Clinical Research Facility,
Centre for Health Science,
The introduction of closed system devices for the preparation of monoclonal antibodies has impacted positively on the pharmacy service at NHS Highland
NHS Highland is a nationally funded health board that co-ordinates and delivers primary and hospital care to people living in the north of Scotland. A population of around 310,000 is spread over an area of 32,568km2. This is about 6% of Scotland’s population spread over 11% of the surface area of the UK, an area similar in size to Belgium.
The main hospital is located in Inverness, with smaller hospitals located in other towns. The combination of remote location, sub-optimal transport infrastructure and frequent inclement winter weather means that many patients face long journeys to hospitals for treatment.
Monoclonal antibody use
The introduction of monoclonal antibodies (mAbs) into clinical practice in NHS Highland started with trastuzumab (Herceptin®) and was followed soon after by rituximab (MAbThera®). As these agents were used to treat malignant disease and doses were calculated by mg/m2 body surface area or mg/kg body weight. Preparation took place in the Aseptic Dispensing Unit (ADU) of the pharmacy in Raigmore Hospital in Inverness. This allowed for vial sharing to ensure that, wherever possible, content of the vials was not wasted, thereby minimising cost. Also, as these were novel agents, it was considered that administration and post-infusion patient monitoring should take place at Raigmore Hospital, where oncologists and haematologists were present.
As mAb infusions for non-malignant disorders were brought to market, the preparation of these was also undertaken in the ADU. These included infliximAb (Remicade®), natalizumab (Tysabri®) and tocilizumab (RoActemra®). In addition, the licensed indications for rituximab were extended to include rheumatoid arthritis. The high uptake of these products soon led to pressure on the ADU with consequent delay to other patients, particularly those requiring anticancer therapies.
mAb service provision
The initial plan was to have mAbs dispensed from the ADU in advance. This proved to be wasteful as, on occasion, treatment would not proceed as planned. At up to £2000 per infusion, this was unacceptably costly. A plan attempted to link infusion dates with days when clinical nurse specialists were visiting local hospitals. The aim was to send the prepared mAbs to the hospital for the nurse to administer the medicine to the patients. This proved a logistical challenge requiring a significant amount of staff time and also cost as taxis were often required to transport the pre‑prepared product.
In 2002 the Scottish Government’s Clinical Resource and Audit Group (CRAG) published Preparation of Injections in Near Patient Areas.(1) The guidance was intended to support the rationalisation of locations in which medicines were prepared. Hospitals were required to conduct a risk assessment on all the injectable products that were prepared in the institution and allocate preparation to the appropriate location. Products identified as being high-risk, such as parenteral nutrition (for example, complex formulation and risk of consequences of microbiological contamination) and cytotoxic chemotherapy (for example, risk of occupational exposure) were required to be prepared in aseptic dispensing facilities whereas lower risk products could be prepared on the ward or in the clinic for immediate administration to the patient.
Assessing the risk of mAb production
Preparation of Injections in Near Patient Areas did not address the risks associated with preparing mAbs for injection outside of a negative pressure pharmaceutical isolator and, in particular, the risk of occupational exposure.(2–5) Because these were novel agents with a range of serious side/adverse effects, including sensitisation and progressive multifocal leukoencephalopathy, the risk to staff could not be determined, so applying the standard risk assessment tool to the process led to a requirement that mAbs were prepared in a contained environment until further data became available.
In 2009, one of the authors attended a National meeting called to address the issue. Unfortunately the outcome of the meeting was that there was no consensus as to where monoclonal antibodies should be prepared because there was very little evidence available to inform the debate.
Shifting care into communities
In 2008 the Scottish Government published Shifting the Balance of Care,(6) which recommended that the NHS in Scotland redesign services so that hospital services that could be provided better in the community be shifted to the community.
The pressure on the ADU, the delay to patients receiving their mAb and Shifting the Balance of Care required a service‑wide rethink. In addition, there was a need to reduce length of patient journeys but still have the mAb infusions administered in locations where experienced nursing staff could assess the patients immediately before the infusion, and medical staff were nearby should the patient have a reaction to the mAb. Alongside these changes there also needed to be a way of ensuring that the infusions were prepared in a manner that protected staff and avoided wastage due to unnecessary preparation.
