Transcript Slide 1

So you thought they were
clean enough?...
Harpreet Kaur
Introduction
 The extensive use of cytotoxic drugs in the treatment
of cancer patients represents a health risk for all staff
involved in the preparation and handling of such
drugs.
 This qualifies as an occupational health hazard and
the two groups with the highest levels of exposure
are pharmacists who dispense these drugs and
nursing staff who administer them [1]. Equally other
staff involved in their compounding, as well as
logistical and training personnel are likely to be
exposed.
Introduction
 According to the ISOPP Standards of Practice [7],
manufacturers are obliged to provide cytotoxics in
containers guaranteed to be free from contamination.
Further, manufacturers should be able to provide
certification that the vials and primary packaging are not
contaminated with cytotoxics.
 While there are no thresholds on the permissible levels of
contamination on the surface of vials and primary
packaging [1], the ISOPP guidelines recommend that the
purchase of such drugs should preferentially be from
manufacturers who can verify the absence of such
contamination [7].
Background: So why the concern?

-
NIOSH Definition of Hazardous Drugs:
Carcinogenicity
Teratogenicity or other developmental toxicity
Reproductive toxicity
Organ toxicity at low doses
Genotoxicity
Structure and toxicity that mimic existing hazardous drugs
(NIOSH, 2004)
 Although increased incidence of cancers for occupationally
exposed groups has been investigated with varying results, a
formal risk assessment of occupationally exposed pharmacy
workers by Sessink et al. [8] estimated that
cyclophosphamide causes an additional 1.4 to 10 cases of
cancer per million workers per year [2].
Background: Contamination of vials a
real risk
 Several studies [2,3,4,5] have shown that the cytotoxic drug
vial itself can be a source of such exposure as residues of
the drug may remain on the outer surface of the vial during
the filling process during manufacture [6].
 Favier et al.: External Contamination of Vials
-Vials of 5-FU, Etoposide, Ifosfamide, Cyclophosphamide,
Doxorubicin, Docetaxel
-100% had contamination on outer surfaces
-Contamination/vial ranged 0.5-2500ng
-Differences between manufacturers
(Favier et al: J Oncol Pharm Pract (2003); 9:15-20)
Background
 Since the 1970s there have been worldwide attempts to
prevent exposure of healthcare workers
 Measures include [1]:
-centralisation of cytotoxic drug preparation in hospital
pharmacies
- provision of equipment and clothing for personal
protection
-development of specific guidelines and protective
measures
-training development for safe handling of cytotoxic drugs
-establishment of continuous monitoring of workers’ health
and safety to ensure that correct handling, treatment,
storage, and disposal procedures are being followed
Background: So how should vials be
cleaned?
 Decontamination may be defined as cleaning or
deactivating.
 Deactivating a hazardous substance is preferred but no
single process has been found to deactivate all currently
available hazardous drugs.
 The MSDSes for many hazardous drugs recommend
sodium hypochlorite solution as an appropriate
deactivating agent [2].
Question: So what other deactivating agents may be used?
Cleaning Effectiveness: No. Wipes to
Remove Drug (<LOD)
Test
detergent
5-FU
(WFI)
5-FU
(N/S)
CP
(WFI)
CP
(N/S)
DOX
(WFI)
DOX
(N/S)
WFI
1
3
1
1
1
1
Criti-Klenz
1
1
1
1
2
2
CIP 150
1
1
1
1
3
3
CIP 100
1
1
1
1
2
2
RenuKlenz
1
1
1
1
1
1
NpH-Klenz 1
1
1
1
1
1
CageKlenz
1
1
1
1
1
1
CIP 220
1
1
1
1
1
1
CIP 200
1
1
1
1
1
1
IMS
1
1
1
1
1
1
Hazardous Medicines: Current Issue and Future Challenges (Graham Sewell, Professor of Clinical Pharmacy,
Kingston University).
Cleaning Effectiveness of other agents






Criti-Klenz- Alkaline liquid detergent
CIP 150, 100- Phosphate-free alkaline detergents
Renu-Klenz, NpH Klenz- pH neutral detergents
Cage-Klenz- Acid-based detergent
CIP 220, 200- Hydroxyacetic acid based detergents
IMS- 70% alcohol
-Water has relatively good efficacy
-However, the most effective are the neutral, acid-based and
hydroxyacetic acid-based detergents, and 70% alcohol.
Purpose of this study?
 Exposure to cytotoxic drugs= Health Hazard
 Contamination of vials = Real Risk
 So what is our risk of exposure to these drugs?
 Ideal method would be to swab outside of vials
and determine the level of contamination- not
feasible
 So we set out to obtain information from the
various manufacturers on the procedures that
they had in place…
Aims of the study
1. To identify all the injectable cytotoxic drugs
used in ROHP and their alternative brands
licensed for use in the Irish market, and the
manufacturers.
2. To compare drug brands and their
manufacturing companies on their outer vial
decontamination procedures on the basis of the
information provided.
3. To rate the manufacturing companies on their
decontamination procedures using an in-house
rating system.
Methods
 1. All the injectable cytotoxic drugs used in ROHP and
their manufacturers were identified and data entered into
a Microsoft Excel® spreadsheet.
 2. The generic drug name was used to search for other
manufacturers in Ireland of the same drug on the Irish
Medicines Board website. This was used to establish the
various brands available of the drugs used in ROHP, and
their manufacturers.
 3. Manufacturing companies were then contacted via
email/ telephone, and information on outer vial
decontamination procedures of the drugs of interest
requested. Reminders were sent, where necessary.
 4. The information provided was then evaluated
Results: A comparison of the brands
of injectable cytotoxics and their
manufacturers






