Critically ill paediatric patients often receive a large number of parenteral drugs via only a few available intravenous accesses. This poses the risk of incompatibilities. The aim of our study was to investigate the compatibility of etacrynic acid and theophylline with other parenteral drugs used in a paediatric cardiological intensive care unit. These include ampicillin and sulbactam, cefazolin, furosemide, glucose 50 % solution, meropenem, pantoprazole, paracetamol, potassium chloride 7.46 % solution and sodium bicarbonate 8.4 % solution.
Trastuzumab biosimilar SB3 (Ontruzant®), a HER2 binding monoclonal antibody, is available as powder for concentrate for solution for infusion. According to the summary of product characteristics, the reconstituted solution (21 mg/mL) is physicochemically stable for 7 days when stored refrigerated at 2–8 °C. The objective of this focused study was to determine the extended physicochemical stability of trastuzumab SB3 reconstituted with water for injection and stored in the original glass vials under refrigeration or at room temperature over a period of 28 days.
Active pharmaceutical ingredients for paediatric patients are formulated at hospital pharmacy services and compounding pharmacies when they are not commercially available. This work evaluated the quality and stability of lozenges, an orodispersible dosage form, elaborated by a simple and low-cost moulding process.
Training and certification of personnel in capsule preparation are essential procedures, overseen by the pharmacist who delegates these tasks. These procedures aim not only to ensure the efficacy and safety of operations but also to establish a clear chain of responsibility. They align with established best practices. Certification grants formal authorization to qualified individuals to perform specific tasks. For new hires, a comprehensive training program is designed to facilitate their integration and empower them from the onset. We propose training objectives structured around a competency-based approach, highlighting objective evaluation criteria applicable in real-world practical settings. These training objectives address critical aspects such as the handling of hazardous substances, weighing and mixing of powders, and capsule filling. They also emphasize the importance of documentation and traceability. Specialized preparations and tools are offered to facilitate the assessment of learning outcomes.
Abstract Objectives To the best of our knowledge, few studies have been published on the stability of cabazitaxel in infusion bags. Stabilis® database has selected a study demonstrating the stability of this molecule at 0.15 mg/mL for 28 days at 4 °C and 25 °C in polyolefin bags. The aim of this work was to study the physicochemical stability of Cabazitaxel Zentiva® solutions in vials after “opening” with a vented ChemoClave® Spike, at 25 °C, protected from light and in solutions diluted at 0.1 and 0.26 mg/mL in 0.9 % sodium chloride (0.9 % NaCl) or dextrose 5 % (D5W) in 3 types of infusion bags (Easyflex® and Viaflo® at 25 °C, Freeflex® between 2 and 8 °C, protected from light). Methods The chemical stability was analyzed after preparation and then after 14 and 28 days of storage by high performance liquid chromatography (HPLC), coupled to a diode array detector, at the analysis wavelength of 232 nm. The method has been validated according to ICH Q2 (R1) standards. For the study in infusion bags, three preparations were realised for each condition. At each time of analysis, for each bag, a sample was prepared and analyzed by HPLC. Two vials after “openings” were kept at 25 °C and three samples per vial were prepared and analyzed at the three analysis times (D0, D14 and D28). Physical stability was assessed by visual examination (change in colour, appearance of precipitate, gas formation). The pH of the solutions prepared in infusion bags was evaluated at each analysis time. Results Cabazitaxel solutions at 0.1 and 0.26 mg/mL diluted in 0.9 % NaCl or D5W in Easyflex® (polyolefin), Viaflo® (multilayer high density polyethylene, polyamide, polypropylene) bags retained more than 95 % of the concentration after 28 days at 25 °C. In the Freeflex® bag (polypropylene multilayers), cabazitaxel solutions at 0.1 and 0.26 mg/mL diluted in 0.9 % NaCl or D5W retained more than 95 % of the initial concentration between 2 and 8 °C for 28 days. In vials with a Spike, cabazitaxel solutions at 20 mg/mL retained more than 95 % of the initial concentration for 28 days at 25 °C. For all the conditions studied, no visual modification was observed. The pH of solutions in bags were constant during the stability study. Conclusions Cabazitaxel Zentiva® diluted at 0.1 and 0.26 mg/mL in 0.9 % NaCl or D5W was stable for 28 days at 25 °C and between 2 and 8 °C. These stability data allow preparations to be made in advance. The remainder of the cabazitaxel vial fitted with a Spike was stable for 28 days at 25 °C, allowing the remainder of the vial to be used over several days.
