Inc.,
Boston, Massachusetts.

This article is arepublication of anarticle published in theInternational Journalof Pharmaceutical
Compounding’s November/
December 2021 issue,
within which Table 2 waspublished incorrectly by
the Journal. Our sincere
apologies to both theauthors and our readers.

IJPC.comPeer Reviewed | Other

Introduction

Over 18.1 million patients in 2018 were diagnosed with cancer,
which is the second leading cause of death worldwide.1,2 Given
the rising global cancer burden along with the constant improvement/development of chemotherapy treatments, the numberof patients receiving first-course chemotherapy is expected toincrease over the next two decades, ranging from 9.8 to 15 million
per year.3 As chemotherapy becomes more prevalent, potential
exposure of antineoplastic agents during preparation/administration pose an occupational hazard to over eight million healthcare
workers annually, and frontline healthcare professionals face thehighest risk.4-6 Without appropriate precautions, oncology nurses,
pharmacy personnel, and other clinical staff are at risk of acquiring acute or chronic adverse health conditions from exposure toantineoplastic drugs.4-7
The U.S. Center for Disease Control’s (CDC) National Instituteof Occupational Safety and Health (NIOSH) has classified multiple
antineoplastic drugs to be hazardous based on their carcinogenicity, teratogenicity, reproductive toxicity, and/or organ toxicity
when exposed to healthy cells.8 NIOSH recommends the use of
closed-system transfer devices (CSTDs) as part of a comprehensive program to mitigate exposure risk and prevent spillage.9
NIOSH defines CSTDs as drug transfer devices that mechanicallyprohibit the transfer of environmental contaminants into thesystem and the escape of hazardous drug or vapor concentrations
outside the system.9 The United States Pharmacopeial Convention,
Inc. (USP) in its latest guidelines for hazardous drug handling in
the United States Pharmacopeia (USP) Chapter <800> requires
CSTD use during antineoplastic administration and highly recommends CSTD use during hazardous-drug compounding.10
Compared with more traditional methods (e.g., needle and syringe),
CSTDs have shown increased efficiency and effectiveness in hazardous-drug handling through faster preparation times and lower
surface contamination rates.11-13
CSTDs have been implemented throughout many oncology
treatment centers since first cleared in 1997 (Carmel Pharma
AB, Columbus, Ohio).14,15 Recent biotechnological advances haveyielded the development of needle-free CSTDs to protect healthcare professionals from needle-stick injuries, while ensuring thecontainment of hazardous drugs within a closed system during
preparation and administration.16 There exists a need to compare
needle-free CSTDs against needle-based CSTDs and evaluate theirability to minimize occupational exposure risk associated with handling hazardous drugs.
This study’s objective was to compare and evaluate a needle-freeand needle-based CSTD for effectiveness in preventing surface contamination during simulated hazardous drug compounding activities. Wipe samples from work surfaces were collected and analyzed
for surface contamination of cyclophosphamide following vialreconstitution, withdrawal of drug from the vial, and drug injection
into an intravenous (IV) bag.

IJPC.comMaterials and Methods
OUTCOME MEASURESThe outcome was cyclophosphamide surface contamination
defined by the amount of cyclophosphamide (ng) detected on
various work surfaces as well as the concentration of cyclophosphamide by surface area (ng/cm2). Surface contamination wasassessed following the use of a needle-free and needle-based CSTD
during simulated compounding, preparation, and administration of
cyclophosphamide.

