This site is intended for health professionals only

Hazardous drug exposure – preparation to administration

Experts from Europe and the USA described the risks of occupational exposure to cytotoxic drugs and the ways in which risks can be reduced during preparation and administration at a satellite symposium sponsored by Becton Dickinson.

Hazardous drug exposure is important for health care workers because they are involved in the administration process, according to Martha Polovich (Clinical Associate Professor, Georgia State University, Atlanta, Georgia, USA). Hazardous drugs are not limited to chemotherapy – the definition embraces carcinogens, genotoxins, teratogens, reproductive toxins, drugs that cause organ toxicity at low doses and drugs with structures or activity similar to those already classified as hazardous, she continued. “If it looks like chemo and works like chemo, then treat it as chemo”, she said.

The International Agency for Research on Cancer (IARC) classifies carcinogens into three groups – ‘known’, ‘probable’ and ‘possible’. The first group contains 11 single-agent drugs, including azathioprine, cyclophosphamide and melphalan, and two combinations, MOPP (nitrogen mustard, vincristine, procarbazine, prednisolone) and ECB (etoposide, cisplatin and bleomycin).

There is good evidence for adverse outcomes from occupational exposure to hazardous drugs. For example, among nurses exposed to hazardous drugs, there is a 50% increase in the prevalence of DNA single strand breaks and an increase in structural abnormalities in chromosomes, explained Dr Polovich. Moreover, a study of health care workers exposed to alkylating agents published in 2010 had shown changes in chromosomes 5 and 7 – the same type of changes that are associated with myelodysplastic disease. For this study, workers kept a record of ‘handling events’, such as hanging a dose or emptying patient’s urine, over a six-week period. The results showed that 100 handling events were associated with a three-fold increase in the frequency of chromosomal damage and 200 handling events with a nine-fold increase. The study was concerned only with handling of hazardous drugs rather than with spillage, she emphasised.

Previous studies showed increases in the frequency of cancer in pharmacy technicians and increases in leukaemia among nurses exposed to hazardous drugs. In addition, there was evidence of reproductive toxicity including infertility, spontaneous abortion, premature labour and preterm birth. Increased frequency of learning disabilities in offspring has been reported with exposure to heavy metals and this is relevant because platinum is present in a number of chemotherapeutic agents, commented Dr Polovich. Nurses have also complained of acute toxicity. One nurse experienced chronic nasal sores while handling hazardous drugs and another regularly noticed blood in her urine and bladder spasms the day after preparing doses of cyclophosphamide. Haemorrhagic cystitis is a known side effect of cyclophosphamide, she said.

Patients receive a narrow range of drugs over a relatively short time to treat their disease but health care workers can be exposed to low doses of many drugs over long periods. Sub-therapeutic doses can cause changes but not kill cells and, in the long run, this might be worse, explained Dr Polovich. The routes of exposure include dermal absorption, both direct and through contact with contaminated surfaces, ingestion, inhalation and even injection resulting from sharps injuries and breakages. Numerous studies have reported sources of workplace contamination with hazardous drugs, for example, contamination of work surfaces. Since 1992, no fewer than 55 studies have reported excretion of hazardous drugs in the urine of healthcare workers, providing clear evidence of exposure, said Dr Polovich. In recent studies involving nurses and pharmacists, skin contact (with hazardous drugs) in the previous seven days occurred in up to 11% of respondents and up to 24% reported taking home potentially contaminated clothing. When nurses were questioned about spillages, 12% reported spills in the previous seven days; usually several nurses were involved in the cleaning procedure and even staff who did not report spills were found to have hazardous drugs in their urine. Studies of surface contamination in pharmacies and nursing areas carried out in 1999 and 2010 showed similar levels of contamination. “In ten years we have not made much progress”, Dr Polovich concluded.

Closed system transfer devices

Routine handling of antineoplastic dugs results in exposure of health care workers but this can be reduced by appropriate measures. In the hierarchy of control measures replacement of the hazardous product with a less toxic agent is the most effective measure followed by engineering controls such as containment isolators or cabinets (Table 1). These are defined as level 1 and level 2, respectively, by the International Society of Oncology Pharmacy Practitioners (ISOPP). Closed system transfer devices (CSTDs) are also considered to be level 2 controls. A CSTD is defined as a “device which mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapour concentrations outside the system”. Studies have shown that the use of CSTDs reduces environmental contamination with hazardous drugs and can reduce worker exposure.

In order for any control measures to be effective there should be adequate administrative support, explained Dr Polovich. Written policies and procedures are required together with a hazardous drug list, education and competence assessment programmes. Training should cover the correct use of all equipment and devices together with procedures for spill management and acute exposure to hazardous drugs. Competence should be reassessed every 12 months, she said. In addition, there should be routine medical surveillance and provision for alternative duties around pregnancy, she added. Temporary protective reassignment should be possible during pregnancy and breast feeding. Similar provision should be available at the pre-conception phase for both male and female staff and when infertility is an issue.

Dr Polovich offered a number of tips for good work practice controls (Box 1).


Box 1: Recommended work practice controls
  • Label hazardous drugs as ‘hazardous’
  • Transport hazardous drugs in sealed bags
  • Inspect hazardous drugs containers for leaks
  • Avoid spiking and priming without a closed system transfer device
  • Avoid touching unnecessary items with contaminated gloves
  • Avoid wearing PPE outside drug handling areas
  • Discard used IV equipment intact
  • Wash hands after removing PPE


Personal protective equipment (PPE) should be worn when handling hazardous drugs and all PPE should have been tested adequately for use in this situation. Gowns should be disposable, single-use gowns that provide wrist protection. ‘Double gloving’ is required in some situations where drugs are known to penetrate glove material, such as carmustine and thiotepa. “However, the main reason for double gloving is to prevent the transfer of contamination to the hands or other surfaces; you should always consider gloves to be contaminated after handling chemotherapy”, said Dr Polovich. The outer gloves should be removed carefully, turning them inside out. The inner gloves are only removed after all other handling is complete and other protective clothing is removed. Sometimes, eye protection may be required to protect against splashes and a respirator or mask to protect against aerosols or spills, she added.

