Pharm Technol Hosp Pharm 2022; 7(1): 20220004

Sally Bishay, Malgorzata Michalowska-Suterska*, Andrea Edling and Jason Battle

Evaluation of the hazardous drug surface
contamination in pharmacy compounding andadministration clinical setting after adoption ofstandardized cleaning workﬂow and a closed
system transfer device
facilities to retain reduced HD surface contamination, based
upon previously determined threshold values.

https://doi.org/10.1515/pthp-2022-0004
Received March 3, 2022; accepted May 30, 2022;
published online July 21, 2022

Keywords: antineoplastic agents; ChemoClave; ChemoLock; closed system transfer device; drug compounding.

Abstract
Objectives: The compounding and administration of
hazardous drugs present a potential risk to healthcare
worker and patient safety. This study sought to evaluate
the HD surface contamination in multiple pharmacy andnursing areas that include standardized cleaning techniques and utilization of closed system transfer devices.
Methods: This study was conducted at six different areasin the pharmacy and nursing areas. Each area was assessed
three times for five different HD’s surface contamination at
an initial, 3 month, and 6 month follow up. Hazardous drug
surface testing was performed for ﬁve most compounded
HDs. A total of 90 individual samples were taken andanalyzed during the study.
Results: A total of 30 samples were collected at threedifferent timepoints for a total of 90 individual samples
and analysis results. All 90 samples were negative (below
the lower limit of detection; 0.01 ng/cm2), for theirrespective drug residue.
Conclusions: The method and design described in thisevaluation may offer a way to determine if a facility’s current
HD work practices and controls retain reduced HD surface
contamination based upon published threshold values.
Adoption and utilization of standardized work, including
use of a closed system transfer device, and cleaning practices, described in this study, may present an option for*Corresponding author: Malgorzata Michalowska-Suterska,
Inpatient Pharmacy, Bennett Cancer Center Pharmacy, Stamford
Health, One Hospital Plaza, Stamford, CT 06902, USA, Phone: 203276-7508, E-mail: mmichalowska@stamhealth.org
Sally Bishay and Andrea Edling, Inpatient Pharmacy, Stamford
Hospital, Stamford, CT, USA
Jason Battle, ICU Medical Inc, Lake Forest, IL, USA
Open Access. © 2022 the author(s), published by De Gruyter.
License.

Introduction
The risks of occupational exposure to hazardous drugs(HD) have been known for decades. Occupational exposure
to healthcare workers may occur at any point during the
drug receipt, preparation, compounding and administration areas and processes. These exposures may lead toserious adverse reactions including but not limited toasthma, birth defects, miscarriages, and cancer [1].
Although this information was publicly available as
distant as the 1970s, studies continue to show that surface
contamination for HDs is persistent and widespread throughboth the pharmacy and nursing areas, potentially exposing
healthcare workers to adverse reactions. Widespread surface
contamination from multiple antineoplastic agents on avariety of surfaces in the pharmacy preparation andadministration areas in six different centers in the USA and
Canada has been reported with significant measurable
amounts in 75% of the pharmacy and 65% of the administration area samples [2]. These results have been repeated,with lower detection rates but still considerable by investigating the environmental contamination of cyclophosphamide, ifosfamide, and methotrexate in pharmacy andpatient areas, ﬁnding positive samples (52%, 20%, 3%
respectively) for each measured HD [3]. Cyclophosphamide
has been described as potentially the most prevalent environmental contamination of HDs in oncology pharmacies
and outpatient clinics in Canada as part of a surveillance
project also ﬁnding that cyclophosphamide was the HD mostoften found in the surface samples (32.4% of samples withpositive result), followed by gemcitabine (20.3%) [4]. Similar
results were found in which biological and environmental

