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Journal of Oncology Pharmacy Practice
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DOI: 10.1177/1078155212452764
2013 19: 57 originally published online 9 July 2012 J Oncol Pharm Pract
F Sadeghipour, K Ing Lorenzini, C Ziewitz, M Dobrinas, M Fleury and P Bonnabry
hospital pharmacies
Chemical contamination during the preparation of cytotoxics: Validation protocol for operators in

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Oncology
Pharmacy
Practice
Journal of
Original Article
Chemical contamination during the
preparation of cytotoxics: Validation
protocol for operators in hospital
pharmacies
F Sadeghipour
Pharmacy, Hospitals of University of Geneva (HUG), Switzerland; School of Pharmaceutical
Sciences, University of Geneva, University of Lausanne, Switzerland
K Ing Lorenzini
Pharmacy, Hospitals of University of Geneva (HUG), Switzerland; School of Pharmaceutical
Sciences, University of Geneva, University of Lausanne, Switzerland
C Ziewitz
Pharmacy, Hospitals of University of Geneva (HUG), Switzerland
M Dobrinas
Pharmacy, Hospitals of University of Geneva (HUG), Switzerland
M Fleury
Pharmacy, Hospitals of University of Geneva (HUG), Switzerland; School of Pharmaceutical
Sciences, University of Geneva, University of Lausanne, Switzerland
P Bonnabry
Pharmacy, Hospitals of University of Geneva (HUG), Switzerland; School of Pharmaceutical
Sciences, University of Geneva, University of Lausanne, Switzerland
Abstract
Background and objectives: The chemical contamination during the preparation of cytotoxics remains a serious
problem in hospital pharmacies and the operators could contribute to this risk during their manipulations. A validation
protocol was developed using a non-toxic, highly detectable tracer, quinine dihydrochloride.
Method: Further, a method for a high recovery extraction and quantification of this marker, and a protocol covering the
critical operations of cytotoxic preparation, was developed and validated. Various devices were used to fill the syringes
and perfusion bags. All the filled containers and used materials were collected at the end of the protocol and the tracer
was extracted in water. The contaminated water was analyzed by fluorimetry. The number of spots on the working pads
was counted under ultraviolet light. During a total of 28 sessions, the procedure was applied by 20 different operators.
Results: The mean cumulated quantities of contamination were 6.2 mL (0.623.8) and >10 spots (020), which was
considered as high. No correlation was observed between the contamination rate and the operators experience.
Conclusion: This validation protocol facilitates controlling the operators working cleanliness and helps to improve the
initial and continuing training. This simple test presents an effective answer for the important issue of the chemical safety
of operators.
Keywords
Operators validation, cytotoxics, chemical contamination, fluorescent marker, quinine
Corresponding author:
Farshid Sadeghipour, Hospitals of University of Geneva (HUG), Rue
Gabrielle Perret-Gentil, 4, CH 1211, Geneva 14, Switzerland.
Email: farshid.sadeghipour@hcuge.ch
J Oncol Pharm Practice
19(1) 5764
! The Author(s) 2012
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DOI: 10.1177/1078155212452764
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Introduction
Since the early 1980s, the preparation of injectable
antineoplastic drugs and other cytotoxic products for
adult and pediatric oncology units has been regularly
performed in hospital pharmacies. This trend is based
on two core rationales. It is aimed for a better protection
for the nursing and the medical sta, who previously
prepared these toxic medications in unprotected condi-
tions, as well as ensuring better safety for the patients,
supported by the quality assurance system implemented
in the production units of hospital pharmacies.
14
However, an important problem remained after the
transfer of this activity from the nurses to the pharma-
cists. A number of studies have actually reported a con-
tamination of the operators with the cytotoxics,
529
with
two possible sources. These sources include a production
residue on the primary packaging of antineoplastic
drugs
13,16,17,30
or a contamination by the operator
during the production of the nal drug for patients at
the pharmacy.
7,13,28
These mechanisms led to a contam-
ination of the syringes and infusion bags or the work
area in the pharmacy. The follow up to this contamin-
ation has been tended by various methods. These con-
trols can be performed by directly determining the
cytotoxic levels on the working surfaces
7,8,15,20,29
or
from the biological uids (blood and urine) of the oper-
ators.
5,1012,22,27,31
However, the latter techniques pre-
sent several drawbacks, such as the complexity of the
analytical methods
3234
as well as the theoretical risk
of contamination during the analytical process itself.
Moreover, the above mentioned approaches do not dif-
ferentiate between the contamination due to the manu-
facturer and the one related to the manipulation in the
hospital pharmacy. Therefore, it would be interesting to
estimate the contamination produced during the prep-
aration process. This would facilitate taking adequate
measures to improve the teaching of the operators, if
necessary. The selection of a non-toxic, sensitive, and
easily quantiable tracer would make it easier to
bypass these problems. This would allow easy simula-
tion of the routine operations as well as validation of the
procedures and the operators. Several markers have
been proposed in the literature for tracing the contam-
inations. Radioactive substances, such as technetiumare
very sensitive tracers.
35
However, their use is dicult
because of the necessary protective measures to be
taken for their manipulation. Another alternative
solution is the use of uorescent markers.
3638
Fluoresceine, for instance has a higher sensitivity in
comparison to other uorescent tracers, but is incon-
veniently visible (yellow-orange solution). Thus, the
operator could be abnormally attentive during the val-
idation process. Quinine dihydrochloride (QdHCl) is
natively uorescent, non-toxic, invisible to the naked
eye, soluble in water, and relatively easy to detect
under ultraviolet (UV) rays, with a high selectivity and
detectability.
39,40
Thus, it appears to be an ideal tracer
for measuring the contamination during the preparation
procedures.
The present study included two main objectives.
First, it aimed to develop and validate a simple
method using the QdHCl as a tracer. This would facili-
tate evaluating the contamination level by simulating
the preparation of the injectable cytotoxic drugs.
Second, the method was applied through a practical
standard operating procedure (SOP) to dierent oper-
ators for checking their ability to work in a clean
manner. This could help to avoid spreading the con-
tamination in the environment or on the nal prepar-
ation to be delivered to the wards. Based on the
obtained results, new specic training has to be orga-
nized for the operators with the most contamination to
correct their working methods.
Materials
QdHcl BP (Courtin & Warner LTD, UK and Duchefal
Farma, The Netherlands); Luer Lock Syringes 10, 20
and 50 mL (Becton, Dickinson & Co, NJ, USA); syringe
for vesical instillation, Omnix 100 mL (B.Braun,
Germany); needles (Terumo, Belgium); chemo dispen-
sing pin (B.Braun, Germany); transfer-set (Sintetica-
Bioren, Switzerland); tamper evident cap (B.Braun,
Germany); combi stopper (B.Braun, Germany); admin-
istration tubing set, Chemoprotect