Use of closed systems
Tevadaptor™ had been marketed in Great Britain some years before as a vented preparation system designed to protect the person preparing cytotoxic chemotherapy from aerosol product created during the dissolution of product in a vial or the transfer of the product from a vial to a syringe. Tevadaptor™ acts by passing the exhaust gas generated in the preparation of the contents of a vial through a 0.2 micron filter. The evidence available supporting the effectiveness of the Tevadaptor™ system had been gathered using cytotoxic chemotherapy.(7,8)
Cytotoxic chemotherapeutic agents generally have a molecular weight of <1kDa whereas monoclonal antibodies generally have a molecular weight >140kDa. Following discussion with Teva UK and pharmaceutical scientists, it was accepted that the efficacy of the containment process could be extrapolated to include mAbs. Staff tested samples of the Tevadaptor™ and, in principle, it was agreed that they would be suitable for use when preparing monoclonal antibodies in clinics and wards.
This approach was signed off by the NHS Highland Clinical Governance Committee and plans made to introduce the Tevadaptor™ into practice. Bespoke prescription forms were designed that when completed gave staff members administering mAbs the details required for safe administration and monitoring plus any supportive medication required pre- and possibly post-infusion.
In conjunction with Teva UK, staff training materials were drawn up and one of the authors provided training to nursing staff who would administer the mAbs. Product preparation instructions from the Summary of Product Characteristics and Tevadaptor™ information were incorporated into a single standard operating procedure that took staff through the preparation process step-by-step. At the same time, physicians and pharmacists produced protocols for pre-infusion patient assessment, and patient management that covered all that was required of the nursing staff and how to manage the most likely side-effects experienced during and after the infusion.
At this time, patients receiving mAbs for malignant conditions had a dedicated infusions suite but this had insufficient capacity to provide infusions to patients receiving mAbs for other conditions. This meant that these patients had to receive their mAbs in hospital beds – not an effective use of resources or ward day rooms – neither of which were appropriate places for patient observation. One of the authors met with a hospital manager and convinced him that a day infusion unit should be established. The case was accepted and a suite of three offices was turned into a day infusions unit, which now also accommodates outpatients receiving other infusions, such as bisphosphonates and immunoglobulins.
However, it also became clear that despite the benefits an infusion suite would bring, patients with debilitating chronic conditions, such as multiple sclerosis and rheumatoid arthritis, would still have to travel a considerable distance for therapy. Travel across a large hospital campus was an additional problem identified by both patients and carers.
Healthcare staff in the community who were responsible for ongoing support noted that centralisation of care at Raigmore Hospital was undermining their ability to support the patients. General Practitioners (community physicians) were asked if they would arrange for the infusions to take place in their practices, but this was not supported owing to a lack of space in their buildings.
The publication of Shifting the Balance of Care had led to a rethink of the role of community hospitals. Community hospitals were reviewing what additional services they could provide. In discussion with nursing and medical managers of these hospitals, it was agreed that there was sufficient staff and space in these hospitals for the clinical assessment of patients and infusion of mAbs. The assessment and infusion would be undertaken by local nurses who had received training in patient care from colleagues at Raigmore Hospital. This included training on how to use the Tevadaptor™ devices.
Few of the community hospitals had medical staff in the hospital, but most had medical staff nearby who could attend at short notice if the patient became unwell during or after the infusion. These medical staff could also be called if the nurse assessing the patient before the infusion was uncertain as to whether to proceed or not. However, it soon became clear that the roles and responsibilities of each member of staff both in Raigmore Hospital and in the community hospital were not clear, and some community hospital managers had concerns over the governance issues arising from this lack of clarity.
In response to these concerns, shared care protocols were drawn up that defined roles and responsibilities for Raigmore Hospital medical, nursing and pharmacy staff, and community hospital medical, nursing and management staff, which were signed off by all the staff leads.