Abstract Objectives There are concerns about the potency of epinephrine (EPI), norepinephrine (NE), and phenylephrine (PE) stored in syringes for later infusions in clinical care. The objective of our study was to optimize a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine the concentrations EPI, NE, and PE dissolved in normal saline and stored in 50 mL 3-part Becton Dickinson syringes. Methods Medications were diluted in normal saline to 80 μg/mL for EPI and NE, and 100 μg/mL for PE. The solutions were stored in syringes for 0 (fresh), 3, and 7 days in a medical refrigerator. United States Pharmacopeia grade EPI, NE, and PE and their deuterium-labeled analogs were used as calibration standards. Stored samples and standards were diluted and analyzed by LC-MS/MS operated in selected reaction monitoring mode. Results The calculated limit of quantification for EPI, NE and PE were well below the concentrations used in clinical practice. The coefficient of variation remained below 12 % for all samples. The standard linear calibration regressions for EPI, NE, and PE had r 2 values of between 0.96 and 0.98 (p < 0.001). EPI and NE stored in the refrigerator remained within 10 % of the of their initial concentrations at all time points. The concentration of PE in syringe decreased by 19.85 % at 3 days, with no further decrease at 7 days, compared to fresh PE. Conclusions The sample preparation steps and optimized LC-MS/MS method allowed simple and reliable measurements of EPI, NE, and PE.
To date, there is only one study investigating the physicochemical stability of diluted mitomycin (MMC) solutions prepared by using urea-containing Mitomycin medac as starting material. The aim of the study was to test the solubility of the new MMC formulation with regard to highly concentrated solutions and determine the physicochemical stability of clinically relevant MMC concentrations stored under different conditions in various primary containers.
Vaccines are used on a large scale for prevention of disease. Preparing vaccines for administration can be a time consuming process. To increase efficacy of vaccine administration, the Vaxtractor was designed in January 2021. With the Vaxtractor, the desired volume of vaccine is drawn up automatically in syringes from two vials of vaccine simultaneously. We examined the quality of COVID-19 vaccines prepared with the Vaxtractor.
Ceftazidime (CZ) and Vancomycin (VM) are used to treat bacterial keratitis; however, their physicochemical incompatibility does not allow their co-administration. This incompatibility can be managed by buffering the mixture at an alkaline pH or by using cage molecules such as cyclodextrins (CD). The objective of this work was to compare the stability during 168 days of frozen storage of two formulations combining VA and CZ at a final concentration of 25 mg/mL: a CD-free formulation, at a pH=8.5 and a formulation with CD.
Abstract Objectives Durvalumab (Imfinzi®), a PD-L1 monoclonal antibody (mAb) medication is available as concentrate (50 mg/mL) for solution for infusion. The summary of product characteristics provides information about the physicochemical stability of ready-to-administer durvalumab preparations (vehicle solution 0.9 % NaCl, G5%), but not about the concentrate after first opening. The objective of this study was to determine the physicochemical stability of durvalumab concentrate for solution after first opening over a period of 28 days. Methods Imfinzi® vials were punctured and stored refrigerated (2–8 °C) or at room temperature (20–25 °C) light protected. At predefined time points (day 0, 7, 14, 21, 28) the physicochemical stability of the concentrated solution was determined by ion-exchange/size-exclusion high-performance liquid chromatography (IE-/SE-HPLC) with photodiode array detection and pH measurement. Vials were inspected with regard to changes of color, clarity, and visible particles at any time point. Results Regardless of the storage temperature, durvalumab 50 mg/mL solutions remained physiochemically stable for 28 days in punctured vials. The concentrations of durvalumab monomer remained unchanged and no secondary peaks (fragments, aggregates) were observed in any of the SE-HPLC chromatograms. The IE-HPLC test results showed no substantial changes of the peak areas of the main peak and of the acidic and basic charge variants during the whole storage period. Appearance and pH of the test solutions remained unchanged until the end of the study. Conclusions Regardless of storage conditions none of the analytical methods indicated physicochemical instability of the intact durvalumab monomer over the 28 days of the study. To avoid microbiological instability storage under refrigeration is recommended.