gloves (Codan,
Germany); original Perfusor-Leitung PE (B.Braun,
Germany); infusion bag NaCl 0.9% 50 mL (Sintetica-
Bioren, Switzerland); gloves Micro-Touch PF
2
(Ansell,
NJ, USA); Fluorescence Spectrometer LS 50 (Perkin
Elmer, USA); and UV lamp (Camag, Switzerland).
Methods
Development and validation of the quantification
of the tracer
A 0.1 mM solution of QdHCl in water for injection
(WFI) was prepared to establish its uorimetric spec-
trum. An excitation wavelength and an emission wave-
length at 330 nm and 380 nm, respectively, were
determined. The limits of detection and quantication
were determined by the Eurachem approach based on
the use of a target value for the area of the relative
standard deviation (RSD).
41
The calibration curves
were carried out at concentrations between 0.1 and
1 mM in WFI to test the linearity at ve points. This
was done three times for each point (0.10, 0.15, 0.25,
0.50, 0.75, and 1.0 mM). Precision and accuracy were
tested at 0.1 and 1.0 mM.
58 Journal of Oncology Pharmacy Practice 19(1)
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Development and validation of recovery of the
tracer from the contaminated devices
The contamination of the working pads was evaluated
semi-quantitatively by counting the number of stains
found under the UV light, owing mainly to the
absorbent nature of the liners. It was necessary to
develop a simple and ecient quantitative extraction
method to recover the contaminant (QdHCl) dropped
on the gloves and the infusion bags. A number of
previous studies have been based on wiping pads
7,8,42
wetted with organic solvents (methanol) or alkaline
solutions, where the contaminants were later extracted
in another solvent.
In the present study, the tracer being used was well
soluble in water. Thus, the extraction method was
tested by complete immersion of the gloves, bags, and
other contaminated devices in a glass beaker, contain-
ing 500 mL of WFI. This solution was stirred for 5 min.
The contaminated water was directly analyzed by
uorimetry. The recovery was tested at two dierent
levels of contamination: low (1 mL) and high (5 mL)
and on two dierent devices: 50 mL NaCl 0.9% infu-
sion bags and sterile non-powdered gloves. Either 1 or
5 mL of the 0.1 M solution of QdHCl was placed on
each device. Subsequent to drying of the solution, the
device was immerged in 500 mL of WFI.
To control the recovery rate, the uorescence mea-
sured on the devices was compared with the standard
solutions of 0.1 and 1.0 mM of QdHCl. The test on each
device was repeated six times per day, for 3 days.
Development of the operators validation protocol
To simulate the preparation of the lyophilized cyto-
toxics, 10 mL vials were lled with 10 mL of a 0.1 M
solution of QdHCl. Later, they were placed in an oven
at 90

