The standards under which injections are prepared in hospitals vary from country to country across Europe, according to a 2011 survey, and there needs to be greater standardisation, Paul LeBrun (Quality Assurance Pharmacist, Central Hospital – The Hague, The Netherlands) told the audience at the 20th European GERPAC conference.
A Council of Europe Resolution (CM/Res AP(2011) recommended that high-risk parenteral injections should be reconstituted in pharmacies rather than on wards or in clinical areas. However, ‘high-risk products’ were not clearly defined and a later resolution (CM/Res(2016)2) provided clarification.
The 2016 resolution was designed to increase safety for patients receiving high-risk injectable medicines, he continued. It calls for hospitals to determine which products require reconstitution in a pharmacy, based on risk assessment. Awareness of the resolution among European healthcare professionals varies widely.
Reconstitution is the process of preparing an injection (parenteral dose) in accordance with the manufacturer’s instructions (SMPC) Anything beyond this, for example, extending the shelf-life or using alternative solutions for reconstitution, falls under the heading of ‘preparation’ and the pharmacist is responsible for the quality of the product, explained Dr LeBrun.
The 2016 resolution contains a checklist “for identification, assessment and reduction of risk posed by the reconstitution of medicinal products in clinical areas”, explained Alison Beaney (former Quality Assurance Specialist Pharmacist, Newcastle-upon-Tyne, UK).
The checklist covers product-related risks, such as susceptibility to microbial contamination and possibilities for calculation errors, risks to staff, such as hazardous constituents, and risk reduction measures that are in place, such as the availability of ready-to-use (RTU) or ready-to-administer (RTA) products or the use of closed system transfer devices.
If risk reduction measures are in place, then the residual risk of reconstituting the product is reduced, added Dr Beaney. There is insufficient capacity in hospital pharmacies to prepare all injectable doses and the use of the risk assessment checklist allows hospitals to determine a hierarchy of products and then remove the highest-risk items from clinical areas and provide them in a RTU/RTA form.
Turning to the practical implications of the resolution, Dr Beaney said that each hospital should have a risk management system in place. The product profile of the hospital aseptic unit should be based on risk and patient safety. Staff in clinical areas should be made aware of which products are available from the hospital pharmacy, and pharmacy staff should be involved in training ward staff in reconstitution techniques.
In addition, hospital pharmacies need to hold discussions with the pharmaceutical industry about the products that are needed in a RTU/RTA format. Finally, the risk management system should incorporate regular reviews of risks because the position can change, for example, by the introduction of new RTA products.
Dr Beaney said that a core list of high-risk products was available in the UK, as a starting point for hospitals identifying their own lists. This list could be shared with other countries, if desired.
Developments
Key developments in recent years have included dose-banding (also known as dose-rounding), isolator technology, robotic compounding and novel approaches to quality assurance. The advantages of dose-banding for patients are more timely administration and less time spent waiting for doses to be prepared.
From the pharmacy viewpoint, dose-banding can reduce waste, allow better scheduling of work, save time and improve quality assurance. However, prescribers in France still fear loss of control of the doses that patients receive and the risk of increased toxicity, and therefore wish to continue to use doses calculated according to body surface area (BSA).
It was noted that the relationship between BSA and drug clearance is not as close as was first assumed. In practice, there is no difference in effect between BSA-based doses and banded doses. If dose-banding were to be integrated into the drug development process by manufacturers, then hospital pharmacists would be much more relaxed about adopting the approach, commented Professor Sylvie Crauste-Manciet (University Hospital of Bordeaux, France).
One common question among users of isolators was whether to use peracetic acid or hydrogen peroxide as sterilising gases. Originally, peracetic acid was widely used because it was the cheaper alternative, but now that compounding equipment is frequently put into isolators, it is not suitable because it is too corrosive. In addition, the smell of peracetic acid is difficult to avoid.
Another common question was whether to install positive-pressure or negative pressure isolators for preparation of chemotherapy injections. Some argued that the product was best protected by using a positive-pressure isolator. However, Professor Pascal Odou (Pharmacy Department, University Hospital of Lille, France) disagreed, arguing that the risks to staff should take priority. Staff in the aseptic unit are likely to work with an isolator for many hours and should be protected by the use of a negative-pressure isolator, he said.
Compounding robots reduce the risk of staff exposure to cytotoxic drugs because they are closed systems. They also eliminate the risk of musculoskeletal problems amongst staff while increasing productivity and improving quality assurance. However, largely autonomous, compounding robots cannot be left to work unattended at night.