MATERIALS
This preliminary investigation was conducted in a controlledlaboratory (RJ Lee Group, Inc., Waynesburg, Pennsylvania)
equipped with a Class 5 cleanroom (ISO14644-1) and a Class
II (EN 12469 standard) biological safety cabinet (BSC) (Model
NU-440-660, Series 30, Nuaire, Plymouth, Minnesota. The workspace was demarcated into four defined surfaces: two sides of the
BSC workbench (left/right), the BSC grill, and the BSC airfoil.
Cyclophosphamide was selected due to its common clinical use as
well as the availability of a sensitive analytical method to detect
trace levels of surface contamination. Vials of Cyclophosphamide
Powder USP, one gram (Lot 2E765; Baxter Healthcare Corporation,
Deerfield, Illinois) were used for the study.
Two CSTDs were evaluated; each system consisted of a vial
access device, syringe adaptor, and IV bag spike. The needle-free
CSTD (ChemoLock, ICU Medical, San Clemente, California)
used was a single-motion, “click-to-lock” system that incorporated a CSTD vented (air-cleaning) vial access device (Lot2648079, CL-70; ICU Medical), a CSTD needle-free syringe
adaptor (Lot 2608114, CL2000S; ICU Medical), and an CSTD IV
bag spike (Lot 2649838, CL-12; ICU Medical). The air-cleaningvial adaptor was equipped with a 0.22-micron filter that is permanently attached to the vial designed to equalize pressure in
the vial and prevent the escape of hazardous drug while allowing
air to escape. To connect the system and open the fluid path, thesyringe was attached to the CSTD syringe adaptor and, as a single unit, was pushed into the mating CSTD port of the vial accessdevice until an audible click was heard, ensuring that the locking mechanism was engaged (FIGU RE 1A). The combined syringe
and CSTD adaptor unit was disconnected from the vial accessdevice port by pushing the two release clips on the sides of theadaptor to disengage the locking mechanism after the desired
dosage of contents from the vial was drawn into the syringe. To
administer cyclophosphamide into an IV bag (VisIV Container;
ICU Medical) the drug-filled syringe and CSTD adaptor unit was
pushed into the CSTD port of the IV bag spike, until the audible
click was heard, ensuring a secure connection between the
CSTD syringe and CSTD IV bag (FIGU RE 1B). Disconnecting thesystem required pushing the two release clips on the sides of theadaptor and pulling away from the IV bag port.

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Peer Reviewed | OtherF IGUR E 1 .
COMPONENTS OF THE NEEDLE-FREE CLOSED-SYSTEM TRANSFER DEVICE.
A. Locking Universal Vented Vial Access Device (CL-70) with theSpinning ChemoLock syringe adaptor (CL2000S)

B. Intravenous bag access using the Bag Spike with ChemoLock Additive
Port and Dry Spike (CL-12)

The needle-based CSTD (PhaSeal; BD, Franklin Lakes, New
Jersey) was a “push-turn-push” system that utilized a vial accessdevice with a locking port (Lot 8290406, Protector P50; BD), asyringe adaptor with an enclosed needle (Lot 11020964 Injector
Luer Lock N35; BD), and an IV bag spike with a locking CSTD port
(Lot 9230585, Infusion adapter C100; BD). The vial access adaptor
was equipped with barrier technology through a pressure-equalization device that is permanently attached to the vial to establish andmaintain neutral pressure when air or fluid is injected into or aspirated from the vial. A disposable syringe was attached to the syringe
adaptor, and as a single unit, was inserted into the CSTD port of thevial access device by a “push-turn-push” mechanism. The enclosed
needle was pushed into the port to open the fluid path between thevial and syringe, allowing a sheath which covers the enclosed needle
to retract simultaneously (F IG U R E 2 A). Once the desired dosage of the
drug was drawn from the vial into the syringe, the coupled syringe
and adaptor unit was disconnected by a “pull-turn-pull” mechanism

to remove the mating components. To gain access to the IV bag, thedrug-filled syringe and adaptor unit was inserted into the CSTD
port of the IV bag spike, and the fluid path was opened and closedwith the same methods used for vial access (FIGU RE 2B).

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STUDY PERSONNEL
A chemotherapy-certified pharmacy technician, previously
trained in the use of each system, performed all simulated compounding and preparation activities. A Certified Industrial
Hygienist (CIH) conducted all wipe sampling activities using standard techniques.17

STUDY PROCEDURES
Since drug residue can exist on exterior surfaces of drug
vials due to the commercial manufacturing process,18,19
manufacturing-related contamination was minimized using a
multi-step decontamination procedure. This procedure included

