Stéphanie Genay

Experimental study on infusion devices containing polyvinyl chloride: To what extent are they di(2-ethylhexyl)phthalate-free?

The use of medical devices containing highly criticized phthalates including di(2-ethylhexyl) phthalate (DEHP) has been challenged by European directive 2007/47/CE, put into effect in March 2010. New plasticizers are now being used to soften PVC in medical devices: trioctyltrimellitate (TOTM), di-isononyl-cyclohexan-1,2-dicarboxilate (DINCH) and di(2-ethylhexyl) terephthalate (DEHT). To quantify DEHP in nine DEHP-free medical devices made of PVC softened by alternative plasticizers, high performance liquid chromatography analysis with ultraviolet detection at 220 nm wavelength was achieved. An NMR spectroscopy was performed to confirm DEHP presence. Only two medical devices out of the nine tested were truly without DEHP. One of them showed traces of DEHP exceeding the threshold contamination of 0.1% in plastic mass set by REACH regulations. TOTM plasticizer is still incriminated when polyvinyl-chloride (PVC) is contaminated with DEHP. Manufacturers must verify the purity of their raw material, not only on PVC, but also on other soft plastics entering into the composition of medical infusion devices. The clinical consequences of exposure to certain levels of DEHP have not been evaluated. A solution could be to use alternative PVC-free materials.

Quantification of five plasticizers used in PVC tubing through high performance liquid chromatographic-UV detection.

Searching for alternatives to di-(2-ethylhexyl)-phthalate, a plasticizer that has been widely used in the manufacturing of PVC medical devices, has become a major challenge since a European regulation underlined some clinical risks. The aim of this study is to develop an HPLC-UV method to quantify the currently used alternative plasticizers to DEHP. Five plasticizers, acetyl tributyl citrate, di-(2-ethylhexyl)-phthalate, di-(ethylhexyl)-terephthalate, di-isononyl-1,2-cyclohexane-dicarboxylate, and trioctyl trimellitate, were separated on a C8 stationary phase (2.6 μm, 100 mm × 4.6mm) under gradient elution in 13 min. They were detected at 221 nm leading to a quantification threshold from 0.3 to 750 μg/mL as a function of the plasticizer. Within-day and between-day precisions were inferior to 0.9% and 18%, respectively. The assays were validated according to the accuracy profile method. Plasticizers were extracted from PVC-tubing by dissolving PVC in THF then precipitating it in methanol with a yield of over 90% for each plasticizer. This assay could feasibly be used to quantify plasticizers in PVC medical devices.

How to solve the problem of co-elution between two compounds in liquid chromatography through the first UV derivative spectrum. A trial on alternative plasticizers to di(2-ethylhexyl) phthalate

To meet new regulations, alternative plasticizers to di(2-ethylhexyl) phthalate (DEHP) are now commonly used in the manufacturing of medical devices. These are: acetyl tri-n-butyl citrate (ATBC), bis (2-ethylhexyl)adipate (DEHA), dioctyl terephtalate (DEHT), di-isononylphtalate (DINP), diisononylcyclohexane-1.2-dicarboxylate (DINCH) and trioctyltrimellilate (TOTM). An HPLC-UV analysis was previously developed to characterize four of them. However, two compounds were systematically co-eluated: DEHP with DEHA and DEHT with DINP. The first derivative of UV spectra and photodiode array detection allow the quantification of DEHA and DINP. Moreover, for each plasticizer, maximum wavelength absorbance was chosen to be as specific as possible. Quantification ranged from 0.3 to 750µg/mL according to the plasticizer. The assays were validated by analysis of variance. Our method was validated by determining the following parameters: specificity, linearity, limits of detection and quantification. The relative biases were inferior to 5% for ATBC, DEHP, DEHA and DINCH and inferior to 10% for DEHT, DINP and TOTM. Plasticizers were extracted with tetrahydrofuran and methanol. The developed method was then used to determine the composition of plasticizers in several medical devices used in clinical service. The major plasticizers were quantified from 19% to 40% w/w, traces of DEHT were found in six medical devices and DEHP in five.

Criteria for choosing an intravenous infusion line intended for multidrug infusion in anaesthesia and intensive care units

OBJECTIVE The aims are to identify critical parameters influencing the drug mass flow rate of infusion delivery to patients during multidrug infusion and to discuss their clinical relevance. DATA SOURCES A review of literature was conducted in January 2016 using Medline, Google Scholar, ScienceDirect, Web of Science and Scopus online databases. DATA EXTRACTION References relating to the accuracy of fluid delivery via gravity-flow intravenous (IV) infusion systems and positive displacement pumps, components of IV administration sets, causes of flow rate variability, potential complications due to flow rate variability, IV therapies especially at low flow rates and drug compatibilities were considered relevant. DATA SYNTHESIS Several parameters impact the delivery of drugs and fluids by IV infusion. Among them are the components of infusion systems that particularly influence the flow rate of medications and fluids being delivered. By their conception, they may generate significant start-up delays and flow rate variability. Performing multidrug infusion requires taking into account two main points: the common dead volume of drugs delivered simultaneously with potential consequences on the accuracy and amount of drug delivery and the prevention of drug incompatibilities and their clinical effects. CONCLUSION To prevent the potentially serious effects of flow rate variability on patients, clinicians should receive instruction on the fluid dynamics of an IV administration set and so be able to take steps to minimise flow rate changes during IV therapy.

