Aggregate Formation and Antibody Stability in Infusion Bags: The Impact of Manual and Robotic Compounding of Monoclonal Antibodies.

Monoclonal antibodies (mAbs) can be damaged during the aseptic compounding process, with aggregation being the most prevalent form of degradation. Protein aggregates represent one of several risk factors for undesired immunogenicity of mAbs, which can potentially lead to severe adverse drug reactions and less effective treatments. Since data on aggregate and particle formation by robotic compounding is missing, we aimed to compare the antibody stability between robotic- and manual compounding of mAbs with regard to formation of (sub)visible aggregates. Infliximab and trastuzumab were compounded into infusion bags with the APOTECAchemo robot or manually by nurses or pharmacy technicians. The products were analyzed by quantifying (sub)visible particles with nanoparticle tracking analysis, dynamic light scattering (DLS), light obscuration, micro-flow imaging, high pressure size exclusion chromatography (HP-SEC), and visual inspection. HP-SEC showed high percentages monomers in trastuzumab (99.4 % and 99.4 %) and infliximab (99.5 % and 99.6 %) infusion bags for both manual and robotic compounding, respectively. DLS indicated more consistent and reproducible results with robotic compounding, and confirmed monodisperse samples with a higher polydispersity index for manual compounding (0.16, interquartile range; IQR 0.14-0.18) compared to robotic compounding (0.12, IQR 0.11-0.15). This study shows that the studied compounding methods had a minor impact on the number of aggregates and particles, and that robotic compounding of mAbs provided at least similar quality as manual compounding.

Acute Kidney Injury in the ICU during Ganciclovir Treatment, an Observational Study.

The aim of this study is to investigate the relationship between ganciclovir exposure with TDM and the development of AKI in ICU patients. This retrospective single-center observational cohort study included adult ICU patients treated with ganciclovir who had a minimum of one ganciclovir trough serum level. Patients receiving less than two days of treatment and patients with fewer than two measurements of serum creatinine, RIFLE scores, and/or renal SOFA scores were excluded. Acute kidney injury incidence was assessed with the difference between the final and first values of the renal SOFA score, RIFLE score, and serum creatinine. Nonparametric statistical tests were performed. In addition, the clinical relevance of these results was evaluated. A total of 64 patients were included with a median cumulative dose of 3150 mg. The mean difference in serum creatinine during ganciclovir treatment was reduced by 7.3 µmol/L (p = 0.143). The RIFLE score decreased by 0.04 (p = 0.912), and the renal SOFA score was reduced by 0.07 (p = 0.551). This single-center observational cohort study showed that ICU patients using ganciclovir with TDM-guided dosing did not develop acute kidney injury as measured by serum creatinine, RIFLE score, and renal SOFA score.

Analysis of production time and capacity for manual and robotic compounding scenarios for parenteral hazardous drugs.

BACKGROUND: The increasing amount of hazardous preparations in combination with shortages leads to a call for more efficient compounding methods. This research aims to evaluate the required amount of time, production capacity and direct labour costs of the manual, manual software-supported and robotic compounding of parenteral hazardous drugs. METHODS: This multicentre study was conducted at the clinical pharmacy departments of three Dutch hospitals with different compounding methods: St Antonius hospital (manual software-supported compounding), Amsterdam University Medical Centre (Amsterdam UMC) (both robotic compounding and manual compounding without software support) and OLVG (robotic compounding). Time measurements of individual hazardous drugs were performed in all three hospitals. At Amsterdam UMC and St Antonius hospital, the times per compounding phase, the production capacity and the direct labour costs per preparation were also determined. To reflect real-world situations, the combination of robotic and manual compounding was also studied. RESULTS: The total compounding process, including the actions before compounding and the release-time and cleaning time, lasted 6:44 min with robotic compounding and was faster than manual compounding with and without software support (6:48 and 9:48 min, respectively). The production capacity of one full-time equivalent (FTE) on 1 day (P1FTE1day) was 15 preparations per FTE per day with manual compounding with and without software support, and 57 preparations per FTE per day with only robotic compounding. If manual and robotic compounding were combined, the production capacity was 30 preparations per FTE per day. In this setting, the direct labour costs per preparation were €5.21, while these costs were €13.18 with only manual compounding. CONCLUSION: Compared with manual compounding, robotic compounding was faster over the total compounding process. A combination of manual compounding and robotic compounding could lead to 100% more preparations per FTE and 2.5 times lower direct labour costs compared with manual compounding.

