Beruflich Dokumente
Kultur Dokumente
1093/intqhc/mzn052
Advance Access Publication: 10 December 2008
Abstract
Address reprint requests to: Nicolas Martelli, Department of Pharmacy, Hopital Européen Georges Pompidou, 20 rue
Leblanc, Paris, France. Tel: þ33-156-093-244; Fax: þ33-156-093-247; E-mail: ph.upio@egp.aphp.fr
preparation of anti-cancer drugs. The HACCP method is a of the cancer chemotherapy process to which the HACCP
systematic method for the identification, assessment and concept was applied. The HACCP team checked and
control of safety hazards. Historically, the HACCP program evaluated the whole process according to seven principles:
has been considered as a food safety management system, (i) analysis and identification of potential risks (hazard analy-
but its use has been successfully applied to medical products sis); (ii) identification of critical control points; (iii) definition
[15, 16]. The risk analysis, following the guidelines of the of limits (target levels and critical limits); (iv) in-process
HACCP method and the monitoring of critical steps during control (critical control points monitoring); (v) the establish-
the process, was applied to the preparation of anti-cancer ment of corrective measures; (vi) the confirmation system
drugs [17, 18]. Our analysis led us to establish a preventive (HACCP system verification); (v) the documentation system
monitoring system based on an effective concept for quality ( procedures and records).
assurance. The experience of this HACCP application is The application of these aspects was partly facilitated by a
described in this study. computerized program (HACCP Expressw, Version 2000)
developed by Controls, Studies and Formation for Food
Quality Improvementw (CEFAQ w, Barcelonne du Gers,
Methods France, 2000) [19]. This program helped us to summarize
and analyse all the collected data. This work was performed
Setting and study period in compliance with the ISO 9000:2000 standard.
The HACCP team listed all of the critical points that
45
Bonan et al.
Non-conformities monitoring
Each non-conformity was systematically collected during the
production process. This follow-up was used to assess the
HACCP program and to submit specific corrective actions
for each critical control point. At the chemotherapy com-
pounding unit, non-conformities were collected by pharma-
cists and pharmacy technicians and reported in a follow-up
document over 10 months. Each page of this report form
was divided into four parts: the name of the event reporter,
a description of the non-conformity detected, the step of the
process which was concerned and the corrective action
undertaken. To help the reporter, a complete list of possible
events (for each step of the process) was included in the
document. If the event was not mentioned in the list, the
reporter could explain it briefly as a free comment.
Description of the product Figure 1 Flow chart of the anti-cancer drug preparation
The HACCP team defined the product as an individual process.
sterile anti-cancer drug preparation. Moreover, this medical
product can be delivered in a container, syringe or an critical point consists of checking protocol reference
infusor. The product is cytotoxic and sterile. Consequently, documents and the patient medical file. The pharmacist calls
precautions are required to protect pharmacy technicians the oncologist to modify the prescription as a corrective action.
during the handling and preparation process. Computerized prescription system errors. To control this point,
the pharmacist must calculate the dose required on his or
her own and check the prescription’s consistency with the
Critical control points analysis and corrective
chemotherapy protocol. If a system error occurred (like a
actions
bug), only the software editor can fix the problem.
Among the 11 steps, we identified 11 critical control points Drug storeroom temperature conditions. The temperature of the
of higher importance (39 overall) with a calculated risk index drug storeroom was measured daily. During the study period
above 50. The critical control points and their risk indices (226 days), 193 (85%) temperature reports were higher than
are detailed in Table 2. From October 2004 to August 2005, the warning level (temperature between 158C and 188C or
16 647 preparations were made up by the chemotherapy 228C and 258C) and 33 (25%) reached the action level
compounding unit for 1335 patients. During the same (temperature up to 258C or down 158C).
period, pharmacists and pharmacy technicians reported 1225 Compounding sheet errors. A wrong batch number (drugs,
non-conformities in the follow-up document. In the present containers or infusors) may be reported on the
study, we described only the non-conformities of the 11 criti- compounding sheet. This type of error was considered as a
cal control points of higher importance, which represented non-conformity and should be closely and systematically
94% (1157 non-conformities) of the total non-conformities monitored by the pharmacy technician. Among 11 866
reported. The number of non-conformities for each critical compounding sheets considered, there were 693 non-
control point is shown in Table 3. conformities (5.84%) reported. To reduce these errors, the
Prescription errors. Pharmacists validated 8511 prescriptions use of an intermediate storage system within the
over this period. The most frequent error was the choice of a compounding room with a unique batch number for each
wrong protocol by the oncologist. The monitoring of this product was established.
46
The HACCP method in the preparation of anti-cancer drugs
............................................................................................................................................................................................................................................
Total
Commercial product defects. Before use, commercial products
50
50
50
50
50
50
50
50
125
100
100
(drugs or containers) were systematically checked. For
example, particles or crystals inside drug solutions (due to
Severity inappropriate storage conditions) can be identified. As a
corrective action, the pharmacy technician must put the
10
10
10
10
10
10
10
10
5
5
5
product in quarantine and inform the physicochemical
control laboratory that a thorough analysis should be
Occurrence
performed.
Microbial contamination. Microbial contamination rates were
evaluated twice a month on both positive pressure isolators
5
1
5
5
1
5
1
1
1
10
10
5
1
1
1
5
5
10
10
Analytical non-conformities
the range.
Critical control points
1
2
4
16
25
26
28
30
35
36
37
Discussion
Physicochemical control
Material preparation
Delivery
10
11
3
5
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Bonan et al.
