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Management of chemotherapies is a strategic issue for european healthcare. Dose-banding enables to reduce waiting time of patients in day care units and drug wastage. The aim of this study was to assess the stability of 5-Fluorouracile (5-FU) at standardised rounded doses of 4 and 5 g in MyFuser® portable infusion pump for in-advance preparation. Ten MyFuser® (4 and 5 gr 5-FU added to NaCl 0.9%) were prepared under aseptic conditions and stored at room temperature (23 ± 2 °C) for 28 days then at 30 °C for three days. Physical stability tests were periodically performed: visual and microscopic inspection, pH measurements and optical densities. The concentration of solutions was measured by High Performance Liquid Chromatography/UV detector. Results confirm the stability of 5-FU at selected SRD of 4 g and 5 g with NaCl 0.9% in MyFuser® for at least 28 days at room temperature and three days at 30 °C, allowing in-advance preparation.

The aim of the European Council’s Resolution CM/res(2016)2 on good reconstitution practices in health care establishments for medicinal products for parenteral use is to guide the health care establishment’s decision as to where reconstitution should take place: in the pharmacy or the clinical area. Injectable preparation in hospital pharmacy is performed in Centralised Intra Venous Additive Services (CIVAS). Nevertheless, challenges such as ensuring the sterility of the preparation, the physicochemical stability of the product, and process validation for instance should be taken into account. This opinion paper examines the challenges, impacts, and responsibilities for pharmacists, nurses, and hospital management related to implementing the resolution, regarding the experience of countries where CIVAS are already implemented. It also discusses the opportunities of implementing CIVAS with regard to patient care safety and potential financial savings.

In hospitals, a major part of the drugs is administered via the intravenous route. When one wants to evaluate or know the stability of a drug in solution, it is necessary to know several physico-chemical parameters. Several reference works are available to help the hospital pharmacist with this research. However, reading these different sources can make you discover conflicting data. It is therefore necessary at this time to obtain the publications with contradictory results and to read them again. Seven criteria have been identified for judging the quality of a publication on physicochemical stability: full description of equipment, methods and analytical conditions of molecules studied; complete description of the procedures used to validate the analytical method; full indication of time testing and measurement bases or control; documentation on the analytical reproducibility; adequate statistical analysis; appropriate conclusions; appropriate references. In conclusion, everything in a compatibility study is important.

