Diane Langleben BPharm MRPharmS
Pharmaceutical writer and editor
Pharmacists are obliged to work to high standards of quality and have certain responsibilities. However, they cannot do it alone; they need the doctors, nurses and patients, all going in the same direction. This was the message of Johan Vandenbroucke, Head of Production, University Hospital, Ghent, Belgium, speaking about the quality of pharmacy chemotherapy services and how to protect the patient and staff. Mr Vandenbroucke, who is also the president of the International Society of Oncology Pharmacy Practitioners (ISOPP), stressed that quality and safety are interlinked at all stages of cytotoxic handling, from the writing of the prescription itself through to its dispensing, manufacture, administration and monitoring. However, it is during dispensing, manufacturing and administration that hospital staff are in contact with the products.
Mr Vandenbroucke said that quality is important because cancer treatment is associated with a very complex therapy involving complicated calculations, handling and administration. The products have an intrinsic toxicity and a narrow therapeutic index, leading to room for errors. There are also the problems of side effects, over- and underdosing, and interactions associated with polypharmacy.
He continued by mentioning the impact that cancers have on the lives of patients, not only physically but also psychologically. Their immune systems are impaired so they can acquire infections easily, compliance with treatment is needed, possibly for a lifetime, and there is a need for correct and honest information, which is not always the case.
Mr Vandenbroucke described two ‘myths’: the ‘perfection myth’ and the ‘punishment myth’. The former suggests that, if people try hard enough, they will not make any mistakes, but this does not work. The second myth suggests that, if one punishes people hard enough, they will make fewer mistakes. This does not work either. “So we have to look for something else,” he said. “We have to work together with our patients, staff and doctors to give the best possible care.”
Quality for patients
Mr Vandenbroucke reminded delegates that it is the basic right of patients to have the correctly prescribed drug at the correct dose in the right medium, at the right concentration. He said that hopefully nobody now allows handwritten, oral or faxed prescriptions for cytotoxic drugs. Handwritten prescriptions can lead to mistakes through bad handwriting and incorrect interpretation of abbreviations.
The chance of mistakes is enormous with oral orders and there is no legal redress. Faxed prescriptions can be marred by dust on the machine that translates as an ink spot, which can mask a number or decimal.
Mr Vandenbroucke referred to various studies that looked at the number of prescription errors. In one French study, 87 errors were found in 5000 prescriptions for cytotoxic medicines, an error rate of 1.7%. Of these, 10% were deemed to have a fatal outcome or major side effect.(1)
In 2010, the Journal of Oncology Pharmacy Practice published a report showing an error rate of 2%.(2) Of these errors, 75% were in prescriptions (although 71% did not reach the patient), 21% in preparation of the cytotoxic agent (of which 15% reached the patient) and 1.8% during administration (Figure 1).
“Is electronic order entry the ultimate answer?” posed Mr Vandenbroucke. He thinks it is but with some reservations. There needs to be validation of the programme in the system. Some of the programmes help the doctor to prescribe but do not take into account what to do if the situation of the patient changes, or if there is an interaction.
Mr Vandenbroucke stressed that there is no replacement for common sense; the doctor has to think about the patient constantly. He discussed a study that shows that, although electronic prescribing cuts the error rate, the severity of the errors is greater, and even life threatening. This does not surprise him; in a computerised system the doctors are pressing buttons and often do not stop to think about which buttons they are pressing.
For example, calculation of dose, often based on body surface area, can also go amiss in such a system. In some European countries, a decimal point is written as a comma. If the doctor, prescribing for a child, enters 3,5kg instead of 3.5kg for the patient’s weight, the computer does not recognise the comma and misses it out. Potentially the patient can receive a dose relating to a 35kg adult instead of a 3.5kg child.
Clinical pharmacists can have an influence on standardising treatments. “We are in the best position to look out for the possibility of errors and interactions,” said Mr Vandenbroucke. When the pharmacist intervenes, the doctor will listen if alerted that something needs to be changed.
