Band 8, Heft 1

Objectives 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. Methods One batch of piperacillin/tazobactam syringes followed by one batch of meropenem syringes were compounded daily for three consecutive days by one operator. For each batch two hundred syringes were filled. During each batch, three stationary air samples (two inside and one outside the compounding device), and one personal air sample were collected. At the end of the compounding process, the outside of 40 syringes was tested for drug contamination by wipe sampling. The drug compounded was checked for cross-contamination with the other drug compounded in the previous batch. Liquid chromatography tandem mass spectrometry was used for the analysis of piperacillin and meropenem. Results Piperacillin was measured in environmental air inside the device (8.1–335 ng/m 3 ), outside the device (5.2–21 ng/m 3 ), and in the personal air samples of the operator (15 and 155 ng/m 3 ) during two batches. Meropenem was not detected during meropenem compounding. Piperacillin was found in the air samples of the operator during two batches (12 and 15 ng/m 3 ). Meropenem was not detected in any of the air samples. The drug compounded was found on the outside of the syringes for all batches (piperacillin: 1.35–30 ng/cm 2 ; meropenem: 0.07–0.65 ng/cm 2 ). Piperacillin was detected on the syringes in all meropenen batches (0.56–11 ng/cm 2 ), and meropenen in two piperacillin batches (0.07 and 0.46 ng/cm 2 ). The drug solutions show no cross-contamination with the other drug for any of the batches. Conclusions Cross-contamination was not found and the drug concentrations in environmental air were below the Occupational Exposure Limit of 0.1 mg/m 3 . The automatic compounding device meets the criteria for a safe compounding of sensitizing drugs for patient and operator.

Objectives 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. Methods Beforehand, a stability indicating method (SIM) was developed. Samples were analysed after 1, 3 and 6 months, and after 12, 24 and 72 h after defrosting. Analyses performed were the following: visual inspection, chromaticity, turbidity, osmolality and pH measurements, particles counting, CZ and VM quantification, breakdown product research, and sterility assay. Results The developed SIM allowed the simultaneous quantification and breakdown products research of both VM and CZ, without interference of the breakdown products. The analyses showed the presence of a visually detectable precipitate and increased turbidity as early as the first day after thawing for CD-free formulation and on the third day for the formulation with CD. CZ concentrations systematically decreased after thawing for both formulations whilst VM concentrations remained stable. Osmolality and pH remained unchanged, and no microbial growth was detected throughout the study. Conclusions CD delayed precipitation by 48 h compared to the CD-free formulation but did not permanently eliminate it. Both formulations showed very limited physicochemical stability after thawing.

Objectives 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. Methods Sterility tests and uniformity of dosage units tests were performed. For the sterility test, 22 syringes were filled with 0.5 mL Tryptic Soy Broth and these were incubated at 25 °C for seven days followed by seven days at 30 °C. For the dosage unit test, the difference between the filled and empty syringe was used to compute the volume of the injectable volume. A time analysis was performed on manually and semi-automatically prepared vaccines. Results The sterility tests showed no signs of growth of micro-organisms. After optimizing the Vaxtractor, none of the Comirnaty ® vaccines deviated more than 10 % and none of the Spikevax ® vaccines deviated more than 5 % compared to the mean mass of the injectable volume. The acceptance value for uniformity of dosage units of both vaccines was below 4 (requirement <15). Preparing vaccines with the Vaxtractor was faster compared to manually prepared vaccines. Conclusions The Vaxtractor can be used to safely prepare Spikevax ® and Comirnaty ® vaccines. Further studies should explore the applicability of the Vaxtractor for the preparation of other vaccines. If applicable, this will contribute to effective upscaling of vaccination programs.

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.

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.

Objectives 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. Methods Mitomycin medac was dissolved with water for injection to achieve MMC concentrations of 1 mg/mL and 2 mg/mL. Additionally, 1 mg/mL MMC solutions were further diluted with normal saline to obtain 0.2 mg/mL and 0.4 mg/mL solutions. According to clinical practice, 1 mg/mL solutions were stored in original glass vials and 2 mg/mL, 0.2 mg/mL, and 0.4 mg/mL solutions were stored in plastic syringes. All solutions were stored either refrigerated or at 20–25 °C light protected for up to 8 days. Samples were taken immediately after dissolution or dilution and at predetermined time points. Physicochemical stability was determined by reversed-phase high-performance liquid chromatography (RP-HPLC) with photodiode array detection, pH and osmolality measurement, and inspection for visible particles or color changes. Results 2 mg/mL MMC solutions were achieved at room temperature and physicochemical stability was given for 8 h, independent of the storage temperature. Between 8 and 12 h of storage, crystallization occurred in almost all samples. In 1 mg/mL MMC test solutions, stored under refrigeration, crystallization occurred in 2 of 3 vials after 2 and 4 days of storage, respectively. In the vial without signs of crystallization, MMC concentration amounted to >90 % of the initial measured concentration after 6 days. When stored at room temperature, crystallization was not seen, but MMC concentration declined below the 90 % stability limit at about 15 h of storage. In 0.2 mg/mL and 0.4 mg/mL MMC test solutions crystallization was not observed at all. When stored refrigerated, preparations were physicochemically stable for 5 and 3 days, respectively. When stored light protected at room temperature, physicochemical stability was given for at least 6 h, irrespective of the MMC concentration. Conclusions Mitomycin medac enables the preparation of 2 mg/mL MMC solutions without additional heating and shaking due to the hydrotropic activity of urea contained as excipient. However, in 2 mg/mL MMC solutions crystallization is the most dominant stability limiting factor, especially under refrigerated storage. Hence, storage at room temperature is recommended for this concentration. In 1 mg/mL MMC solutions crystallization is less prominent. To avoid increased chemical degradation at room temperature, refrigerated storage is recommended. Both, 2 mg/mL and 1 mg/mL MMC solutions should always be checked for the formation of crystals before use. In diluted 0.2 mg/mL and 0.4 mg/mL MMC solutions, crystallization was not an issue and refrigerated storage extends physicochemical stability to maximum 5 and 3 days, respectively.

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.

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.

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.

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.