Antitumoral drugs (antineoplastic drugs or chemotherapy) are cytotoxic by their very nature: their pharmacological mechanism of action kills cells or arrests cell growth. For this reason they are recognised as hazardous: workers handling these drugs during pharmaceutical preparation (as chemotherapy unit-doses) or administration to the patient are advised to follow protective procedures aimed at guaranteeing the “lowest possible degree of exposure”.
It is important to remember that unlike the first international document published by the American Society of Health-System Pharmacy in 1985 entitled ASHP technical assistance bulletin on handling cytotoxic drugs in hospitals, the new document – updated in 1990 and completely revised in 2004 – is now entitled ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs.(1,2) On the basis of new scientific knowledge, progress in pharmacology and case histories over the last 15 years, all international documentation and guidelines have adopted this definition, which includes classical cytotoxic antiblastic drugs and other compounds having antiviral or immunomodulating, biological or enzymatic activity to which a potential risk value is ascribed during the preparation and manipulation phases. Detailed lists are available in NIOSH, OSHA and US National Clearinghouse guidelines.
Drugs that may represent occupational hazards(3,4) include those that exhibit one or more of the following characteristics:
- Genotoxicity (mutagenicity or chromosome disruption or breakage) in short-term test systems.
- Carcinogenicity in animal models, in the patient population, or both, as reported by the International Agency for Research on Cancer.(5)
- Teratogenicity or reproductive toxicity in animal studies or treated patients.
- Evidence of serious organ or other toxicity at low doses in animal models or treated patients.
Currently available guidelines
These guidelines reflect the best research available to date, as they cover the most important topics, as well as anecdotal reports which can contribute to better worker protection. Thus, anyone responsible for managing and coordinating a centralised pharmacy unit for producing cytotoxic personalised doses is recommended to read and become familiar with all available regulations on the subject. If possible, all procedures in a centralised pharmacy should be based on published data and the international guidelines cited above; in any case, an “observational”, process-based description of current work practices, equipment and the physical layout of work areas where hazardous drugs are handled can be a useful approach when undertaking initial assessment of appropriate and inappropriate practices.(6)
In general, each health institution or government entity follows these guidelines to produce specific legal regulations. In Italy, for example, the key legal regulations on this topic are: Law Lgs. D. 626/94, the guideline document from the State-Regions Conference (1999) and the new norms of good preparation (NBP) included in the National Pharmacopoeia XI. They all incorporate measures for safe handling and workers’ protection, as well as rules for safe and appropriate organisation of centralised services for hazardous drug preparation.(7,8)
Work control in practice
Utilising appropriate and updated work practices is of fundamental importance in reducing occupational exposure to hazardous drugs. Certain working procedures may result in more security, with only a few changes in key steps required.
For example, in order to reduce surface contamination:
- Avoid exiting and re-entering the biological safe cabinet (BSC) to retrieve materials, substances and devices without removing protective gloves; instead, technicians could be helped by another operator.
- Clean final containers using a damp cloth before delivering them to the final destination.
- Clean up spills or drug residues on disposables that have long administration times (such as infusion pumps) more thoroughly.
- Avoid contamination of working areas while removing personal protective equipment (PPE).
- Prime IV tubing with normal saline solution or another diluent and not with the hazardous drug before delivering it to hospital departments or single patients.
- Periodically evaluate batches of commercial drugs purchased by manufacturers and their safe shelf-stocking.
- Periodically review all work process in team meetings and discussions.
- Update education and information to all operators handling hazardous substances at least once a year.
Remember that continuous direct observation and monitoring of our own actual working conditions may always be useful to improve our practice.
Safety, quality and sterility of injectable drugs
In certain hospital settings a very large number of therapies must be prepared, especially in the case of day hospital services, and it is only possible to proceed by planning and rationalising work phases and specific procedures. For example, many parenteral hazardous drugs require reconstitution (they are supplied in liophilised powder form) and others are originally produced in liquid solution. Manufacturers are currently required to indicate on the datasheet or package insert the length of stability and storage conditions (refrigerator or room temperature). This is to ensure that microbiological sterility requirements can be maintained; therefore, for native liquid drugs, this recommendation does not directly relate to chemical stability data.
Moreover, many chemotherapeutic substances cited do not contain preservatives. Limited shelf-life is a basic security requirement, and a protective measure against any microorganism introduced during preparation procedures. However, the pharmacist or technician preparing the medication is expected to work under aseptic conditions, to guarantee the basic requirement of microbiological sterility of injectable hazardous drugs. In much the same way, the shelf-life of native liquid drugs can be discretionally extended by the hospital pharmacist in charge on the basis of his or her experience and by performing quality-control tests. It is therefore preferable to set up process control mechanisms that periodically verify the sterility of the substances, and in so doing ensure the total quality of our working processes in order to anticipate the preparation of substances to standard and/or predisposed doses in such a way as to rationalise the workload. A sample case is given here with reference to the Centro di Riferimento Oncologico in Aviano, Italy. In this 150-bed oncology and research hospital, we use microbiological tests to verify sterility. Cytotoxic preparations are analysed using two different methods: one to improve and compare sensitivity, and another to culture and recover bacteria and fungi.(9) To date, all tests performed have been negative, attesting to the existence of a high-quality working process and fulfilment of sterility requirements.
Conclusion
Handling of hazardous substances and preparation of cytotoxic/antitumoral therapies for oncological patients is a process requiring dedication, accuracy and continuous controls. It is certainly a field of medical care in which, in order to obtain the best results and quality of preparations, it is always necessary to compare competencies and scientific backgrounds and secure a strong competency of individual healthcare providers. Additional evaluations and periodic “renewed evaluations” of procedures and work methods, as well as implementing “small” changes, can contribute to improving quality while reducing workers’ exposure and risks and ensuring patient safety.
Authors
Paolo Baldo
PhD
Pharmacist
Renzo Lazzarini
Director
Pharmacy Unit
Centro di Riferimento Oncologico
Aviano
Italy
References
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