Pharmacists from all over Europe heard experts discuss aspects of the safety of injectable medicines at the B Braun IV Symposium. Topics included outsourcing, use of prefilled syringes, environmental contamination and smart pumps
Christine Clark PhD FRPharmS FCPP(Hon)
Outsourcing of the preparation of ready-to-administer injections can be done very well or very badly, according to Alison Beaney (Regional Quality Assurance Specialist, North East England). The problems of successful outsourcing are illustrated by several real-life examples. In one case, a manufacturer had subcontracted delivery to a reputable company, which then further subcontracted the work. One of the drivers was an ex-felon. When a delivery went missing, the parcels were eventually found opened, in a rubbish skip. A second example concerned the purchase of aseptically-prepared chemotherapy doses. The chosen supplier claimed to have the appropriate ‘Specials’ manufacturing licence, whereas, in fact, its licence was for prepacking. Chemotherapy doses were being made in a laminar flow cabinet in a domestic living room.
A third example involved the purchase of oral demeclocycline suspension. The product, made by opening capsules and suspending the powder, was given a 90-day shelf-life. There were no supporting data for the shelf-life and the suspension was prepared under a Section 10 exemption (that is, under the direct control of a pharmacist) rather than as a product licensed by the Medicines and Healthcare Products Regulatory Agency (MHRA). The manufacturer charged £500 for this product. In each case, a detailed purchasing specification and proper assessment of the supplier could have avoided the problems, said Dr Beaney.
It is appropriate to outsource aseptic compounding in order to liberate capacity to prepare high-risk products in house, but it is important to check that the contractor has sufficient capacity to meet the terms of the contract. Furthermore, the contract should specify the action to be taken if the contractor cannot maintain the supply, advised Dr Beaney.
One of the main drivers for outsourcing is the conviction that it is cheaper than preparing products in-house. However, it is important to take into account the costs of drafting the product specification to ensure the safety of the patients. There should also be a technical agreement. The MHRA recommends that the technical agreement should be separate from the service level agreement. The technical agreement lists the responsibilities for both contract-giver and the contract-acceptor. “It is in everybody’s interest to know who is responsible for what”, she emphasised. “The pharmaceutical industry is good at this but we need to ask how robust the NHS process is”, she added.
“Outsourcing can work well if it is done for the right reasons, involves carefully-assessed commercial partners, defines responsibilities clearly and allows the preparation of high-risk products to be taken into NHS pharmacy facilities”, concluded Dr Beaney.
Surface contamination with cytotoxic agents
Acute toxicity of cytotoxic agents is important in the therapeutic context but delayed toxicity, including reproductive and carcinogenic effects, are more important for healthcare workers who could be exposed to small amounts of these drugs over long periods, Paul Sessink (Managing Director, Exposure Control Sweden AB) told the audience. Genotoxic carcinogens act immediately on DNA and as little as one molecule can be sufficient to induce cancer, but biological protection measures usually prevent this, he continued.
Basic occupational hygiene measures are followed to protect workers from exposure to cytotoxic agents. Exposure is reduced through the use of closed systems, ventilated facilities (isolators and biological safety cabinets) and personal protection such as gloves, gowns and masks.
There are two major sources of contamination in a hospital – the pharmacy department, where the drugs are stored and prepared, and the wards where they are administered. In the pharmacy, contamination starts with residual drug on the outsides of vials supplied by the manufacturer. ‘Sleeving’ of vials in plastic sheaths has reduced environmental contamination considerably. Spillages and waste handling are additional sources of contamination, he added.
On wards, cytotoxic surface contamination can be found in the areas where the drugs are administered, nurses’ rest rooms and the patients’ toilets. Chemical contamination is found wherever the patient goes, he said. Since the early 1990s, there have been progressive improvements in handling techniques for cytotoxic agents and falling levels of environmental contamination have been reported. In particular, the use of closed system transfer devices (CSTDs) can remove 95% of surface contamination.