C and their content was completely desiccated.

After the vials were sealed with stoppers and capsu-
lated, they were washed and checked under UV light
for absence of any outside contamination.
A preliminary test was developed to check the
feasibility of the operators protocol. A laboratory
chemical fume hood was used to simulate the working
conditions in the negative pressure biological safety
cabinets class III.
For the preliminary test, a working pad was installed
with all the necessary materials. For the entire test, the
operator wore Chemprotect

gloves covered by a pair

of other sterile non-powdered surgical gloves. Three
vials of desiccated QdHCl were reconstituted with
5 mL of WFI. Overall, 2 mL of the solution was
removed from each vial and added to a separate
50 mL NaCl 0.9% infusion bag. The covering gloves
were changed after each bag.
At the end of the procedure, the working pads were
observed under UV light to count the number of spots
(only the number and not the dimensions were con-
sidered). A semi-quantitative scale was used to deter-
mine the contamination rate: low (05 spots), medium
(610 spots), and high (>10 spots). The diameter of the
spots was not taken into account as the average size of
the spots was less than 3 mm.
The contamination on the covering gloves and the
infusion bags were separately measured by the previ-
ously developed quantitative method.
Operators validation protocol
The developed method was nally implemented in the
real working environment, that is, the negative pressure
biological safety cabinets class III placed in a class C
GMP (ISO 7) clean room. Every operators validation
session was performed in the presence of another val-
idation operator, a junior hospital pharmacist, who
controlled all the manipulations and the process
timing (not exceeding 1 h).
All pharmacists and pharmacy technicians working
in the cytotoxic preparation unit were required to pre-
pare a xed number of syringes and infusion bags in the
isolator with a solution of QdHCl in a limited period of
time. They were asked to follow precise instructions
and adopt the same working procedures such as those
used for the cytotoxics preparations.
For each operator, 10 desiccated vials of 0.1 M
QdHCl were prepared, as previously described. The
rst step for the operator involved dissolving the
desiccated QdHCl powder with 5 mL of WFI for all
the 10 vials. Subsequently, the entire contents (50 mL
in total) were transferred into an empty 50 mL sterile
and clean vial. A short administration tubing set was
installed on an infusion bag, and 15 mL of the QdHCl
solution was transferred using a 20 mL syringe into
the bag. A 100 mL vesical instillation syringe was
lled with 15 mL of quinine solution and locked
with a special cap. Another 50 mL infusion bag was
completely emptied with a 50 mL syringe and the
remaining QdHCl solution in the 50 mL vial was
transferred with the help of a transfer-set into this
bag. Finally, all the materials were collected in seven
separate plastic bags (quinine vials, two infusion bags,
vesical instillation syringe, other operational syringes,
covering gloves, absorbent working pad and small
wipes used to avoid aerosolization during solution
retrieval from the vials).
The spots of the QdHCl solution on the working pad
were counted under UV light. The contamination on
the external surface of the objects was measured by the
previously developed quantitative method. The correl-
ation between rates of contamination (expressed in
Sadeghipour et al. 59
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cumulated quantities of contamination in mL) and the
operators years of experience was evaluated.
Results
Development and validation of the quantification
of the tracer
The LOD and the LOQ of the spectrouorimetric
method were determined at 0.008 mM and 0.025 mM,
corresponding to a contamination of 0.05 and 0.15 mL
of a 0.1 M solution of QdHCl, respectively.
The linearity was tested in the range of 0.11 mM.
The correlation coecients (r) obtained from the plot
of experimental values as a function of theoretical
