Lucie Bouchoud

Determination of potassium, sodium, calcium and magnesium in total parenteral nutrition formulations by capillary electrophoresis with contactless conductivity detection

A simple method based on capillary electrophoresis with a capacitively coupled contactless conductivity detector (CE-C(4)D) was developed for the determination of potassium, sodium, calcium and magnesium in parenteral nutrition formulations. A hydro-organic mixture, consisting of 100 mM Tris-acetate buffer at pH 4.5 and acetonitrile (80:20, v/v), was selected as the background electrolyte. The applied voltage was 30 kV, and sample injection was performed in hydrodynamic mode. All analyses were carried out in a fused silica capillary with an internal diameter of 50 microm and a total length of 64.5 cm. Under these conditions, complete separation between all cations was achieved in less than 4 min. The CE-C(4)D method was validated, and trueness values between 98.6% and 101.8% were obtained with repeatability and intermediate precision values of 0.4-1.3% and 0.8-1.8%, respectively. Therefore, this method was found to be appropriate for controlling potassium, sodium, calcium and magnesium in parenteral nutrition formulations and successfully applied in daily quality control at the Geneva University Hospitals.

Compatibility of Intravenous Medications With Parenteral Nutrition In Vitro Evaluation

BACKGROUND AND AIM Hospitalized patients requiring parenteral nutrition (PN) often need to receive intravenous (IV) medications as well. Y-site administration is occasionally necessary, but physicochemical incompatibilities can occur between the medications and PN. The aim of the present study was to assess the physical compatibility between 25 frequently coadministered IV medications and a commercially available ready-to-use total PN. METHODS PN (NuTRIflex Lipid Special; B. Braun Medical AG, Sempach, Switzerland) and medications were mixed in 1:1 (v/v) proportions, and the stability was assessed at the time of mixing and after 1 and 4 hours. The stability of lipid emulsion was observed by microscopic investigation, visual inspection, dynamic laser light scattering, and laser light obscuration. The binary admixtures of PN (without lipid emulsion) and medications were used to detect discoloration, visibly detectable precipitates, and subvisual particles. RESULTS Two of 25 medications were incompatible with the lipid emulsion (serum albumin 20% and tropisetron), 2 showed signs of degradation (discoloration) over time (esomeprazole and pantoprazole), and 1 precipitated at high concentrations (5-fluorouracil). The other 20 medications were considered compatible when administered by Y-site. CONCLUSION The present study validated the compatibility of 1 commercially available PN and 20 medications. These results offer new solutions to support the implementation of complex therapeutic schemes in practice, when coadministration via Y-site cannot be avoided.

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.

Multiple-test assessment of devices to protect healthcare workers when administering cytotoxic drugs to patients

Purpose: Evaluation of containment safety devices designed and introduced to protect preparers and administrators of hazardous drugs, through a multiple-test assessment. Methods: Six devices were compared: (1) Kis1 gravity-fed infusion set (Doran International, France), (2) Tevadaptor Spike Port Adapter (Teva Pharma AG, France), (3) Phaseal Infusion Adapter C100 (Carmel Pharma AB, France), (4) Codan Connect Z (Codan, France), (5) Pchimx with or without a cap (Doran International, France), and (6) Clave extension set 011-H1225 with or without Spiros (Hospira, France). Assessment of exposure to hazardous drugs was performed using quinine as fluorescent marker. Mechanical tests included tightness, tension tests, and estimation of the force required to connect the infusion device to the bag. Ergonomic tests were performed by six pharmaceutical technicians. Microbiological contamination was tested with media-fill, on connected bag. Results: No cytotoxic contamination was detected when using Phaseal, Tevadaptor or the Clave extension set with Spiros, Pchimx with a cap or Connect Z devices. For mechanical tests, all devices complied with the norm. Microbiological growth was observed neither in bags nor in tubings. The ergonomic study revealed differences between the devices for potential cytotoxic contamination risk only, but not for handling. Conclusions. The use of containment safety devices offers improved handling conditions of hazardous compounds. As this study takes various selection criteria into account, its results offer assistance in choosing the most suitable device.

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.