Turning to the question of acceptable levels of contamination, Dr Sessink described how a risk matrix that combines urine levels of cyclophosphamide and surface levels (from environmental wipe samples) has been constructed. Cyclophosphamide is used as a marker because it is a persistent drug that penetrates the skin readily and can be measured easily. It is now known that if surface contamination with cyclophosphamide amounts to less than 0.1ng/cm2, then there will be no measurable exposure of the workers and therefore no positive urine samples. The risk matrix has a green range (minimal action needed), yellow and amber ranges, where there is moderate risk and some action is needed, and a red range that should prompt an immediate closure of the facility and remedial action.
The question of cleaning of cytotoxic working areas is very difficult to answer, said Dr Sessink. “Some people think they are cleaning but really they are just moving the cytotoxic residues around”, he commented. He recommended the use of an alkaline detergent followed by a water rinse then an acid detergent followed by a water rinse, and, finally, swabbing with alcohol to disinfect the area.
In summary, Dr Sessink said that his key messages were to use clean vials and closed systems for preparation, coupled with ongoing staff training to ensure adherence to good practice.
The use of prefilled syringes in surgery and anaesthesia leads to greater patient safety, saves nursing time and reduces the amount of waste generated, said David Whitaker (Consultant in Anaesthesia and Intensive Care, Manchester, UK). Medication errors in anaesthetic practice are estimated to occur at the rate of 1 in 133, and 1 in 250 of these is fatal. One anaesthetist reported administering morphine instead of atracurium because he was distracted by talking to a student and neglected to label the syringes that he had previously prepared. In another incident, syringes were labelled wrongly as an anaesthetist and trainee chatted. There is ample good guidance available. All syringes should be labelled immediately after preparation but empty syringes should not be labelled in anticipation, he said.
The Anaesthesia Patient Safety Foundation recommends standardisation of drugs, concentrations and equipment and the adoption of technology such as drug identification and delivery systems and automated information systems. It also recommends the use of prefilled syringes whenever possible and that a clinical pharmacist should be part of the peri-operative team.
Up to 9% of injectable preparations have twofold errors and these are often products that require complex calculations and paediatric products, according to Mark Borthwick (Consultant Pharmacist, Oxford University Hospitals, UK).
One of the biggest barriers to the introduction of prefilled syringes is the change process itself, he argued. The Intensive Care Society (in the UK) has published a list of standardised concentrations for commonly-used injectable drugs and the industry should use the list when planning new products, he suggested. Cost can be a barrier when only small quantities are being made, and there could be capacity problems for the industry because there is only a limited number of manufacturers that are able to make prefilled syringes.
Unexpected events can also create serious problems in this area. An example was a change in the specification of a haemofiltration pump with an integral heparin pump – from a flow rate of 0.1ml per hour to 0.5ml per hour (to improve accuracy). As a result, the prefilled syringes that had been in use were no longer suitable. The hospital was left with the choice of changing the pump or changing the concentration of prefilled heparin injection.
Members of the audience commented that the introduction of prefilled syringes offers the opportunity to drive practice forwards and improve safety and should not simply reflect current practice. It was also noted that it is important for a hospital to have adequate buffer stocks so that front-line staff do not suddenly have to prepare injections when they are no longer familiar with the process.
Smart pumps can alert the user to settings that do not match agreed drug administration guidelines and it is the presence of an integral ‘drug library‘ that converts a conventional pump into a smart pump. Describing her experience of implementing smart pumps, Kath Phillips (Medicines Information and Formulary Pharmacist, Southport and Ormskirk NHS Trust, UK) said that there were a number of things that could go wrong when smart pumps are used. For example, staff could choose not to use the drug library or could over-ride ‘soft limits’ in when setting up an infusion. Other types of errors that can occur are administering a drug to the wrong patient, accidentally administering a dose that has already been given, administering an infusion that is within the agreed limits but is incorrect for the patient, or choosing the wrong drug from the library.
