Judith Thiesen

Physico‐chemical stability of docetaxel premix solution and docetaxel infusion solutions in PVC bags and polyolefine containers

We assessed the physical and chemical stability of docetaxel infusion solutions. Stability of the antineoplastic drug was determined 1.) after reconstitution of the injection concentrate and 2.) after further dilution in two commonly used vehicle‐solutions, 0.9% sodium chloride and 5% dextrose, in PVC bags and polyolefine containers. Chemical stability was measured by using a stability‐indicating HPLC assay with ultraviolet detection. Physical stability was determined by visual inspection. The stability tests revealed that reconstituted docetaxel solutions (= premix solutions) are physico‐chemically stable (at a level ≥ 95% docetaxel) for a minimum of four weeks, independent of the storage temperature (refrigerated, room temperature). Diluted infusion solutions (docetaxel concentration 0.3 mg/ml and 0.9 mg/ml), with either vehicle‐solution, proved physico‐chemically stable (at a level ≥ 95% docetaxel) for a minimum of four weeks, when prepared in polyolefine containers and stored at room temperature. However, diluted infusion solutions exhibited limited physical stability in PVC bags, because docetaxel precipitation occured irregularly, though not before day 5 of storage. In addition, time‐dependent DEHP‐leaching from PVC infusion bags by docetaxel infusion solutions must be considered.

Stability of irinotecan-loaded drug eluting beads (DC BeadTM) used for transarterial chemoembolization

Purpose. The aim of this study was to determine the loading efficiency, physicochemical stability, and release of irinotecan-loaded DC BeadsTM (bead size 100—300 μm, 300—500 μm) before and after mixing with nonionic contrast medium (Accupaque® 300, Imeron® 300, Ultravist ® 300) during a prolonged period of time (28 days) when stored at room temperature or refrigerated. Methods. DC Beads TM were loaded with 50 mg irinotecan (Campto®) per milliliter beads in a 2 h loading period. Drug loading efficiency and stability were determined by measuring the irinotecan concentration in the excess solution. A free-flowing in vitro elution method for a period of 2 h and phosphate buffered solution (PBS, pH 7.2) as elution medium were used to analyze the integrity of the irinotecan-loaded. Stability of irinotecan-loaded beads after mixing with an equal volume of three different nonionic contrast agents was determined by measuring irinotecan concentrations in the excess solutions. Vials with loaded beads were stored protected from light at room temperature. Mixtures with contrast media were stored protected from light under refrigeration (2—8°C). Samples were taken periodically over a 4 week period (day 0, 1, 3, 7 and 28). A reversed phase HPLC assay with ultraviolet detection was utilized to analyze the concentration and purity of irinotecan. Results. The loading procedure of DC BeadsTM with irinotecan drug solution resulted in a loading percentage of 96% (bead size 100—300 μm) independent of the storage time. No differences in loading levels and no irinotecan degradation products were observed over the period of 28 days, while the test vials were stored light protected at room temperature. Integrity of loaded irinotecan was also given over that same period of time according to the purity and concentration of irinotecan measured after intentional elution with PBS. Mixing of irinotecan-loaded beads (bead size 100—300 μm, 300—500 μm) with nonionic contrast media decreased the irinotecan loading efficiency by ∼5—10% during a maximum period of 24 h. However, no further elution or degradation was observed during a 4-week period when stored protected from light under refrigeration. Conclusions. Irinotecan-loaded DC BeadsTM are shown to have adequate physicochemical stability over a period of at least 28 days when stored light protected at room temperature. Due to concerns of microbiological overgrowth refrigeration should always be considered. The preparation of admixtures of irinotecan-loaded beads with contrast medium in centralized cytotoxic preparation units is not recommended, because of rapid elution of 5—10% of irinotecan from the loaded beads. Furthermore, physicians see no advantages of admixtures due to the wide variation of mixing ratios of drug-loaded beads with contrast medium. In addition varying volumes of 0.9% sodium chloride solution are to be admixed during the chemoembolization procedure

Stability of topotecan infusion solutions in polyvinylchloride bags and elastomeric portable infusion devices