Abstract Objectives Milk related materials are frequently used as a vehicle for drug product administration. Therefore, drug solubility information in milk related vehicles is desirable for prediction of how they may influence in vivo drug release and bioavailability. However, there are very limited data published on this topic. This study explored a practical method to address the key challenges associated with solubility assessment in milk, including the sample equilibration time and cleanup procedures. Methods Amitriptyline, acetaminophen, dexamethasone, nifedipine, piroxicam, and prednisolone were selected as model drugs to represent a wide range of physicochemical properties. Their solubilities were determined at room temperature in pH 6.8 phosphate buffer, skim milk, whole milk, reconstituted milk powder, and unprocessed raw milk. Results The overall results confirmed that milk greatly improves the solubility of poorly water-soluble drugs. However, the extent of improvement and mechanism of solubilization appeared unique for each drug, highlighting the importance of evaluating milk solubility experimentally. Conclusions The method used in this exploratory study can be applied in future investigations of a broader range of drugs and milk-related vehicles.
To measure cross-contamination between batches of different sensitizing drugs, contamination on the outside of compounded syringes, and drug concentrations in environmental air when using an automated compounding device.
Abstract Objectives The measurement of osmolality is used by many authors as an additional stability criterion of a drug in solution. In the current state of knowledge, no scientific publication correlates the osmolality values and the stability of a solution. To study the relevance of this analytical technique by measuring the osmolality of injectable solutions whose instability has been chemically demonstrated by high performance liquid chromatography (HPLC). Methods Selection of 13 drug preparations whose chemical instability has been demonstrated in the literature. Realization of three identical samples per selected preparation and measurements of the osmolality of the freshly prepared solutions, then, at various storage times until a chemical degradation of the molecule validated by HPLC of at least 10% and possibly up to 40%. Results Measurements of the osmolality were performed on five antibiotics (amoxicillin/clavulanic acid, cefepime, cefoxitine, meropenem and temocillin and cefoxitin) and five anticancer drugs (azacitidine, bendamustine, busulfan, fotemustine and oxaliplatin). Osmolality varied from −6.30 to 11.10% for antibiotics and from 0.57 to 2.04%. Conclusions Among the preparations tested, only two formulations have a variation in osmolality in accordance with the chemical degradation. For the other 11 formulas, the variations in osmolality values where not correlated with the degradation measured by HPLC. In view of these results, osmolality does not seem to be a criterion of choice for the study of drug stability. In the majority of the unstable solutions studied, the variation of osmolality measurements does not correlate with the loss of concentration and the appearance of degradation products.
