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In opening the symposium, Laurence Goldberg (Independent Pharmacy Consultant, UK) made reference to two of the conclusions from a recent report from the European Biosafety Network – “Closed system transfer devices (CSTDs) should be used in the preparation and administration of systemic anticancer treatment (SACT)” and “Universal, frequent, comprehensive monitoring of surface contamination should be implemented” (See resources).
Hazardous drug contamination
“There is a definite risk of transfer of hazardous drug residues from pharmacy to clinical areas and isolators are part of the problem”, according to Graham Sewell (Head of School of Health Professions and Associate Dean Research, University of Plymouth, UK) “The evidence is now sufficiently compelling to implement a register of health care staff handling cytotoxic drugs and a record of environmental monitoring”, he continued.
In the 1990s, studies showed that frequent handling of cytotoxic drugs presented a risk to reproductive health and wellbeing. Contamination of external surfaces of manufactured vials later turned out to be one of the main sources of contamination and this was reduced by the manufacturers. However, studies showed that many pharmacy sites and administration areas were contaminated with cytotoxic drugs. Even nanogram quantities pose a risk because a single molecule of a cytotoxic drug can cause a cancerous transformation in a living cell, said Professor Sewell.
Isolators – solution or problem?
Isolators are containment devices so the interiors become heavily contaminated with cytotoxic drugs. This contamination is transferred to surfaces of compounded products and is carried to areas outside the pharmacy, said Professor Sewell. Effective cleaning of isolators is difficult and there is frequent contamination of surfaces of prepared syringes and bags. However, the introduction of a CSTD (Tevadaptor) was associated with reductions in contamination “ranging from eight-fold to 1000-fold inside the isolator”, according to his studies. Consequently, the amounts of drugs on the surfaces of syringes and bags leaving the isolator fell dramatically.
These findings were consistent with those reported by other authors. Professor Sewell noted that a recent Cochrane review of the use of CSTDs that had produced inconclusive results had been heavily criticised by other experts for its inappropriate methodology. He concluded that regulators should now mandate keeping a register of exposure to cytotoxic drugs and regular environmental monitoring.
During the discussion Professor Irene Krämer commented that studies in her department showed that syringes prepared in a robot had very little surface contamination.
Alison Simons and Samantha Toland (Senior lecturers, Birmingham City University, UK) contrasted the limited protective clothing worn by nurses (when administering SACT) with the robust, complete protection worn by pharmacy technicians preparing injections. In an anonymous online survey of 200 nurses, 46% reported experiencing adverse events while administering SACT. Headache, dizziness and nausea were most common but one nurse reported vomiting when she unwrapped bags of chemotherapy. Another reported reversible hair thinning, and itchy noses and sore hands were also frequent complaints.
A second survey explored awareness of risks. Although 90% of respondents believed there were risks, only 2% said the drugs were carcinogenic. About 20% routinely wore protective clothing and many had no recent training in SACT handling.
The researchers concluded that adverse drug events (ADEs) are being experienced but nurses appear not to understand the risks. “We were surprised to see how much guidance is available – and is ignored!” they said. “We ignore the advice to use closed systems and rely heavily on personal protective equipment (PPE) that is not very good”, they added. They recommended that there should be sanctions for failure to adhere to guidance and that closed systems should be mandatory.
When making a business case for closed systems, they recommended finding the most appropriate product for local needs and involving pharmacy and procurement departments. Health and safety personnel should also be consulted because they are obliged to follow the Health and Safety Executive (HSE) guide. A business case template is available at www.SACTsafety.com.
Closed system administration
A ‘big bang’ approach to the introduction of closed systems for administration of SACT was adopted at Lewisham and Greenwich NHS Trust, explained Lisa McGarry (Lead Chemotherapy Nurse\Matron Cancer Services). The previous administration equipment had been “clumpy, noisy and prone to breaking down and left nurses feeling vulnerable”, she added.
A total of 40 new volumetric pumps and 20 syringe pumps were introduced. The service started with a unit comprising eight chemotherapy chairs staffed by four chemotherapy nurses with the capacity to handle 35 patients per day. The service was stepped up in two further phases to include a medical ward and a further ten chemotherapy chairs.
The new system allowed safe delivery of multiple-drug regimens and decreased SACT exposure for staff, said Ms McGarry. In addition, nurses could see at a glance what SACT had been administered and use of the B Braun Cyto-Set with Airstop (which prevents air from entering the line) meant that there was no need for disconnections, resulting in fewer alarms and less disruption for patients and nurses.
