Farshid Sadeghipour

Use of a systematic risk analysis method to improve safety in the production of paediatric parenteral nutrition solutions

Background: Until recently, the preparation of paediatric parenteral nutrition formulations in our institution included re-transcription and manual compounding of the mixture. Although no significant clinical problems have occurred, re-engineering of this high risk activity was undertaken to improve its safety. Several changes have been implemented including new prescription software, direct recording on a server, automatic printing of the labels, and creation of a file used to pilot a BAXA MM 12 automatic compounder. The objectives of this study were to compare the risks associated with the old and new processes, to quantify the improved safety with the new process, and to identify the major residual risks. Methods: A failure modes, effects, and criticality analysis (FMECA) was performed by a multidisciplinary team. A cause-effect diagram was built, the failure modes were defined, and the criticality index (CI) was determined for each of them on the basis of the likelihood of occurrence, the severity of the potential effect, and the detection probability. The CIs for each failure mode were compared for the old and new processes and the risk reduction was quantified. Results: The sum of the CIs of all 18 identified failure modes was 3415 for the old process and 1397 for the new (reduction of 59%). The new process reduced the CIs of the different failure modes by a mean factor of 7. The CI was smaller with the new process for 15 failure modes, unchanged for two, and slightly increased for one. The greatest reduction (by a factor of 36) concerned re-transcription errors, followed by readability problems (by a factor of 30) and chemical cross contamination (by a factor of 10). The most critical steps in the new process were labelling mistakes (CI 315, maximum 810), failure to detect a dosage or product mistake (CI 288), failure to detect a typing error during the prescription (CI 175), and microbial contamination (CI 126). Conclusions: Modification of the process resulted in a significant risk reduction as shown by risk analysis. Residual failure opportunities were also quantified, allowing additional actions to be taken to reduce the risk of labelling mistakes. This study illustrates the usefulness of prospective risk analysis methods in healthcare processes. More systematic use of risk analysis is needed to guide continuous safety improvement of high risk activities.

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.

Analysis of amphetamines by capillary electrophoresis and liquid chromatography: application to drug seizures and cross-validation

Two methods, capillary electrophoresis (CE) and liquid chromatography (LC), have been developed for the separation and quantitation of amphetamines found in illicit drug seizures. These methods allowed us to determine, within less than 8 min and without interference from adulterants, the presence of six current amphetamines. No significant statistical differences between both validated methods were observed as linearity, precision, accuracy and limits of detection and quantitation were similar. However, the order of elution of amphetamines and of adulterants was different; hence, these methods proved to be orthogonal which is very convenient for forensic analysis. Further, CE and LC were applied to the analysis of 13 seized tablets with quantitative results statistically similar. Qualitative results were also confirmed by GC-MS procedure.

Rapid determination of amphetamines by high-performance liquid chromatography with UV detection

Abstract A liquid chromatograpic method with UV detection was developed for the separation and quantification of six amphetamines in the presence of adulterants in illicit drugs. Comparison was made between a regular reversed-phase and a base-deactivated column. The mobile phase composition was optimized by studying the influence of pH, buffer composition and the organic solvent type. Validation was accomplished by examination of the linearity, precision, accuracy, limits of detection and limits of quantification of the method. Amphetamines were quantified in eight tablets obtained from illicit drug seizures and the results were verified by a GC-MS procedure.

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

SummaryNative 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.

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.

Long-term physico-chemical stability of standard parenteral nutritions for neonates ☆

BACKGROUND & AIMS Two ready-to-use parenteral nutritions (PN) have been developed, for the first days of life of the premature newborn, along with syringes of lipid emulsion with or without vitamins. Long-term physico-chemical stability for storage in wards was assessed. METHODS Physico-chemical stability of PN: visual inspection, particle size, pH, osmolarity measurement, amino acids, glucose, and electrolytes dosages. Physico-chemical stability of lipid emulsion: visual inspection, globule size, peroxide level and vitamins A, E, and C dosages. Stability was studied for 12 weeks on refrigerated (2-8 °C) and room temperature (30 ± 2 °C) samples. RESULTS No precipitation was detected in any PN. A brown coloration was observed in PN stored for four weeks at room temperature but not in the refrigerator. Concentrations of all the nutrients remained constant over the 12 week-study period. Phase separation of the lipid emulsion occurred after three weeks, but particle size complied with the USP limits for 12 weeks. Peroxide content increased only in the samples without vitamins at room temperature. Vitamins remained stable for one week under refrigeration. CONCLUSION The PN did not present a detectable change of the tested properties when refrigerated for 12 weeks. The lipid emulsion with vitamins is stable for one week when refrigerated.

