In-use stability of ready-to-administer daratumumab subcutaneous injection solution in plastic syringes.

OBJECTIVE: In multiple myeloma patients, daratumumab is preferably injected subcutaneously. The summary of product characteristics of daratumumab subcutaneous injection solution specifies physicochemical stability for the prepared syringe for 24 hours at 2-8°C protected from light, and another 12 hours at room temperature (15-25°C) in ambient light conditions. The aim of this study was to determine the in-use stability of ready-to-administer daratumumab subcutaneous injection solution in different types of syringe and different conditions over a 28-day period. METHODS: Daratumumab subcutaneous (DARZALEX 1800 mg) injection solution was withdrawn into disposable three-piece Luer-Lock syringes (20 mL, 50 mL), capped, and stored light protected at 2-8°C or at room temperature (22±2°C) over a maximum period of 28 days. Samples were taken immediately after preparation (day 0) and after 2, 7, 14, 21, and 28 days. Physicochemical stability was determined by ion-exchange high-performance liquid chromatography (IE-HPLC) and size-exclusion high-performance liquid chromatography (SE-HPLC) with ultraviolet detection, pH measurement and visual inspection for particles or colour changes. RESULTS: In the IE-HPLC assay, peak areas and peak-to-peak area ratios remained unchanged over the whole study period, and showed no additional peaks of degraded daratumumab charge variants. In the SE-HPLC assay, neither a formation of aggregates nor of fragments was detected. Daratumumab monomer concentrations exceeded 95% of the initially measured concentrations over the entire test period. pH values remained constant. Test solutions remained clear, and no colour changes or visible particles were detected. All results were independent of storage conditions. CONCLUSION: Daratumumab subcutaneous injection solution proved to be physicochemically stable in capped three-piece plastic syringes for at least 28 days when stored light protected at 2-8°C or at room temperature (22±2°C). For microbiological reasons aseptic preparation and refrigerated storage are recommended. In-use stability of ready-to-administer daratumumab subcutaneous syringes prepared under appropriate aseptic conditions is given for 28 days.

Viability of selected microorganisms in parenteral preparations for novel systemic anti-cancer therapy.

BACKGROUND: Risk factors for aseptic preparation of parenteral medicines encompass the growth-promoting nature of the preparation. Although many aqueous parenteral preparations do not have growth-promoting properties, inadvertently introduced microorganisms may remain viable. Knowledge about the viability of microorganisms in parenteral preparations can add useful information for assigning shelf life to preparations used to treat cancer patients. AIM: The aim of the study was to assess the viability of four different facultative pathogenic microorganisms in 20 ready-to-administer parenteral preparations aseptically prepared in hospital pharmacies. METHODS: Samples of 20 different biologics and small molecules for systemic anti-cancer therapy were inoculated either with different bacteria (i.e., Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium) or with Candida albicans suspension. The resulting test concentrations were 104-105 microorganisms per mL. Aliquots of inoculated test solutions were transferred in duplicate to tryptic soy agar plates at the time points 0, 4, 24, 48, 144 h. The plates were incubated for 24 h (bacterial strains) and 72 h (C. albicans) at 37 °C and colony forming units (CFUs) were counted. RESULTS: In most test solutions, especially in monoclonal antibody solutions, increased CFU counts of P. aeruginosa and unchanged or increased CFU counts of E. faecium and S. aureus were registered. Pronounced nutritive properties of monoclonal antibodies and filgrastim were not registered. Azacitidine, pixantrone and vinflunine containing test solutions revealed species-specific bacteriostatic and even bactericidal activity. All test solutions, except nivolumab and pixantrone containing solutions, showed constant or increasing CFU counts of C. albicans after incubation. CONCLUSION: Viability of the selected pathogenic microorganisms was retained in most of the tested biological and small molecule preparations used to treat cancer patients. Therefore, in pharmacy departments strict aseptic conditions should be regarded and the lack of antimicrobial activity should be considered when assigning shelf life to RTA parenteral preparations.

Physicochemical stability of ready-to-administer mitomycin C solutions for intravesical instillation.