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separate applications of solutions containing detergent, sodium
hypochlorite (NaOCl), and sodium thiosulfate/benzyl alcohol(Na2S2O3/C7H8O), followed by wiping with lint-free towels andrinsing.20 Surface wipe samples were collected for laboratory
analysis from the vials after drying.
Before each device’s evaluation, all four BSC surfaces were decontaminated using the same cleaning procedure for vial decontamination. A total of eight pre-trial wipe samples (four samples per
device) were collected from the demarcated BSC surfaces and analyzed to determine if the surfaces were free from cyclophosphamide
contamination prior to CSTD testing.
During each trial, keeping within the demarcated areas of the
BSC, the technician performed all simulated compounding activities using personal protective equipment (PPE) and cleanroom
garb, including coveralls, shoe covers, hair covers, surgical facemask, splash-proof gowns with tight-fitting cuffs, and chemotherapy-protective nitrile inner gloves. Three consecutive individual
trials were performed for each system utilizing the same BSC,
yielding a total of six separate trials. The technician donned a newpair of nitrile outer gloves at the beginning of every trial. Each trial
included four preparation cycles to simulate hazardous drug compounding and preparation in a pharmacy setting. To start a preparation cycle, 1) the technician inserted the CSTD vial spike into the
one-gram cyclophosphamide vial and reconstituted with 50 mL of
0.9% sodium chloride, resulting in a concentration of 20 mg/mL,
according to the drug and CSTD instructions of use; 2) an IV
bag was accessed with the CSTD bag spike and placed on the BSC
workbench, ensuring that the access ports were inside the demarcated area; 3) the technician attached the CSTD syringe adapter tothe syringe, withdrew 48 mL of reconstituted cyclophosphamide

F IGU RE 2 .
COMPONENTS OF THE NEEDLE-BASED CLOSED-SYSTEM TRANSFER DEVICE.
A. Protector vial access device with external chamber (P50) andInjector Luer Lock (N35) syringe adaptor

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B. Intravenous bag access using the Infusion Adaptor (C100) IV bag
spike and Injector Luer Lock (N35) syringe adaptor

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Peer Reviewed | Other

from the vial, and 4) transferred three separate volumes of 16 mL
into the IV bag, disconnecting the syringe from the bag after each
16-mL transfer. Every preparation cycle thus included one connection to the vial with three transfers to the bag. Therefore, the CSTD
syringe combination made four connections in total. A total offour preparation cycles with separate CSTD syringe combinations
were required per trial, utilizing four reconstituted vials of cyclophosphamide and four IV bags. Given that three trials per CSTD
were completed, the technician utilized 36 CSTD components andperformed 36 fluid transfers totaling 576 mL of solution containing
11.52 g of cyclophosphamide.

FI GURE 3.
BIOLOGICAL SAFETY CABINET WORKBENCH AND WIPESAMPLE COLLECTION.
A. Demarcated areas of BSC work area

DETECTION OF SURFACE CONTAMINATION
Surface contamination was assessed with wipe sample analyses
prior to the first trial of each device and following the completionof each device trial. A total of eight pre-trial wipe samples were collected (one sample from four demarcated BSC surfaces per device)
and analyzed (F I GURE 3 A). Post-trial wipe samples were collectedfrom all four BSC surfaces and the technician’s gloves which were
replaced after every trial (F IG U R E 3 B). A total of 30 post-trial wipe
samples (five samples following each device trial) were analyzed inthis study. The amount of area sampled from each BSC surface was
400 cm2 for both pre- and post-trial wipe samples.
Wipe samples were obtained using sampling media kits (RJ
Lee Group, Inc.) and analyzed using generally accepted industrial hygiene techniques.17 All wipe samples were stored ator below minus 70°C before laboratory preparation. Samples
were analyzed using a HPLC-MS/MS (Sciex API 4000 Mass
Spectrometer, Framingham, Massachusetts), with a Shimadzu
10VP LC System (Columbia, Maryland) following a validated
methodology. Field blank samples (sampling media not wiped on
surfaces) were submitted along with survey samples for quality
control. The limit of detection for cyclophosphamide was two
nanograms (ng) per sample.

B. Wipe sample collection

Results

PRE-STUDY WIPE SAMPLE RESULTS
No cyclophosphamide was detected on the exterior of the vials
sampled following decontamination and prior to use.

PRE-TRIAL WORK AREA SURFACE WIPE SAMPLERESULTSOn the BSC workbench (right), at a concentration of 0.008 ng/cm2
prior to the needle-free CSTD trials, 3.3 ng of cyclophosphamide
was detected, whereas no cyclophosphamide was measured on anyof the surfaces prior to the needle-based CSTD trials (TA B LE 1).