An economic evaluation of vial sharing of expensive drugs in automated compounding.

Background Manual compounding of expensive cytotoxic drugs often leads to drug wastage, due to residual product in vials not being used. Aim To determine the cost savings that can be achieved by implementing an automated compounding process with a vial sharing strategy, instead of manually compounding drugs. Method The drug wastage during automated compounding was compared with that of three simulation scenarios using manual compounding, in a general teaching hospital. All automatically compounded preparations of rituximab, pemetrexed, bevacizumab, and trastuzumab from September 2019 and up until February 2020 were included. A vial sharing strategy was implemented during the automated compounding process (scenario 1). In this scenario, all residual drugs could be reused for up to seven days. Two of the simulation scenarios for manual compounding were executed using a batch compounding strategy, for an entire working day (scenario 2), and twice a day (scenario 3). The third manual compounding simulation was executed without making use of a batch compounding strategy (scenario 4). Results There was no drug wastage during automated compounding with vial sharing (scenario 1). The cost of drug wastage for 1001 preparations, over a period of six months for rituximab, pemetrexed, bevacizumab, and trastuzumab combined, were € 34,133 for scenario 2, € 46,688 for scenario 3, and € 88,255 for scenario 4. The estimated total cost savings between 2017, when the compounding robot was commissioned, and 2021, was more than € 280,000. Conclusion Vial sharing of expensive drugs during automated compounding can prevent drug wastage, resulting in an economic and environmental advantage as opposed to manual compounding.

[Allergic reactions to COVID-19 vaccines]. / Overgevoeligheidsreacties op covid-19-vaccins.

In 2021 many people in the Netherlands will be vaccinated against COVID-19. The mass vaccination and the new types of vaccines trigger questions about the safety of these vaccines. In this paper we discuss: (1) what reactions are expected from COVID-19 vaccines, (2) what precautions are needed when vaccinating people, and (3) how to act when allergic reactions occur. The COVID-19 vaccines include the first vaccines produced with the mRNA platform. The most frequent adverse reactions are comparable with other vaccines. Allergic reactions to COVID-19 vaccines are rare but can occur. These reactions may be related to excipients in the vaccines, like polyethylene glycol. In case of a possible allergic reaction, a doctor, in consultation with an allergist, can investigate whether vaccination is safe in the future and whether precautions are necessary. Allergic reactions to vaccine components must be recorded completely and unambiguously in the patient file.

The assessment of environmental and external cross-contamination in preparing ready-to-administer cytotoxic drugs: a comparison between a robotic system and conventional manual production.

OBJECTIVES: The primary aim of the study was to compare environmental and external (cross-) contamination of traces of cytostatics, during preparation of 5-fluorouracil and cyclophosphamide using a robotic system (APOTECAchemo) or the conventional manual compounding procedure. The secondary aim was to validate the cleaning procedure of the robot. METHODS: Eighty ready-to-administer (RTA) infusion bags with 5-fluorouracil, cyclophosphamide or sodium chloride were compounded using both techniques on 3-5 days. Wipe samples were taken from several locations in the compounding room before and after cleaning, and also from the technician's gloves. These samples were analysed for 5-fluorouracil and cyclophosphamide concentrations using GC/MS/MS. KEY FINDINGS: A total of 284 wipe samples were collected during the study (113 from the manual and 171 from the robotic process). External contamination on the outside of infusion bags was 3.75% for both manual and robotic compounding. For manual compounding, external cross-contamination occurred on 2.5% of the prepared infusion bags. External cross-contamination occurred on 1.25% of the infusion bags for the robotic procedure. Inside the compounding room, 9% of the environmental wipe samples were contaminated in case of manual production and 24% for robotic compounding. Since 50% of the contaminated environmental samples for the robotic system were taken after cleaning, the cleaning procedure was extended and parameter setting for cyclophosphamide handling was performed. After this, residual environmental or external contamination was no longer detectable. CONCLUSION: Comparison of both preparation methods showed that external (cross-)contamination of infusion bags was lower using the robotic system. An optimized cleaning procedure showed the best results in environmental contamination for the robot.