Ann Occup Hyg 2005 Hedmer 629 37
Ann Occup Hyg 2005 Hedmer 629 37
Ann Occup Hyg 2005 Hedmer 629 37
629637, 2005
# 2005 British Occupational Hygiene Society
Published by Oxford University Press
doi:10.1093/annhyg/mei042
Workplaces, e.g. hospital pharmacies and hospital departments, where antineoplastic drugs are
handled might be contaminated with these drugs, and pharmacy personnel and health care
workers may be exposed. In this study potential sources for exposure of antineoplastic drugs
were investigated. Unbroken drug vials and tablet blister packages, both containing cyclophos-
phamide (CP) and their outer packaging were wipe sampled. Analysis was performed by liquid
chromatography combined with tandem mass spectrometry (LC-MS/MS). The result showed
that almost every part of the primary packaging was contaminated with CP and ifosfamide (IF).
However, the amounts of CP and IF were low, and most likely not harmful for the personnel
handling these packaging in association with drug preparation. The contamination must origin-
ate from the pharmaceutical manufacturer. Different surfaces in the preparation unit of a
Swedish hospital pharmacy were also investigated at two different occasions by wipe sampling.
In the preparation unit CP and IF were found as contaminants on the majority of the invest-
igated surfaces. After the first measurement the hospital pharmacy improved its routines.
Lower amounts of CP and IF were detected at the second measurement. A low degree of
contamination with CP and IF was also detected on the floor outside the preparation unit
and this indicated a small distribution of antineoplastic drugs to the surroundings.
629
630 M. Hedmer et al.
primary packaging of antineoplastic drugs delivered Wipe tissues for collection of wipe samples
from the pharmaceutical manufacturers. were non-woven swabs with a size of 5 5 cm
Cyclophosphamide (2-[bis(2-chloroethyl)amino]- (Hartmann-ScandiCare, Anderstorp, Sweden). Poly-
tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide; CP) ethylene bottles (50 ml) with wide mouth (Kautex
and ifosfamide (3-(2-chloroethyl)-2-[(2-chloroethyl)- Textron, Bonn, Germany) were used for storage of
amino]tetrahydro-2H-1,3,2- oxazaphosphorine 2-oxide; wipe samples.
IF) are two commonly used oxazaphosphorines. The
alkylating agents CP and IF are prodrugs and require
biotransformation before their metabolites can cause Wipe sampling of primary packaging
cell death by interacting with DNA. CP but not IF Primary packaging of CP (Sendoxan), commer-
is classified as carcinogenic to humans by the cially available on the Swedish market, was investig-
International Agency for Research on Cancer (IARC, ated in the study. The Sendoxan packaging was
1981, 1987). manufactured by Baxter Medical (Halle, Germany)
Previous studies of primary packaging containing and three package sizes of CP were investigated.
CP have only studied contamination on the outer wall Two packagings of tablets containing 50 mg CP
of drug vials and outside the caps (Sessink et al., (batch 1L713A) and 10 of each drug vial containing
1992; Ros et al., 1997; Pethran et al., 2001; Favier 200 mg CP (batch 3A105D) and 1000 mg CP (batch
in the preparation and dressing room, bottom of a The mobile phase consisted of water (A) and
shaker, a plastic folder and bottom of a refrigerator methanol (B), both containing 0.5% acetic acid.
box. However, at this measurement other surface The separation was performed using gradient elution.
areas such as different door handles, floor of the Initially, the mobile phase started with A:B, 60:40
corridor outside the preparation unit and a box in a isocratic elution for 6 min, followed by a 2 min gra-
delivery closet were also wipe sampled. This was dient to A:B, 0:100. Then, during 0.1 min the eluents
performed to investigate if contamination also returned to A:B, 60:40. At 60:40 the column was
could be detected on surfaces outside the preparation re-conditioned for 2.9 min. The mobile flow rate
unit. Wipe tissues were also collected as blanks was 0.2 ml min 1 and sample aliquots of 20 ml
(N = 6) in the investigated work place by wetting were injected.
