University of Plymouth PEARL https://pearl.plymouth.ac.uk 04 University of Plymouth Research Theses 01 Research Theses Main Collection 2014 Effectiveness of a closed system device in reducing occupational exposure and environmental concentrations of anticancer drugs Vyas, Nitin http://hdl.handle.net/10026.1/3049 Plymouth University All content in PEARL is protected by copyright law. Author manuscripts are made available in accordance with publisher policies. Please cite only the published version using the details provided on the item record or document. In the absence of an open licence (e.g. Creative Commons), permissions for further reuse of content should be sought from the publisher or author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the author’s prior consent. i ii Effectiveness of a closed system device in reducing occupational exposure and environmental concentrations of anticancer drugs by Nitin Vyas Volume 1 of 1 A thesis submitted to Plymouth University in partial fulfilment for the degree of Doctor of Philosophy School of Geography, Earth and Environmental Sciences March 2014 iii Nitin Vyas Effectiveness of a closed system device in reducing occupational exposure and environmental concentrations of anticancer drugs. iv Abstract Owing to their non-selective nature, anti-cancer drugs affect both cancerous and non- cancerous cells and present a major health risk to healthcare staff working with them. This project was conducted at Derriford Hospital, Plymouth, to investigate the extent of contamination with anti-cancer drugs on work surfaces and the environmental emissions of these drugs. In the Isolator study, surface contamination arising from the preparation of five anticancer drug infusions (epirubicin, fluorouracil, cisplatin, oxaliplatin and carboplatin) in a pharmaceutical isolator and external surfaces of infusion bags and syringes using a conventional syringe and needle technique was investigated and compared with that obtained using a closed system drug transfer device (Tevadaptor). Wipe samples were taken for a period of one week from pre-defined areas in a pharmaceutical isolator and from the surface of prepared Intra-Venous (IV) infusion bags and pre-filled syringes to obtain baseline data. Gloves and preparation mats used during this period were also collected. Following a one-week operator familiarisation period, the Tevadaptor device was then introduced for cytotoxic preparation and wipe-sampling of surfaces and collection of consumables was continued for a further week (intervention period). The samples obtained were then analysed by HPLC and ICP-MS. The baseline contamination data from Tevadaptor isolator study was undetected to 0.9 ng cm-2 (epirubicin), undetected to 3.58 ng cm-2 (5-FU) and 0.05-0.92 ng cm-2 (Pt) in the wipe samples from the pharmaceutical isolator surfaces; amounts on glove samples were 1100-6100 ng/glove (epirubicin), 300-8100 ng/glove (5-FU) and 1-6 ng/glove (platinum). During the intervention phase isolator surface contamination was not detected in all samples for 5-FU and epirubicin and platinum was detected on the isolator surfaces in the range of 0.002-0.09 ng cm-2. The use of Tevadaptor resulted in a reduction of contamination on external surfaces by a factor of 10 or more for all marker drugs. A ward study investigated the surface contamination in the oncology out-patient department caused by cisplatin, oxaliplatin, carboplatin and gemcitabine. The study compared the effect of using the Tevadaptor to prepare and administer anticancer drugs infusions on ward surface contamination to the current UK standard practice. A v questionnaire was also distributed to participating staff members to assess the user- friendliness of Tevadaptor. Wipe samples were taken from pre-defined areas from the oncology out-patients department and gloves used by nursing staff for assembly and administration of the above drugs were also collected. Sample collection followed a similar schedule to the Tevadaptor isolator study. The baseline ward surface contamination ranged from undetected to 4.97 ng cm-2 (gemcitabine) and 3.1 ng cm-2 (platinum). In the case of gloves used by nursing staff the levels of contamination ranged from undetected to 1251 ng/glove (gemcitabine) and 405.4 ng/glove (platinum). The contamination on ward surfaces during the intervention phase ranged from undetected to 3.21 ng cm-2 (gemcitabine) and 2.69 ng cm-2 (platinum) and contamination levels on gloves ranged from undetected to 9252 ng/glove (gemcitabine) and 1319 ng/glove (platinum). During the intervention phase there was a reduction in frequency of contamination, even though the total amount of surface