Dr Polovich has studied the factors that influence the application of hazardous drug precautions by nurses. Strong predictors of compliance with precautionary measures are the absence of barriers, a good workplace safety climate and fewer patients per day. Typical barriers to use included lack of availability, inconvenience, expense or equipment that was difficult to use.

Dr Polovich concluded that our working environment is still not completely safe but that there are now many interventions that can improve safety.

CSTD comparison

The use of BD PhaSeal significantly reduces chemical contamination with antineoplastic drugs, Nicolas Simon (Assistant Professor of Clinical Pharmacy, Centre Hospitalier Régional et Universitaire, Lille, France) told the audience.

A study was conducted to compare the use of the BD PhaSeal CSTD with the standard method in the pharmacy compounding unit at Lille University Hospital. The hospital has 5000 beds and the pharmacy prepares 40,000 doses of antineoplastic drugs each year.

Previous studies have used a ‘before and after’ design but the opening of a new compounding unit with two isolators provided the opportunity for a controlled, prospective study, explained Dr Simon. As the isolators were new, there was no pre-existing contamination. The standard method for drug transfer was used in one isolator and BD PhaSeal in the other. The workload was organised in such a way as to ensure that a core list of drugs was compounded in both isolators (Box 2).


Box 2: Core list of drugs compounded 
  • Cyclophosphamide
  • Doxorubicin
  • Irinotecan
  • Ganciclovir
  • Gemcitabine
  • Fluorouracil
  • Cytarabine
  • Dacarbazine
  • Methotrexate
  • Ifosfamide


Wipe samples were collected using a standard method before and after a standard cleaning procedure. Samples were collected from three sites – the worktop, the window and gloves. Sampling was undertaken daily for the first two weeks, then weekly for three months and monthly for a further three months. The samples were analysed using a liquid chromatography–mass spectrometry technique.

During the study period 12,554 doses were compounded using the standard method and 7543 using BD PhaSeal. A total of 335 samples were collected from the standard isolator and 334 from the BD PhaSeal isolator.

Significantly greater quantities of cytarabine and methotrexate were compounded using BD PhaSeal but the amounts of all the other drugs compounded were similar for both methods. There were no vial breakages during the study but there were a small number of incidents using BD PhaSeal. There was a 50% reduction in contamination after six months on isolator gloves and a 50% reduction in overall contamination rate inside isolators. The absolute amounts of individual drugs handled did not appear to influence the degree of contamination. At the end of the six-month study period there was a 72% reduction in the amount of drug contamination detected on the worktop when BD PhaSeal was used.

The pharmacy technicians who routinely undertake the compounding work were satisfied with the BD PhaSeal device and felt that it provided a high standard of safety.

As a result of the findings of this study, BD PhaSeal is now used routinely at Lille University Hospital for the most problematic contaminating drugs, said Dr Simon.

Improving the safety of syringes

The management of risks related to hazardous drug exposure is an important concern for health care professionals. In paediatric patients treated for various cancers, cytotoxic drugs are often prepared in syringes in order to minimise injection volumes.

Leakage of cytotoxic injections from administration tubing prompted an evaluation of the BD PhaSeal devices in a children’s hospital, as a possible way to resolve the problem according to Karine Morand (Hospital Pharmacist, The Armand-Trousseau Hospital, Paris, France). The Armand-Trousseau Hospital has 35 paediatric onco-haematology beds that are served by a satellite pharmacy situated near the ward. The satellite pharmacy prepares 7000 doses per year. About 50% of doses are prepared in 5ml syringes to minimise the risk of fluid overload. All preparations, whether in bags or syringes, are secured with closed system devices to minimise the risk of exposure of nurses and patients to hazardous drugs.

However, leakage had been reported with the existing administration tubing, and for this reason an alternative device had been sought. It was essential to have a Y-site extension tube primed with the diluent and connected to the cytotoxic drug syringe and a secure connection between the extension tube and the patient’s IV line. In addition, the device had to ensure that there was no contact with the hazardous drug when it was disconnected. The BD PhaSeal Injector and Connector C80 appeared to satisfy these criteria and so an evaluation was undertaken.

Nurses from the haematology team were trained in the use of the new system. The new devices were introduced into regular use in place of the previous device. Nurses awarded good scores for both security and ease of manipulation. The dry connections in the BD PhaSeal system were felt to be a particularly valuable safety feature, commented Dr Morand. No breakages or leaks were reported. One minor problem that emerged was that the connector tubing was too short when several IV pumps were used simultaneously. The problem was solved by the use of an additional line. Another small problem was that the complete system – syringe, Injector and Connector – was too large to fit in the pass-through hatch of the isolator and so nurses make the connection between the Injector and Connector at the time of administration.

The Armand-Trousseau Hospital is the first teaching hospital in France to use the BD PhaSeal system to administer intravenous cytotoxic drugs via syringe pumps, said Dr Morand. The introduction of this device for routine use has improved the safety of cytotoxic drug administration without compromising efficiency, she concluded.

The satellite symposium, Latest evidence and risks associated with hazardous drug exposure from preparation through to administration, took place during the 20th EAHP Congress held in Hamburg, 25–27 March 2015.

Be in the know
Subscribe to Hospital Pharmacy Europe newsletter and magazine