In addition, it may be necessary to rebuild a facility to accommodate a compounding robot and the roles of staff have to change. The robot may not be able to handle all sizes and types of containers and validation may be difficult.
Professor Irene Kraemer (Director of Pharmacy, University Medical Centre, Mainz, Germany) said that in her experience compounding robots were not suitable for suspensions or dose-eluting beads. When her department first started using a compounding robot, it was used for the most labour-intensive products.
Experience has shown that it can be used for about two thirds of the total workload. The technician’s role has changed to that of engineer or IT specialist, she added.
Chemical contamination
New methods for measuring chemical contamination could be useful in screening for contamination, validating cleaning methods and evaluating worker technique, according to Thomas Connor (National Institute of Occupational Health and Safety (NIOSH), Cincinnati, Ohio, USA).
Direct contact with drug solutions or contaminated surfaces can lead to dermal uptake of drugs and most drugs with molecular weights of less than 500 Daltons can be absorbed through the skin. Some larger molecules (up to 1000 Daltons) can also be absorbed in this way. Surface contamination is measured by collecting wipe samples and chromatographic analysis (by means of GC-MS/MS or LC-MS/MS). Such techniques are very sensitive and can detect picogram quantities. However, they rely on expensive equipment and highly-trained personnel and are not available in most hospitals.
In addition, it may take many days or weeks to obtain a result. Immediate results would be useful in practice and NIOSH has recently developed two methods that might make this possible – lateral flow immuno-assay (LFIA) and fluorescence covalent microbead immunosorbent assay (FCMIA). “LFIA has been used, so far, mainly for ‘yes/no answers’, such as in pregnancy test kits”, said Dr Connor.
Some semi-quantitative methods are now being developed, for example, an ‘instant-read’, lateral flow assay for methamphetamine. So far, LFIAs have been developed for 5-fluorouracil, doxorubicin and paclitaxel. FCMIAs may be able to perform a simultaneous assay of multiple antineoplastic drugs. The ideal would be an array of six drugs, suggested Dr Connor.
Jellyfish mucus
Jellyfish mucus is able to trap some nanoparticles and may therefore be useful for decontaminating waste water containing, for example, nanoparticles of medicinal compounds, Philippe Barthélemy (ChemBioPharm, University of Bordeaux, France) told the audience.
Nanoparticles are widely used in industrial processes, cosmetics and, increasingly, in medicines. A number of nanomedicines have already been authorised. Engineered nanoparticles are known to have toxic effects on micro-organisms and higher species, and for this reason the handling of nano-waste materials is important.
Nanoparticles cannot be filtered out of waste water because they are too small. However, some naturally-occurring gels, such as the mucus secreted by stressed jellyfish, are able to trap and remove nanoparticles, explained Professor Barthélemy. His work has focused on the use of natural and artificial, biomimetic gels.
“We now have a whole arsenal of gels that can be used on surfaces and in solutions – only small amounts are needed for decontamination”, he said. One of the current challenges is to find a way to store jellyfish mucus, he added.
Triple-wrap or spray-wipe?
The use of triple-wrapped, pre-sterilised consumables in aseptic preparation saves time compared with the traditional ‘spray and wipe’ process for surface disinfection, according to Laura-Jane Keating (Quality Control, Pharmacy Department, Royal Gwent Hospital, Newport UK). Items that are transferred into the aseptic working area of an isolator or laminar flow hood need to be sterile and over-wrapped or need to undergo surface disinfection by spraying and wiping with suitable agents.
Guidance issued in January 2015 by the Medicines and Healthcare products Regulatory Agency in the UK mandates the use of a sporicidal agent (such as hydrogen peroxide) in addition to the conventional disinfectant (usually 70% isopropyl alcohol (IPA)), in a two-step process.
Triple-wrapped, sterilised packs of consumables for specific tasks were obtained. A combination of three bespoke packs and four standard packs covered 85% of processes. At each transfer stage, a layer of wrapping is removed rather than spraying and wiping with sporicide and then with IPA.
Time savings were significant when the packs were used, with only a minimal increase in cost. The use of packs was “only marginally more expensive than the spray-wipe process because of the relatively high cost of the sporicide”, said Ms Keating. Other benefits have included a reduction in bioburden and ‘out-of-specification’ results and rationalisation of the processes and consumables used, she added.
The 20th European GERPAC conference took place in Hyères, France, 4–6 October 2017. GERPAC stands for Group for Evaluation and Research on Protection in Areas under Control.
Authors
Laurence Goldberg FRPharmS
Christine Clark PhD FRPharmS FCPP(Hon)