This work is licensed under the Creative Commons Attribution 4.0 International

2Bishay et al.: Evaluating hazardous drug surface contamination with a CSTD and standard workflow

exposure to cyclophosphamide in nurses was evaluated anddetermined that elevated levels were present in one third of
the participating nurses [5].
Although these studies show the continued consistency of HD surface contamination; the situation may be
more serious than previously anticipated since each ofthese studies were limited in the number of HDs evaluated.
Other HDs, not sampled, in these and other studies, may
well be present.
Evidence of persistent and widespread HD surface
contamination has led researchers and hospitals to implement surface wipe sampling as part of the standard workplace environmental monitoring procedures. But, as inprevious decades, published studies continue to show thatconsistent contamination and the potential for worker
exposure remains, as does the surface contamination ofHDs. Published studies have indicated that standard
cleaning procedures may not be sufficient to decrease or
eliminate the HD surface contamination to acceptablelevels. Previous evaluations have determined that 14 out of
23 surfaces sampled (61%) prior to current cleaning practices were contaminated with methotrexate or cyclophosphamide and while the post-clean contamination levels
were generally lower, the concentration of the methotrexate
was similar, and some samples had higher post-clean
contamination levels [6].
Development of guidance, safe handling precautions,and environmental and engineering controls have occurredbut, concentration of HD surface contamination continues
to be reported in healthcare settings globally and at multiple
timepoints throughout the production, receipt, preparationand compounding, and administration of hazardous [7–16].
Multiple cleaning agents have been investigated fortheir effectiveness in eliminating HD surface contamination[17, 18]. In conjunction with the knowledge that no single
product or formulation has been proven to be 100% effectivein the removal of antineoplastic contamination on work
surfaces, the decontamination of HD requires continuous
efforts or knowledge of the presence of an HD contaminationand further highlight the beneﬁts of preventative controls.
Guidance on the assessment and controls recommended to reduce exposure of HDs are widely available
from institutions such as: OSHA and NIOSH. To further
enhance protection of healthcare workers against potentially hazardous exposures during the compounding andadministration, USP 800 Chapter includes a section on
containment supplemental engineering controls such as
the use of closed system drug transfer devices (CSTDs) thatmechanically prohibit the transfer of environmental contaminants into the system and the escape of the HD orvapor concentrations outside the system. The use of CSTDs

have become accepted as part of HD safety programs andused in conjunction with engineering controls.
Although published studies indicate that the implementation of CSTDs, along with standard work practices,
may help to eliminate or reduce accidental exposure theHDs [19–26], including evidence that indicates that the
CSTD alone, may help to reduce the potential exposure [23],the implementation cost and lack of regulatory complianceor requirements, especially in emerging countries, may
hamper their adoption.

Objectives
This study sought to survey potentially high-risk surfaces
for HD surface contamination to determine the level of
effectiveness of current work practices and proceduresfor cleaning and decontaminating in minimizing HD surface contamination, based upon previously publishedthreshold values (at or below 0.01 ng/cm2) [2]. The areas
evaluated included the continued implementation of asecondary control in the form of closed system transfer
devices (ChemoLock and ChemoClave, ICU Medical, San
Clemente, CA, USA), which is designed to reduce or eliminate HD surface contamination This routine evaluation
included multiple functional areas, representing both thenursing and administration clinical settings.
This study may also present a method for the routine
evaluation of surface contamination to verify that selectedareas are free from HD contamination and further identify
opportunities for updating cleaning procedures or otherenvironment or facility controls to improve the ability tolimit or eliminate HD surface contamination.
By demonstrating the effectiveness of the work practices of the facility, and the controls that are utilized in the
preparation and administration of HDs, this may offer asolution by which facilities which struggle or are investigating the modification of work practices to reduce staff orpatient exposure to HDs.

