Download The Usefulness of a Closed-system Device for the Mixing of

Translation authorized by the author.
This article was originally published in
Journal of Japanese Society of Hospital Pharmacists,
Vol. 46 No. 1, 113-117 (2010).
The Usefulness of a Closed-system Device for
the Mixing of Injections to Prevent Occupational
Exposure to Anticancer Drugs
Rena Nishigaki*†1, Eri Konno1, Miki Sugiyasu1, Masahito Yonemura2, Tomonobu Otsuka1, Yasutaka Watanabe1,­
Takahiro Gunji1, Yukari Totsuka3, Keiji Wakabayashi3, Kazushi Endo2, Hiroshi Yamamoto1
Department of Pharmacy, National Cancer Center Hospital1, Department of Pharmacy, National Cancer Center
Hospital East2, Cancer Prevention Basic Research Project, National Cancer Center Research Institutes3
1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
[email protected]
Abstract
Many anticancer drugs are mutagenic, teratogenetic and/or carcino­
genic, and medical professionals who continuously handle the different
types of anticancer drugs are likely to be chronically exposed to these
drugs, and their health can therefore be affected. For this reason, it is
necessary to consider measures to prevent their exposure to anticancer
drugs. We have created an anticancer drug model preparation system
using sodium fluorescein and cyclo­phosphamide, and have carried out
a comparative investigation of chemical contamination between the
traditional prep­aration (using needles and syringes) and preparation
using closed system devices (Clave® Oncology System and
PhaSeal®).
Results of this investigation showed that preparation using needles and
syringes had a significantly higher frequency of contamin­ation, and at
clearly higher concentrations than prep­aration using the closed system
devices. This suggests a high risk of pharmacists involved in prep­
aration being exposed to these chemicals. It has also been shown that
the use of closed system devices can signi­ficantly prevent the contam­
ination of biological safety cabinet surfaces, as this is used as an
indication of environmental exposure to anticancer drugs.
Keywords – Exposure to anticancer drugs, cyclophosphamide, Clave®
Oncology System, PhaSeal®, sodium fluorescein (FL), liquid chromato­
graph – electrospray, tandem mass spectrometry (LC/ESI/MS/MS)
J. Jpn.Soc.Hosp.Pharm. – Vol. 46 No. 1, 113-117 (2010).
Introduction
To ensure the safety of medical
professionals, it is extremely
important to assess their exposure
in the handling of anticancer drugs
in terms of preparation techniques,
as well as to establish appropriate
methods of preparation.
The process by which cont­amin­
ation coming from anticancer
drugs is most likely to occur is
during the preparation of these
drugs. Guidelines in Japan and
overseas recommend that appro­
p­riate prep­aration equipment is to
be used to prevent exposure
to anticancer drugs1-3, and it has
been reported that closed-system
devices are useful for this
purpose.4,5 Closed system devices
with the purpose of preventing
exposure to anticancer drugs and
which are sold in Japan are
PhaSeal® and Clave® Oncology
System. The two distinct kinds of
vials from each preparation model
were used. These vials contained
fluorescein sodium (FL) (which
1
can be detected visually by UV
irradiation with a high level of
sensitivity) and cyclophosphamide
(CPA), (which is both highly
car­c inogenic to humans, and
highly dangerous to handle due to
the vaporization of the drug). The
vials were used to simulate the
sterile preparation process in a
biological safety cabinet (BSC)
for the assessment of the useful­
ness of closed system devices in
preventing ­contamination in the
same facility.
Methods
1. Subjects
Techniques were compared for 28
pharmacists involved in the prep­
aration of anticancer drugs, in the
pharmacy departments of the
National Cancer Center Hospital
and National Cancer Center
Hospital East. Tests using anti­
cancer drug vials of the FL model
were carried out for 9 pharmacists
with less than 1 year of total
parent­eral nutrition (TPN) and
sterile preparation of anticancer
drugs, as well as for 19 pharma­
cists with more than one year
of such experience, for a total
of 28 pharmacists. Also, out of
these pharmacists, the degree
of contamination for the mixing
process using the marketed
CPA vial were compared for 3
pharmacists with less than one
year of the above experience and
for 3 pharmacists with one year or
more of such experience.