Purpose. The purpose of this study was to determine the physicochemical stability of topotecan after reconstitution and after further dilution in two commonly used infusion fluids (0.9% sodium chloride, 5% dextrose) in both polyvinylchloride (PVC) bags and elastomeric portable infusion devices. Methods. Each vial of topotecan (Hycamtin®) was reconstituted with sterile water for injection, yielding a nominal concentration of 1 mg/mL. Topotecan infusion solutions were aseptically prepared by further dilution of reconstituted topotecan solutions with either 0.9% sodium chloride or 5% dextrose in both PVC bags and portable elastomeric infusion devices, in amounts yielding topotecan concentrations of 10 mg/mL, 25 mg/mL, or 50 mg/mL. Test solutions were stored light-protected at room temperature (25°C) or under refrigeration (2-8°C) in parallel. One test solution of the nominal concentration of 10 mg/mL topotecan in a 0.9% sodium chloride PVC infusion bag was stored under ambient light conditions (mixed daylight and normal laboratory fluorescent light) at room temperature. Topotecan concentrations were obtained periodically throughout a 4-week storage period via a stability-indicating high performance liquid chromatography assay with ultra-violet detection. In addition, measurements of pH values were performed regularly, and test solutions were visually examined for colour change and precipitation. Results. The stability tests revealed that the currently available topotecan formulation is stable (at a level of

Physicochemical stability of irinotecan injection concentrate and diluted infusion solutions in PVC bags

90% topotecan) after reconstitution and dilution, independent of temperature (refrigerated, room temperature), the vehicle (0.9% sodium chlo-ride, 5% dextrose), the concentration (10 mg/mL, 25 mg/mL, or 50 mg/mL), or the container material (PVC bags, elastomeric portable infusion devices). The results were obtained over a test period of

Media-fill simulation tests in manual and robotic aseptic preparation of injection solutions in syringes

4 weeks. Topotecan infusion solutions exposed to daylight were stable for only 17 days. Conclusions. Reconstituted and diluted topotecan infusion solutions are shown to be physicochemically stable for 4 weeks. Light protection during administration is not necessary.

Viability of Selected Microorganisms in Non-Cytotoxic Aseptic Preparations

Purpose. To determine the physicochemical stability of irinotecan injection concentrate and irinotecan infusion solutions after dilution in two commonly used infusion fluids (0.9% sodium chloride, 5% dextrose) in PVC bags, stored under refrigeration (2-8°C) or at room temperature either light protected or exposed to light. Methods. Stability of irinotecan injection concentrate was determined in the original amber glass vials. Diluted irinotecan infusion solutions were aseptically prepared by further dilution of irinotecan stock solution with either 0.9% sodium chloride or 5% dextrose in PVC bags, in amounts yielding irinotecan concentrations of 0.4, 1.0, or 2.8 mg/ml. Test solutions were stored under refrigeration (2-8°C) or at room temperature either light protected or exposed to light (mixed daylight and normal laboratory fluorescent light) in parallel. Irinotecan concentrations were determined periodically throughout a 4-week storage period via a stability-indicating HPLC assay with ultraviolet detection. In addition, measurements of pH values were performed regularly and test solutions were visually examined for colour change and precipitation. Results. Irinotecan injection concentrate and infusion solutions are shown to be physicochemically stable (at a level of >90% irinotecan) for 4 weeks when stored under refrigeration or light protected at room temperature, independent of the vehicle (0.9% sodium chloride, 5% dextrose) or the concentration (0.4, 1.0, or 2.8 mg/ml). Irinotecan infusion solutions exposed to daylight exhibited concentration-dependent instability, solutions were stable for only 7 to 14 days. Conclusions. Irinotecan injection concentrate and diluted infusion solutions are shown to have adequate physicochemical stability for convenient pharmacy-based centralized preparation.

Loading, release and stability of epirubicin-loaded drug-eluting beads:

Objective The purpose of this study was to evaluate the contamination rate of media-fill products either prepared automated with a robotic system (APOTECAchemo™) or prepared manually at cytotoxic workbenches in the same cleanroom environment and by experienced operators. Media fills were completed by microbiological environmental control in the critical zones and used to validate the cleaning and disinfection procedures of the robotic system. Methods The aseptic preparation of patient individual ready-to-use injection solutions was simulated by using double concentrated tryptic soy broth as growth medium, water for injection and plastic syringes as primary packaging materials. Media fills were either prepared automated (500 units) in the robot or manually (500 units) in cytotoxic workbenches in the same cleanroom over a period of 18 working days. The test solutions were incubated at room temperature (22℃) over 4 weeks. Products were visually inspected for turbidity after a 2-week and 4-week period. Following incubation, growth promotion tests were performed with Staphylococcus epidermidis. During the media-fill procedures, passive air monitoring was performed with settle plates and surface monitoring with contact plates on predefined locations as well as fingerprints. The plates got incubated for 5–7 days at room temperature, followed by 2–3 days at 30–35℃ and the colony forming units (cfu) counted after both periods. The robot was cleaned and disinfected according to the established standard operating procedure on two working days prior to the media-fill session, while on six other working days only six critical components were sanitized at the end of the media-fill sessions. Every day UV irradiation was operated for 4 h after finishing work. Results None of the 1000 media-fill products prepared in the two different settings showed turbidity after the incubation period thereby indicating no contamination with microorganisms. All products remained uniform, clear, and light-amber solutions. In addition, the reliability of the nutrient medium and the process was demonstrated by positive growth promotion tests with S. epidermidis. During automated preparation the recommended limits < 1 cfu per settle/contact plate set for cleanroom Grade A zones were not succeeded in the carousel and working area, but in the loading area of the robot. During manual preparation, the number of cfus detected on settle/contact plates inside the workbenches lay far below the limits. The number of cfus detected on fingertips succeeded several times the limit during manual preparation but not during automated preparation. There was no difference in the microbial contamination rate depending on the extent of cleaning and disinfection of the robot. Conclusion Extensive media-fill tests simulating manual and automated preparation of ready-to-use cytotoxic injection solutions revealed the same level of sterility for both procedures. The results of supplemental environmental controls confirmed that the aseptic procedures are well controlled. As there was no difference in the microbial contamination rates of the media preparations depending on the extent of cleaning and disinfection of the robot, the results were used to adapt the respective standard operating procedures.

Physico-chemical stability of eribulin mesylate containing concentrate and ready-to-administer solutions.

Abstract Background: Numerous ready-to-use parenteral solutions are aseptically prepared in pharmacy-based aseptic preparation units. Microbiological stability of the preparations is influenced by the cleanroom environment, the complexity of the aseptic process, conditions during administration and the microbiological vulnerability of the products. Object: The aim of the study was to evaluate the ability of four different pathogens related to hospital infections to grow in ready-to-use, non-cytotoxic parenteral products aseptically prepared in hospital pharmacies. Method: In four consecutive series the antimicrobial activity of the following products was tested: caspofungin 35 mg or 70 mg in 250 mL 0.9 % NaCl solution (NS), micafungin 0.5 mg/mL in NS, vancomycin 5 mg/mL in G5/G10, heparin-sodium 1 IE/mL in NS, epinephrine 0.02 mg/mL in G5, norepinephrine 0.01 mg/mL in G5, phenylephrine 0.1 mg/mL, KCl solution 0.8 mmol/mL, trace elements 1:1 in G5/G10, midazolam 1 mg/mL injection solution, tranexamic acid 100 mg/mL injection solution, 50 % glucose solution, SMOFlipid 20 % lipid emulsion, 1 % propofol injection. Nine milliliter aliquots of each test solution were inoculated with 1 mL suspension of selected strains, i. e. S. aureus, P. aeruginosa, E. faecium or C. albicans. Samples of the inoculated solutions were taken in predefined intervals up to 144 h and transferred to tryptic soy agar plates. The plates were incubated at 37 °C and colony forming units (CFUs) counted after 24 h for bacteria and after 72 h in the case of C. albicans. Results: Most of the tested preparations induced no growth inhibition of the tested organisms. The selected strains lost viability in preparations containing vancomycin, phenylephrine or midazolam after a period of a few hours or days. Glucose 50 % w/v solution generated antimicrobial activity against P. aeruginosa and C. albicans immediately after inoculation. In tranexamic acid solutions only P. aeruginosa lost viability after 48 h of inoculation. In the lipid containing emulsions, CFUs increased rapidly. Low pH values and high osmolality are probably the reason for growth inhibition in midazolam and 50 % glucose solutions, respectively. The antimicrobial activity of phenylephrine solutions is caused by the excipient sodium metabisulfite. Conclusion: The lack of antimicrobial properties of ready-to-use, non-cytotoxic solutions should be considered while determining the shelf-life of the products. Ready-to-use preparations should be kept refrigerated whenever possible to inhibit the multiplication of any contaminating organism.