Table 3 Number of nonconformities detected for the 11 critical control points of higher importance identified by the
HACCP team
delivery and is a waste of time for health workers (especially However, informing pharmacy technicians of the importance
for pharmacy technicians and nurses) and patients. Finally, of wearing nitrile gloves at all times inside the compounding
destroyed preparations are lost and are economically unac- room and of the importance of changing their nitrile gloves
ceptable. With the HACCP method, non-conformities are every 30 min should represent an alternative solution to
detected by in-process monitoring and are corrected with contain this hazard [25 – 27]. On the other hand, no correc-
defined actions. This approach has underscored the strong tive action appears to be adequate for needle-stick injuries.
points and weaknesses of our cancer chemotherapy process. The use of needle-free medical devices could be a preventive
Many critical control points have been highlighted thanks to action to protect handlers and reduce the risk of exposure to
the HACCP team’s efforts. The risk index calculation helped anti-cancer drugs [28]. Thereafter, this risk could be avoided
to identify the most important critical points and to establish definitively. To reduce prescription errors and provide for
our priorities in terms of risk management. better working conditions, we decided to reorganize prescrip-
Nevertheless, the HACCP method did not always provide tion planning in close cooperation with the oncologists [29].
solutions to all of the issues raised, and may even hide some As far as possible, oncologists prescribe cancer chemothera-
issues. For example, ‘microbial contamination of the com- pies several days before the patient’s arrival. Depending on
pounding room’ did not obtain a high-risk index (.50), the anti-cancer drug’s stability, we prepared and stored the
while ‘microbial contamination of the positive pressure isola- preparations until the prescriber dispensing order was
tor’ did. However, the microbial contamination of the com- received. These early prescriptions allowed us to regulate the
pounding room should be taken into account because of its activity and improve handling conditions. The prescription
potential impact on the isolator sterility. This item is a good validation by the pharmacist also takes place earlier, which
indicator of the area’s hygiene quality. It also gives infor- improves the detection of prescription errors. Finally, some
mation about hand hygiene practices of pharmacy technicians corrective actions defined in our process may not be appli-
who carry out manufacturing in the positive pressure isolator. cable for use in other hospitals. For example, the intermedi-
We can also consider another issue highlighted by the ate storage system in the compounding room with a unique
HACCP, such as the monitoring of the drug storeroom batch number for each product implies a significant daily
temperature. This monitoring showed that 85% of tempera- production and the systematic control of the products
ture reports were higher than the warning level. The main ordered.
explanation is that most of these reports were performed The HACCP is a precise method that highlights issues
during the hot season. Moreover, the temperature range and explains a complex process in detail. This method is
defined for the warning level was inadequate and was recon- helpful for focusing on the production steps, which may
sidered. The high temperature range for the warning level have a critical influence on the quality of the product. With
was modified to 24 – 258C. the HACCP method, we can concentrate our limited
Among the 11 critical points of greater importance resources on the identified critical points. Finally, the hazard
described, we did not draw up corrective actions or monitor- analysis also provides a revision of the documented data
ing for some of them. Chemical contamination hazards such as standard operating procedures, production and
cannot be monitored for the time being in our department. check-up protocols.
48
The HACCP method in the preparation of anti-cancer drugs
On the other hand, the HACCP method is extremely 9. Descoutures JM. Preparation of antineoplastic agents (in
demanding on time and human resources. This point rep- French). Ann Pharm Fr 2006;64:7 –16.
resents the major limitation of the method. Risk indexes 10. Cazin JL, Gosselin P. Implementing a multiple-isolator unit for
were obtained based on the experience of HACCP team centralized preparation of cytotoxic drugs in a cancer center
members and hindsight of the cancer chemotherapy process. pharmacy. Pharm World Sci 1999;21:177–83.
The criticality of the different points may not be relevant and
11. Mason HJ, Blair S, Sams C et al. Exposure to antineoplastic
can be open to discussion. Scores for the different critical drugs in two UK hospital pharmacy units. Ann Occup Hyg
control points were calculated on the basis of explicit and 2005;49:603 –10.
objective criteria insofar as possible.
In conclusion, the present study demonstrates the interest 12. ASHP. Guidelines on Handling Hazardous Drugs. Am J Health
Syst Pharm 2006;63:1172 –91.
of the application of the HACCP method in the preparation
of anti-cancer drugs. The efficiency of the HACCP method 13. Good Manufacturing Practices (in French). Agence Française de
is relevant when this method is used to target a specific Sécurité Sanitaire et des Produits de Santé 2000.
process. Critical points were identified and led to improve- 14. Good Preparations Practices (in French). Agence Française de
ment of our process. Following the implementation of the Sécurité Sanitaire et des Produits de Santé 2007.
corrective actions, a reassessment of our process is planned
15. Jahnke M, Kuhn KD. Use of the hazard analysis and critical
in view of the future certification of our unit.
control points (HACCP) risk assessment on a medical device
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Bonan et al.
28. Maragakis LL, Bradley KL, Song X et al. Increased catheter- 29. Slama C, Jerome J, Jacquot C et al. Prescription errors with
related bloodstream infection rates after the introduction of a cytotoxic drugs and the inadequacy of existing classifications.
new mechanical valve intravenous access port. Infect Control Pharm World Sci 2005;27:339 –43.
Hosp Epidemiol 2006;27:67 –70.
Accepted for publication 30 October 2008
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