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A nonpharmacist’s view on some of the recent changes and remaining specific issues in terms of protecting staff who handle cytotoxic drugs
Hygiene Unit, Health
Health & Safety
As a nonpharmacist, my perspective on issues regarding health and safety and cytotoxic drugs may be slightly different from those of readers. Certainly cytotoxics include highly toxic drugs, constituting a significant hazard for pharmacy staff undertaking cytotoxic drug preparation. Regulatory toxicology generally still struggles with defining the risk of ill-health from chronic, low-level exposure to mixtures of chemicals. This, together with some cytotoxics as reprotoxicants, proven (eg, cyclophosphamide, thiotepa) or suspect human carcinogens (eg, cisplatin, teniposide, bleomycin) suggest that reducing exposure to as low as possible for everyone except the patient must be the default approach. While pharmacies show some unique characteristics, they also show many similarities in health and safety issues to other “industries” employing highly toxic chemicals. On a workflow basis, the hospital pharmacy receives cyotoxic drugs from pharmaceutical manufacturers, formulates the drugs into appropriate dosages for transportation to clinical staff, who then administer to oncology patients; the pharmacy also has to handle toxic waste. This is no different from many other ‘workplaces’ employing highly toxic chemicals, where issues about appropriate packaging and labelling throughout the workflow processes are important, albeit in combination with other factors such as staff training, operating procedures, appropriate engineering controls and personal protective equipment (PPE).
In the last 10-15 years within the UK and many other European countries, significant changes have been made to cytotoxic preparation that have substantially lessened potential exposure to the wider hospital staff. These changes include the tendency to centralise cytotoxic formulation within specialised pharmacy units, reducing or eliminating the amount of manipulation of administration sets on wards and side-rooms by clinical staff. Ongoing increases in oncology services and centralisation of cytotoxic manipulation may have potentially increased risk to the staff working in such units. Certainly in the UK, concomitant increased use of high containment devices such as isolators to formulate the drug, incorporation of specific health and safety (H&S) training and aseptic techniques for those formulating the drugs and other practices probably have done much to counter the potential for increased exposure. However, there have been relatively few published monitoring studies, especially longitudinal, to characterise changes in potential and actual levels of exposure to pharmacy staff (eg, floor and surface contamination outside enclosures, and urine monitoring), reviewed to 20021 and latterly.[2-6] Cautious interpretation of those largely cross-sectional published
monitoring studies focusing on cytotoxic exposure to pharmacy staff would suggest that there may have been significant decreases in many countries.
One of the issues that has arisen in the pharmaceutical industry in general and also specifically with cytotoxic drug formulation is whether control measures put in place involving either engineering controls or PPE can naturally be assumed to serve both to maintain sterility of product and protect the worker from exposure to the drug. My experience is that this should not always be assumed. This possible dichotomy between operator and product protection has been highlighted recently for commercial devices, such as Chemoprotect and PhaSeal.
Transport to hospital by the manufacturer of cytotoxics drugs may involve compliance with the carriage of dangerous goods regulations, involving specific UN labelling, and is regulated by international and European Directives. However, “labelling” is a complex area and we are entering a period of change as new European regulations on classification, labelling and packaging (CLP, 2009) begin to be applied. These will actually help by bringing global consistency in the “Hazard Pictograms” and wording that is to be used on packaging. Several studies[8-11] have highlighted low-level contamination on the external surfaces of some vials delivered from the manufacturer, and significant contamination of surfaces in pharmacy stores. Occurrences of breakages of vials have also been occasionally reported in delivered consignments. Low-level contamination of external surfaces of vials may cause potential build-up of contamination within the pharmacy, including “unpacking” areas and any “spraying sanitisation” step if prior to entry into an enclosure for formulation. Breakages within supplied packaging may significantly expose those staff unpacking and handling deliveries, and who traditionally in any “industry” tend to have had less training and hazard awareness. Both of these issues with delivered goods are a route of introducing uncontrolled contamination into the pharmacy environment, and introduce issues about both cleaning regimes that remove cytotoxics and spillage procedures.