The hospital decided to introduce smart pumps to three care areas – intensive care, general wards and obstetrics and gynaecology. Pumps were tested and checked to verify that they alarmed appropriately and the drug library was compiled. A number of critical lessons were learned in the process. Key points were that the process was more time-consuming than had been anticipated, the IT department should be involved from the outset, and more discussion was needed with the medical equipment library. As yet there is no wireless connectivity, and this creates a problem when the drug library has to be updated, commented Ms Phillips.
Safe use of IV paracetamol
Misplaced familiarity can lead clinicians to prescribe and administer toxic doses of paracetamol to some patients, according to Gillian Cavell (Consultant Pharmacist & Deputy Director of Pharmacy, King’s College Hospital NHS Foundation Trust, London, UK). There are three dosing regimens for paracetamol that take into account body weight and liver function, she explained. In general, it is assumed that adults weigh more than 50kg and can safely be given a 1-g dose of paracetamol by any route. However, this is not always the case, and fatalities have been reported when adults with low body weights have been given ‘normal adult’ doses of paracetamol.
An audit of 63 patients who received paracetamol in critical care, surgery and hepatology wards at King’s College Hospital showed that body weight was documented in all but ten patients and three patients weighed 50kg or less. A total of 48 patients were prescribed ‘multiroute’ (intravenous and oral) paracetamol and most (61) patients were prescribed 1000mg doses. Eight patients were prescribed total daily doses greater than 75mg/kg (range 75–97.6mg/kg), which could put some at risk of staggered overdoses, noted Ms Cavell. As a result of this work, a prescribing template for intravenous paracetamol was built into the hospital’s electronic prescribing system. The template limits the maximum daily dose by this route to 3g for patients with risk factors for hepatotoxicity.
Turning to paediatric paracetamol therapy, Ms Cavell pointed out that the dose is 15g/kg for children weighing 10–50kg and 7.5mg/kg for those under 10kg. This leads to complex calculations and a number of tenfold errors in dosage have been reported. Part of the problem is that the dose is first calculated in milligrams and then has to be converted in to a volume for administration, she acknowledged. However, another significant factor is that for many doses, less then one tenth of the contents of an original pack are required for the dose. For example, a child weighing 5kg would need a dose of 37.5mg, in a volume of 3.75ml (of a 10mg/ml solution). As the presentations available contain 50 or 100ml of paracetamol injection 10mg/ml, the opportunity for error exists. “There is no safety net here. The easiest way to give an overdose is have an overdose available”, said Ms Cavell.
Existing pack sizes are a major contributory factor to paediatric fatalities; what is required is a presentation of 75mg in 7.5ml, she concluded.
Point-of-use labelling for IV medicines
Studies investigating the risks associated with poor labelling of injectable medicines resulted in the design of a peelable label that contained all the information required at the point of use, explained Miriam Klein (Assistant Director of Pharmacy, Medication Safety, Kings County Medical Center, New York, USA). The peelable label is fixed to the original ampoule underneath the original cover label so that it can be peeled off and transferred to the syringe ready for administration. The label also has space to write the dose and the patient’s name.
An award-winning initiative to prevent selection errors with insulin has been implemented both at Kings County Hospital Center in New York and in a British hospital. Insulin is a ‘high-alert’ product and selection errors are common because of look-alike and sound-alike names, explained Dr Klein.
She developed eye-catching labels that could be attached to clear plastic insulin storage trays. The labels mirrored the colours of the insulin packaging and also included the words ‘high risk’ in the shape of a traffic stop sign, to prompt staff to double check the product. Pharmacy staff were educated about the changes, paying particular attention to the difference between Humalog and Humalog Mix 25, which had been involved in many errors. Between 2009 and October 2010, before the implementation of the safer labelling system, ten incidents relating to incorrect insulin/form of insulin were reported. There has only been one reported incident in which the incorrect insulin was selected since the introduction of the new labelling scheme.
The B Braun medical seminar, ‘Changing practice to improve safety’, was held at the International Convention Centre, Birmingham, UK on 9 October 2013