In early May 2010, a month before the new service was due to start, Teva UK decided to withdraw Tevadaptor™ from the UK market for commercial reasons. Teva UK managed to secure a six months’ supply of Tevadaptor™ for the Highland service, which left time to consider alternative products. An alternative device from Carmel Pharma (recently acquired by Becton Dickinson), the BD PhaSeal™ system, was selected via the risk assessment process described above. The BD PhaSeal™ system is a closed system drug transfer device (CSTD) that mechanically prohibits the transfer of environmental contaminants into the system and the escape of drug or vapour concentrations outside the system, thereby minimising individual and environmental exposure to drug vapour, aerosols and spills. The BD PhaSeal™ protector also prevents microbial ingress into the drug vial for up to 168 hours, or one week.
During drug preparation, a sealed pressure equalising expansion chamber contains all hazardous drug vapours and aerosols and the BD PhaSeal™ double membrane technology further ensures dry, leak proof connections and disconnections during drug preparation and administration. The BD PhaSeal™ CSTD has been validated by 30 independent published studies.
Since 2011, staff training was provided to enhance the correct use of the BD PhaSeal™ system.
The Tevadaptor™ and the BD PhaSeal™ devices cost approximately £10 (€12) each per infusion prepared, which is small amount to pay when placed alongside the cost of the mAb, which can run to almost £2000 (€2400) per infusion. Staff who have used both devices are content with either product; they preferred the way the Tevadaptor™ connected with an obvious ‘click’, but they like the reassurance that the exhaust gases generated when using the BD PhaSeal™ device were trapped in the plastic balloon. In all cases, the devices have worked faultlessly as designed. Any problem with the device has been related to operator error, particularly in the early days of their use.
The introduction of the devices to enable the mAbs to be prepared once the patient is present and assessed fit to receive the infusion has reduced wastage, which was running at one or two doses per month.
It might be that the preparation of mAbs using traditional needle and syringe causes no occupational exposure risk to staff, but the introduction of the Tevadaptor™ and BD PhaSeal™ devices allowed NHS Highland to redesign processes to improve patient care and keep costs down while at the same time minimising occupational exposure. Unsolicited patient comments such as: “so much less time spent travelling”, “the local staff know about me and can keep an eye on me” and “I don’t have to wait” are common.
The impact has been positive, with the service taking much less pharmacy time to manage than before because much more of the patient and mAb infusion scheduling is now carried out by the medical and nursing staff. And lastly, the ADU has been freed to concentrate only on items that it is required to prepare, which helps reduce waiting times for the patients it serves.
Therefore, improving quality can improve patient care and reduce cost.
- Pharmacists are ideally placed to influence patient-centred service development.
- Pharmacists are ideally placed to work between medical staff, nursing staff and managers to facilitate service development.
- The use of closed system devices has allowed NHS Highland to improve patient care, reduce costs and minimise occupational exposure.
- Impact has been positive, with the service taking much less pharmacy time to manage than before because much more of the patient and mAb infusion scheduling is now carried out by the medical and nursing staff.
- Scottish Government, Clinical Resource and Audit Group. Preparation of Injections in Near Patient Areas;2002.
- Langford S et al. Assessing the risk of handling monoclonal antibodies. Hospital Pharmacist 2008;15:60–4.
- Malson G. Should pharmacies prepare all monoclonal antibodies. Clin Pharmacist 2009; 1:302–4.
- National Institute for Occupational Safety and Health (NIOSH). NIOSH alert 2004–165. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings wwwcdc.gov/niosh/docs/2004–165/pdfs/2004–165.pdf (accessed 29 September 2012).
- de Goede A, Mandvliet M, Kosterink J. Occupational risk of anticancer monoclonal antibodies. Eur J Hosp Pharm Pract 2011/2;17:62–4.
- NHS Scotland. Improving outcomes by shifting the balance of care, improvement framework. Shifting the Balance of Care Delivery Group, July 2009. www.shiftingthebalance.scot.nhs.uk/improvement-framework/ (accessed 29 September 2012).
- Teva UK. Internal communication, 2009.
- Nygren O, Olofsson E, Johansson L. Spill and leakage using a drug preparation system based on double filter technology. Ann Occupational Hygiene 2008;52(2):95–8.