Total number of injectable cytotoxics
used in ROHP= 23; current
manufacturers= 15
Total number of alternative brands for
23 drugs= 39; new manufacturers
identified = 2
76.5% of the total number of
manufacturers had a decontamination
procedure in place
61.5% of these manufacturers had
validated the procedure
The identification of a LOD was seen
to be the least complied with measure
and was performed by only 2
manufacturers for a total of 5 out of the
62 brands of interest
Therefore, despite having a validated
procedure in place, most
manufacturers could not guarantee
that their vials were free from
contamination (and below a predetermined LOD)
Criterion
Drug
brands
(n=62)
Manufactu
rers
(n=17)
Decontamin
ation
procedure
57
13
Procedure
validated
41
8
Physical
barrier on
vial
(e.g.
Oncotain®)
30
5
Limit of
detection
5
2
Table 1. In-house criterion as applied to drug
brands and their manufacturers
Results: A comparison of the brands of
injectable cytotoxics and their manufacturers
Number
60
50
40
Drug brands (n=62)
30
20
Companies (n=17)
Limit of
detection
identified
Physical barrier
on vial
Decontamination
procedure
validated
Decontamination
procedure in
place
10
0
Figure 1. Overview of external vial decontamination
•The decontamination procedure common to all manufacturers, who observed such a
procedure, was the rinsing of the outside of the vials with purified water followed by their blowdrying with compressed air (Water has been shown to be an effective agent- Slide 9).
•HPLC was the validation procedure of choice
•Some manufacturers also used spiked vials in worst case scenarios to further evaluate their
decontamination procedures
Results: In-house rating system as
applied to manufacturers
Rating
Decontt pro
Pro
validated
Phy barrier
on vial
Limit of
detection
*1
No
No
No
No
2
Yes
No
No
No
3
Yes
No
Yes
No
4
Yes
Yes
No
No
5
Yes
Yes
Yes
No
6
Yes
Yes
No
Yes
7
Yes
Yes
Yes
Yes
Table 2: Criteria used in rating manufacturers
*Companies that did not provide the requested information were also placed in this category.
Results: In-house rating system as
applied to manufacturers
 The order of preference employed in the rating system : Decontamination
pro> Pro validated >Limit of detection > Physical barrier on vial
 ‘Physical barrier on vial’ was placed last in the order of preference because
in the information provided by manufacturers there was nothing to suggest
that this was done in surroundings distinct from the manufacturing area.
Consequently, there may be contamination present on the outside of the
barrier itself.
Companies
5
4
3
2
1
0
1
2
3
4
5
6
7
Rating
Figure 1. Manufacturers’ performance as per the rating system
Results: So how did the manufacturers
compare?
Rating level
Nos.
Names
1
4
Schering Plough, Asta Medica,
Genzyme, Celgene
2
2
Medac, Pfizer
3
3
Teva, Pharmachemie BV, Eli Lilly
4
4
Baxter, Ebewe, Fresenius Kabi,
GSK
5
2
Hospira, Actavis
6
2
Sanofi Aventis, Pierre Fabre
7
1
Accord
Conclusions



Several studies have shown that external vial
contamination is a cause for concern for healthcare
staff involved both directly and indirectly with cytotoxic
drugs.
The results from this study suggest that the majority of
manufacturers (76.5%) had a procedure in place to
ensure that their cytotoxic drug vials were free from
contamination and 61.5% of these manufacturers had
their procedure validated. However, none of the
manufacturers were able to meet all the criteria of our
study.
38.9% of manufacturers were not able to provide any
form of certification to guarantee that the vials
underwent decontamination procedures before they
left the manufacturing site.
Conclusions
 The trends of compliance with our in-house criteria were
proportional across the various drug brands and their
manufacturers, with the specification of a limit of
detection being the least complied with requirement
suggesting the lack of quantification of any possible
contamination. This implies that most manufacturers
cannot guarantee absence of contamination.
 While internationally recognised guidelines such as
ISOPP provide the necessary framework, there is a need
for strict legislative measures that ensure that all vials of
cytotoxic drugs are free from external vial contamination
before leaving the manufacturing site, and that
manufacturers demonstrate full compliance with such a
requirement.
References
1.
2.
3.
4.
5.
6.
7.
8.
Preventing occupational exposures to cytotoxic drugs in hospital
pharmacies. EJHP Practice 2010/3; 16: 26-29
Sessink PJM, Boer KA, Scheefhals APH, et al. Occupational exposure to
antineoplastic agents at several departments in a hospital: Environmental
contamination and excretion of cyclophosphamide and ifosamide in urine
of exposed workers. Int Arch Occup Envron Health. 1992; 64: 105-12
Kiffmeyer TK, Ing KG, Schoppe G. External contamination of cytotoxic
drug packing: Safe handling and cleaning procedures. J Onc Pharm
Practice. 2000; 6: 13.
Connor TH, Sessink PJM, Harrison BR, et al. External contamination on
chemotherapy drug vials: defining the problem and evaluation of new
cleaning techniques. Am J Health Syst Pharm 2005; 62: 475-84
Favier B, Gilles L, Ardiet C, et al. External contamination of vials
containing cytotoxic agents supplied by pharmaceutical manufacturers. J
Oncol Pharm Pract 2003; 9: 15-20
ASHP Guidelines on Handling Hazardous Drugs, November 2005
ISOPP Standards of Practice: Safe Handling of cytotoxics. J Oncol
Pharm Pract 2007(supplement); 13: 1-81
Sessink PJM, Kroese ED, van Kranen HJ, et al. Cancer risk assesssment
for health care workers occupationally exposed to cyclophosphamide. Int
Arch Occup Environ Health. 1995; 67: 317-23.