Original research chloride at 4°C and 23°C. No precipitate was noted for the low concentration when stored at 4°C; however, at the intermediate and higher concentrations tested, precipitation was noted and as previously reported. Similarly, in another study aciclovir 5 mg/ mL solution in 0.9% sodium chloride did not precipitate when stored at 4°C with stability demonstrated for at least 21 days of refrigeration. 12 A recent study with similar conditions reported an extended fridge stability at 5 mg/mL concentrations of >63 days. 13 Continuous infusions of antimicrobial agents, traditionally given in multiple daily doses, are convenient for OPAT services and patients where appropriate stability allows. Elastomeric devices delivering a continuous infusion of antimicrobials are often prefilled, stored in a fridge for up to 14 days for conve- nience, then attached to the patient for 24-hour infusion. Previous studies have shown that the temperature of the anti- microbial solution in OPAT infusion pumps exceeds the usual ambient room temperature of 25°C. Generally, 32°C is consid- ered the maximum in-use temperature reached in most parts of the world although, in some hot climate zones, this may reach up to 34°C. 14 Unfortunately, no stability data exist for aciclovir at these in-use temperature conditions and including the range of doses of clinical interest, as required by the UK National Health Service (NHS) protocol for the assessment of the stability of small molecules, the Yellow Cover Document (YCD). 15 The lack of regulatory-compliant stability data has limited the usage of aciclovir in OPAT despite the high clinical interest. The aim of this study was to investigate the suitability of continuous infusion of aciclovir in the OPAT setting by evaluating its stability in two elastomeric infusion devices. Stability was assessed in line with the requirements of the UK NHS YCD, with the excep- tion of the room temperature storage condition which was not compliant with the requirement of 25±2°C. Acetonitrile HPLC Lichrosolv (Merck, Darmstadt, Germany) was HPLC grade. Disodium hydrogen phosphate was AR grade from Merck (Darmstadt, Germany). Aciclovir for calibrators and quality control samples (QCs) was DBL aciclovir IV infusion (Batch: H161213AA, Hospira Australia, Mulgrave, Australia), the same batch used to generate the test samples. Guanine (used for degradation identification) was sourced from Sigma-Aldrich (St Louis, USA). Water used was Milli-Q. Two infusion devices, Easypump II LT 270–27-S (lot no 19E29GE221; B Braun Ltd, Sheffield, UK) and Accufuser VAWC0100L (lot no 1BBC170; Vygon UK Ltd, Swindon, UK) were used. Normal saline (0.9% w/v NaCl) was obtained from Baxter Healthcare Pty Ltd, New South Wales, Australia. MATERIALS AND METHODS Materials Assay method Calibrators were prepared by dilution of the aciclovir pharma- ceutical product with water to concentrations of 0.4, 0.6, 0.7, 0.8, 0.9 and 1 mg/mL. QCs were prepared by dilution of the aciclovir pharmaceutical product with water to concentrations of 0.833, 10 and 18.75 mg/mL. Calibrators were stored in sepa- rate aliquots at −80°C until required. The chromatography was adapted from the stability-indicating method of Malabagal et al , 16 using an Acquity UPLC BEH C18 (1.8 µ m) 2.1×30 mm analytical column (Waters, Milford, USA) as the stationary phase. The mobile phase was 97% 25mM phosphate buffer at pH 3.0 with 3% acetonitrile delivered isoc- ratically at 0.4 mL/min with a 3 min run time. Aciclovir and
guanine were detected at wavelengths of 252 nm and 247 nm, respectively. Calibrators, QCs and test samples were thawed at room temperature then vortex mixed. Calibrators and low concentra- tion (0.833 mg/mL) QCs and samples were centrifuged and then directly injected. Samples and QCs at the intermediate and high concentrations were centrifuged and then diluted with a dilution factor of 12.5 (50 µ L of sample combined with 575 µ L water) and 22.5 (40 µ L of sample combined with 860 µ L water), respec- tively, prior to injection. Assay performance Calibrators from 0.4 to 1 mg/mL (n=7 levels) were used to create the calibration curve, covering a range of 48–125% of the nominal test concentration. Linearity of the method was established from three separate calibration lines: slopes were 4434, 4504 and 4468; intercepts were −95178 to –4504 and −90900; correlation coefficients (r 2 ) were 0.99992, 0.99881 and 0.99934, with all calibrators being within 0.3%, 1.6% and 1.3% of nominal, respectively. Precision (%RSD) of the assay, demonstrated by replicate analysis (n=9) of QCs, was 1.2% at 0.833 mg/mL and 1.2% at 18.75 mg/mL. Accuracy (% bias) from the same QCs was −0.2% (0.833 mg/mL) and −1.1% (18.75mg/mL). With regard to specificity, aciclovir gave a peak at retention time 1.33 min. Guanine eluted with baseline separation prior to aciclovir at 0.47 min. Huidobro et al 17 reported that impurities were all more strongly retained than aciclovir, so a secondary chromatographic method that included a gradient of acetonitrile from 3% to 20% was used to search for the impurities during validation, but none were found. The mean peak purity index for chromatograms of the samples was 1.000. Preparation of aciclovir-filled infuser devices The required volume of aciclovir solution for IV infusion was transferred into a sterile measuring cylinder in a Class II biosafety cabinet and subsequently diluted to volume with normal saline to make a centralised stock solution at the desired concentration. Three concentrations of aciclovir were tested. These concentra- tions were selected to cover the clinical range of doses (concen- trations) corresponding to low dose (200 mg/240 mL=0.833 mg/ mL), intermediate dose (2400mg/240mL=10mg/mL) and high dose (4500mg/240mL=18.75mg/mL) when the devices are filled to the volume of 240 mL. The nominal reservoir fill volume of 240 mL was transferred from the central stock solu- tion to each device using a 60 mL syringe; devices were prepared in triplicate at each concentration. Flow restrictors and in-line filters were removed from all devices to enable sampling and the outlet line was clamped. Aciclovir-filled devices were stored at room temperature (reported as <20°C). Each device was wrapped with aluminium foil to completely cover its surfaces and prevent exposure to light during storage and sampling. Following the 14 days of room temperature storage, the devices were stored within an incubator at the maximum expected in-use temperature of 32°C for 24 hours. Duplicate samples were collected from each indi- vidual device for the two device types that were tested at three concentrations in triplicate devices at 11 different time points which included 0, 12, 24, 48, 96, 168, 240 and 336 hours at room temperature and 344, 348 and 360 hours at 32°C in-use temperature (running phase). A total of 396 samples were collected and an aliquot of 0.5 mL of each sample was immedi- ately stored in a −80°C freezer for concentration measurement.
Sime FB, et al . Eur J Hosp Pharm 2023; 0 :1–6. doi:10.1136/ejhpharm-2023-003784
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