At an ASHP 2007 seminar sponsored by Carmel Pharma, speakers described how to achieve leakproof containment of hazardous drugs and estimate levels of risk to personnel.
Cancer chemotherapy presents a clear hazard for healthcare workers and safety precautions based on sound medical evidence should be established in the workplace, according to James Jorgenson, administrative director for pharmacy services and associate dean for pharmacy, University of Utah, Salt Lake City, Utah, USA.
Hazardous drugs are defined as those which cause carcinogenesis, teratogenesis, reproductive toxicity, genotoxicity or specific organ toxicity at low doses. Cancer patients typically receive high doses of a limited number of drugs for a short period of time, whereas healthcare workers can be exposed to low doses of multiple drugs over long periods, he explained. Published studies show that long-term exposure is linked to reproductive problems including spontaneous abortions, infertility and premature labour. Teratogenic effects can also occur, with the risk being greatest during the first trimester of pregnancy. Cancer treatments can themselves cause cancer and a number of chemotherapeutic agents are classified as human carcinogens by the International Agency for Research on Cancer (IARC; see Resources). Genotoxic effects have been reported in both patients and healthcare workers. Once again, duration of exposure appears to be the most significant factor, Mr Jorgenson noted.
Closed system transfer devices
Reducing the sources of exposure to cytotoxic agents is a critical part of any safety protocol. No fewer than 27 studies have described surface contamination with cytotoxic agents and contaminated areas have included biological safety cabinets, floors, computer keyboards, gloves, patients’ tables and waste containers, Susan Spivey, pharmacy manager, Ambulatory Treatment Center, University of Texas MD Anderson Cancer Center, Houston, Texas, USA, told the audience. Importantly, contamination was often detected in adjacent areas where cytotoxic drugs were not being handled.
A study designed to demonstrate the source of contamination to pharmacy technicians mimicked the processes of reconstitution, transfer, administration and disconnection. Fluorescein solution was used in place of active drugs and conventional needles and syringes were compared with the PhaSeal closed system. When inspected under UV light significant leakage was evident with the conventional system, whereas there was no leakage with the PhaSeal system, Dr Spivey said.
The PhaSeal system incorporates two features that ensure containment of the drug during preparation and administration. These are:
- Double membranes at each connection that prevent leakage of the drug into the environment.
- An expansion chamber that is permanently fixed to the drug vial. This neutralises the under- and overpressures that occur during reconstitution and aspiration of the drug. Under- and overpressures can cause the release of drug aerosols when traditional syringe and needle techniques are employed.
A later study had examined the effectiveness of a number of reconstitution devices for containing vapours during the reconstitution process. Titanium tetrachloride, which forms white smoke on contact with moist air, was used to simulate cytotoxic vapours. The PhaSeal device was the only one of five tested that prevented the formation of titanium smoke outside the transfer device. The authors concluded that it was the only device that met the definition of a closed-system transfer device (CSTD) laid down by the US National Institute for Occupational Safety and Health. The results were further reinforced by a recent study in which four transfer devices were tested to determine whether they were leakproof. Closed system transfer devices are now required to be leakproof and airtight in addition to the previous requirements, Dr Spivey explained (see Box 1). On this occasion an acidic solution was used as a substitute for active drug and blue litmus paper was used to test for leaks. The devices tested were the ICU Medical Clave® and SpirosTM connections, the B Braun/TevadaptorTM system, the Cardinal Health/Alaris system and the PhaSeal® system. The test procedure was designed to simulate both the reconstitution and administration stages. Leakage occurred with all but the PhaSeal system.
If a transfer device uses a filter to equalise air pressure, then it is not a closed system, Dr Spivey pointed out. Pharmacists should ensure that they select products that meet the NIOSH definition of a closed system drug transfer device and should ask for independent studies to validate products, she recommended.
Contamination sources
When handling cytotoxic drugs there are several sources of contamination and potential exposure, explained Paul Sessink, managing director, Exposure Control BV, Wijchen, Netherlands. Apart from spillage or leakage during preparation and administration there can be contamination of the external surfaces of vials when they come from the manufacturer, and the isolator or biological safety cabinet can be contaminated from previous spillages. Studies have shown that routine cleansing of working areas with alcohol alone is not sufficient to remove all traces of cytotoxic drugs. Other possible sources include the patient (urine, sweat, vomit, and so on), pharmaceutical waste and laundry. Gloves worn during the preparation of cytotoxic drugs commonly become contaminated and everything that is subsequently touched also becomes contaminated, said Dr Sessink.