2. Methods of Preparation
One preparation procedure with a
total of three preparation
methods, namely; the normal
­method of prep­aration (abbrevi­
ated as “normal preparation”)
using an 18 G1/2 “SB needle”
2
(Terumo ­Corporation) and a luerlock syringe, as well as preparation
methods using the closed system
devices PhaSeal® (Carmel Pharma
Japan K.K) and the Clave ®
Oncology System (Palmedical,
Inc.), were combined into one
prep­aration “set.” Three sets of
prep­­aration were carried out by
each pharmacist, with the order
of preparation changed for each
set. In order to eliminate the influ­
ence of the order of preparation,
two types of order in which the
drugs were to be prepared were
decided upon and subjects were
allocated so that there was no
bias caused by the hospital they
belonged to or by their experi­
ence in preparation. Preparation
methods were accord­ing to tech­
niques and methods usually used
and followed the anticancer drug
preparation manual, while the
operation of each closed system
device was carried out according
to the operation pro­cedure set for
each device. For preparation
using the Clave® Oncology Sys­
tem, a Clave® Preparation System
GENIE (CH-77), a Clave® Prepa­
ration System (CH-10) and
Clave ® Oncology Set (CH2000C) were used. For preparation
using PhaSeal® a PhaSeal Protec­
tor (P50J), PhaSeal Infusion
Adapter (National Cancer Center
Hospital: L-connector, National
Cancer Center Hospital East:
C100J), and a PhaSeal® Injector
Luer Lock N35J were used. Since
PhaSeal® has been adopted at the
investi­gational site the technique
of preparation has been learned
by subjects. The Clave® Oncol­
ogy System has not been used
at the site, so examination was
carried out after the learning of
prep­aration technique.
3. Operation using test anti­
cancer drug preparation vials
containing FL
Vials containing 1 g of D-mannitol
and 5 mg of FL were adjusted
to 15 ml with NS and used to
simulate drug vials. The test
prescription was to be 11 mg of FL
in an infusion container con­taining
100 ml of physiological saline,
mixed inside a safety cabinet. The
time required for preparation was
measured each time.
Observational checking for con­
tamination was carried out for
surfaces of rubber caps or
connecting parts (which were
expected to be contaminated by
the vials), infusion containers, the
syringe adapters, as well as for
all surfaces of the BSC (working
surface, sides, back, and glass
surfaces). The scattering of
the fluorescent test drug was
measured in terms of the number
and size of droplets, where the
size was measured on three levels
(±: <1 mm, +: 1–5 mm, ++: > 5
mm). Assessment of surface
contamination was first done
visually, and was then checked
by fluorescence under UV irradia­
tion. Also, since in some cases
the state of contamination was
difficult to see due to the fluor­
escence of the solution in the
preparation device reflecting upon
the equipment, the checking for
adhered solution was carried out
by applying pH indicator paper to
the surface of the equipment, as it
absorbs moisture, and contamina­
tion can be checked for by changes
in its color. Where there were
deviations from the normal opera­
tion method these cases were
excluded from the evaluation.
4. Investigation of the anti­cancer
drug preparation model using
CPA
For the test prescription, 800 mg
of CPA was mixed and prepared in
an infusion container containing
100 ml of physiological saline.
alliance HT 2795, Waters Micro­
mass® Quattro UltimaTM Pt).
In the analysis, 0.1 % formic acid
– acetonitrile was used as the
mobile phase, and a Synergi 4 u
Fusion-RP 80A (3.0 X 150 mm,
Phenomenex) column was used.