values were always greater than 0.9985. It was observed
that the intercepts and the slopes were not signicantly
dierent from 0.00 and 1.00, respectively (Student t-
test, P<0.05). Thus, the method provided a linear
response without systematic errors (xed or relative).
Repeatability and reproducibility were calculated as
relative standard deviations (RSD): repeatability results
were in the range of 2.15.0% (0.1 mM) and 0.82.0%
(1.0 mM) and reproducibility results were in the range of
2.6% (0.1 mM) and 1.1% (1.0 mM) for the six replicate
determinations.
Development and validation of the recovery of the
tracer from the contaminated devices
For the immersion method, with a contamination of 1
or 5 mL of the 0.1 M solution diluted in 500 mL, the
nal concentration remained in the linearity limits vali-
dated previously. The recovery rates for each device are
presented in Table 1.
Development of the operators validation protocol
The rst tests were performed with nine operators in
simulated working conditions (fume hood). They con-
rmed the feasibility of the recovery method, while
giving a preliminary overview of the contamination
rate for each operator. Further, they also permitted
the improvement of the protocol for the validation of
the operators in the real conditions of a sterile BSC
class III.
The preliminary results for the rate of contamin-
ations extracted from the bags and the gloves (mL) as
well as the spots detected on the working pad are pre-
sented in Figure 1.
Operators validation protocol
The procedure was applied by 20 dierent operators
during 28 validation sessions. Some operators per-
formed twice the full procedure. For each session, the
total contamination rates measured on the surfaces of
the material and the number of spots left observed on
the working pad is presented in Figure 2.
The mean cumulated quantities of contamination at
the end of the whole procedure (duration: minimum
45 min, maximum 60 min) were 6.2 mL (0.623.8) and
>10 spots (020), which was considered as high.
No signicant correlation was observed between the
contamination rate (mL) and the operators experience
(years) (Figure 3).
Discussion
A simple method was developed to measure the rates of
contamination during the preparation of cytotoxics
using a novel tracer, which targeted the spillage
during the production process. It was observed that
the protocol was easy to implement in any facility
and was an important support to the quality assurance
of the operators training.
The results showed signicant contamination rates
with a large inter-individual variability, which con-
rmed the interest of the conducted experiment. In
most of the validation sessions (22/28), the contamin-
ation rates on the devices were less than the mean value.
However, for the spots, only seven of them could be
considered as clean (zero spot) and more than half had
a high contamination. In the real-life scenario, the
working pads were changed after each production ses-
sion (maximum of 1.5 h), according to the operating
procedures. There was no strong relationship between
the contaminant quantity collected on the surface of the
dierent devices and the number of spots detected on
the working pad, as shown in Figure 2. The number of
spots was high for one third of the operators having
Table 1. Recovery rates of the tracer from the contaminated
devices at low and high contamination levels.
Day
1 mL (n 6) 5 mL (n 6)
Recovery
(%)
RSD
(%)
Recovery
(%)
RSD
(%)
Infusion bags
1 96 2.0 97 1.3
2 107 2.3 99 2.3
3 101 6.2 100 4.9
Mean recovery (%) 101 99
Gloves
1 103 6.3 100 4.8
2 108 6.1 102 1.2
3 102 6.1 97 2.8
Mean recovery (%) 104 100
RSD: relative standard deviation.
60 Journal of Oncology Pharmacy Practice 19(1)
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0
.
6
0
.
6
0
.
7
1
.
1
1
.
2
1
.
7
1
.
7
1
.
8
2
.
0
2
.
3
2
.
83
.
3
4
.
2
4
.
3
4
.
5
4
.
7
4
.
7
5
.
0
5
.
2
5
.
3
5
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17
.
4
1
3
.
3
1
7
.
3
2
0
.
0
2
3
.
5
2
3
.
8
6
.
2
0.0
5.0
10.0
15.0
20.0
25.0
1 2 5 3 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
C
o
n
t
a
m
i
n
a
t
i
o
n