Abstract Objectives Bevacizumab was first marketed in 2005. Since then, its stability has been extensively studied. The arrival of numerous biosimilars on the market has called into question these stabilities and organisation within reconstitution units. To study the stability of the Bevacizumab biosimilar Alymsys® marketed by Zentiva laboratory in ready-to-use vials at a concentration of 25 mg/mL and following dilution to obtain final concentrations of 1.4 and 16.5 mg/mL and storage in polyolefin IV bags at 4 °C. In parallel, the impact of a storage temperature excursion at 25 °C for three days and storage of the vial before opening at room temperature (25 ± 2 °C) and after opening at 4 °C was studied. Methods The vials were supplied by Zentiva laboratory. The vials (three batches) were diluted to the final concentrations of 1.4 or 16.5 mg/mL in 100 mL IV bags of NaCl. The IV bags and vials were stored at 4 °C and at room temperature throughout the duration of the study. The physico-chemical stability was tested using the following methods: turbidimetry, UV spectrometry and fluorescence, dynamic light scattering, ion exchange and steric exclusion chromatography, pH, osmolality and density. Results Out of all the parameters studied, for the two concentrations and standard storage conditions (90 days at +4 °C) or after a three-day temperature excursion at +25 °C, no modification was detected for the three batches tested with respect to physical and chemical stability. Hence, no signs of physical instability were observed, with, in particular, the absence of formation of submicron or micron sized aggregates and particles. The steric exclusion chromatography profiles did not demonstrate any oligomer formation or molecular structure rupture. Ion exchange chromatography did not demonstrate any significant modification in the distribution of charge variants. Derivative UV and fluorescence spectral analysis did not demonstrate any modification. The thermal denaturation curves were identical, suggesting the absence of thermodynamic destabilisation. Identical results were observed for the vials stored for 60 days at 4 °C after opening. Finally, only ion exchange chromatography demonstrated a slight change after 45 days of storage at 25 °C for vials before opening. Conclusions After dilution in sterile conditions with 0.9% NaCl in polyolefin IV bags, at the usual concentrations of 1.4 and 16.5 mg/mL, the Bevacizumab biosimilar Alymsys® is stable for at least three months at 4 °C protected from light and after a three-day temperature excursion at +25 °C. The same conclusions can be reached for the 25 mg/mL vials stored for 60 days at +4 °C after opening. However, the stability of vials stored at 25 °C before opening is no longer guaranteed beyond 15 days.
Abstract Objectives The compounding and administration of hazardous drugs present a potential risk to healthcare worker and patient safety. This study sought to evaluate the HD surface contamination in multiple pharmacy and nursing areas that include standardized cleaning techniques and utilization of closed system transfer devices. Methods This study was conducted at six different areas in the pharmacy and nursing areas. Each area was assessed three times for five different HD’s surface contamination at an initial, 3 month, and 6 month follow up. Hazardous drug surface testing was performed for five most compounded HDs. A total of 90 individual samples were taken and analyzed during the study. Results A total of 30 samples were collected at three different timepoints for a total of 90 individual samples and analysis results. All 90 samples were negative (below the lower limit of detection; 0.01 ng/cm2), for their respective drug residue. Conclusions The method and design described in this evaluation may offer a way to determine if a facility’s current HD work practices and controls retain reduced HD surface contamination based upon published threshold values. Adoption and utilization of standardized work, including use of a closed system transfer device, and cleaning practices, described in this study, may present an option for facilities to retain reduced HD surface contamination, based upon previously determined threshold values.
Abstract Objectives Amiodarone hydrochloride is a class III antiarrhythmic drug indicated for the treatment of ventricular and supraventricular tachycardias. Oral amiodarone is only available in a tablet dosage form, which is not suitable for pediatric use. The stability of amiodarone hydrochloride suspension at 5 mg/mL was assessed in SyrSpend® SF PH4 (liquid) but oral amiodarone is typically given as a loading dose of 10–15 mg/kg/day for 4–10 days and then reduced to a maintenance dose of 5 mg/kg/day, making the 20 mg/mL concentration a better option. A hospital preparation of 20 mg/mL amiodarone hydrochloride oral suspension was developed. The purpose of this study was to determine the physicochemical stability of a 20 mg/mL amiodarone hydrochloride oral multidose suspension in a commercial compounding excipient, SyrSpend® SF PH4 (liquid) at ambient temperature and under dark conditions. Methods Three batches of oral suspension were prepared using amiodarone hydrochloride powder and SyrSpend SF PH4 (liquid). The suspensions were stored at room temperature and protected from light (amber glass vials). A sample was withdrawn from each bottle immediately after preparation and at 1, 2, 5, 10, 15, 30, 60, and 90 days. After additional dilution to an expected concentration of 100 μg/mL with methanol, the samples were assayed in triplicate using a stability-indicating high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The physicochemical properties (pH, osmolality, amiodarone concentration, macroscopic changes) were assessed over 90 days at each day of analysis. Stability was determined by evaluating the percentage of the initial concentration remaining at each time point and defined as retention of at least 95% of the initial concentration of amiodarone hydrochloride. Results After 90 days, the study showed that amiodarone hydrochloride concentrations did not go below 95% of the initial drug concentration. Neither degradation products nor changes of physicochemical properties were detected. Conclusions Compounded oral suspensions of 20 mg/mL amiodarone hydrochloride in SyrSpend® SF PH4 (liquid) were stable for at least 90 days when stored in amber glass bottles at room temperature.