OBJECTIVE: The aim of the study was to investigate the physicochemical stability of mitomycin-containing medicinal products for bladder instillation, formulated with urea as excipient (mito-medac®, Mitomycin medac). For comparison, the stability of reconstituted Urocin® and Mitem® bladder instillation was studied. METHODS: Mitomycin-containing medicinal products were either reconstituted with the prepackaged 0.9% NaCl solution, nominal volume 20 mL (mito-medac®, Mitem®, Urocin®) or with 20 mL water for injection (Mitomycin medac, Mitem®, Urocin®) to a nominal concentration of 1 mg/mL and stored at room temperature (20-25°C). Samples were taken immediately after reconstitution and after 24 hours. Physicochemical stability was determined by reverse-phase high performance liquid chromatography with photodiode array detection, measurement of pH and osmolarity, and inspection for visible particles or colour changes. RESULTS: The initial pH values of the test solutions reconstituted with prepackaged 0.9% NaCl (5.2-5.6) were significantly lower than those reconstituted with water for injection (6.6-7.4). Solutions reconstituted with 0.9% NaCl solutions rapidly degraded and concentrations fell below the 90% limit after 24 hours of storage. When reconstituted with water for injection, degradation was less rapid. Concentrations of Mitomycin medac and Urocin remained above the 90% limit after 24 hours. CONCLUSIONS: The physicochemical stability of mitomycin 1 mg/mL bladder instillation prepared with prepackaged 0.9% NaCl in prefilled PVC bags is less than 24 hours at room temperature. Unfavourable pH values of the solvents cause rapid degradation of mitomycin. Mitomycin solutions reconstituted at the point of care should be administered immediately to avoid degradation and loss of efficacy. Urea added as excipient did not accelerate degradation.

Physicochemical Stability of Generic Thiotepa Concentrate and Ready-to-Administer Infusion Solutions for Conditioning Treatment.

The objective of this study was to determine the physicochemical in-use stability of recently approved Thiotepa Riemser concentrate in the original vial and diluted ready-to-administer (RTA) infusion solutions in prefilled glucose 5% and 0.9% NaCl polyolefin bags. Thiotepa Riemser 10 mg/mL concentrates and infusion solutions (1 mg/mL, 2 mg/mL, 3 mg/mL) were prepared in triplicate and stored at 2-8 °C or 25 °C for 14 days. Thiotepa concentrations were determined using a stability-indicating RP-HPLC assay. In parallel, pH and osmolality were measured. Sub-visible particles were counted on day 0 and 14. Thiotepa Riemser concentrate was revealed to be stable for 14 days when stored at 2-8 °C, or for 24 h when stored at 25 °C. Thiotepa concentrations in infusion solutions stored at 2-8 °C remained above 95% of the initial concentrations for at least 14 days, regardless of the type of vehicle solution. When stored at 25 °C, thiotepa infusion solutions in glucose 5% proved to be physicochemically stable for 3 days (1 mg/mL), 5 days (2 mg/mL) or 7 days (3 mg/mL). Thiotepa infusion solutions in 0.9% NaCl remained physicochemically stable for 5 days (1 mg/mL) or 7 days (2 mg/mL, 3 mg/mL). At these points in time, the specification limit of ≤0.6% monochloro-adduct was fulfilled. In parallel, an elevation of the pH values was registered. Thiotepa concentrates and infusion solutions should be stored at 2-8 °C due to temperature-dependent physicochemical stability, and for microbiological reasons. Glucose 5% infusion solution is recommended as a diluent, and stability-improving nominal 2 mg/mL to 3 mg/mL thiotepa concentrations should be obtained.

Physicochemical stability of carmustine-containing medicinal products after reconstitution and after dilution to ready-to-administer infusion solutions stored refrigerated or at room temperature.

INTRODUCTION: The aim of this study was to determine and compare the physicochemical stability of two carmustine-containing medicinal products licensed and marketed in Europe as Carmustin Obvius (Medac GmbH) and Carmubris (Tillomed Pharma GmbH). Reconstituted stock solutions and diluted ready-to-administer infusion solutions of the two products were investigated. METHODS: Reconstituted carmustine stock solutions (3.3 mg/mL) and ready-to-administer infusion solutions (0.2 mg/mL, 1.0 mg/mL) prepared in prefilled 5% glucose injection solution PP/PE bags were stored at 22°C or 2-8°C over a maximum period of 66 hours protected from light. Samples were taken immediately after reconstitution or dilution and after 3.5, 6, 8.5 and 11 hours when stored at 22°C or after (12), 24, 48 and 60 hours when stored at 2-8°C, followed by 3- and 6-hour storage at 22°C (60+3 hours, 60+6 hours). Physicochemical stability was determined by reversed-phase high-performance liquid chromatography with UV detection, measurement of pH, osmolarity and inspection for visible particles or colour changes. RESULTS: Carmustin Obvius and Carmubris reconstituted stock solutions were physicochemically stable for at least 48 hours when stored at 2-8°C. Carmustin Obvius and Carmubris infusion solutions 0.2 mg/mL were physicochemically stable for at least 8.5 hours and 60 hours when stored at 22°C and 2-8°C, respectively. After subsequent storage of the 60-hour refrigerated test solutions for 3 hours at 22°C, the carmustine concentrations averaged the 90% limit and fell below the 90% limit after 6 hours. Carmustin Obvius infusion solutions 1.0 mg/mL were physicochemically stable for at least 8.5 hours when stored at 22°C and for 60 hours when stored at 2-8°C. CONCLUSION: According to the physicochemical stability data, the shelf life (95% limit) of the refrigerated stock solutions is 48 hours and the shelf life (90% limit) of ready-to-administer infusion solutions (0.2 mg/mL, 1.0 mg/mL) is 60 hours at 2-8°C or 8.5 hours at 22°C under light protection. These results facilitate the use of both medicinal products in a pharmacy-based centralised cytotoxic preparation unit.