Quality in preparation
Mr Vandenbroucke asked how pharmacists can guarantee a correct dose. He answered that it all came down to control, at each and every step of preparation. Although many of these stages can be taken over by robots and computers, they still have to be validated, otherwise there will be problems.
Verification of the prescription is also important. Mr Vandenbroucke referred to his own country, Belgium, where pharmacists are co-responsible for the administered dose. He said there were several cases of involuntary manslaughter where the dose had been incorrect. Mr Vandenbroucke advises using protocols approved by pharmacists, nurses and doctors to ensure the controls have been carried out. The ideal situation is to carry out quality control, but this means investing in time and people to do the task. Mr Vandenbroucke stated: “The patient is worth it. We cannot afford an error that costs far more and even the death of the patient”.
Another aspect that has to be checked is microbiological contamination. Cancer patients have compromised immune systems and they need to be given sterile preparations. Not all chemotherapeutic agents kill all microorganisms. It is therefore important to ensure good quality control in this area. Although the Pharmaceutical Inspection Convention publishes a guide to good practice for the preparation of medicinal products in healthcare establishments, not all hospital are able to invest in such a service.(3)
Quality in administration
Mr Vandenbroucke reminded delegates that, despite all the warnings, patients are still dying because a drug has been given by the wrong route, giving the example of vincristine given by intrathecal injection, which should now be administered in a 50ml infusion bag, in line with recommendations from both the Institute for Safe Medication Practices and ISOPP. Mr Vandenbroucke also warned that the drug must be given at the correct speed and to the intended patient.
There is now a trend for patients to be treated at home and Mr Vandenbroucke expressed concern about what could happen there. Although a pharmacist is not present, it is important for the patient to have adequate information to ensure mistakes are not made.
Quality for staff
The health risks associated with cytotoxic drugs are well known and can be acute or delayed. The classical drugs are not tumour specific and can lead to bone marrow suppression, cystitis, gastrointestinal disturbances, cytopaenia, alopecia or sterility. Inevitably, exposure to such drugs presents a risk to healthcare professionals. Approximately 5% of patients will present a secondary cancer, eight to 10 years after first being exposed to drugs used in the treatment of their first cancer. Unlike patients, who have rest periods between bouts of treatment, healthcare professionals are exposed to the risks day after day.
Mr Vandenbroucke said that there were several studies looking at the adverse reproductive outcomes in workers handling cytotoxic material. For example, the level of cyclophosphamide in the urine of nurses was much higher in those working in oncology units compared with those who are not, while working in the same hospital. DNA damage in lymphocytes was significantly higher than in the controls.(4) An important study was published in 2010 looking at DNA damage in acute myeloid leukaemia that was linked to lost chromosomes. In staff who had handled cytotoxics 100 times, there was a 20% increase in chromosome abnormality; in those who handled the drugs 500 times there was a 2.5-fold increase.(5)
Healthcare staff are vulnerable to problems with cytotoxic drugs in several ways. It can be from external contamination of the vials, drug preparation, drug administration, patients’ excreta and waste.
Mr Vandenbroucke believes that the pharmaceutical industry has a huge responsibility in ensuring that risks are minimised. He congratulated Fresenius Kabi for being the first company to comply with the recommendations of ISOPP, which had asked for analysed reports and improvements in production methods and packaging.
“Of course, what we want is no contamination whatsoever of our people,” said Mr Vandenbroucke. Although this can probably never be achieved, contamination should be as low as reasonably possible and staff must protect themselves.
Mr Vandenbroucke reminded delegates that a good place to start is with the ISOPP guidelines, which are the gold standard accepted by its global membership. He concluded by saying that quality is needed and it need not be expensive. It is the mindset that needs to change and this is for free.
Responsibilities of the oncology pharmacist
“The oncology pharmacist has a key role in patient care and safety,” so said Professor Graham Sewell, head of the School of Health Professions and Associate Dean, Faculty of Health, Education and Society, University of Plymouth, UK. His presentation on ‘Responsibilities of the oncology pharmacist – safety of colleagues and care of the environment’ opened with the acknowledgement that pharmacists have unique scientific and clinical knowledge with a deep understanding of risks and errors.