Abstract Objectives In adult intensive care patients, epinephrine is mostly administered by continuous injection with syringe pumps. The objective of this study was to investigate the physicochemical stability of pharmacy prepared ready-to-use epinephrine (E) 0.02 mg/mL injection solutions (total volume 50 mL) for assigning shelf-life. Methods E 0.02 mg/mL injection solution in 50 mL amber type l glass vials was produced batch-wise in the pharmacy department. Stability of the refrigerated (2–8 °C) product was investigated in real time over a period of 36 months by analyzing E concentrations, osmolality, pH, and sub-visible particles at predefined time-points. For E concentration measurements a stability-indicating, validated reversed-phase HPLC-PDA assay was used. Results The autoclaving process of E 0.02 mg/mL injection solution in 50 mL amber type I glass vials caused 5% loss of the active substance. The finished product remained stable over the study period of 36 months when stored refrigerated. Conclusions Batch-wise production of ready-to-use E injection solution 0.02 mg/mL in 50 mL amber glass vials was successfully implemented in our pharmacy department. According to the stability tests, a shelf-life of 36 months can be assigned to the finished product stored refrigerated. Studies concerning stability at room temperature would be useful.
Abstract Objectives Patients hospitalized in intensive care units often require multiple drug infusions. Due to limited intravenous accesses, concomitant administration of drugs in the same infusion line is often necessary. Compatibility studies of Y-site administration are available in the literature, but data of several combinations are lacking. Previous work from d’Huart et al. have performed an observation of the administration of injectable drugs in three adults ICUs and identified a list of Y-site administration without compatibility data. The objective of this study was to test the physical compatibility of the main drugs of this list used in pairs in Y-site infusions in critical care units, in order to provide new compatibility data to the literature, and to secure the administration of intravenous drugs. Methods The physical compatibility in Y-site of nine drugs with other drugs commonly used in intensive care units has been tested. Examinations were performed on 75 mixtures after their preparation, after 1 and 4-h storage. This evaluation included a visual examination with a search for precipitation formation, color change, gas formation, and a subvisual evaluation: absorbance measurements by UV-visible spectrophotometry at 350, 410 and 550 nm, and Light Obscuration Particle Count Test. The pH evaluation was performed at each time of analysis. Results Laboratory tests led to an overall compatibility of 68.0% for all mixtures obtained in this study. Nefopam was found to be quite compatible with other drugs (95.0%). Amiodarone hydrochloride (84.6%), acetylsalicylic acid (80.0%), clonidine hydrochloride (75.0%) and insulin (71.4%) were compatible with other drugs too. Atenolol (42.9%), furosemide (25.0%), heparin sodium (25.0%) showed less compatible results. Pantoprazole sodium (0.0%) was not at all compatible with the other drugs analyzed. Conclusions By the results of these laboratory tests, missing compatibility data are now available, providing additional information to the literature.