POST-TRIAL SURFACE WIPE SAMPLE RESULTS
Following each needle-free CSTD trial, no cyclophosphamide was
detected on any BSC work surface (TA B LE 2). Wipe sample analyses

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following trials 2 and 3 of the needle-based CSTD measured cyclophosphamide concentrations of 0.223 ng/cm2 and 0.021 ng/cm2
on the right workbench, respectively. No cyclophosphamide was
detected on the technician’s gloves following any of the CSTD trials(TA BLE 2).

QUALITY-CONTROL (FIELD BLANK) WIPE SAMPLERESULTSNo cyclophosphamide was detected on the field blank samples.

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Discussion

TABLE 1 .

Considering the increasing
SUMMARY OF PRE-TRIAL SAMPLE RESULTS.
focus on hazardous-drug expoPRIOR TO NEEDLE-FREE
PRIOR TO NEE D L E - B ASE D
sure in oncology and oncology
CSTD EVA LUA TION
CSTD EVA L U AT IO N
pharmacy settings, this study
Work Area Surface
Area, (cm2)
CP Concentration, (ng/cm2)
CP, (ng)
CP Concentration, (ng/cm2)
CP, (ng)utilizes an effective method toanalyze surface contamination
Workbench left
400
<0.005nd<0.005nd
following simulated preparaWorkbench right
400
0.008
nd
<0.005
3.33
tion and IV administration
BSC Grill400<0.005nd<0.005ndof cyclophosphamide. More
BSC Airfoil
400<0.005nd<0.005nd
importantly, this study shows
Note: Cyclophosphamide levels and concentrations in each column were from wipe samples taken from four work area surfaces prior to the separatethat when compared to a neeevaluation of each device in their three respective consecutive trials under the same BSC.
dle-based CSTD, a needle-free
BSC = biological safety cabinet; CSTD = closed-system transfer device; CP = cyclophosphamide; nd = not detected (<2.0 ng/sample).
CSTD is similarly capable ofminimizing cyclophosphamide
surface contamination following simulated compounding, preparemaining two needle-based trials were conducted without issues.
ration, and administration.
Overall, the needle-based system was also effective in reducing
A low level of cyclophosphamide was detected on the BSC
detectable contamination, which is comparable to several studworkbench before the needle-free system evaluation, whereas
ies reporting the system’s ability to reduce surface contamination
no contamination was observed following any of the needle-freelevels of hazardous drugs when compared to standard preparation
trials. This indicates that the cyclophosphamide detected priortechniques (i.e., needle and syringe).12,21-24 Adding to the growing
to these trials was reduced to undetectable levels due to the wipe
body of evidence, needle-free systems yield similarly favorable
sampling process, and no detectable contamination resulted fromsurface contamination results to that of a needle-based CSTD,
the CSTD use. At the end of the second needle-based CSTD trial,with a lower risk of occupational hazards.16 With a needle-free
the technician observed that the internal needle was unintentionsystem, needlestick injury risk is non-existent, whereas needleally exposed. A small component of the syringe adaptor appeared
based CSTDs still potentiate the possibility of occupational
to have cracked, and a fluid droplet was observed on the tip of theneedlestick injury even with the “enclosed” needle design.
needle (F I GURE 4). The cyclophosphamide detected following the
USP Chapter <800> highlights a comprehensive set of guidesecond trial could potentially be attributed to this crack. However,lines for handling hazardous drugs, and includes environment
no droplet was visually observed on any work area surface, and thequality and control, appropriate PPE, work practice, personnel

TA B L E 2 .
SUMMARY OF POST-TRIAL SAMPLE RESULTS.
POST-TRIA L 2

POST-TRIA L 1

POST- T R IAL 3

W O RK AREAS URFACE

AREA(CM 2 )

CP, ng

CP Concentration(ng/cm2)

CP, ng

CP Concentration(ng/cm2)

CP, ng

CP Concentration(ng/cm2)