A study involving 22 US hospital pharmacies compared the levels of environmental contamination with cyclophosphamide when standard preparation techniques were employed and when the PhaSeal system was used. The results showed significantly lower levels of environmental contamination when the latter system was used. Cyclophosphamide levels of more than 100 ng/cm2 were recorded when standard techniques were used, Dr Sessink noted. Closed handling really does help to reduce contamination, he added.
A study of pharmacy technicians and nurses in the Netherlands had shown that the technicians involved in preparing cytotoxic injections had low exposure (average daily urinary output of cyclophosphamide: 0.18 μg) whereas the nurses involved in administration of cytotoxic drugs had moderately high exposure (average daily urinary output of cyclophosphamide: 0.80 μg).
It is estimated that these levels of exposure could lead to 1.4–10 extra cancer cases per year for technicians and 10–50 extra cancer cases per year for nurses.
Cytotoxic risk chart
Dr Sessink has designed a chart that links the information about contamination and exposure to cyclophosphamide with the risk of developing cancer. This chart enables pharmacy managers and staff to translate measurements of cyclophosphamide contamination and exposure into risk levels – terms that are understood by risk managers and hospital chief executives. It also shows when action should be taken and what monitoring is required.
The chart utilises four levels, which are colour-coded for ease of use. The minimum acceptable level is green and requires no action; low (yellow), medium (orange) and high (red) levels of contamination all require action to reduce risks to personnel. A “red” risk level requires immediate cessation of work. The level of environmental contamination is measured using wipe samples of the working areas and the level of worker exposure is measured using urine levels of cyclophosphamide. Values are compared with the ranges on the chart and the risk level determined.
The target for everyone should be the “green” minimum risk level, Dr Sessink explained. At this level, one extra cancer case per million workers per year can be expected. The high-risk (red) level is calculated to cause 100 extra cases of cancer per million workers per year. According to this scheme, the nurses in the study described above were in the orange risk category – equivalent to 10–50 extra cases of cancer per million workers per year.
“We know that many hospitals in the USA, Japan and Europe are currently in the red or orange risk categories,” Dr Sessink explained.
Practical implementation
Firouzan Massoomi, pharmacy operations coordinator, Nebraska Methodist Hospital, Omaha, Nebraska, USA, described the practical considerations that are important in implementing safe handling of hazardous drugs. In his pharmacy some 10,000 doses of hazardous drugs are prepared each year.
It is important not to forget the people who receive and dispose of drugs when designing working systems, he reminded the audience. Another critical element is regular medical surveillance of personnel involved in handling cytotoxic drugs – guidelines for this can be found on the NIOSH website (see Resources). Moreover, staff should be educated about handling hazardous products and encouraged to tell their physicians about possible occupational exposure to these hazards.
One useful measure that had been adopted at Nebraska Methodist Hospital (NMH) was to conduct a “gap analysis” to find out how far practice differed from policy. This exercise had uncovered a “surprising lack of knowledge” particularly when staff had been asked to read current guidelines.
Effective decontamination in the pharmacy is essential. “If your cabinet is contaminated (with cytotoxic drugs) then the bags that you send out will also be contaminated,” Dr Massoomi warned. At NMH a two-step procedure is followed using SurfaceSafe®. This provides a pad soaked with 2% sodium hypochlorite for the first step and a pad soaked with 1% sodium thiosulphate and 0.9% benzyl alcohol for the second step.
For administration of cytotoxic drugs, everyone involved, including doctors, should have their skills assessed and should undergo appropriate training if required. The hospital policy should clearly state that administration sets should not be removed from the original bags after the infusion has been given.
There should be suitable measures for good housekeeping on the wards, for example proper cleaning procedures and suitable labelled containers for hazardous waste. Should the hospital have a pneumatic tube system, then blood and urine specimens that could be contaminated with hazardous drugs should not be sent through this system. Finally, linen management protocols should make it clear that potentially contaminated bed linen should be treated as hazardous for up to seven days after treatment has ended.
In conclusion, Dr Massoomi reminded the audience that the US Occupational Safety and Health Administration recommends routine monitoring of staff “in a systematic programme of medical surveillance to prevent occupational injury and disease”.
Resources
International Agency for Research on Cancer (IARC):
www.iarc.fr
US National Institute for Occupational Safety and Health (NIOSH):
www.cdc.gov/niosh
International Society of Oncology Pharmacy Practitioners (ISOPP):
www.isopp.org
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