Centralized preparation of parenteral products in the pharmacy can ensure a higher quality but requires a stability of the drugs in the chosen primary packaging and a sufficient production capacity. Aseptic Technologies has developed an automated primary packaging filling system using a closed, sterile and ready-to-use cyclic olefin copolymer vial called ‘‘Crystal® vial’’. This vial is filled through the elastomeric septum and then immediately re-sealed by laser, thus reducing the risk of microbial contamination.We have evaluated risks linked to the use of Crystal® vials:- Sorption risk is correlated with substance lipophilicity. During 3 months, we have evaluated concentration evolution of 8 cytotoxic drugs (with different water/octanol partition coefficients) by HPLC/MS. Same methodology was used to measure concentration evolution of 3 platinum-derived drugs by NMR during 24 hours.- About the permeation risk, we have evaluated concentration evolution of phenol and metacresol in a 1UI/mL insulin solution during 50 days by HPLC/UV in Crystal® vials stored upright and upside down. Two stoppers formulations exist and were tested.- Extreme pH solutions can lead to the presence of particles in the parenteral product. Impact of these solutions in Crystal® vials on particles contamination was studied and particles characterized.- Plasticizers may migrate from the primary packaging to the parenteral products. After isopropanol reflux extraction on the COC body and thermoplastic elastomer stopper, potential plasticizers were identified and quantified using NMR.Finally, stabilities of ready-to-use cefuroxime, midazolam and noradrenaline solutions in Crystal® vials were determined and compared to polypropylene syringes.The 8 cytotoxic drugs mean concentrations were between 90% and 110% at day 62 with no correlation with partition coefficient. Lack of interactions was demonstrated too for the oxaliplatin and carboplatin solution by NMR. Accuracy of NMR cisplatin quantification was not sufficient.Studies performed on preservatives highlighted a metacresol permeation risk during storage at 25°C/60%RH for 50 days (loss of 19.7% and 20.3% respectively for Crystal® vials stored upright and upside down). Use of the second formulation stopper allowed a large decrease of permeation (loss of 2.6% at day 50).An important particles contamination was observed only with extrem alkaline pH and contact with the stopper (6820 particles 10µm in a 20mL Crystal® vials stored upside down during 7 days). Particles are fibrous and essentially composed by non-organic substances.NMR analysis highlighted presence of plasticizers in both COC body and elastomer stopper but concentrations were below the 1000µg/g threshold described by the REACH regulation.Cefuroxime solution (1mL at 10mg/mL) was stable 365 days at -20°C. Midazolam solution (50mL at 1mg/mL) and noradrenaline solution (20mL and 50mL at 0.2mg/mL ; 50mL at 0.5mg/mL) were stable 365 days at 5°C. Same results were achieved in polypropylene syringes.Crystal® vials were not subject to sorption phenomena. There was no risk of plasticizer migration. Metacresol permeation risk was controlled using the new stopper. Packaging of alkaline solution must be monitored. Solutions of cefuroxime (-20°C), midazolam and noradrenaline (5°C) are stable 1 year. In regards to storage in polypropylene syringes, Crystal® vials could be prefered for their automated aseptic filling process and for logistic considerations particularly taking into account the space gains., La centralisation de la préparation des médicaments injectables à la pharmacie permet d’assurer un haut niveau de qualité mais nécessite une stabilité du médicament dans le conditionnement choisi et une capacité de production suffisantes. Aseptic Technologies a développé un système de remplissage automatisé de conditionnement primaire utilisant un flacon en copolymères d’oléfines cycliques (COC) clos, stérile et prêt à l’emploi appelé « flacon Crystal® ». Ce flacon est rempli à travers le bouchon et est re-scellé par laser, réduisant ainsi le risque de contamination microbiologique.Nous avons évalué les risques liés à l’utilisation du flacon Crystal® :• Le risque de sorption est corrélé à la lipophilie de la substance conditionnée. Pendant 3 mois, nous avons évalué l’évolution de la concentration de 8 molécules cytotoxiques (de coefficients de partage octanol/eau différents) par CLHP/MS. Une méthodologie identique a permis le suivi des concentrations, pendant 24 heures de 3 molécules dérivées du platine par RMN.• Concernant le risque de perméation, nous avons évalué l’évolution des concentrations en phénol et métacrésol dans une solution à 1UI/mL d’insuline conditionnée dans des flacons Crystal® conservés droits et retournés pendant 50 jours par CLHP/UV. Deux formulations différentes de bouchons ont été testées.• Les solutions de pH extrêmes peuvent conduire à la présence de particules dans la solution injectable. L’impact sur la contamination particulaire du conditionnement de ces solutions dans les flacons Crystal® a été étudié et les particules caractérisées.• Les plastifiants peuvent migrer du conditionnement primaire vers la préparation parentérale. Après extraction par reflux à l’isopropanol sur le corps en COC et le bouchon en élastomère, les éventuels plastifiants ont été identifiés et dosés par RMN.Enfin, les stabilités de solutions de céfuroxime, midazolam et noradrénaline conditionnées en flacon Crystal® ont été déterminées et comparées à la seringue en polypropylène (PP).Les concentrations moyennes des 8 molécules cytotoxiques étaient comprises entre 90% et 110% à J62 sans corrélation avec le coefficient de partage. L’absence d’interaction a aussi été démontré pour le carboplatine et l’oxaliplatine par RMN. La précision de la quantification par RMN du cisplatine n’était pas suffisante.Il existe un risque de perméation du métacrésol lors du stockage à 25°C/60%RH pendant 50 jours (perte de 19,7% et de 20,3% pour les flacons Crystal® droits et retournés respectivement). La seconde formulation du bouchon permet de maîtriser le phénomène (perte de 2,6% à J50).Une contamination particulaire importante a été observée lors du conditionnement d’une solution basique et d’un contact avec le bouchon pendant 7 jours (6820 particules 3; 10µm dans un flacon Crystal® de 20mL) Les particules sont fibreuses et composées essentiellement de molécules inorganiques.Les analyses RMN mettent en évidence la présence de plastifiants dans le corps en COC et le bouchon à des concentrations largement en-dessous de la limite de 1000µg/g définie par la réglementation REACH.La solution de céfuroxime (1mL à 10mg/mL) était stable 365 jours à -20°C. Les solutions de midazolam (50mL à 1mg/mL) et de noradrénaline (20mL et 50mL à 0,2mg/mL ; 50mL à 0,5mg/mL) étaient stables 365 jours à 5°C. Des résultats similaires ont été obtenus lors de la conservation en seringue PP.Les flacons Crystal® ne sont pas sujets aux phénomènes de sorption. Il n’y a pas de risque de migration de plastifiants. Le risque de perméation du métacrésol est contrôlé par l’utilisation du nouveau bouchon. Le conditionnement de solutions basiques doit être surveillé. Les solutions de céfuroxime (à -20°C), de midazolam et de noradrénaline (à 5°C) sont stables 1 an. Par rapport à la seringue PP, le flacon Crystal® pourrait être préféré de par son système de remplissage aseptique automatisé ainsi que pour des considérations logistiques, en particulier le gain de place.

