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OBJECTIVES Outpatient parenteral antimicrobial therapy (OPAT) services using continuous infusions (CIs) of antimicrobial agents in elastomeric devices require evidence of acceptable stability of the agent over the infusion period. A period of refrigerated storage of filled devices, followed by the CI period, is useful for OPAT services but can present a significant challenge to the stability of drugs. The aims of this study were to review fresh-filled stability data on antimicrobials which would be useful for OPAT services and to identify suitable candidates for further assessment. METHODS Searches identified papers relating to stability assessments of antimicrobials for immediate use tested above 31°C using a stability-indicating method. RESULTS We identified 18 stability studies published in 12 papers between 2015 and 2020, assessing the stability of 10 agents. Aminopenicillins like ampicillin and amoxicillin appear too unstable for CI, while benzylpenicillin may benefit from buffering to improve its stability. Cephalosporins vary in their stability and CI periods of 24 hours may not be achievable. Of the carbapenems, there are insufficient data for doripenem but meropenem has been extensively studied and is unsuitable for CI longer than 6 hours. Voriconazole may be suitable for CI but needs further investigation. CONCLUSIONS Some drugs identified in our review are unlikely to be suitable for continuous infusion in OPAT services due to instability. Using a 'fresh-fill' approach, without refrigerated storage, may make some drugs useful while other agents should be considered for further assessment to Yellow Cover Document standards. The impact of buffering for penicillins should be assessed further.

Objectives The aim of this study was to assess the stability of pemetrexed disodium (Alimta), reconstituted in 100 mL sodium chloride 0.9% w/v intravenous infusion bags (Baxter Viaflo) at two target bag concentrations (2.0 and 13.5 mg/mL) during storage at 2–8°C for 28 days (protected from light), followed by 24 hours at 25±2°C with 60±5% relative humidity (RH) (protected from light). This study was commissioned by NHS England and NHS Improvement to generate data to aid shelf life extensions for aseptic products compounded in National Health Service (NHS) hospital aseptic facilities. Methods A high performance liquid chromatography (HPLC) assay was developed and validated to monitor pemetrexed concentration and related substance levels in accordance with NHS yellow cover document requirements. This assay and analysis of related substances was used alongside visual inspection, pH monitoring and sub-visible particle count analysis to monitor stability. The stability of three preparations of each concentration of pemetrexed disodium in Viaflo saline bags (0.9% w/v) was assessed at various time points. Results Pemetrexed assay concentrations remained >97.0% of initial concentration at all points during the study (including the period at elevated temperature). Appearance remained consistent with the Summary of Product Characteristics, particle count data remained within the British Pharmacopoeia limits, and pH remained within 0.43 units of T=0 at all times. The increases in related substance levels during the study were found to be the limiting factor for shelf life assignment. Conclusion The data for appearance, pH, sub-visible particle count analysis and pemetrexed assay would support a shelf life of 28 days stored at 2–8°C (protected from light) followed by 24 hours at 25±2°C with 60±5% RH (protected from light). However, given the increase in related substance levels, a shelf life of 21 days stored at 2–8°C (protected from light) was deemed to be appropriate.

Background To assess the feasibility of its use in OPAT via continuous infusion, the stability of temocillin solutions at clinically relevant concentrations in two elastomeric infusion devices (B. Braun Medical Ltd Easypump® II LT 270-27- S and Spirit Ltd Medical Dosi-Fuser® L25915-250D1) was evaluated during 14 days of (2°C–8°C) fridge storage followed by 24 h exposure in-use temperature at 32°C, when reconstituted with 0.3% citrate buffer at pH 7. Methods Stability testing was conducted in accordance with the standard protocols for deriving and assessment of stability of small molecule aseptic preparation as per the latest UK National Health Service Pharmaceutical Quality Assurance Committee Yellow Cover Document (YCD) requirements. A stability indicating assay method was developed with an ultra-HPLC (UHPLC) system using photodiode array detector. Temocillin concentrations corresponding to low (500 mg/240 mL), intermediate (4000 mg/240 mL) and high (6000 mg/240 mL) dose in triplicate devices were tested with duplicate samples at 11 timepoints during 14 days of fridge storage followed by 24 h in-use temperature exposure at 32°C. Results A total of 396 samples were collected and assayed. The percentage of temocillin remaining after 14 days of fridge storage was greater than 97% in both devices and at all concentrations tested. During in-use temperature, 95% stability limit was achieved for 12 h for all doses and devices tested except for the high concentration in the Dosi-Fuser® device, which met this criterion for only 10 h of in-use temperature exposure. Conclusions Temocillin reconstituted with 0.3% citrate buffer at pH 7 in elastomeric infusion devices can be stored in a fridge (2°C–8°C) for 2 weeks, meeting the YCD acceptance criteria of