Material and methods
Evaluated environment – compounding and nursing
The test areas that were analyzed were based upon several factors.
Firstly, all the areas analyzed had significant potential exposure to
HDs and were of high concern for HD leakage or accidental spill. The
areas also represented surfaces which may have prolonged exposure
to HD containers and may offer an increased chance of significant
detection. These areas sought to replicate worst case scenarios byBishay et al.: Evaluating hazardous drug surface contamination with a CSTD and standard workflow

which the work practices and controls incorporated into the procedures would be most challenged.
The compounding environment tested included the biologicalsafety cabinet hood and pharmacy pass thru to nursing area in theCancer Center Pharmacy as well as the staging counter in HD buffer
room and pharmacy pass thru in main pharmacy HD compounding suit.
The Nursing staging area in the Cancer Center infusion suite andthe chemotherapy storage bin on inpatient oncology nursing floor
were tested.

CSTD devices
The ChemoLock and ChemoCLave are needlefree, single-use, CSTDs.
These devices have been incorporated into practice in both the preparation and administration areas. The CSTDs have a mechanicalmeans to prevent the transfer of environmental contaminants into thesystem, and the escape of HD or vapor concentrations outside thesystem. The systems include closed vial and bag access devices, aclosed syringe adapter and closed patient administration sets. Allcomponents of the system include passive, self-sealing mechanisms
which cannot be deactivated and remain protective through disposal.
Both ChemoLock and ChemoClave CSTDs are designed to preventthe transfer of environmental contaminants into the system and theescape of drug or vapor concentrations outside the system. The ChemoLock utilizes a click-to-lock design which keeps the connection
secure while an integrated membrane-to-membrane seal creates amechanically closed system. The ChemoClave uses a luer-based
connection to secure the connection and retain the closed system.
Both have received FDA clearance as “Closed System Transfer Devices”, under classification product code ONB (Closed Antineoplastic
and Hazardous Drug Reconstitution and Transfer System).
Hazardous drug compounding was performed using the ChemoLock CSTD for cyclophosphamide and paclitaxel. For the otherstudied HDs (fluorouracil, methotrexate, and doxorubicin), these areprepared using a kit that includes the ChemoClave vial adapter andmale luer connector (Spiros, ICU Medical, San Clemente, CA, USA).
Intravenous or subcutaneous administration utilized the ChemoClave with the male luer on the distal end of the secondary tubing.
For HD delivery for secondary administration a ChemoLock secondary
tubing set, which has a ChemoLock port at the proximal end and abonded male luer on the distal end of the tubing set.

3

The monthly additional cleaning includes the same procedure of
the daily with the addition of one application of another broadspectrum disinfectant (Peridox Disinfectant, Contec, Inc, Spartanburg, SC, USA) that also contains sporicidal characteristics. The use of
these products is supported by work identifying those solutions containing 10−2 M anionic surfactants and 20% isopropyl alcohol havebeen demonstrated to be most effective in the removal of HD surface
contamination [17]. Cleaning is performed by trained pharmacy andhospital staff, at regular timepoints. All cleaning agents are allowed tosit on the surfaces for the recommended period of time and thenremoved via wipes.
There were no modifications to the standard cleaning procedures
or frequency throughout the course of the study.

Standardized work practices
Procedure: This environmental wipe sampling was conducted in six
areas that included pharmacy and nursing in select locations with fiveHDs in six different locations in order to assess a baseline levelcontamination, and subsequent follow up surface wipes to assess
surface contamination in the same sample locations with the sameHDs in accordance with Table 1, below.
The initial (t=0) surface wipe sample collection coincided with the
opening of the new pharmacy area. No HDs had been handled in thepharmacy prior to the initial sample collection for the pharmacy areas in
the Cancer Center. For all other areas, the wipe samples were conducted
after compounding or handling was performed, including the ﬁve HDs
sampled in the study. For all collections, except for the samples takenfrom the initial pharmacy testing, the samples were collected midday,
between standard compounding and administration activities andstandard cleaning activities. Images displaying the areas and demarcation of areas to be sampled are shown in Figures 1, 2 and 3, below.
There was a total of two follow up surface wipe sample collections. The follow up surface wipe collections were conducted at
3 months and 6 months after the initial surface wipe sample collection
and followed the same sampling patterns as the initial surface wipe
sampling.
Table : Drug and sample location.
Hazardous drugs