‘Manual preparation of cytotoxic injections can be associated with a number of problems including variable operator performance, assumed accuracy, limited documentation and risk of repetitive strain injury in operators’
Working in partnership with the company, nurses had been able to contribute to the development of a bespoke primary line infusion set for the delivery of SACT. Critical modifications included reducing the number of ports from three to two and shortening the line, explained Ms McGarry. Future work could include a trial of the Tevadaptor to reduce further the risk of exposure to SACT, she added.
Robotic compounding of cytotoxic injections offers advantages in accuracy and safety and frees technical staff to handle complex injectable products, such as liposomal formulations and loading of medicated, injectable beads, according to Irene Krämer (Director of Pharmacy, University Hospital Mainz, Germany).
Manual preparation of cytotoxic injections can be associated with a number of problems including variable operator performance, assumed accuracy, limited documentation and risk of repetitive strain injury in operators. In contrast, automated preparation is associated with proven accuracy, full traceability, workflow integrated with electronic prescribing and low physical stress for operators. There are also improvements in quality and increases in productivity with robotic preparation, she said. However, there can be considerable psychological stress, she acknowledged.
Ideally robotic systems should allow insertion of urgent doses into the preparation schedule and also be able to handle dose-banded products. They should also provide batch numbers and serial numbers to comply with the Falsified Medicine Directive requirements and incorporate automated waste disposal in sealed waste bags. Containment fail-safe mechanisms and gravimetric verification of dosage accuracy are also essential.
The APOTECA chemo (Loccioni) robot is used in the hospital pharmacy in Mainz. Evaluation of 2500 prepared doses showed accuracy of –5% to +2.5%. “You are unlikely to see this level of accuracy with a manual process”, she said. In addition, studies showed no microbiological contamination and lower levels of chemical contamination than those seen with manual preparation. The robot can prepare a maximum of 90 products per day during 7.4 hours of work.
‘Pharmacists should take responsibility for the safe use of advanced therapy medicinal products because there was a danger that doctors might regard them as “just another medicine”‘
At present some 50,000 doses per year are prepared by the pharmacy department, of which 33% are compounded in the robot. “Think of the robot as a team member, taking work off your hands rather than as a difficult machine”, she urged.
Advanced therapy products
Pharmacists should take responsibility for the safe use of advanced therapy medicinal products (ATMPs) because there was a danger that doctors might regard them as “just another medicine”, according to Anna de Goede (Pharmacist and Qualified Person, Radboud University Medical Centre, The Netherlands). Dr de Goede is involved in the provision of ATMPs “from bench to bedside” in her hospital and routinely deals with a number of cell-based treatments including natural killer cells (NK) and dendritic cells.
ATMPs are biological medicines that comprise gene therapy products, cell therapy products, tissue engineered products and combined ATMPs. All are precisely defined in EU Regulation EC/1394/2007. Good manufacturing practice for ATMPs came into force in May 2018. Cell therapy products are cells that have been ‘substantially manipulated’. Stem cell transplants are not classified as ATMPs because the cells have not been substantially manipulated and they are for homologous use, said Dr de Goede. ‘Non-homologous use’ means that the cells have a different function from that which they had in the donor.
Eight ATMPs are currently on the market and more will soon become available, said Dr de Goede.
There are many challenges in the handling of ATMPs as the products are so different from conventional medicines. The production process is difficult to standardise as the methods are different from conventional medicines.
For example, the NK cell product takes at least 36 days to manufacture in Dr de Goede’s laboratory and the final product (cells) cannot be sterilised or filtered. Fully-closed, automated equipment is now used and this helps to keep the product clean. The final product often has an extremely short shelf-life. It may have to be stored and transported at minus 80°C in liquid nitrogen and then be thawed and rinsed (to remove cryopreservation products), all of which calls for specialist handling techniques. For example, “Are your technicians trained to thaw cells and count them under a microscope?” she asked.
Chimeric antigen receptor (CAR) T-cell therapy is now rapidly advancing and two products – Kymriah and Yescarta – have marketing authorisations. This treatment involves first harvesting mononuclear cells from a patient’s blood by means of apheresis. In a laboratory, a viral vector is then used to transform cells so that they express tumour antigen (CD19) receptors. When injected, the T-cells bind to tumour antigens and lyse the tumour cells. Second-generation CAR T-cells are now used and these bind directly to tumour cells without need for antigen-presenting cells. However, the manufacturing process is complex and it takes at least one month to expand (grow) the therapeutic cells, explained Dr de Goede.