Some pharmacies have reacted by upping the levels of PPE used by staff handling any cytotoxic packaging and incorporating within-enclosure (isolator) procedure for vial decontamination on arrival. However, this latter response seems a “downstream” and expensive approach, where elimination of such contamination issues should be addressed at the manufacturing stage. Indeed, there has been reaction from some manufacturers about the issues of delivering externally uncontaminated and better breakage-protected cytotoxics to pharmacies. Some manufacturers have upped the level of washing of vials post-filling or increased the sophistication of packaging, including sleeving or sophisticated secondary packaging (eg, OncoSafe or OncoGuard) to reduce the risk of vial leakage. The use of PVC or similar coatings applied to the outer glass wall of reagent containers to reduce the risk of drop or shock breakages for highly toxic or high-value reagents has become relatively common in the general chemistry field and is reflected in Tevaguard/VialShield, which is applied after cytotoxic filled vials are washed, thus trying to reduce both issues. However, evidence appears lacking on the extent of improvement in these issues. A cross-sectional study in UK pharmacies, albeit five years ago, suggested a lower use of appropriate PPE in hospital pharmacies stores and training for those staff responsible for initial receipt and handling of delivered cytotoxics. Consensus on hazard labelling of primary product from manufacturers, together with appropriate training and use of PPE by “stores” staff needs to be ensured.
As much as the manufacturer of cytotoxics supplying the pharmacy, the pharmacy itself has a duty of care in terms of delivering appropriately labelled and packaged drugs, such that risks to those transporting and receiving the drugs are minimised. The pharmacy should ensure that formulated cytotoxics are transported to the ward, day clinic, and so on, in an appropriately labelled and packaged form that minimises risks to porters and clinical staff administering the drug. For the latter staff, in many European countries, this is by reducing any necessary manipulation of the giving set before administration to the patient. Consideration needs to be given, similarly to the drug manufacturers, to the fact that formulated product has minimal external contamination before being primary packaged
in the pharmacy.
Labelling per se is not necessarily an effective means of ensuring that ‘due care’ is taken, and research continues into the complex relationships between ‘label messages’ and behavioural attitudes toward them. Labelling with appropriate information/training is a far more effective route to ensure compliance; for example, porters are not only transporting the drugs properly packaged and in an appropriately constructed and labelled container, but have also had some level of “training” about the nature of the hazard that they are transporting. Our 2004 questionnaire in UK pharmacies undertaking cytotoxic preparation suggested that there was widespread use of the secondary flexible or rigid box system labelled as ‘Cytotoxic Drugs’ to contain the formulated drug during transport, with a quarter using double plastic wrapping of the formulated drug as the primary enclosure. Heat-sealed plastic wrapping, whether single or double wrapping, was highlighted by a third of respondents, reflecting both the increasing availability of desktop heat sealers for use after any checking stage of final product and plastic heat-sealed exit systems that can be made integral to some isolators or workflow processes. Obviously any packaging needs to be appropriate to the physical nature of the formulation and any issues about chemical stability.
Handling of cytotoxic waste invariably involves procedures for the storage, transport and means of destruction that must comply with specific environmental legislation as well as health and safety considerations. Such regulations may be national or national implementations of pan-national regulations such as European Directives, such as the Hazardous Waste (England & Wales) Regulations 2005. Obviously operating procedures compliant with national regulations are key, but care has to be taken that waste procedures do not introduce increased contamination. Often relatively greater quantities of waste cyotoxics are produced in oncology wards and clinics than in the pharmacy units during formulation of cytotoxics, but return of contaminated waste to pharmacies after administration (eg, used giving sets) may complicate this, and care needs to be taken that any return processes do not counter the gains from centralisation of cytotoxic formulation. Whatever the issues about compliance with regulations about disposal, material contaminated with cytotoxic drugs, including contaminated ‘sharps’, needs to be taken out of any formulation enclosure, put into larger-lidded and appropriately labelled receptacles for storage for some period, before collection and transportation for disposal, invariably by incineration.
Appropriate rigid containers meeting UN3291 and BS7320 standards and identified as ‘Cytotoxic and Cytostatic Waste and Contaminated Sharps’ are available. In the UK, as well as many other countries, pharmacies must segregate this specialised waste from other pharmacy waste. Depending on the size of the pharmacy and its policies, the frequency of removal of cyotoxic waste containers from the pharmacy may vary considerably. There is the potential for contamination from the waste process of floors, especially around cyto-waste containers and on their lids and surfaces. There seems a need for development of best practices here that could be helped through monitoring studies.
One strength of pharmacies handling cytotoxics in comparison with most other occupational sectors involving highly toxic chemicals is the involvement of various professional bodies and their commitment to training and CPD. These bodies and other ad-hoc cross-profession groupings, such as MARCH, which is developing guidelines related to cytotoxics and health and safety issues, tend to be nationally based. However their considerations and outputs are likely to be valuable pannationally given the commonalities in the safe handling of cytotoxics.
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13. Management and awareness of risks of cytotoxic handling.
MARCH guidelines. www.marchguidelines.com