In 2004, the US National Institute for Occupational Safety and Health declared that closed systems are vital in handling cytotoxics. But are the systems currently on the market as safe as can be reasonably achieved?
Yaakov Cass
MSc FRPharmS
Regional Pharmaceutical Officer, Israel Ministry of Health, Ramle, Israel
This article was authored in a private capacity, and should not be interpreted as reflecting the official position of the Israel Ministry of Health.
Much has been written concerning the safe handling of cytotoxic drugs (chemotherapy) and its history.[1-4] It is instructive to review this history in order to learn from our mistakes, correct them and proceed to a safer future.
When chemotherapy drugs became part of the physician’s armamentarium in the 1950s and ’60s, the accepted practice was for nurses to prepare chemotherapy doses on the wards. For decades most healthcare workers were oblivious to the risks posed to them by chemotherapeutic agents.
There is no way to estimate how much harm has been caused through careless handling. A case of leukaemia diagnosed in a nurse or pharmacist today might be the product of workplace exposures in the ’70s or ’80s. Indeed, in many instances, the connection between unsafe handling of chemotherapy and oncological disease later in life has never been made.[5]
In the mid-’70s chemotherapy drugs were shown to be mutagenic, carcinogenic and teratogenic.[4-7] When the nursing fraternity became aware of the possible dangers of handling chemotherapy, they declined to reconstitute these drugs.
Hospital managers, thinking logically, requested pharmacists – experts in drug handling – to take on the role. Thus, in the mid-’70s, preparation of cytotoxics relocated from the wards to specialised, pharmacy-managed units. Large budgetary allocations were provided by hospital managers to equip these new units appropriately.[8-10]
Preparing chemotherapy seemed ideally suited to pharmacists, enabling them to use both their compounding skills and knowledge of aseptic techniques. In retrospect, it would appear that they had underestimated the risks involved. Cytotoxics were reputed to be dangerous, but mutagenicity, teratogenicity and carcinogenicity were invisible.
Lack of sensitive and reliable methods for monitoring exposure, degree of absorption and early biological effect made it difficult to establish safe levels of any possible exposure. Pharmacists were convinced that hazardous drug exposure could be minimised, or even eliminated, with good handling practice and appropriate protective measures. Safe handling precautions were based on the ALARA principle, an unscientific formula: As Low As Reasonably Achievable.
In order to protect both the environment and those working in these pharmacy units, measures based on the established hierarchy in the setting of standards for industrial hygiene were put into place. Various new pieces of equipment were brought into practice. This included items such as luer lock needles, gloves, gowns and “cytotoxic-safe” needles and spikes.
The most basic and familiar piece of equipment was the vertical laminar flow hood (VLFH). Preparation itself took place in the VFLHs, usually located in a conventional cleanroom.[2-5,8-10] The objective was to “guarantee” 100% protection for all concerned. For many years, the prevailing point of view was that the product and the handler were uncompromisingly protected, with little or no room for improvement!
This supposition was clearly disproved when, many years after the reconstitution of cytotoxics was transferred to the jurisdiction of the pharmacy department, reports were received of environmental exposure from cytotoxic drugs in hospitals. Researchers using wipe samples detected cytotoxics inside and outside biological safety cabinets, workstations and at points distant from the pharmacy.[11]
Despite strict safety standards, widespread contamination was found in hospital pharmacies, IV admixture facilities, nursing stations and patient care areas in hospitals across Europe. Wipe samples from about 30 US hospitals indicated that drug handling in over two-thirds of them was unsatisfactory and that employee exposures were greater than those found in Europe.[11-14]
This research led the US National Institute for Occupational Safety and Health (NIOSH) to issue an alert in 2004.[15] They warned healthcare providers that “antineoplastics still pose a workplace hazard.” They described current measures to prevent environmental contamination and employee exposure to cytotoxics as “inadequate”.
NIOSH recommended the use of “closed system” protective devices for transferring from primary packaging – such as vials – to dosing equipment (ie, infusion bags, bottles or pumps) and for other drug transfers within the pharmacy.[16] It is now clear that the use of closed systems is just as important in the administration of chemotherapy on the wards.
While there is no argument that these systems make handling of cytotoxics safer, there has been a great deal of discussion as to how to define a closed system.
[[HPE39.63]]
There is a clear need to differentiate between a closed system in the context of microbiological contamination and in the context of chemical and occupational exposure. The International Society of Oncology Pharmacy Practitioners (ISOPP) guidelines consider the NIOSH definition as the most comprehensive and satisfactory for this purpose. NIOSH defines a “closed system” as “a drug transfer device which mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapour concentrations outside the system.”[18]
Currently there are four commercially available systems suitable for the safe handling of cytotoxic agents, and all of them claim some level of approval from the US Food and Drug Administration (FDA). Each significantly differs, however, in the manner in which it attempts to contain cytotoxics. See Tables 1-4 for manufacturers’ information on these systems.
Whilst all of these systems claim high efficacy in containment of cytotoxic contamination, the majority of them do not adhere to the aforementioned definition of a closed system. One of the problems currently facing hospital pharmacists is how to choose an appropriate system. The situation is complicated by the fact that NIOSH gives no performance standard or test system for
this type of device. The ASHP guidelines issued in 2005 do demand efficacy testing, but, again, do not specify how.[18] A uniform test system with a performance standard applicable to all the closed-system transfer devices is imperative. This testing should be conducted in clinical settings, evaluating all of the available devices, in comparable settings, for an equal length of time. This will provide the only valid method of comparison between devices, allowing confounding factors, such as ease
of use, worker acceptability, handling expertise and economic factors, to be accounted for.
Pharmacists rely on published, peer-reviewed, scientific data measuring contamination levels, but this is not always available. Thus far, only one of the manufacturers of closed systems has evaluated surface contamination and worker urine contamination.[14,19,20] Results of testing single devices in a noncomparative way may even be biased against the device undergoing evaluation, because of other causes of environmental contamination, such as spillage. Clearly, newer devices are disadvantaged, given that they are unable to provide
conclusive safety data information until their device has been in clinical use for a length of time.
Commissioned laboratory studies, while preferable to no studies, do not allow clinical interpretation by the average oncology pharmacy practitioner, who must make safety decisions for themselves or for their staff.[21,22]
Conclusion
The ALARA principle has outlived its usefulness. Improved technology now enables us to measure contamination levels. Priority should be given to a definition and mandate for “safe” levels of contamination in the environment, on work surfaces and for healthcare providers.
The drug companies should be strongly encouraged to participate and should assist in financing this project.
With a standard in hand, we can then work towards monitoring and limiting exposure levels of individual workers handling cytotoxic drugs. Mandatory use of closed systems must be part of such a programme.
Despite the evidence that open-transfer systems in laminar flow hoods have failed to protect both the environment and the worker, there are still hospitals failing to provide a budget for closed systems. It must be made clear to hospital managers that this situation is now unacceptable.
References
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