The most common problem with CAR T-cell therapy is cytokine release syndrome and so tocilizumab (an anti-IL-6 receptor antibody) has to be available for treatment. Furthermore, CAR T-cell therapy does not always work – there may not be enough CD19 antigens on the tumour or the CAR T-cells might have degraded, said Dr de Goede.
This treatment costs €300,000 per product per patient and it requires “tight coordination between pharmacy, cell facility and the clinical team’’.
It presents opportunities for hospital pharmacists to use their knowledge and expertise “to fill the knowledge gap, she said. Two documents published in the UK could be a useful starting point, she concluded (See resources).
Acute, post-operative pain must be treated aggressively because patients who are in pain cannot be sent home, José Luis Diéguez (Anaesthesia and Critical Care Consultant, Denia Hospital, Alicante, Spain) told the audience. The availability of injectable ibuprofen, 600mg/100ml, offers an important new option for clinicians. Loco-regional anaesthesia is not always possible or effective and opioids can cause problems with vomiting. Ibuprofen injection formulated with arginine has anti-inflammatory and analgesic effects. The 600mg dose, in a ready-to-administer presentation, is ideal and enables dosing in the range 1200–2400mg per day. “There is no advantage in giving an 800mg dose – it has no advantage over the 600mg dose”, he said. Proper use at this dose level decreases the need for remedication or rescue medication, he explained.
In addition, once the patient is able to eat and drink, oral treatment can be started. Dose adjustment is not required when making the switch.
Contradictory or incomprehensible information about injectable medicines has been a contributory factor in some intravenous drug errors, according to Matthew Jones (Department of Pharmacy and Pharmacology, University of Bath, UK) The Medusa database is commonly use to find information about injectable drugs. It is compiled by pharmacists but used by nurses.
One study of paediatric resuscitation found 44 errors in extracting information from Medusa in 181 doses. On 31 occasions, users were unable to find the correct guide and on 13 occasions, unable to extract the correct information.
In order to improve performance, researchers asked nurses to use two monographs to find specific information, as they would in a real-life situation. The monographs were real but the product names were changed to eliminate bias. The questions were designed to assess ease of finding information and ease of understanding.
Displacement volume was a concept that was poorly understood and caused confusion. Other problems arose from failure to read through monographs. Users expected information to be presented in the order in which it would be used, but this was not always the case. Calculations were repeated causes of stress and confusion. Some changes have been made and work is in progress to test the new monographs in a simulation situation, said Dr Jones.
Many people write guidance about medicines but it needs to be done better. “We concentrate on accuracy and comprehensiveness but we need to focus on usability too”, said Dr Jones. “Get input from users”, he recommended.
Hospital aseptic compounding
“There is insufficient capacity in hospital aseptic compounding services to meet the demand, in the wake of the Carter Report”, according to Richard Bateman (Regional Procurement Specialist – South East Coast, UK). Many factors including lack of capital investment and workforce planning issues, have contributed to this situation. Furthermore, pharmacy managers have tended to tackle increases in workload by absorbing the work and then asking for funds. In this situation the management board will only see an increase in productivity and expect it to be repeated, he warned. A business case for planned expansion should be submitted before increases in workload are implemented, he said.
Outsourcing is another option but is still susceptible to shortages and suppler failures. Rationalisation and dose-banding are two steps that could alleviate some of the pressures on hospital aseptic services, he suggested.
Changing practice to improve safety was held at Birmingham ICC, UK, on 14 March 2019.
1 The Role of Pharmacy in the Successful Delivery of Advanced Therapy Medicinal Products (ATMPs) Information for Chief Pharmacists. Ed 1; February 2017.https://atmpmanufacture.org/wp-content/uploads/2017/03/ATMP-V1-Advice-for-Chief-Pharmacists.pdf (accessed March 2019).
2 Chimeric antigen receptor T cells. A briefing document for Chief Pharmacists Issued by: The ATMP Working Party – a subgroup of the Pharmaceutical QA Committee. December 2017. www.bopawebsite.org/sites/default/files/publications/SPS%20CAR%20-%20T%20briefing%20for%20Chief%20Pharmacists.pdf (accessed March 2019).
3 Observatory on current biosafety practice in European Oncology. European Biosafety Network. February 2019. www.europeanbiosafetynetwork.eu/wp-content/uploads/2019/03/Observatory-on-current-biosafety-practice-in-European-Oncology-1.pdf (accessed March 2019).