A vial of commercial CPA 500 mg Measurement was carried out
was dissolved in physiological with positive ion conditions for
saline on the day of the trial to a LC/ESI/MS/MS, using the Multi­
concentration of 20 mg/ml, which ple Reaction Monitoring mode.
was then used for the trial. In order Tran­sitions m/z 261 → 140 and
to eliminate the influence of the 261 → 92 were selected for CPA
CPA on the vial, the CPA vial was and IFO.
washed with 70 % ethanol and
running water beforehand. After There was no adhesion of CPA
the reconstitution using physio­ and IFO on the membrane filter
logical saline, vials were again (recovery rates: CPA: 100 ± 5 %,
IFO: 103 ± 3 %) and the standard
washed and used for the trial.
curve was linear from 0.1 pg to
The time required for preparation 10 pg (CPA: R2 = 0.9995, IFO: R2
was measured on each occasion, = 0.9997). The injected volume
and wipe samples were obtained was to be 20 μL and the concen­
for contamination detection. tration of the sample was diluted
Medical cotton (4 x 4 cm), wetted to match the concentration in
with 1ml of ultra-purified water which there was linearity shown
was used to wipe the surfaces of for the purpose of measurement.
rubber caps and connections The quantification limit had
(which were expected to be a signalnoise ratio of 10, and
contaminated) and on the vials, the measured as 0.1 pg for both CPA
infusion container, the syringe and IFO. For the wipe samples,
adapter, the palm side of both the those obtained before preparation
left- and right-hand gloves as well were used as blank values when
as the working surface of the BSC calculating measured values. Also,
(70 x 49 cm). Cotton was stored in where there were any deviations
a 50 ml plastic tube at 20 ℃ until from standard operation methods
measurement. Ultrapurified water during preparation, the values
and 20 ng ifosphamide (IFO) as an were excluded. Furthermore,
internal standard were added to the in order to investigate whether
tube, to make the total volume contamination can be eliminated
up to 20 ml, and extraction was by cleaning, medical cotton soaked
carried out after 1 hour of stirring well with 70 % ethanol was used
and shaking. The extract was to wipe the surface of the infusion
filtered using a 0.20 μm membrane container and infusion adaptor
filter, and was analyzed using liq­ once. After the conclusion of
uid chromatograph–electrospray the mixing operation, this second
tandem mass spectrometry (LC/ wipe sample was collected and
ESI/MS/MS, Waters HPLC analyzed.
5. Statistical analyses
Statistical analyses were carried
out using SPSS 15.0J for Windows
(SPSS Advanced Statistics, SPSS
Regression Models), and a hazard
ratio of 5 % was set as the standard
of significance. A chi-squared test
was used to compare the frequency
between groups, and Student’s
paired t-test or an analysis of
variance was used to compare
measured values. Also, where n
was insufficient for the chi-squared
test, Fisher’s exact test was used
instead.
Results
1. A comparative investigation of
mixture preparation technique
using the anticancer test drug
containing FL.
Comparing the two groups of prep­
aration experience of less than one
year and one year or more,
the average time required for
all preparation methods was
significantly longer for those with
less than one year of experience
(normal preparation: Less than one
year: 434 ± 164 seconds, one
year or more 292 ± 68 seconds
(p < 0.001), Clave® Oncology Sys­
tem: 499 ± 95 seconds, 432 ± 100
seconds (p = 0.005), PhaSeal®: 449
± 92 seconds, 382 ± 95 seconds
(p = 0.003)), however, there were
no significant differences observed
in the frequency of contamination
(Table 1).
There was no contamination
observed in any parts of any
observed cases for preparation
using PhaSeal®, regardless of prep­
aration experience. However, in
the prep­aration using the Clave®
Oncology System, all vials, most
infusion containers and syringe
adapters, but not the surface of
3
safety cabinets, were contaminated
for 3/4 of pharmacists with experi­
ence of 1 year or more. From the
investigation of the size of the
scattered droplets, it was shown
that the size of the droplets in all
observed parts of normal prepara­
tion varied from < 1 mm to > 5
mm. Contamination over a wide
range with droplets of > 5 mm or
more was only observed with nor­
mal preparation, however with
preparation using the Clave ®
Oncology System, most scattered
droplets were 1 mm or less in all
observed parts (Table 2).
2. Difference in surface contam­
ination by CPA, according
technique
When normal preparation was
carried out using CPA model vials,
the maximum values were signifi­
cantly higher in all observed parts
compared to when the closed
system devices were used (Table 3).