Maximizing Calcium and Phosphate Content in Neonatal Parenteral Nutrition Solutions Using Organic Calcium and Phosphate Salts

BACKGROUND The provision of high amounts of calcium and phosphate in parenteral nutrition (PN) solution for neonates is important for bone mass accretion. Because of the risk of calcium phosphate precipitation, a well-documented incompatibility for inorganic salts, the concentrations of these electrolytes in PN are generally limited to 5 mmol/L. The aim of this study was to assess the risk of precipitation of calcium phosphate when organic calcium and phosphate salts are used instead of inorganic salts. METHODS Precipitation curves were determined for inorganic and organic calcium and phosphate salts in a PN solution favorable to precipitation (low concentration of amino acids and glucose) using visual inspection and particle counts. RESULTS The use of organic phosphate salt was associated with a decreased risk of precipitation of calcium phosphate. No precipitation occurred up to a concentration of 50 mmol/L of calcium and phosphate. In contrast, organic calcium salt only slightly decreased the risk of precipitation. CONCLUSION Up to 50 mmol/L of organic calcium and phosphate salts can be safely mixed in PN, even in unstable conditions, making it possible to follow the current European recommendations for requirements in neonates.

Evaluation of chemical contamination of surfaces during the preparation of chemotherapies in 24 hospital pharmacies

Purpose To evaluate the chemical contamination of surfaces by cytotoxic agents during preparation of injectable chemotherapies in hospital pharmacies. Methods 526 wipe samples collected in 24 Swiss hospital pharmacies were analysed using a validated liquid chromatography–mass spectrometry/mass spectrometry method able to quantify 10 cytotoxic agents: cytarabine, gemcitabine, cyclophosphamide, ifosfamide, methotrexate, etoposide phosphate, irinotecan, doxorubicin, epirubicin and vincristine. Information on chemotherapies produced, equipment and production processes used were collected from all the hospital pharmacies on a voluntary basis in order to investigate their association with contamination rates. Results In two pharmacies, no trace of the 10 cytotoxic agents was detected. Chemical contamination was found in the other 22 hospital pharmacies, with combined total contamination of the 10 cytotoxic agents ranging from 8 ng to more than 41 000 ng per sample. Most contaminated samples came from inside biosafety cabinets, but some came from other clean room areas and logistics rooms. Statistically significant associations were observed between contamination rates and sampling locations, the number of chemotherapies prepared per year and types of cleaning solutions used. Conclusions This study demonstrated that most of the hospital pharmacies tested had some contamination of surfaces by different cytotoxic agents. Even if highest levels of contamination were mainly detected inside biosafety cabinets, technicians were also exposed to cytotoxic agents detected in logistical and storage areas. Protective measures should therefore be maintained or even reinforced in these areas in order to limit technicians’ risks of exposure when handling cytotoxic products.

Reliability of chemotherapy preparation processes: Evaluating independent double-checking and computer-assisted gravimetric control

Background and objectives Centralized chemotherapy preparation units have established systematic strategies to avoid errors. Our work aimed to evaluate the accuracy of manual preparations associated with different control methods. Method A simulation study in an operational setting used phenylephrine and lidocaine as markers. Each operator prepared syringes that were controlled using a different method during each of three sessions (no control, visual double-checking, and gravimetric control). Eight reconstitutions and dilutions were prepared in each session, with variable doses and volumes, using different concentrations of stock solutions. Results were analyzed according to qualitative (choice of stock solution) and quantitative criteria (accurate, <5% deviation from the target concentration; weakly accurate, 5%–10%; inaccurate, 10%–30%; wrong, >30% deviation). Results Eleven operators carried out 19 sessions. No final preparation (n = 438) contained a wrong drug. The protocol involving no control failed to detect 1 of 3 dose errors made and double-checking failed to detect 3 of 7 dose errors. The gravimetric control method detected all 5 out of 5 dose errors. The accuracy of the doses measured was equivalent across the control methods (p = 0.63 Kruskal–Wallis). The final preparations ranged from 58% to 60% accurate, 25% to 27% weakly accurate, 14% to 17% inaccurate and 0.9% wrong. A high variability was observed between operators. Discussion Gravimetric control was the only method able to detect all dose errors, but it did not improve dose accuracy. A dose accuracy with <5% deviation cannot always be guaranteed using manual production. Automation should be considered in the future.