Needle-free CSTD

GlovesWorkbench left
Workbench right
BSC Grill
BSC Airfoil

n/a
400
400
400
400

nd
nd
nd
nd
nd

n/a
<0.005<0.005<0.005<0.005

nd
nd
nd
nd
nd

n/a
<0.005<0.005<0.005<0.005

nd
nd
nd
nd
nd

n/a
<0.005<0.005<0.005<0.005

Needle-based CSTD

GlovesWorkbench left
Workbench right
BSC Grill
BSC Airfoil

n/a
400
400
400
400

nd
nd
nd
nd
nd

na
<0.005<0.005<0.005<0.005

nd
nd
89.1
nd
nd

n/a
<0.0050.223<0.005<0.005

nd
nd
8.56
nd
nd

n/a
<0.0050.021<0.005<0.005

DEVICE TYPE

Note: Each set of “post-trial” results represents cyclophosphamide surface contamination identified by wipe samples taken from five work surfaces after the completion of each trial. Each device was
evaluated separately with three consecutive trials (1 to 3).
BSC = biological safety cabinet; CSTD = closed-system transfer device; CP = cyclophosphamide; n/a = not applicable; nd = not detected (<2.0 ng/sample).

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Peer Reviewed | OtherF IGURE 4 .
NEEDLE-BASED SYSTEM WITH UNINTENTIONALLY EXPOSEDNEEDLE AND VISIBLE FLUID DROPLET AS OBSERVED BY THE
TECHNICIAN AT THE END OF THE SECOND TRIAL.

tard derivative is a single class of cytotoxic agents and may not be
representative of all commonly used antineoplastic drugs.

Conclusion

It is evident that without the use of CSTDs, frontline
oncology professionals are at increased risk of occupational
exposure during hazardous-drug handling. Using a standardized
methodology for surface contamination analysis, this study
verified the ability of a needle-free CSTD to mechanically
prevent the escape of cyclophosphamide outside of the CSTD
during simulated compounding and preparation, as shown by
undetectable cyclophosphamide levels following wipe sample
analyses on work surfaces. These findings suggest that needlefree systems warrant thorough consideration in the effort aimed
at creating safer hazardous-drug handling practices in oncology
infusion areas. Future large-scale clinical studies are necessary toevaluate the effectiveness and ease-of-use of needle-free CSTDs.

Acknowledgment
training, and engineering controls such as ventilated BSCs.10 As
CSTD implementation becomes a growing priority among administrators and health systems striving for USP Chapter <800>compliance, it is important to consider newer strategies for handling hazardous drugs, specifically with CSTD systems offering
improved features, such as membrane-to-membrane connection
systems and vial access adaptor technologies designed to better
protect end-users from workplace exposure.
Device ease of use, suitability, and safety are important factors
to consider when evaluating CSTDs. A recent study evaluatedease-of-use between three CSTDs — one needle-free and twoneedle-based devices — during hazardous drug preparation andadministration, and reported that nursing staff and pharmacy
technicians preferred the needle-free system over the other two
devices when provided with open-ended, Likert-scale questionnaires.11 Furthermore, pharmacy technicians and nursing staff
are at risk for developing cumulative stress-induced injuries
stemming from repetitive motions such as opening and closing
vial caps, attaching vials to syringes in addition to drawing andpushing solutions from vials to IV bags.25,26 Thus, user friendliness metrics based on minimizing stressful repetitive motions, asreported by end-users, should also be prioritized when comparing
various CSTDs.
This study has several limitations. First, even with the substantial number of transfer steps, the sample size was small, limiting
the statistical evaluation and comparison of the relative effectiveness in preventing surface contamination. Second, there is a lackof a universal performance standard for evaluating this adjunctengineering control. Lastly, cyclophosphamide as a nitrogen mus-86

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The authors would like to thank Mr. Matthew D. Zock, CIH,
from RJ Lee Group, Inc., for his technical support to this study.
The authors would also like to acknowledge Dr. Halit O. Yapici
from Boston Strategic Partners, Inc. (supported by ICU Medical)
for his editorial support.

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26. Davis KG, Kotowski SE. Prevalence of musculoskeletal disorders for nurses in hospitals, long-term care facilities, and homehealth care: A comprehensive review. Hum Factors. 2015;
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Address correspondence to Scott Soefje, PharmD, MBA, BCOP,
FCCP, FHOPA, Pharmacy Cancer Care, Mayo Clinic, 200 First
Street SW, Rochester, MN 55905. E-mail: Soefje.Scott@mayo.edu

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