contamination by anticancer drugs did not always decrease in comparison to baseline data, presumably due to unaccounted spillages. A drain study investigated the presence of platinum in hospital wastewater as a measure of contamination caused by the excretion of platinum-based anticancer drugs by patients. Platinum was measured over a three week period in one of the main drains and in the effluent of the oncology ward. The study showed the presence of measurable quantity of platinum which ranged from 0.02 to 140 μg L-1 in the oncology effluent and 0.03 to 100 μg L-1 in the main drain. Data from this study was coupled with published measurements on the removal of the drugs by conventional sewage treatment and then concentration of platinum arising from each drug was predicted in recipient surface waters as a function of water flow rate. Although predicted concentrations were below EMEA guidelines warranting further risk assessment, the presence of potentially carcinogenic, mutagenic and teratogenic substances in surface waters is cause for concern. The results showed that a closed system drug transfer device (CSTD) used in conjunction with an isolator is highly efficient in reducing surface contamination with anti-cancer drugs. However, despite current best practice contamination on ward surfaces remained even after the use of a CSTD. Nursing as well as healthcare staff should be educated of these results and the risks of occupational exposure to low levels vi of anti-cancer drugs and the use of PPE should be emphasised. Results of the drain study form the basis of preliminary estimates of the likely concentrations of platinum- based drugs in surface waters and their potential environmental impacts. vii Glossary 5-FU 5-Fluorouracil ABS Acrylonitrile-Butadiene-Styrene ADA Adenosine Deaminase AIDS Acquired Immuno Deficiency Syndrome ALARA As Low as Reasonable Achievable amu Atomic Mass Units API Active Pharmaceutical Ingredients ASHP American System of Health-Systems Pharmacists ASTM American Society for Testing and Materials BCNU Bis-chloroethylnitrosourea BSC Biological Safety Cabinet CIVAS Central Intravenous Additive Service CLL Chronic Lymphocytic Leukaemia COSHH Control of Substances Hazardous to Health CSTD Closed System Drug Transfer Device DC Direct Current DEHP Di-ethyl-hexyl phthalate DHFR Dihydrofolate reductase DNA Deoxyribonucleic Acid DPMU Derriford Pharmacy Manufacturing Unit ELA Experimental Lake Area EWC European Waste Catalogue FBAL α-fluoro-β-alanine FDA Food and Drug Administration FUTP Fluorouracil Triphosphate GFAA Graphite Furnace Atomic Absorption GI Gastro-intestinal GMP Good Manufacturing Practices HCL Hairy Cell Leukaemia HDPE High Density Polyethylene HEPA High-Efficiency Particulate Air HPLC High Performance Liquid Chromatography viii HPV Human Pappiloma Virus IARC The International Agency for Research on Cancer ICP Inductively Coupled Plasma ICP-OES Inductively Coupled Plasma Optical Emission Spectrometry ISOPP International Society of Oncology Pharmacy Practitioners IUPAC International Union of Pure and Applied Chemistry IV Intravenous LFC Laminar Flow Cabinet LOD Limit of Detection LOQ Limit of Quantification MBR Membrane Bioreactor System MHRA Medicines and Healthcare products Regulatory Agency MS Mass Spectrometry MTX Methotrexate ND None Detected NHS National Health Service NIOSH National Institute for Occupational Safety and Health PEEK Polyetheretherketone PPE Personal Protective Equipment PTFE Polytetrafluoroethlylene PVC Polyvinyl Chloride QA Quality Assurance QC Quality Control RCN Royal College of Nursing REC Research and Ethics Committee Rf Radio frequency RNA Ribonucleic acid RPC Reverse Phase Chromatography RSD Relative Standard Deviation SCE Sister Chromatid Exchange SHPA Society of Hospital Pharmacists of Australia SOP Standard Operating Procedure SPE Solid Phase Extraction ix TPN Total Parenteral Nutrition UN United Nations UV Ultraviolet UV-VIS Ultra Violet-Visible VHP Vaporised Hydrogen Peroxide WFI Water for Injections x Contents Chapter 1: Introduction ..................................................................................................... 1 1.1 General introduction and rationale ................................................................................ 1 1.2 Cancer ................................................................................................................................ 1 1.3 Antineoplastic agents ...................................................................................................... 2 1.3.1 Pyrimidine antimetabolites ............................................................................... 3 1.3.2 Purine