Formulation and Administration of Biological Medicinal Products".

Monoclonal antibody (Mabs) containing medicinal products are widely used in clinical practice. Prior to parenteral administration, licensed Mab containing medicinal products are transferred to the ready-to-administer (RTA) forms. Reconstitution and/or preparation should follow the guidelines for Good Reconstitution/Good Preparation Practice. Preparation in the pharmacy must take place within the framework of a suitable quality management system. The responsible pharmacist must apply a risk assessment on the process to ensure the appropriate quality of the RTA preparation, especially because the extent of quality testing is limited by batch size (often one single unit) and time restraints. In these cases, appropriate quality is to be assured by means of qualification activities, environmental monitoring, process validation with growth medium and in-process controls. Correct labelling of the Mab containing RTA preparations includes a suitable storage advice and a defined shelf life. Physicochemical stability of a given Mab preparation can be assessed based on a specific stability study (supplied by the manufacturer in the SmPC or scientific journals, study published by an expert in a peer-reviewed scientific journal). Physicochemical stability studies require the use of various orthogonal physicochemical methods to detect accurately the degradation changes that may result from the deamidation, oxidation, disulfide formation, aggregation or fragmentation during storage. Complementary, biological activity can be measured. Compatibility studies of Mabs and devices used for preparation and administration are still scarce. Microbiological stability of Mab preparations is related to the complexity of the preparation process, the growth supporting nature of the preparation and the integrity of the container or container/closure combination. In use viability tests revealed that the potential of Mab preparations to support microbial growth was similar to that of the pure vehicle solutions used as control solutions. The enumerated microbial counts varied according to the species utilized and the type of Mab preparation. If sterility testing of the individual preparation is impossible, maximum permitted shelf life can be assessed empirically with regard to the maximum shelf lives defined in the USP <797> monograph. Finally, microbiological and physicochemical stability are to be considered concurrently when determining the shelf life of an individual Mab preparation. In each case, shelf life should be limited according to the shorter period of proven stability, either derived from the microbiological or physicochemical stability data.

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

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.

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

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.

Compatibility of irinotecan-loaded DC Bead with different volumes and types of non-ionic contrast media.

OBJECTIVES: Irinotecan-loaded microspheres are used for simultaneous embolisation and chemotherapy of liver metastases of colorectal carcinoma. The aim of the study was to evaluate the compatibility of recently introduced DC BeadM1 (bead size 70-150 µm) loaded with irinotecan after admixture with different types and volumes of non-ionic contrast media over a maximum period of 24 h and storage at room temperature. METHODS: Test suspensions were prepared by loading 2 mL DC BeadM1 with 100 mg irinotecan within 2 h. The loading efficiency was determined by measuring the concentrations of irinotecan in the excess solutions via a reversed phase high pressure liquid chromatography (RP-HPLC) assay with ultraviolet detection. The compatibility of irinotecan-loaded DC BeadM1 with different types and volumes of contrast media was studied by mixing 2 mL loaded bead slurry each with up to four different volumes (5, 10, 20, 30 mL) of seven different contrast media. Samples were withdrawn after 30 min, 1, 2, 4, 8 and 24 h. Admixtures were stored light protected at room temperature over the observation period. The concentrations of eluted irinotecan were measured in triplicate samples using the RP-HPLC assay. RESULTS: Mixing of irinotecan loaded beads with non-ionic contrast media decreased the irinotecan loading efficiency between minimum 2.5% and maximum 17% over the observation period of 24 h. The rate and amount of irinotecan eluted from the beads varied relying on the type and volume of contrast medium admixed. However, no further elution or degradation was observed after the rapid release during the first 8 h. CONCLUSIONS: Because of the rapid and extensive release of irinotecan, it is not recommendable to prepare admixtures of irinotecan-loaded DC BeadM1 with contrast media in centralised cytotoxic preparation units in advance. Admixture should be performed with the smallest possible amount by the radiologists immediately prior to the delivery procedure.

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

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.

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

PURPOSE: The aim of this study was to determine the loading efficiency, physicochemical stability, and release of irinotecan-loaded DC Beads (bead size 100-300 microm, 300-500 microm) 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 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 degrees 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 Beads with irinotecan drug solution resulted in a loading percentage of 96% (bead size 100-300 microm) 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 microm, 300-500 microm) with nonionic contrast media decreased the irinotecan loading efficiency by approximately 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 Beads 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.