The maximum values on the BSC
working surface, regarded as
an indication of environmental
exposure, were 514.9 µg for
normal preparation. In contrast,
the maximum value was 0.3 ng for
Clave® Oncology System and 0.5
ng for PhaSeal®, showing the most
significant difference between
normal preparation and prepara­
tion using closed system devices.
Furthermore, in measurements for
the working surface of the working
cabinet, CPA was detected from
40 % of measured samples in
normal preparation; however, for
preparation using closed system
devices, 90 % of the measured
samples were at or below the limit
of detection for both devices.
surface of the connecting parts for
all equipment when the Clave®
Oncology System was used, how­
ever the concentration was lower
than that with normal preparation.
With preparation using PhaSeal®,
CPA was detected on the surfaces
of vials, infusion containers and
syringe adapters, in contrast to the
test results of the fluorescence
observation using UV irradiation.
However, the amounts measured
were extremely small relative to
those with the Clave® Oncology
System (1/500, which is extrem­
ely low).
Also, the observation of high
frequen­cies and concentrations of
contamination on the surface of
infusion containers in the prepara­
tion method using needles and
syringes suggests the potential for
contamination with anticancer
drugs spreading from the surface
of infusion containers. The high
rate of reduction of contamination
on the surface of infusion contain­
ers using 70 % ethanol suggests
that the cleaning of the surface
of infusion containers using an
alcohol gauze is not only to be
carried out for disinfection
purposes but also is useful in
When the surface was cleaned with reducing anticancer drug contami­
70 % ethanol after preparation, the nation that occurs during
median concentrations of CPA on preparation.
the surfaces of infusion containers
and adaptors after cleaning (mini­ However, although the rate of
mum and maximum) were 2.5 ng reduction is high, it is difficult to
(0.4~100.1 ng) for normal prepa­ completely eliminate high-concen­
ration, 1.1 ng (0.2 ~ 2 5 4 . 0 n g ) tration contamination and the
for Clave® Oncology System and importance of preventing contam­
0.5 ng (0.1~2.0 ng) for PhaSeal®, ination at the preparation stage has
showing a low amount in all cases. become apparent.
Discussion
In carrying out normal prep­aration,
contamination was observed in all
examined parts for tests using FL,
regardless of the number of years
of preparation experience. Con­
tamination was observed at high
frequencies and concentration
even for those with many years’
experience in preparation and even
when preparation was carried
out according to guidelines. This
sugg­ests that the prevention of
contamination for traditional prep­
aration methods using needles and
syringes is extremely difficult, and
the risk of medical professionals
handling anticancer drugs being
Similarly to the test results using exposed to high concentration
FL, CPA was detected on the levels of contamination is high.
4
In tests using the Clave® Oncology
System, both FL and CPA were
detected on the surface of the
equipment. The Clave® Oncology
System is built so that the pipes are
closed when removing equipment
connections, thereby preventing
the leakage of chemicals.
However, there is a possibility that
small amounts of residual chemi­
cals inside the pipe on the
connection surface side may be
dispersed when taking apart the
connections. It is necessary that
connections are to be taken apart
slowly, taking into account the
possibility of attachment of chemi­
cals on the surface of the equipment.
Although chemicals were detected
on the surface of the equipment,
chemicals had not scattered to
other parts and the contamination
on the surface of the safety cabinet
was almost the same as with using
PhaSeal®.
In tests using PhaSeal®, there was
no scattering of chemicals on the
surface of equipment and BSC for
tests using FL, and the results of
tests using CPA showed very low
amounts of CPA detected on the
surface of equipment, showing
that PhaSeal® is highly effective in
preventing exposure.
Since CPA was detected on the
equipment surface for both closed
system devices, it is believed that
caution is required for handling
of equipment in the use of high
concentration anticancer drugs,
even if these closed system devices
are used.
The National Institute for Occupa­
tional Safety and Health (USA)
Guidelines state that closed system
devices are useful in preventing
exposures but do not substitute
BSC, personal protection equip­
ment needs to be worn, and
appropriate preparation methods
need to be carried out.1
preparation processing of anti­
cancer drugs is 500 yen. Most of
the cost of personal protection
equipment and closed system
devices for preventing exposure to
anticancer drugs are currently paid
for by the hospital. This economic
issue causes difficulties in the
discussion of measures to prevent
exposure to anticancer drugs.