two wipe tissues with sodium hydroxide and putting The analyses were performed using ESI with an ion
them into a bottle. All the wipe samples were placed spray voltage of 3000 V and temperature of 400 C.
in 50 ml bottles and kept in a freezer for 3 weeks, The instrument operated in a positive ion mode using
until work-up procedure. multiple reaction monitoring at m/z 263.1/142.1 for
CP, m/z 261.0/92.2 for IF and m/z 267.1/140.3
Preparation of standards for CP-D6. As control fragments, m/z 261.0/140.3
Stock solutions of CP and IF were prepared by for CP and m/z 261.0/154.1 for IF were used. Declus-
Table 1. Median amounts of CP and IF detected on different parts of the primary packaging of vials containing 200 mg CP
Sampled surface Median Range Surfaces contaminated
contamination above the limit of
detection (%)
CP per IF per CP IF CP IF
samplea (ng) samplea (ng)
Outside outer packaging 0.5 NDb 0.21.2 100 0
Inside outer packaging 3.2 10 1.46.7 3.425 100 100
Package leaflet 0.06 ND ND 0.1 ND1.7 90 10
Outside drug vial and 13 24 4.924 ND59 100 90
vial cap cover
Inside vial cap cover ND ND ND0.6 ND0.4 20 20
Rubber membrane ND ND ND0.1 10 0
a
Median of 10 samples.
b
Not detected.
Table 2. Median amounts of CP and IF detected on different parts of the primary packaging of vials containing 1000 mg CP
made of laminate, stainless steel and plastic flooring Table 3. Median amounts of CP detected on different
parts of the primary packaging containing 50 mg CP
material resulted in relative recoveries between
8494% and the CV ranged between 48%. Sampled Median Range Surfaces
surface contamination contaminated
by CP per above the limit of
sample (ng) detection (%)
RESULTS Outside outer 2.6a 1.83.3 100
packaging
Wipe samples from primary packaging Inside outer 1.9a 1.82.0 100
packaging
The results from the study of the primary packag-
Blister 0.5b 0.23.5 100
ing of Sendoxan are presented in Tables 13. package
CP was found on the outside of all outer packagings
of Sendoxan (50, 200 and 1000 mg). Amounts of CP No amounts of IF above the limit of detection were quantified
and in these packaging there were no package leaflets.
between 0.25.1 ng per sample were found. The outer a
Median of 2 samples.
packaging of Sendoxan 50, 200 and 1000 mg had a b
Median of 20 samples.
size of 200, 130 and 240 cm2, respectively. There
were very small amounts of IF (up to 0.08 ng) packaging of Sendoxan 200 mg. Quantities of CP
detected on the outside of five outer packagings of (up to 7.4 ng per sample) and IF (up to 1.7 ng per
Sendoxan 1000 mg. sample) were detected on the package leaflets
CP was also quantified in all wipe samples taken belonging to Sendoxan 1000 and 200 mg, respec-
from the inside of the outer packaging. The highest tively. The package leaflets had an area of 630 cm2.
median contamination inside the outer packaging, CP was detected on the outside of all the drug vials
3.2 ng, was quantified at Sendoxan 200 mg. Up to and vial cap covers. The median contamination of
25 ng IF was detected on the inside of the outer Sendoxan 200 and 1000 mg were 13 and 19 ng CP