q
u
a
n
t
i
t
y

[

L
]
M
e
a
n

c
o
n
t
a
m
n
a
t
i
o
n
Validation Sessions
SPOTS
MEDIUM
LOW
ZERO
HIGH
SPOTS : Low : 1 -5 ; Medium : 6 -10 ; High : 11-20
Figure 2. Contamination rate of the operators for the validation sessions (20 different operators participated to these 28 validation
sessions).
0
.
4
4
.
0
5
.
4
7
.
9
0
.
0
0
.
0
0
.
0
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2
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4
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i
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a
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i
o
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u
a
n
t
i
t
y

[

L
]
Operators
SPOTS
LOW
ZERO
SPOTS : Low : 1 - 5 ; Medium : 6 - 10 ; High : 11-20
Figure 1. Preliminary results of the contamination rate of the operators for the validation development phase at low and high
contamination levels.
Sadeghipour et al. 61
by guest on May 18, 2014 opp.sagepub.com Downloaded from
low surfaces contamination. It showed that most of the
operators had to learn to manage the nal preparation
contamination and the working site contamination.
No signicant correlation was observed between the
years of experience of the operators and the contamin-
ation rate, even if all contamination quantities over
10 mL were related to the operators with 5 or less
years of experience (Figure 3). This suggested that spe-
cic individualized training is necessary to control
chemical contamination and that the working appro-
priateness is not automatically obtained after several
years of activity.
The present method in comparison to some of the
previous studies,
35,37,43
using tracers to set the general
scoring and validation of the sta, focused more on the
quantitative and detailed evaluation of their cleanli-
ness. The nal goal was to identify the more contam-
inating operators, review their training and through
comparison, decrease the mean contamination rate
over time. At rst glance, the results obtained could
be considered as an acceptable level of contamination.
However, according to the very strict 0.1 mL limit of the
Georgiadi et al. study, the results could be considered
to be extremely high.
35
As both conclusions remain
very subjective and as the protocols cannot be directly
compared, there is a diculty in interpreting the
observed contamination rates in terms of risk and
xing an acceptable limit. In the context of the Food
and Drug Administration specications for the estab-
lishment of cleaning validation methods, some limits
have been proposed by industry representatives.
44
These include analytical detection levels (10 PPM), bio-
logical activity levels (1/1000 of the normal therapeutic
dose), and organoleptic levels (no visible residue).
45
If
these limits are applied to the contamination levels of
the operators, the potential risk associated with the
mean value of 6.2 mL would depend on the pharmaco-
logical activity of the active ingredient of the prepared
cytotoxic drug.
For instance, for 5-uorouracil with a daily dose of
1000 mg, the acceptable 1/1000 limit corresponded to
1 mg or 20 mL of contamination for a usual 50 mg/mL
solution. For the tested operators, the contamination
was equal to ca. 0.031.2 mg. It should be noted that if
the measured contamination of a relatively low active
substance such as 5-uorouracil is acceptable for 90%
of the operators, then, for two operators, a new specic
training to learn cleaner working procedures and reval-
idation would be mandatory.
Conversely, with a highly active cytotoxic substance
such as vincristine with a daily dose of 2 mg, the accept-
able 1/1000 limit would correspond to 2 mg or 2 mL of
contamination for a usual 1 mg/mL solution. In the
present case, the contamination is below the acceptance
limit for only 8 of 28 sessions. Thus, the training of a
majority of the operators would have to be revised.
The two examples are helpful for evaluating
the limits of the acceptance criteria for the contamin-
ation levels. However, an absolute risk level for the
operators could not be clearly set up. Large-scale stu-
dies such as Monitoring-Eekt-Studie fu r Wischproben
in Apotheken (MEWIP
46
or monitoring-eect study for
wiping samples in pharmacies) are used for evaluating
the surface contamination of Carcinogenic, mutagenic,
toxic for reproduction (CMR) substances in pharma-
cies preparing cytotoxic injectable drugs in Germany.
25.0
20.0
15.0
10.0
5.0
0.0
0 2 4 6
Experience (Years)
C
o
n
t
a
m
i
n
a
n
t

