Use of a prospective risk analysis method to improve the safety of the cancer chemotherapy process

Objective. To perform a risk analysis of the cancer chemotherapy process, by comparing five different organizations. To quantitatively demonstrate the usefulness of centralization and information technologies, to identify residual risks that may be the target of additional actions. Study design. A reengineering of the process started in 1999 and was planned to be finished in 2006. The analysis was performed after the centralization and at the beginning of information technologies integration. Setting. Two thousand two hundred beds university hospital, with medical, surgical, haematological, gynaecological, geriatric, paediatric oncological departments. Twelve thousand cancer chemotherapies each year. Methods. According to the failure modes, effects and criticality analysis (FMECA) method, the failure modes were defined and their criticality indexes were calculated on the basis of the likelihood of occurrence, the potential severity for the patients, and the detection probability. Criticality indexes were compared and the acceptability of residual risks was evaluated. Results. The sum of criticality indexes of 27 identified failure modes was 3596 for the decentralized phase, 2682 for centralization, 2385 for electronic prescription, 2081 for electronic production control, and 1824 for bedside scanning (49% global reduction). The greatest improvements concerned the risk of errors in the production protocols (by a factor of 48), followed by readability problems during transmission (14) and product/dose errors during the production (8). Among the six criticality indexes remaining superior to 100 in the final process, two were judged to be acceptable, whereas further improvements were planned for the four others. Conclusions. Centralization to the pharmacy was associated with a strong improvement but additional developments involving information technologies also contributed to a major risk reduction. A cost-effect analysis confirmed the pertinence of all developments, as the cost per gained criticality point remained stable all over the different phase

Wipe sampling procedure coupled to LC-MS/MS analysis for the simultaneous determination of 10 cytotoxic drugs on different surfaces

A simple wipe sampling procedure was developed for the surface contamination determination of ten cytotoxic drugs: cytarabine, gemcitabine, methotrexate, etoposide phosphate, cyclophosphamide, ifosfamide, irinotecan, doxorubicin, epirubicin and vincristine. Wiping was performed using Whatman filter paper on different surfaces such as stainless steel, polypropylene, polystyrol, glass, latex gloves, computer mouse and coated paperboard. Wiping and desorption procedures were investigated: The same solution containing 20% acetonitrile and 0.1% formic acid in water gave the best results. After ultrasonic desorption and then centrifugation, samples were analysed by a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in selected reaction monitoring mode. The whole analytical strategy from wipe sampling to LC-MS/MS analysis was evaluated to determine quantitative performance. The lowest limit of quantification of 10ng per wiping sample (i.e. 0.1ngcm−2) was determined for the ten investigated cytotoxic drugs. Relative standard deviation for intermediate precision was always inferior to 20%. As recovery was dependent on the tested surface for each drug, a correction factor was determined and applied for real samples. The method was then successfully applied at the cytotoxic production unit of the Geneva University Hospitals pharmacy. Figure Wipe sampling procedure for the determination of cytotoxic drug

Simultaneous quantification of ten cytotoxic drugs by a validated LC-ESI-MS/MS method

A liquid chromatography separation with electrospray ionisation and tandem mass spectrometry detection method was developed for the simultaneous quantification of ten commonly handled cytotoxic drugs in a hospital pharmacy. These cytotoxic drugs are cytarabine, gemcitabine, methotrexate, etoposide phosphate, cyclophosphamide, ifosfamide, irinotecan, doxorubicin, epirubicin and vincristine. The chromatographic separation was carried out by RPLC in less than 21min, applying a gradient elution of water and acetonitrile in the presence of 0.1% formic acid. MS/MS was performed on a triple quadrupole in selected reaction monitoring mode. The analytical method was validated to determine the limit of quantification (LOQ) and quantitative performance: lowest LOQs were between 0.25 and 2ngmL−1 for the ten investigated cytotoxic drugs; trueness values (i.e. recovery) were between 85% and 110%, and relative standard deviations for both repeatability and intermediate precision were always inferior to 15%. The multi-compound method was successfully applied for the quality control of pharmaceutical formulations and for analyses of spiked samples on potentially contaminated surfaces. Figure Preparation of cytotoxic formulations at the Pharmacy of Geneva University Hospital

Automated on-line dialysis and liquid chromatography of methylenedioxylated amphetamines in plasma and serum samples

An automated on-line dialysis coupled to a trace enrichment method has been developed for the separation and quantification of four methylenedioxylated amphetamines in serum and plasma, using liquid chromatography coupled to a fluorimetric detector. The on-line dialysis method was optimized and validated on fresh human serum and plasma samples. This sample preparation method allowed the quantification of methylenedioxylated amphetamines in serum or plasma, at concentrations as low as ca. 10 ng ml-1, with good repeatability, reproducibility and accuracy. The automated on-line dialysis method took less than 30 min. This method was applied to seven toxicological cases and results showed that the concentration of methylenedioxylated amphetamines in blood was in the range of 20-484 ng ml-1

Enantiomeric separation of four methylenedioxylated amphetamines on β-cyclodextrin chiral stationary phases

Native and derivatized β-cyclodextrins such as chiral stationary phases (CSP) were used for the simultaneous enantiomeric separation of four methylenedioxylated amphetamines (MDA, MDMA, MDEA and MBDB) by liquid chromatography. Fluorimetric detection was used in order to enhance sensitivity and selectivity. The mobile phase was, optimised by studying the influence of pH, triethylamine concentration, organic solvent type, column temperature and flow rate of the mobile phase. This method was validated by determining linearity, precision, accuracy, limits of detection and quantification, and was applied to the stereoselective analysis of illicit tablets (23 samples) and of human whole blood samples (spiked samples and two post-mortem cases). Whereas no significant deviation from a racemic ratio was observed in the tablets contents, the analysis of blood samples showed an enantioselective metabolism of MDMA

Sensitive and selective determination of methylenedioxylated amphetamines by high-performance liquid chromatography with fluorimetric detection

A rapid, sensitive and selective liquid chromatographic method with fluorimetric detection was developed for the separation and quantification of four methylenedioxylated amphetamines without interference of other drugs of abuse and common substances found in illicit tablets. The method was validated by examining linearity, precision and accuracy as well as detection and quantification limits. Methylenedioxylated amphetamines were quantified in eight tablets from illicit drug seizures and results were quantitatively compared to HPLC-UV analyses. To demonstrate the better sensitivity of the fluorimetric detection, methylenedioxylated amphetamines were analyzed in serum after a liquid-liquid extraction procedure and results were also compared to HPLC-UV analyses

Development of a generic sample preparation method using dispersive liquid–liquid microextraction for the monitoring of leachable compounds in hospital pharmacy-prepared prefilled drug products

Performant sample preparation is mandatory in any leachable study to clean and preconcentrate analytes within the sample to offer the best possible extraction recovery as well the best precision for any given substance.</p