634 M. Hedmer et al.
Table 4. Results from wipe samples taken at different surface areas (400 cm2) in the hospital pharmacy at two different occasions
Location No. of wipe Median amount Range Median amount of Range
samples of CP quantified IF quantified
(pg cm 2) (pg cm 2)
First measurement
Floor in preparation rooma 8 200 110260 7.4 1.278
Floor in dressing rooma 4 520 130870 78 0.3180
Floor in office 2 2.6 2.22.9 NDb
Working surfaces in BSC 15 9.2 2.7200 21 1.9740
Different working surfaces in preparation unit 8 18 2.454 11 2.538
Second measurement
Floor in preparation rooma 2 46 4646 7.2 7.17.3
Floor in dressing rooma 5 59 29170 1.2 0.387
Floor in delivery room 1 59 110
Floor in corridor outside preparation unit 4 17 2.534 44 5.2100
After the first measurement, the pharmacy changed several cleaning routines. The second measurement was performed several
per wipe sample, respectively. The corresponding were prepared and in total 13.8 g CP was handled
values for IF were 24 and 1.6 ng per wipe sample, in the BSC during the measurement. Also, two infu-
respectively. Amounts up to 130 ng CP per sample sion mixtures containing 4.1 g IF in total were pre-
and 59 ng IF per sample could be found on the outside pared. The second measurement was performed after
of Sendoxan drug vials. a normal workday and, altogether, infusion mixtures
Only small amounts of CP and IF were found inside containing 8.1 g CP and 18.8 g IF had been prepared.
the vial cap covers. Amounts up to 190 ng CP per During these two measurements normal working
sample were detected on the rubber membranes at conditions prevailed and many different antineo-
Sendoxan 1000 mg, but mostly small amounts of plastic drugs were prepared in the preparation unit,
CP were present on the membranes. IF was not but only CP and IF were studied. During the first
detected in any of these samples. measurement, in association with preparation of an
CP was quantified in all wipe samples from the infusion mixture containing IF, a small volume of
blister packages. The amounts detected were within liquid that had been spilled was visually seen on
the range 0.23.5 ng per sample (median 0.5 ng). the absorbent sheet.
From this result it was not possible to see any pattern Results from the measurements on the two different
of contamination on the numbered blister packages. occasions are presented in Tables 4 and 5. CP was
The total amount of CP on the primary packaging quantified in all wipe samples collected from differ-
of the drug vials varied between 6.528 ng (Sendoxan ent working areas and from floors in the preparation
200 mg: median 17 ng) and 10216 ng (Sendoxan unit. IF was quantified in the majority of these
1000 mg: median 38 ng). The corresponding values samples (96%). In the first measurement, the median
for IF were 3.585 ng (Sendoxan 200: median 35 ng) contamination of CP on floors in the preparation
and 1.54.0 ng (Sendoxan 1000: median 2.4 ng). The room, dressing room and office was 200, 520 and
contamination on the two investigated outer packag- 2.6 pg cm 2, respectively. The corresponding median
ing (inside and outside) of tablets was found to be amounts for IF were 7.4, 78 and <0.1 pg cm 2. The
3.8 and 5.1 ng CP, respectively. The total CP con- highest amounts of CP and IF on the floor were quan-
tamination on the entire tablet packaging was 8.6 and tified in the dressing room. Median amounts of CP
15 ng CP, respectively. No IF was detected on the and IF in samples from the working area in the BSC
tablet outer packaging or on the blister packages. and from other working areas in the preparation unit
In 22 out of 24 blanks no amounts of CP and IF were found to be 9.2 and 21 pg cm 2 and 18 and
detected, but small amounts of CP, 0.03 and 0.4 ng, 11 pg cm 2, respectively. Amounts of CP up to
were detected in two blanks. 200 pg cm 2 and amounts of IF up to 740 pg cm 2
were found on the working area in the BSC.
At the second measurement the floors in the pre-
Wipe samples from the preparation unit paration and dressing room were sampled again and
Wipe sampling was performed twice in the prepara- the results this time showed lower median amounts of
tion unit at the hospital pharmacy with several months CP, 46 and 59 pg cm 2, respectively. The correspond-
between the measurements. On the first occasion ing median amounts for IF were 7.2 and 1.2 pg cm 2.