Q
u
a
n
t
i
t
y

(
m
L
)
y = 0.3727x + 8.1294
R
2
= 0.0488
8 10 12 14
Figure 3. Correlation between years of experience and contamination rate of the operators.
62 Journal of Oncology Pharmacy Practice 19(1)
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These help to establish the average limits and the
statistical milestones by benchmarking. This is an inter-
esting approach that can be applied to the present pro-
cedure when a larger number of results will be
accumulated.
The present validation protocol oers an eective
answer for the important issue of chemical security of
the operators by following the well-known schemes of
media-ll tests for microbiological contamination.
Thus, the implementation of such validation protocols
in other hospital pharmacies preparing cytotoxic inject-
able drugs parallel to the mandatory media-ll valid-
ation tests for operators would help to standardize the
preparation methods. Further, it would also help to
decrease the contamination levels through the improve-
ment of the operating procedures, not only from a
microbiological point of view but also regarding the
hazardous drugs contamination.
This protocol can also be used to check the appro-
priateness of the devices used for preparing the inject-
able cytotoxic drugs. Further, it can be used to easily
evaluate whether some of these devices could be con-
sidered as a closed-system, as regard the chemical
contamination.
The present study does not set any objective limit for
the acceptable level of contamination. Thus, the ana-
lysis of these results cannot be directly correlated to the
risks for the operators health. However, they provide
rather a quantitative indicator for the contamination
level and a tool available to conduct education pro-
grams, in a continuing improvement spirit. In our set-
ting, we considered that any operator having a
contamination level above the mean level is a candidate
for a new training program.
Conclusion
QdHcl solution, as a simulating working solution, is
an ideal tracer for testing the contamination during
the preparation of cytotoxic injectable drugs. As
a non-hazardous marker, it is easy to detect using a
sensitive method. Further, it is also invisible to the
naked eye.
The present validation method helps in testing all
operators at least once per year. The obtained results
show how the hospital pharmacy sta has successfully
or not mastered the control of the chemical contam-
ination. Every new operator should also be tested after
the initial training to verify the ability to prepare cyto-
toxic drugs in a safe and professional manner.
In future, applying this protocol to other hospitals
could facilitate better evaluation of the mean contam-
ination level. In addition, this benchmarking could also
permit the standardization and improvement of the
operating procedures to decrease the chemical
contamination of the nal preparation and the produc-
tion sites.
Funding
This research received no specic grant from any funding
agency in the public, commercial, or not-for-prot sectors.
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