In vitro comparison of two changeover methods for vasoactive drug infusion pumps: quick-change versus automated relay.

Abstract This study aimed to compare in vitro two syringe changeover techniques to determine which was better at minimising variations in norepinephrine (NE) delivery: the manual quick-change or automated technique. NE concentration was measured continuously using a UV spectrophotometer, and infusion flow rate was monitored by an infusion pump tester. Syringe changeovers were made with either of the two techniques studied. Relays induced disturbances in drug delivery. The temporary increase in NE mass flow rate was significantly higher with manual relays than with automated ones. The automated relay offered a better control of the amounts of NE administered than the quick-change technique.

Clinical implications of intravenous drug incompatibilities in critically ill patients

OBJECTIVE The aim of this review is to analyse the clinical consequences of intravenous drug incompatibilities in critically ill patients, especially the incidence of organ dysfunctions and mortality. METHODS A review of literature was conducted according to the PRISMA statement in June 2017, using Medline, ISI Web of Science and Clinicaltrials.gov. DATA EXTRACTION Eligible studies were case reports and randomised controlled trials (RCTs) that assessed the effects of drug incompatibilities in critically ill patients on morbidity or mortality as primary or secondary outcomes, or adverse events. Two investigators independently reviewed the eligibility of the study from abstracts or manuscript data. DATA SYNTHESIS Twelve articles met the selection criteria. The six articles reporting RCTs concern only four RCTs. RCTs were single-centre studies comparing infusion with or without filter. One of them included adult patients. The others included paediatric and neonatal intensive care unit patients. Primary endpoints were SIRS, organ failure, overall complication rate, bacteraemia, sepsis, phlebitis and length of stay. The results are mixed with one RCT reporting a reduction in SIRS, organ failure and overall complication rate, two studies in disagreement over the occurrence of sepsis and one study reporting no impact on length of hospital stay. The six articles on case reports show different drug incompatibility situations. They report pulmonary toxicity. CONCLUSION Little data is available on this topic. Infused particles may induce organ failure, in particular pulmonary toxicity and SIRS. Further studies are needed to establish a link between the level of exposure to drug incompatibilities and clinical implication.

Stability of 10 mg/mL cefuroxime solution for intracameral injection in commonly used polypropylene syringes and new ready-to-use cyclic olefin copolymer sterile vials using the LC-UV stability-indicating method

Abstract Context: Injecting intracameral cefuroxime has been found beneficial in reducing the risk of postoperative endophthalmitis but its use has been limited through a lack of approved marketing and of ready-to-use single-units as well as the problem of aseptic compounding. Objective: Our aim was to assess a new automated primary packaging system which should ensure a higher level of sterility, thanks to its closed, sterile, ready-to-use polymer vial called “Crystal® vial”. The chemical stability of a 10 mg/mL cefuroxime solution was compared in 1 mL Crystal® vials and 1 mL Luer-lock polypropylene syringes (actual reference) to eliminate any potential and specific interactions with its cyclic olefin copolymer (COC) body and elastomer stopper. Methods: Cefuroxime solution was introduced into vials and syringes and stored at −20 °C, +5 °C and +25°C/60% Relative Humidity. Cefuroxime concentration and the relative amount of the main degradation product (descarbamoyl-cefuroxime) were both determined by an HPLC/UV method indicating stability. Solutions were considered steady if the concentration remained at over 90% of the initial value. In the adapted storage conditions, the evolution of osmolality, pH and sterility was assessed. Results: Stability profiles were identical between vials and syringes in all storage and temperature conditions. The solution was stable (cefuroxime concentration, pH and osmolality) and still sterile for 365 days at −20°C. The concentration fell below 90% after 21 days at +5 °C and after 16 h at +25°C/60%s relative humidity. Conclusions: The COC and thermoplastic elastomer of the vials had no impact on the degradation process confirming its possible use for a ready-to-use cefuroxime solution single-unit dose.