Stability of Ready-to-Administer and Ready-to-Use Epinephrine and Norepinephrine Injection Solutions

Purpose The aim of this study was to determine the loading efficiency, physico-chemical stability and release of epirubicin-loaded DC Bead™ (Biocompatibles UK Ltd, a BTG International group company) (bead size 70–150 µm (=DC BeadM1™) and 100–300 µm) after loading with epirubicin solution (2 mg/ml) or reconstituted powder formulation (25 mg/ml) and controlled storage. Methods DC Bead™ were loaded with 76 mg epirubicin solution (Epimedac™, Medac GmbH) or 75 mg epirubicin powder formulation (Farmorubicin™, Pharmacia Pfizer GmbH) per 2 ml of beads. Drug loading efficiency and stability were determined by measuring the epirubicin concentration in the excess solution after predetermined intervals (maximum 24 h) and different agitation conditions. Syringes with loaded beads were stored protected from light at room temperature. At predetermined intervals the beads were transferred into 200 ml phosphate buffered solution (pH 7.2) as elution medium and stirred automatically for 2 h not followed or followed by addition of 200 ml of 20% sodium chloride (=NaCl) solution and stirred for another 2 h to analyse the drug release and integrity of the epirubicin-loaded beads. Elution experiments were performed and samples taken periodically over a four-week period (day 0, 7, 14 and 28). A reversed-phase high-performance liquid chromatography assay with ultraviolet detection was utilized to analyse the concentration and purity of epirubicin. Results The loading procedure for DC Bead™ with epirubicin drug solutions resulted in a loading percentage of 95–99% within 6 h dependent on the bead size, epirubicin concentration in the loading solution and loading conditions. Loading levels remained stable and no epirubicin degradation products were observed over the period of 28 days, while the loaded beads were stored light protected at room temperature. Release of epirubicin into 200 ml phosphate buffered solution elution medium and additionally followed by release into the admixture with 200 ml 20% NaCl solution amounted to 5% and about 20% of the loaded epirubicin, respectively. Integrity of loaded epirubicin was proven over 28 days. Conclusions Epirubicin can be loaded into DC Bead™ of different sizes using the epirubicin powder formulation (25 mg/ml) or epirubicin injection concentrate (2 mg/ml). Physico-chemical stability is maintained over a period of at least 28 days when stored light protected at room temperature. Elution of epirubicin is dependent on the volume and cation exchange capacity of the elution medium.

Physicochemical Stability of Mozobil® (Plerixafor) Solution for Injection in Glass Vials and Plastic Syringes over a Three-Month Storage Period

Objectives The aim of this study was to determine the stability of commercially available eribulin mesylate containing injection solution as well as diluted ready-to-administer solutions stored under refrigeration or at room temperature. Methods Stability was studied by a novel developed stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) assay with ultraviolet detection (detection wavelength 200 nm). Triplicate test solutions of eribulin mesylate containing injection concentrate (0.5 mg/mL) and with 0.9% sodium chloride solution diluted ready-to-administer preparations (0.205 mg/mL eribulin mesylate in polypropylene (PP) syringes, 0.020 mg/mL eribulin mesylate in polypropylene/polyethylene (PE) bags) were stored protected from light either at room temperature (25℃) or under refrigeration (2–8℃). Samples were withdrawn on day 0 (initial), 1, 3, 5, 7, 14, 21 and 28 of storage and assayed. Physical stability was determined by measuring the pH value once a week and checking for visible precipitations or colour changes. Results The stability tests revealed that concentrations of eribulin mesylate remained unchanged over a period of 28 days irrespective of concentration, container material or storage temperature. Neither colour changes nor visible particles have been observed. The pH value varied slightly over time but remained in the stability favourable range of 5–9. Conclusion Eribulin mesylate injection (0.5 mg/mL) is physico-chemically stable over a period of 28 days after first puncture of the vial. After dilution with 0.9% NaCl vehicle solution, ready-to-administer eribulin mesylate injection solutions (0.205 mg/mL in PP syringe) and infusion solutions (0.02 mg/mL in prefilled PP/PE bags) are physico-chemically stable for a period of at least four weeks either refrigerated or stored at room temperature. For microbiological reasons storage under refrigeration is recommended.