4 infusion mixtures and 10 stock solutions of CP The sample with the highest amount of CP
Drug contamination on primary packaging and in a hospital pharmacy 635
Table 5. Amounts of CP and IF detected in wipe samples taken Sendoxan packaging used in this study small amounts
at different locations in connection with the hospital
pharmacy, before and after changed cleaning routines
of IF were also detected. The highest median amounts
of CP and IF were found on the outside on the drug
Location Amounts detected vials and vial cap covers. The level of the detected
in wipe samples
(ng per sample) contamination of CP on drug vials and vial cap covers
CP IF corresponds to what earlier investigators also have
First measurement
found (Sessink et al., 1992; Favier et al., 2003),
but is much lower than Connor et al. (2005) reported.
Bottom of shake apparatusa 89 5.3
The median contamination of CP on the 10 blister
Bottom of box in refrigeratora 2100 NDb
packages in Sendoxan 50 mg packaging was found to
Plastic foldera 32 20
be higher than the contamination on the other parts of
Handle on bottle 0.6 5.7 the tablet packaging.
Door handle on refrigerator 11 9.6 The detected contamination on the CP packaging
Door handle on delivery closet/ 17 5.0 must originate from the manufacture or packaging
sluice (inside preparation unit)
process at the pharmaceutical manufacturer, e.g. dust-
Sterilization bench 94 25 ing may occur during the filling process of drug pow-
Second measurement der into drug vials or the vials might be improperly
analysis. The contamination of the blanks originates The second measurement was performed several
probably either from a mix up of the samples or from months after the new routines were implemented.
contamination during the work-up procedure. Repeated wipe sampling on some of the surface
CP and IF were found in almost all wipe samples areas, e.g. floors and refrigerator box, indicated
from both exposure measurements in the hospital that the contamination levels of CP and IF had
pharmacy. In an investigation of six pharmacies decreased. The reduced contamination on surfaces
Connor et al. (1999) it was also reported that CP decreases the potential dermal exposure of CP and
was found in 100% of wipe samples and IF in 75% IF. During the second measurement extended wipe
of the samples. The amounts of CP and IF quantified sampling was also performed on surface areas outside
as a contaminant on different surface areas vary, but the preparation unit. Accordingly, a low degree of
highest amounts of CP and IF were detected at the contamination of CP and IF was detected on the
first measurement. CP is a more commonly used floor outside the preparation unit. This indicated
antineoplastic drug than IF. The hospital pharmacy a small distribution of antineoplastic drugs to the
handled annually larger amounts of CP than IF, and surrounding work environment.
this was also seen in the results from the wipe sam- In comparison with previous studies, the contam-
pling as higher amounts of CP were generally ination levels on the floors in the preparation unit in
detected on the surface areas. this Swedish hospital pharmacy were in the same
antineoplastic drugs inside the BSC, use protective Minoia C, Turci R, Sottani C et al. (1998) Application of
clothing, often change gloves and if possible use high performance liquid chromatography/tandem mass
closed-system device to minimize the contamination spectrometry in the environmental and biological monitoring
of health care personnel occupationally exposed to
levels and thereby the exposure. cyclophosphamide and ifosfamide. Rapid Commun Mass
Spectrom; 12: 148593.
AcknowledgementsThe authors thank Ms AnnSofie Fyhr and Nygren O, Lundgren C. (1997) Determination of platinum in
Ms Lena Jernstrom from the Hospital pharmacy, Lund workroom air and in blood and urine from nursing staff
University Hospital. The authors also thank Ms Gertrud attending patients receiving cisplatin chemotherapy. Int
Wohlfart for the skilful technical assistance. This work was Arch Occup Environ Health; 70: 20914.
supported by the AFA Foundation, Sweden, the Swedish Pethran A, Schierl R, Schmaus G. (2001) Wischproben an
Council for Work Life and Social Research, the Swedish Arbeitsplatzen mit Zytostatika-Exposition. Krankenhaus-
Research Council and the Medical Faculty at Lund University pharmazie; 22: 1115.
in Lund, Sweden. Pethran A, Schierl R, Hauff K et al. (2003) Uptake of antineo-
plastic agents in pharmacy and hospital personnel. Part I:
monitoring of urinary concentrations. Int Arch Occup
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