Objectives To investigate the stability of ceftolozane/tazobactam 5 mg/mL and 20 mg/mL solutions for infusion in two elastomeric devices: FOLFusor LV10 (Baxter Healthcare) and Easypump® II (B. Braun Medical Ltd) and determine if an extended shelf life of up to 8 days storage at 2–8°C plus 24 h ‘in use’ at 32°C was achievable. Methods Testing was as per the latest NHS Pharmaceutical Quality Assurance Committee Yellow Cover Document (YCD) requirements. A stability-indicating LC method was used for assessing the stability of solutions of ceftolozane/tazobactam at 5 mg/mL and 20 mg/mL (combined concentration of both actives) respectively, tested in two batches in triplicate (n = 3) at five timepoints according to the requirements of the YCD. Results Ceftolozane/tazobactam, diluted in 0.9% w/v sodium chloride at 5 mg/mL and 20 mg/mL, degraded during in-use storage at 32°C with Conclusions Solutions of ceftolozane/tazobactam can be administered in outpatient parenteral antimicrobial therapy (OPAT) services following refrigerated storage for up to 8 days, when limited to a 12 h infusion at in-use temperature of 32°C. For UK OPAT services where twice daily dosing is feasible, our data provides another treatment option for challenging infections. In countries where a 10% loss of ceftolozane/tazobactam is acceptable, a 24 h infusion is supported by the data.

Background In order to use aseptically prepared elastomeric infusers, outpatient parenteral antimicrobial therapy (OPAT) services require extended stability data for antimicrobial agents to assign a product shelf-life. In the UK, the relevant standards for stability testing and shelf-life assignment are published in ‘A Standard Protocol for Deriving and Assessment of Stability—Part 1 (Aseptic Preparations—Small Molecules), commonly called the Yellow Covered Document (YCD). A previous systematic review published in 2017 failed to identify data on the stability of antimicrobials in elastomeric devices for OPAT services that met YCD requirements in force at the time. The aim of this review was to update that search, following a subsequent change to YCD requirements in 2017 and 2019 and expand that dataset to identify progress made in providing assurance about the stability of antimicrobial agents for OPAT services. Methods Searches were undertaken for papers relating to extended stability of antimicrobials. Citations were included when antimicrobial shelf-life was assessed using a stability-indicating method and considered a period of storage, either refrigerated or at room temperature, followed by in-use testing at a temperature at or above 32°C. Results Of 267 initial citations, six met the inclusion criteria and underwent full text review for data extraction. Included antimicrobials were cefazolin, ceftazidime, piperacillin/tazobactam, flucloxacillin and ceftolozane/tazobactam. Of these, only flucloxacillin and piperacillin demonstrated YCD compliant stability over the 24-hour infusion period while cefazolin, ceftazidime and ceftolozane/tazobactam could be infused over 12-hour period. Conclusions Contrary to the position found in 2017 review, high-quality data are now available to support the use of a number of antimicrobial agents in extended infusion in elastomeric devices for OPAT services. There is a need to expand the dataset, as well as developing international consensus on the ideal parameters for stability assessment of such infusions in elastomeric devices.