As the number of cancer patients
increases, the number of cases of
anticancer drug preparation, as
well as the number of cases of anti­
cancer drug combination therapy
increases. Therefore it is expected
that the risks of medical professionals
being exposed to anti­­cancer drugs
and having their health affected
due to this will also increase. For
these reasons, it is hoped that the
assessment of costs for treatment
regarding measures for preventing
exposure to anticancer drugs
during preparation will be carried
out in the future.
Acknowledgement
We would like to thank all those in
the Pharmacy Department of the
National Cancer Center Central
Hospital and the Pharmacy Depart­
ment of the National Cancer
East Central Hospital for their
enormous help during this study.
The two types of closed system
devices used in this experiment *The National health insurance
both showed effects of preventing fee has been raised to 1,000 yen as
exposure to anticancer drugs. of April 1st 2010.
However, as the structure and
characteristics of these devices
differ, it is believed that the equip­
ment to be used is to be chosen
according to the circumstances
of the facility of where it is to
be used.
At present time (2009)*, the National
health insurance fee for the sterile
5
References
1) National Institute for Occupa­
tional Safety and Health (NIOSH):
NIOSH ALERT Preventing
Occupational Exposure to Antine­
oplastic and Other Hazardous
Drugs in Health Care Settings.
Cincinnati, USA, NIOSH,
1–61 (2004).
2) American Society of HealthSystem Pharmacists (ASHP):
ASHP Guidelines on Handling
Hazardous Drugs, Am J HealthSyst Pharm, 63, 1172–1193
(2006).
3) Edited by the Japan Society
of Hospital Pharmacists: Guide­
lines for Sterile Preparation of
Injections and Anticancer Drugs.
Yakuji Nippo Limited, Tokyo
2008, pp 3–35.
4) J. Yoshida, G. Tei, et al.:
Use of a closed system device
to reduce occupational contami­
nation and exposure to antineo­
plastic drugs in the hospital work
environment, Ann Occup Hyg,
53, 153-160 (2009).
5) T.H. Connor, R.W. Anderson,
et al.: Effectiveness of a closedsystem device in containing sur­
face contamination with
cyclophos­phamide and ifosfamide
in an i.v. admixture area, Am J
Health Syst Pharm, 59, 68–72
(2002).
6) Edited by the Japan Society
of Hospital Pharmacists: Guide­
lines for the handling of anti-tumor
agents in the hospital, Revised
Edition – Anticancer Drug Prepa­
ration Manual. Jih, Inc., Tokyo,
2005, pp 3–48.
6
Table 1. Observation of surface contamination for each preparation method, by years of preparation
experience (Frequency of fluorescence detection using FL).
Method of
preparation
Average
preparation
time (sec)
Normal preparation
434
Less than
Clave® Oncology
one year of
experience in System
preparation (n
= 9)
PhaSeal®
Normal preparation
One year
or more of
preparation
experience
(n = 19)
Clave® Oncology
System
PhaSeal®
499
449
292
432
382
Number of cases (Proportion)
Vial a
Infusion
container b
Syringe
adapter c
BSC d
No
9 (33 %)
contami­
nation
2 (7 %)
27 (100 %)
17 (63 %)
Conta­
18 (67 %)
mination
observed
25 (93 %)
0 (0 %)
10 (37 %)
No
1 (4 %)
contami­
nation
2 (7 %)
10 (37 %)
26 (100 %)
Conta­
26 (96 %)
mination
observed
25 (93 %)
17 (63 %)
0 (0 %)
No
27 (100 %)
contami­
nation
27 (100 %)
27 (100 %)
27 (100 %)
Conta­
0 (0 %)
mination
observed
0 (0 %)
0 (0 %)
0 (0 %)
No
31 (54 %)
contami­
nation
3 (5 %)
55 (98 %)
40 (70 %)
26 (46 %)
Conta­
mination
observed
54 (95 %)
2 (2 %)
17 (30 %)
No
0 (0 %)
contami­
nation
7 (12 %)
14 (25 %)
56 (100 %)
Conta­
57 (100 %)
mination
observed
50 (88 %)
43 (75 %)
0 (0 %)
No
57 (100 %)
contami­
nation
57 (100 %)
57 (100 %)
57 (100 %)
Conta­
0 (0 %)
mination
observed
0 (0 %)
0 (0 %)
0 (0 %)
Observed parts of a, b, c: rubber caps or connecting sections.