Standardized cleaning procedures
All areas, except for the staging counter in main pharmacy HD bufferroom, are cleaned by separate daily and monthly cleaning procedures.
The main pharmacy HD buffer room receives an additional weekly
cleaning.
The agents utilized for cleaning of the surfaces are a broadspectrum bactericidal and general virucide (PREempt RTU Disinfectant Solution, Contec, Inc, Spartanburg, SC, USA) and 70% isopropyl
alcohol.
The daily cleaning for the surfaces sampled require two applications of the broad-spectrum agent, followed by one application ofsterile alcohol. The daily cleaning for the surfaces sampled was performed once in the morning prior to compounding and administration
activities and again after all compounding and administration activities were complete.

Paclitaxel
Cyclophosphamide
Doxorubicin

Fluorouracil
Methotrexate

Sampling locations
Biological safety cabinet ISO  incancer center pharmacy (type 
stainless steal)Cancer center pharmacy passthru to nursing medication room(stainless steal or epoxypainted stainless steal)
Nursing staging counter in patient Main pharmacy pass thru
infusion room (corian countertop) (stainless steal or epoxypainted stainless steal)
Staging counter in main pharmacy Inpatient Chemo receiving bin
HD buffer room (stainless steal)on oncology nursing ﬂoor (ultra
high-density virgin polypropylene plastic- non-PVC)

4

Bishay et al.: Evaluating hazardous drug surface contamination with a CSTD and standard workflow

Figure 1: HD sampling area inside the BSC.
The sampling was conducted by the facility’s lead sterile
compliance pharmacy technician.
In accordance with the vendor’s direction for use of the surface
wipe kits utilized for sample collection (ChemoGLOW™, Chapel Hill,
NC), a square foot (929 cm2) area was measured and marked for eachsample location. A horizontal and vertical wipe sample were thentaken from each area, after evenly distributing the wiping solution in
the marked area. All samples were then recorded, placed inside acontainer provided by the surface wipe analysis kit vendor and sent tothe vendor laboratory for analysis. All samples were identiﬁed indicating the sampling location, time/date of collection, and initials of
personnel performing the sampling.
Reference testing: The samples to determine surface contamination of
the workplace with HDs were stored at 4 °C, in accordance with thesurface kit instructions for use (ChemoGLO, Durham, NC, USA). Thesesamples were shipped to the ChemoGLO reference lab where they werestored at 4 °C until processed and analyzed. The samples wereanalyzed in accordance with previously published methods [27].
Brieﬂy, the HD samples were extracted using an extraction solution,transferred to a Salivette tube with an insert, and centrifuged at
4,000 rpm for 10 min. A 200 µL aliquot of the resulting solution wasremoved from the bottom chamber of the tube, dried down and thenreconstituted with 30 mL of mobile phase solution. A 200 µL solution
containing internal standards (IS) was added to each swab as theinternal standard.
The sample was then analyzed by liquid chromatographytandem mass spectrometry (LC-MS/MS), as previously described

Figure 2: Compounding activities inside the BSC, prior to HD
sampling activities.

[28–32]. The analyzation of the samples was performed utilizing
assays using an Agilent 6410 Triple Quadrupole with a concentration range for the sampled HDs linear 10–2,000 ng/mL per swab
area.
The ChemoGLO sample kits, method of collection, transport,
and analysis have demonstrated, when used in accordance with the
IFU, to recover >90% of cyclophosphamide, ifosfamide, paclitaxel,
docetaxel, 5-FU and methotrexate from a sample surface area [27].
The methods are aligned with the recommendations of recent
publications, including extraction solution, wiping method, wiping
materials, and instrumental considerations [33].