Background Outpatient parenteral antimicrobial therapy (OPAT) is an established approach to patient care, the benefits of which are clinical, financial and preferred place of care for patients. In order to maximise these benefits ‘once daily’ antimicrobials should be used. Antimicrobial stewardship principles state that, where possible, narrow spectrum, organism specific agents should be used for infection management. Commercially available narrow spectrum agents frequently require administration 2, 3 or more times each day. A dilemma for OPAT services arises therefore to either: (1) use once daily broad spectrum antimicrobials going against stewardship principles; (2) administer narrow spectrum agents as a continuous infusion via a portable medical device. Purpose Medicines administration via a portable device requires appropriate stability data. The Yellow Covered Document (YCD) stipulates the minimum dataset for assessment of stability. To facilitate OPAT services to adhere to stewardship requirements and access stability data for narrow spectrum agents, a comprehensive literature review was undertaken. This review assessed the published antimicrobial stability literature available and its compliance with the dataset required by the YCD. Material and methods Searches were conducted in Medline, EMBASE, Global Health, International Pharmaceutical Abstracts and Biomedical Research Database in April 2014 and November 2015. Results 420 records were identified, 299 of which were excluded following title and abstract review. Full text review of 121 citations identified no papers that met the dataset requirements of the YCD. Conclusion Access to stability data in administration devices is a barrier to service expansion within the antimicrobial stewardship agenda. This review found no published studies that fully complied with YCD standards for shelf-life extension. References and/or acknowledgements The Yellow Covered Document: A Standard Protocol for Deriving and Assessment of Stability- Part 1. Third Edition, 2015. NHS Pharmaceutical Quality Assurance Committee. Conflict of interest: Corporate sponsored research or other substantive relationships: MG and TH serve on the BSAC UK OPAT Initiative Steering Group receiving reimbursement of travel expenses only from the BSAC for attending and speaking at OPAT related events. MG reports attending advisory boards for Merck, Pfizer, Gilead and receiving educational travel and speaker grants from Merck and Astellas Pharmaceuticals/Sanofi, respectively. MS has attended an advisory board for Baxter. TH has received support to attend conferences from Sanofi, Astellas and Novartis and attended advisory board for Cubist, Astra Zeneca, MSD, Novartis and Ferring Pharmaceuticals Ltd.

Background Outpatient parenteral antimicrobial therapy (OPAT) is an established approach to patient care. A lack of data on antimicrobial stability within administration devices is a barrier to service expansion, and poses an antimicrobial stewardship dilemma. Often broad-spectrum, long half-life agents are used instead of narrow-spectrum agents, which need more frequent administration, but could possibly be used if stability data were available. Objectives To complete a comprehensive literature review of published antimicrobial stability data, and assess these against a nationally recognized minimum dataset for medicines compounded into administration devices. Methods Medline, EMBASE, Global Health, International Pharmaceutical Abstracts and Biomedical Research Database were interrogated in April 2014 and updated in November 2015. Results A total of 420 citations were reviewed with 121 selected for full text review. None of these papers met the inclusion criteria stipulated in the national standards. The most frequent reason for study exclusion was the tolerance limit for the level of the active pharmaceutical ingredient being wider than 95%-105% and absence of 'in-use' testing at 37 °C. Conclusions This review found no published studies that comply with UK national standards for stability testing. We recommend further research and publication of antimicrobial stability data to support OPAT within the antimicrobial stewardship agenda.

For the control of the production of medicines quality requirements are essential. Quality requirements cover the quality of the preparation throughout the whole shelf life, from release until the end of the shelf life. Medicines that are produced by the industry or prepared in a pharmacy have to meet the requirements of the European Pharmacopoeia. Status, type and structure of its monographs are dealt with. This chapter explains what quality requirements are. Also the background to the general quality requirements such as identity and content are discussed.

A sharps injury is defined as an incident that causes a needle or sharp object to penetrate the skin.1 Needlestick injuries are the most common cause of sharps injuries and pose a serious risk to healthcare workers. Current UK numbers of needlestick injuries are grossly underestimated due to under-reporting and no coordinated national surveillance programmes. It has been estimated that 100 000 needlestick injuries are reported in the UK each year but these numbers are likely to be an underestimate.2–4 The Royal College of Nursing reported that 48% of nurses polled (n = 4407) had experienced a needlestick injury during their career5 and more than 1 million needlestick injuries are estimated to occur in the European Union each year.6 Injuries from contaminated needles carry a risk of infection from more than 20 blood-borne pathogens, including hepatitis B, C and HIV. The risk of transmission of infection from an individual needlestick injury is small but because instances are so common the potential for infections is large. The introduction of EU Directive 2010/32/EU in 2010 aimed to prevent injuries and reduce blood-borne infections to healthcare workers from sharp instruments including needles. The EU Directive was published in June 2010, and is required to be implemented as national law in all EU countries by May 2013. Following the publication of the Directive there are many implications for hospital pharmacists and support staff as well as other healthcare professionals. The issues will be difficult to address in pharmacy technical services units and radiopharmacies as well as for reconstitution and drawing up of drug solutions on wards. In the more clinical setting and with potential risk of needlestick injuries causing blood-borne infections, including HIV and hepatitis, then the issues are clearer cut, any measures taken to reduce these risks need to …