The thrust of Professor Sewell’s argument was to look beyond the traditional role of pharmaceutical and clinical care, and he illustrated this with two examples where the pharmacists’ expertise can be of great benefit.
He first talked about the risk of occupational exposure to nursing staff. “I really want to challenge our conventional practice where we introduce new technologies, specifically isolators, to try and reduce cytotoxic contamination,” he said. Professor Sewell then discussed a study looking at the external contamination of syringes and infusions prepared in isolators.(6) The study involved the preparation of syringes and infusions of cytotoxic marker drugs in an isolator in a university aseptic clean room and actual cytotoxic drugs prepared in an isolator in a hospital pharmacy cytotoxic unit. Before and after cleaning, the surfaces of the isolator bases, gloves and hatch doors were wiped, as were the external surfaces of the infusion bags and syringes. Samples were then assayed using liquid chromatography. Results showed that there was significant contamination (Figure 2). This was not so surprising but what concerned Professor Sewell more was the amount of contamination on the infusions and syringes. Moreover, the contamination was not only from the drug being prepared, but also from other cytotoxic drugs previously prepared, and this was after cleaning.
Professor Sewell said that he felt a little bit uncomfortable sharing this information but recognised that honesty was needed in oncology pharmacy to bring the problem to the fore. He continued: “The question is, if these things are contaminated when they leave the pharmacy, what happens in the clinic?” He illustrated this with a photograph of a nurse administering a cytotoxic drug with a glove on one hand but not the other. This is something about which oncology pharmacists can only advise but not control.
Professor Sewell next turned his attention to thinking about protection of the environment. He described a systematic study of cisplatin in water, silt and the macroalga, Ulva lactuca, taken from the river bed, estuary and sea.(7,8) The study demonstrated that the drug binds to silt in each of these environments, to varying degrees, and is also taken up by the alga. U. lactuca was not affected by the cisplatin, save for the fact that its photosynthetic processes speeded up a little. This has enormous implications, with the potential for cytotoxic drugs to be incorporated into the food chain.
Professor Sewell stated that there were more papers in the pipeline on this subject. He concluded: “It is an interesting area for a pharmacist to get into and to work with our colleagues in environmental science”.
1. Augry F et al. Order errors in antineoplastic therapy: prospective study with 5,000 prescriptions. J Pharm Clin 1998;17:20–4.
2. Serrano-Fabiá A et al. Multidisciplinary system for detecting medication errors in antineoplastic chemotherapy. J Oncol Pharm Pract 2010;16(2):105–12.
3. Pharmaceutical Inspection Co-operation Scheme. PIC/S GMP Guide. Feb 2010 [cited 2012 Apr 3]. www.picscheme.org/publication.php?id=4 (accessed 13 May 2012).
4. Rekhadevi PV et al. Genotoxicity assessment in oncology nurses handling anti-neoplastic drugs. Mutagenesis 2007;22(6):395–401.
5. McDiarmid MA et al. Chromosome 5 and 7 abnormalities in oncology personnel handling anticancer drugs. J Occup Environ Med 2010;52(10):1028–34.
6. Roberts S. Studies on the decontamination of surfaces exposed to cytotoxic drugs in chemotherapy workstations. J Oncol Pharm Pract 2006;12(2):95–104.
7. Easton C, Turner A, Sewell GJ. An evaluation of the toxicity and bioaccumulation of cisplatin in the marine environment using the macroalga, Ulva lactuca. Environ Pollut 2011;159(12):3504–50.
8. Curtis L et al. Speciation and reactivity of cisplatin in river water and sea water. Environ Sci Technol 2010;44 (9):3345–50.
The Fresenius Kabi satellite symposium ‘Safety in handling & reconstitution of cytotoxics’ was held at The European Association of Hospital Pharmacists Congress in Milan, Italy on 21 March 2012.