TCH-051 Validation of an Automated Compounder Set Up Once a Week For Parenteral Nutrition Solutions

Background Our parenteral nutrition production (PN) decreased after we introduced standard solutions. To keep just a small number of daily PN items cost-effective, we decided to validate a once a week setting up of an automated compounder device (ACD). Purpose To test the operation and performance of an ACD (Baxa MM12) for a once a day and a once a week use. Materials and Methods Accuracy (mean in % of the expected value) and precision (Coefficient of Variation) of the ACD was evaluated by weighing different volumes of water 10 times (0.5 to 40 mL; daily operational qualification) and different volumes of nutrients (0.5 to 100 mL; daily performance qualification) over 3 consecutive days. The concentration of nutrients (glucose, Na and K) in PN, particulate contamination and media-fill tests were checked each day while the machine’s settings were only adjusted once a week (3 consecutive weeks). Some bottles were changed during the week and other remained in place, according to a predefined protocol. The ACD was installed in a laminar airflow hood GMP Class A with a cleanroom Class B background and a temperature around 20°C. Results Daily operational and performance results: 0.5 mL 40 mL 100 mL Accuracy Precision Accuracy Precision Accuracy Precision Water 100.9% 3.2% 98.9% 0.3% Nutrient 99.3–102.7* 2.7–3.9%* 100–100.4%* 0.7–1.5%* * Depending on nutrient The concentrations of nutrients in PN products made weekly always met the specifications (internal limits ±15% for Na, ±10% for glucose and −15% to +10% for K). No particles or microbiological contamination were detected. Conclusions Validation proved the acceptable accuracy, precision and aseptic conditions in the course of the week. A sepsis can only be guaranteed by a strict application of GMP in a high quality compounding environment. In those conditions, PN products can be produced safely for one week with the same settings. Setting it just once a week saves technician time (300 hours/year) and money (15,000 Euro/year). No conflict of interest.

Qualification and Performance Evaluation of an Automated System for Compounding Injectable Cytotoxic Drugs

Abstract Background Use of automated systems for the production of chemotherapy will increase in answer to hospitals’ needs to rationalise production. The aim of the study was to evaluate the performance of a PharmaHelp® automated system for compounding chemotherapy. Methods Viable and non viable particles in air and liquid were measured by particle counter. Surface chemical contamination was simulated with a quinine solution. Microbiological contamination and aseptic processes were studied using media-fill tests. Dose accuracy was evaluated using a gravimetric method, in simulation studies and with real products in daily practice. Productivity was calculated by batch of ten IV-bags. Results No particles or microbiological contamination were detected. Filling was accurate for all the volumes of non-viscous solution studied (97–103 %). Minimum volumes which could be prepared accurately were 2 mL and 5 mL for the non-viscous and viscous solutions, respectively. For 2–5 mL volumes, the robot was less accurate than average, and 0–2 % of bags were rejected (deviation>10 %). Average fill deviations were from 0–3 % for 2–5 mL volumes and<1 % for volumes above 5 mL. Average production time for ten bags was 61±11 min. Conclusions The automated system was able to produce chemotherapy effectively, delivering appropriate quality with productivity comparable to manual preparations. These results confirmed that such automated systems have the potential to guarantee optimal safety for patients and technicians.

1ISG-004 Impact of a lean approach on the organisation of a chemotherapy production unit

Background Our chemotherapy production unit decided to rethink its organisational strategy and to revise its production processes through lean methodology to meet growing activity, in the context budget constraints that limit the increase in staff. Purpose To evaluate the impact of a lean management approach on the efficiency of a chemotherapy unit. Material and methods A five-step lean methodology approach was applied with a team of 12 technicians and five pharmacists supported by a lean expert, from January 2015 to July 2016: DEFINE: objectives, value stream mapping, process flows. MEASURE: steps, process duration, use of stock. ANALYSE: added-value steps, waste, waiting time and causes. IMPLEMENT: imagine and implement solutions. CONTROL: efficiency, performance, satisfaction. Results The team identified 73 items impacting the efficiency of the process during the ‘Measure’ phase. During the ‘Analyse’ step, 18 opportunities divided into four main themes were proposed to improve the organisation: Flow: smoothing the activity and reducing the early morning peak (–12% between 7 and 9 am), producing continuously according to demand of the day (‘Just in time’ eight maximum ongoing preparations), improving occupancy rates of isolators (+25% between 10 and 12 am, and +20% between 1 and 4 pm), revising the steps of double–control and using mistake–proofing resulted in a decrease in crossing time of manufacturing from 9 hour 45 min to 1 hour 45 min. bull; Space: reorganisation with a reduction of unnecessary movements. bull; Management: creation of a position of ‘coordinator of the day’, and daily meetings (‘Obeya’) to reassign tasks. bull; Stock and control: rationalisation of storage and orders. A net gain of 40% full-time equivalent was reached. The satisfaction survey showed a positive acceptance of the project and its conduct. Conclusion The application of a lean methodology allowed the optimisation of the management of our chemotherapy production unit and saved human resources. The main actions were to eliminate waiting time, to smooth daily activity, and to reorganise roles, spatial organisation and storage. The positive impact on the efficiency of our facility and the satisfaction of the team proved that lean methodology is a relevant tool in the hospital pharmacy. No conflict of interest