Abstract Two automation methods for aseptic preparation in hospital pharmacy, robot and peristaltic pump, were compared to manual process both for risk analysis using Failure Modes Effects and Criticality Analysis (FMECA) method and for productivity using time analysis grids built for each process. The results obtained with the different workflow organizations showed that the worst-case conditions for productivity was production “on demand” of tailor-made preparations. in that case, the manual process was not significantly different from the robotic process (p-value=0.72). For the standardized preparations, the semi-automatic process preparing a batch from bulk solution from “to be reconstituted” drugs was significantly superior to the robotic process preparing repetitive series of doses (p-value<0.01). Productivity of the robot was dramatically increased when the robot performed standardized preparations either from ready to use solutions or mixed cycles due to the robot design. When different processes were FMECA analyzed for risk analysis the robotic process was found as the safer process in comparison to others with a total of Criticality Indexes of 1060, 719, 656 for manual, semi-automatic and robot, respectively. Except for the robotic, semi-automatic and manual processes needed additional IT control systems to limit the risk of failures.

The aim of this study was to develop a specific simulation program for the validation of a cytotoxic compounding robot, KIRO® Oncology, for the preparation of sterile monoclonal antibodies and anti-infectious drugs. The impact of excipient formulations was clearly measured using simulation accuracy tests with worst case excipient (i.e. viscous, foaming) and allowed to correct the robotic settings prior to real production. Corrections brought accuracies within the acceptable range of ±5%. KIRO® Oncology robot has also the capacity of self-cleaning and a simulation combining media fill test, and environmental monitoring was able to validate the aseptic process including simulation of worst case conditions and highlighting the areas not accessible to self-cleaning to be corrected by additional manual cleaning measures. The risk of chemical contamination was simulated by using fluorescent dye of the process with high-risk excipient formulation and overpressure vials. Quality control reliability was simulated by using a model drug, and final concentration was determined by high-performance liquid chromatography-ultraviolet detection. Finally, productivity was simulated using different models of production showing the impact of the type of drug, the number of vials and the poor standardization of the process.

Aims: Azacitidine (AZA), a pyrimidine analogue, is validated for high-risk myelodysplastic syndrome or low-blast acute myeloid leukaemia in unfit patients for more intensive treatment. This study assessed the putative link between cardiac failure (CF) and AZA exposure.Methods: Cases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myélodysplasies. A description analysis and a disproportionality analysis using Vigibase, the WHO Global Individual Case Safety Reports (ICSRs) database, were conducted on ICSRs by the Standardized MedDRA Queries (SMQ broad) cardiac failure and by preferred terms cardiac failure and cardiac failure acute. The reported odds ratio (ROR) and its 95% 2-sided confidence interval was computed by comparing the proportion of CF reports with the suspected drug (AZA) and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period. Results:In the 4 case reports, all patients presented a cardiovascular history. In 1 patient, CF recurred after AZA re-challenge. The pharmacovigilance analysis in Vigibase retrieved 307 ICSRs of CF (SMQ) with AZA. Significant disproportionality signals associated with AZA were identified by using the SMQ cardiac failure (ROR 1.3) and the preferred terms cardiac failure (ROR 5.1) and cardiac failure acute (ROR 23.2). Conclusion:This study points to the potential role of AZA in the occurrence of CF. Cardiac evaluation before AZA initiation and regular monitoring of cardiac function during AZA treatment should be performed in patients with a history of cardiovascular disease. K E Y W O R D Santicancer drugs, drug safety, heart failure

In the context of batch production of cytotoxic drugs in hospital pharmacies with the need of sterility testing, the objective was to validate the use of Rapid Microbiological Method (RMM), and to develop adequate neutralization method in case of inhibition of bacterial growth. The potential microbiological growth inhibitory effect of three anticancer drugs (5 fluorouracil, irinotecan and oxaliplatin) selected for batch production was assessed on BacT/ALERT® system. Among cytotoxic drugs, only 5FU exhibited inhibitory effect on microbiological growth using rapid microbiological method. To counteract this effect our purpose was to use neutralizing agents complexing the drug i. e. activated carbon or ion exchange resins. The microbiological bactericidal concentration of 5FU was very low (1.10–4 mg/mL) indicating the absolute need to neutralize the whole drug before sterility test. The complexation was validated by High Performance Liquid Chromatography control of the residual 5FU concentration in solution after the use of neutralizing agents. Only activated carbon was able to fully capture 5FU when previously diluted at 5 mg/mL. Conversely, the resins, in the condition of the study, were not able to fully capture 5FU whatever the dilution. The microbiological growth on BacT/ALERT® system after active carbon treatment was successfully confirmed with Staphylococcus aureus. Based on this validation results a method was then developed to routinely be able to perform sterility test of the batches produced and was confirmed on five microbiological species (i. e. S. aureus, Pseudomonas aeruginosa, Bacillus subtilis, Candida albicans, Aspergillus brasiliensis). Our work gives a new insight for considering sterility testing by rapid microbiological method even for drugs exhibiting inhibitory effect on microbiological growth.