7
Table 2. Contamination frequency by fluorescent test drugs by parts according to preparation method.
Number of cases (Proportion)
Normal preparation
Clave® Oncology
System
PhaSeal®
Vial a
Infusion
container b
Syringe
adapter c
BSC d
Total number of cases
84
84
84
84
No contamination
40 (48 %)
5 (6 %)
82 (98 %)
57 (70 %)
Contamination Observed ( ±e )
36 (43 %)
65 (77 %)
0 (0 %)
23 (27 %)
Contamination Observed ( +f )
12 (14 %)
22 (26 %)
1 (1 %)
9 (11 %)
Contamination Observed (++g)
2 (2 %)
6 (7 %)
1 (1 %)
4 (5 %)
Total number of cases
84
84
84
82
No contamination
1 (1 %)
9 (11 %)
24 (29 %)
82 (100 %)
Contamination Observed ( ±e )
82 (98 %)
73 (87 %)
57 (61 %)
0 (0 %)
Contamination Observed ( +f )
7 (8 %)
10 (12 %)
3 (36 %)
0 (0 %)
Contamination Observed (++g)
0 (0 %)
0 (0 %)
0 (0 %)
0 (0 %)
Total number of cases
84
84
84
84
No contamination
84 (100 %)
84 (100 %)
84 (100 %)
84 (100 %)
Contamination Observed ( ±e )
0 (0 %)
0 (0 %)
0 (0 %)
0 (0 %)
Contamination Observed ( +f )
0 (0 %)
0 (0 %)
0 (0 %)
0 (0 %)
Contamination Observed (++g)
0 (0 %)
0 (0 %)
0 (0 %)
0 (0 %)
Observed parts; rubber caps or connecting sections.
Observed part: Inside surface of BSC.
e
± : Size of droplets < 1 mm.
f
+ :size of droplets 1 mm – 5 mm.
g
++: size of droplets > 5 mm.
a, b, c
d
8
Table 3. CPA contamination level by part for each preparation method.
Vial
Infusion container
Syringe adapter
BSC
Gloves
Detected Detected Detected Detected Detected Detected Detected Detected Detected Detected
Amounta Propor­ Amount Propor­ Amount Propor­ Amount Propor­ Amount Propor­
tion
tion
tion
tion
tion
0.3 ng
(NDc –
514.9
µg)
39 %
(7/18)
0.2 ng
78 %
(ND
(14/18)
15.1 ng)
4.5 µg
100 %
(209.6 ng (18/18)
– 8.7 µg )
0.3d ng
(ND 0.3 ng)
6%
(1/18)
0.2 ng
67 %
(0.1 ng (12/18)
47.0 ng)
4.6 ng
(0.2 ng
– 180.5
ng)
0.5c ng
(ND 0.5 ng)
7%
(1/15)
0.2 ng
(0.1 ng
1.8 ng)
Normal preparation
150.0 ng 100 %
(8.9 ng (36/36)
– 516.1
µg)
500.0 ng 100 %
(10.0 ng (18/18)
– 161.3
µg)
NTb
Clave® Oncology
System
498.7 ng 100 %
(9.2 ng – (35/35)
3.3 µg)
1.9 µg
(20.0 ng
– 6.1 µg)
100 %
(18/18)
PhaSeal®
1.4 ng
94 %
(ND –
(32/34)
69.1 ng)
1.5 ng
(0.5 ng
– 22.3
ng)
100 %
(18/18)
NT
100 %
(18/18)
31 %
(5/16)
Median Value (Min-Max)
NT; not tested
c
ND; not detected
d
n = 1.
a
b
9