Abstract Objectives Azacitidine is a pyrimidine nucleoside analogue whose stability is temperature dependent. Numerous publications have studied the stability of this drug with discordant results. The purpose of this work is to study the stability of azacitidine suspensions under different conditions to allow preparation in advance: vials stored at room temperature or between 2 and 8 °C, reconstituted with refrigerated water for injection (WFI) or frozen/thawed WFI, azacitidine suspensions stored at room temperature, 2–8 °C or at −20 °C. The feasibility of a vented ChemoClave® Spike vial was also tested to reconstitute and collect azacitidine to aid the preparation stage. Methods The stability study was performed by HPLC coupled to a photodiode array detector. The method was validated according to ICH Q2(R1). Two syringes were prepared for each analysis condition and two samples were realised for each syringe at each time of the analysis. For a storage at 2–8 °C, analyses were performed for up to 168 h. The stability was studied after 2 h at room temperature. For frozen storage, the stability was studied after 28 days. Results Azacitidine 25 mg/mL suspensions stored between 2 and 8 °C, prepared with refrigerated WFI or frozen/thawed WFI, retained more than 90% of the initial concentration for 96 h and then for 2 h at room temperature. Prepared with frozen/thawed WFI, azacitidine 25 mg/mL suspensions stored at −20 °C for 28 days and then 72 h between 2 and 8 °C after thawing, retained more than 90% of the initial concentration. When using a Spike system compared to using a needle for reconstitution and collection of the suspension, the results obtained by HPLC showed a decrease of 1.47% in the concentration of azacitidine. The comparisons of the volumes withdrawn after reconstitution were similar when using a Spike system or a needle. Conclusions Azacitidine 25 mg/mL suspensions reconstituted with refrigerated WFI were chemically stable for 4 days when stored at 2–8 °C whatever the storage of vials (refrigerator or room temperature), and 2 h at room temperature. A storage of azacitidine 25 mg/mL suspensions in syringes prepared with frozen/thawed WFI at −20 °C has been validated for up to 28 days, leading to the possibility to prepare in advance. A Spike device can be used to reconstitute and collect azacitidine.
Abstract Objectives Fungal keratitis is a rare but severe cause of infectious keratitis and can lead to blindness. To cure fungal keratitis, antifungal like voriconazole eye drops must be immediately administered. As no brand is available on the market, voriconazole ophthalmic solution is compounded in hospital pharmacies using voriconazole powder for intravenous infusion. The aims of our study were to both assess the physico-chemical and microbiological stability of eye drop solutions stored at +2 to 8 °C. Two different High-Density-Polyethylene (HDPE) eye drop dispensing containers were assessed, one with a sterility preserving cap Novelia®(Nemera) and the other without sterility preserving cap both provided by CAT laboratory. In addition microbiological quality was assessed during 15 days simulated patient use. Methods Multiple batches of voriconazole 10 mg/mL eye drops were prepared and stored at +2 to 8 °C to study their stability over 90 days. All analyses were performed in triplicate. Physical stability was determined, pH determination, osmolarity measurement, and a particle count test was also performed. A high performance liquid chromatography (HPLC-UV) stability indicating method was used to determine chemical stability of the ophthalmic solution over 90 days of storage. For microbiological stability, a sterility test was performed using closed membrane filtration method (Steritest®, Merck Millipore) at D0, D90 and D90+15 days after simulated administration of eye drops (D90+15). Results For both containers, no variation of visual aspect, pH, osmolality, particle count and final concentration were observed. No microbiological growth was observed after 90 days of storage. At the end of the simulated administration period (D+15), unconstant microbiological growth was only observed in HDPE vials without sterility preserving cap, whereas HDPE vials with a sterility preserving cap Novelia®(Nemera) remained sterile. Conclusions Voriconazole 10 mg/mL ophtalmic solution was stable during 90 days at +2 to 8 °C in lightproof HDPE vials without sterility preserving cap and HDPE vials with a sterility preserving cap Novelia®(Nemera). However, vials with classical cap which are not airtight systems, may microbiologically contaminated during patient’s use than vials with Novelia® cap thanks to their innovative valve system.