International audience; Micafungin is a costly treatment and packaging of 50mg or 100mg bottles only are available, while doses lower than 5mg and 20mg are often necessary in neonates and paediatrics patients, respectively. The stability of micafungin sodium in polypropylene syringes and glass bottles was studied at different concentrations. Solutions of micafungin diluted with NaCl 0.9% were prepared in glass bottles (20 and 10mg/mL) or syringes (1 and 0.5mg/mL) and stored at 25°C, 60% humidity (RH), in the dark (ICH conditions). Solutions were also exposed to heat (70°C) or alkaline solution (NaOH) in order to force degradation. Samples were analysed at days 1, 5, 8 (for bottles) and also 15 (for syringes) after the preparation and assayed in triplicate. Stability was studied using a stability-indicating high-performance liquid chromatographic method. Syringes stored at 25°C retained over 90% of their initial concentration over the study period. Temperature and alkaline conditions had significant effect on the stability of micafungin, leading to apparition of degradation products. Moreover, sub visible particles were in the specification of the European Pharmacopeia along 15 days. To conclude, micafungin diluted in NaCl 0.9% and stored in polypropylene syringes was chemically stable for at least 15 days at 25°C in the dark.

Injectable drugs are high-risk products and their reconstitution in hospital wards is a potential source of errors. Thus, in order to secure the reconstitution process and thereby improve safety, the pharmacy department of Lausanne University Hospital is focusing on developing ready-to-use forms (CIVAS). These preparations are compounded in controlled clean rooms and are analyzed prior to release. In the intensive care unit, amiodarone 12.5 mg/mL in glucose 5% is one of the high-risk preparations, which has led the pharmacy to develop a ready-to-use solution. To this end, a one-year stability study was initiated, and the preliminary results (after six months) are illustrated here. A stability-indicating HPLC method was developed and validated for monitoring the concentration of amiodarone. Batches were stored at 5 °C and 30 °C, which were analyzed immediately after preparation, after one, two, four and six months of storage. The pH and osmolality values were monitored at the respective time intervals. It was observed that after six months, all the results were within specifications. However, the pH values started to decrease after two months when amiodarone was stored at 30 °C. After six months, a degradation peak appeared on the chromatogram of these solutions, which suggested that amiodarone is more stable at 5 °C. The preliminary results obtained in this study indicated that injectable amiodarone solutions are stable for six months under refrigerated storage conditions. The study is ongoing.