Results
Surface wipe kits analyzed from the initial (0 month), ﬁrst
follow up (3 month), and second follow up (6 month) all
resulted in below the limit of detection (0.01 ng/cm2),
resulting in non-detectable surface contamination for all
surface/HD combinations. The results are displayed inTable 2, below:
The number of preparations of the five HDs analyzed
during the course of the evaluation are identified inTable 3, below:

Bishay et al.: Evaluating hazardous drug surface contamination with a CSTD and standard workflow

5

Table : HD preparation frequency.
Hazardous drug

Number of preparations






Paclitaxel
Fluorouracil
Cyclophosphamide
Methotrexate
Doxorubicin

Discussion

Figure 3: HD sampling area of the nursing staging area.

Surface contamination remains a concern for hospital andpharmacy workers and a potential hazard to the health ofthese healthcare workers. As discussed with Connor et al.
[2], surface contamination may still be present, creating an
unnecessary risk to staff. Factors outside of the control of thehospital staff may contribute to the presence of surface
contamination. For instance, spills that do not get noticed byhospital staff, or are under or not reported may contribute to
the presence of HD vapor. Also, the presence of contamination may be a result of vial contamination, as reported inprevious studies [34, 35]. The above factors may remain
outside the immediate control of hospital staff and may
warrant additional study to determine factors and strategies
to mitigate or eliminate potential contamination sources.

Table : Initial,  month, and  month surface contamination wipe analysis (ng/cm).
Timepoint

Location

Initial

Biological safety cabinet hood
Pharmacy pass thru to nursing area
Nursing staging area
Main pharmacy pass thru
Main pharmacy counter in mixing room
Inpatient chemo bin nursing
Biological safety cabinet hood
Pharmacy pass thru to nursing area
Nursing staging area
Main pharmacy pass thru
Main pharmacy counter in mixing room
Inpatient chemo bin nursing
Biological safety cabinet hood
Pharmacy pass thru to nursing area
Nursing staging area
Main pharmacy pass thru
Main pharmacy counter in mixing room
Inpatient chemo bin nursing

 month follow up

 month follow up

Paclitaxel

-FU

Cyclophosphamide

Methotrexate

Doxorubicin

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6

Bishay et al.: Evaluating hazardous drug surface contamination with a CSTD and standard workflow

This study supports the value of standardized cleaning
procedures and the presence of a secondary engineering
control, in the identity of a CSTD, to retain reduced environmental exposure of healthcare workers to HD surface
contamination, based upon previously identified thresholdvalues [2]. It should be noted that the choice of cleaning
solution may not be the primary determinant in the effectiveness in its ability to decontaminate HD spills or residue.
As mentioned previously, research has indicated that
additional factors, besides the solution, may be substantial
contributors to the effectiveness including mechanicalaction, which may physically remove the HD and may beaffected by the porosity or makeup of the material used toapply the solution [18].
Surface contamination evaluation by surface wipe
analysis remains an established technique to identify thepresence of HD and potential exposure of healthcare
workers, especially those involved in the preparation,
compounding, and administration of HD. Although this isan established technique, it should be noted that there arelimitations involved in the evaluation. HD stability, and thebreakdown of the HD molecules varies, dependent uponthe HD, and may have the consequence of resulting in false
negative reporting results due to the nature of the HD andbecause of the lack of real time sampling ability. Anotherlimitation is the variable of the surface being sampled,
information may be needed to determine the extent offactors such as: porosity, material makeup, and alignment,
as these factors have all been demonstrated to have aneffect upon recovery rate [36] and may have contributed tothe consistency of sampling results and sample capture
rate.
Research funding: This study was supported by ICU
Medical (San Clemente, CA, USA).
Author contributions: All authors have accepted
responsibility for the entire content of this manuscript
and approved its submission.
Competing interests: Authors Sally Bishay, Malgorzata
Michalowska-Suterska, and Andrea Edling declare nocompeting interests. Author Jason Battle is an employee
of ICU Medical.
Informed consent: Not applicable.
Ethical approval: Not applicable.

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