In vitro assessment of the influence of intravenous extension set materials on insulin aspart drug delivery

Insulin is a frequently prescribed drug in hospitals and is usually administered by syringe pumps with an extension line which can be made of various materials. Two insulin solutions were studied: an insulin analogue, Novorapid® which contains insulin aspart and two phenolic preservatives (e.g. phenol and metacresol) and Umuline rapide® with human insulin and metacresol as preservative. Some studies have indicated interactions between insulin, polyvinyl chloride (PVC) and polyethylene (PE). The aim of this work was to study such interactions between Novorapid® or Umuline rapide® and infusion extension line materials (PVC, PE and coextruded (PE/PVC)). Insulin solution at 1 IU/mL was infused at 2 mL/h over 24 hours with 16 different extension lines (8 in PVC, 3 in PE and 5 in PE/PVC). Ultra-Fast Liquid Chromatography with diode array detection (UFLC-DAD) was performed to quantify insulin (human and aspart) and preservatives (metacresol and phenol). Limited human insulin sorption was observed thirty minutes after the onset of infusion: 24.3 ± 12.9%, 3.1 ± 1.6% and 18.6 ± 10.0% for PVC, PE and PE/PVC respectively. With insulin aspart, sorption of about 5% was observed at the onset of infusion for all materials. However, there were interactions between phenol and especially metacresol with PVC, but no interactions with PE and PE/PVC. This study shows that insulin interacts with PVC, PE and PE/PVC at the onset of infusion. It also demonstrates that insulin preservatives interact with PVC, which may result in problems of insulin conservation and conformation. Some more studies are required to understand the clinical impact of the latter during infusion.

Development and validation of an UHPLC-MS/MS method for simultaneous quantification of ibrutinib and its dihydrodiol-metabolite in human cerebrospinal fluid

Ibrutinib is an orally administered first-in-class irreversible Brutons tyrosine kinase (BTK) covalent inhibitor for the treatment of patients with B-cell malignancies. Several isolated clinical observations reported its efficacy in central nervous system dissemination. Herein, we described the development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) procedure for the quantification of ibrutinib and its active metabolite PCI-45227 in cerebrospinal fluid (CSF). This is the first complete validated method for quantification of ibrutinib and PCI-45227 in CSF. The compounds were eluted on a Waters BEH C18 column (50.0 × 2.1 mm; 1.7 μm) using a gradient elution with a mobile phase composed of ammonium formate buffer 5 mM pH 3.2 and acetonitrile +0.1% formic acid with a flow rate of 400 μL·min-1. Two deuterated internal standards were used to obtain the most accurate quantification. The CSF samples were prepared by a simple and rapid dilution. The method was validated by testing the selectivity, response function, intra-day and inter-day precisions, trueness, limits of detection (LOD) and lower limits of quantification (LLOQ). The validation results proved that the methods were suitable to quantify ibrutinib and PCI-45227 in real biological CSF samples from 0.50 (ibrutinib) or 1.00 (PCI-45227) to 30.00 ng·mL-1. Furthermore, the developed method was adapted to allow the quantification of both compounds in plasma and the results were compared to those reported in literature. The plasmatic samples were treated by protein precipitation and the method was validated to quantify ibrutinib and PCI-45227 in real biological plasmatic samples from 5.00 to 491 ng·mL-1. Lastly, for both matrices, accuracy profiles were plotted from the trueness and precision results using a 20% α-risk (β = 80%) and the tolerance intervals were comprised within the acceptance limits fixed at ±25% for the LLOQ and ±15% for the other concentrations. Finally, these methods were successfully applied to quantify ibrutinib and PCI-45227 in real human CSF and plasma samples.

Stability of midazolam and noradrenaline stored in cyclic olefin copolymer AT-Closed Vials® and polypropylene syringes during 365 days

Introduction: Midazolam (MDZ) and noradrenaline (NA) are drugs commonly used in intensive care units to control sedation and hemodynamic status of patients. They require a dilution step by the nurse several times a day. To decrease preparation risks they could be compounded by the pharmacy, provided that stability is sufficient. Methods: 50mL cyclic olefin copolymer AT-Closed Vials (Aseptic Technologies) and polypropylene syringes (Plastipak, Becton Dickinson) were filled with MDZ or NA (Mylan) diluted in saline at respectively 1mg/mL and 0.2mg/mL. The study was performed according to the SFPC/GERPAC guidelines during 365 days at 2 temperature conditions: –20 °C, 5 °C. Concentrations were determined by an HPLC/UV stability indicating method, expressed as mean ± standard deviation and considered stable if the concentration stayed over 90% of the initial concentration value. Particulate contamination, pH evolution and sterility were followed. Results: Solutionswere stable during 365 days in AT-Closed Vial at –20 °C (MDZ 99.01 ± 0.90%, NA 98.91± 0.54%) and 5 °C (MDZ 97.98± 0.96%, NA 99.52 ± 0.36%) and in syringes at –20 °C (MDZ 99.29 ± 0.85%, NA 98.92 ± 0.98%) and 5 °C (MDZ 97.89 ± 0.51%, NA 99.42 ± 0.51%). There was no modification of pH. Sterility and particle tests were in accordance with European Pharmacopeia after 365 days whatever the storage conditions. Discussion-conclusion: MDZ and NA are stable during 365 days at 5 °C and –20 °C. Storage at 5 °C should be preferred to exclude freezing-thawing issues. AT-Closed Vial could be chosen for their automated aseptic filling process and for logistic considerations particularly considering the space gains.