Irene Krämer

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.

The new world of biosimilars: what diabetologists need to know about biosimilar insulins

Biosimilar pharmaceuticals are emerging as patent protection on the original biopharmaceutical products expires. However, biopharmaceuticals are particularly complex molecules, and biosimilar insulins present special challenges. In part this reflects their structure and chemical modification after synthesis to attain a biologically active form. Their therapeutic window is narrow and the accuracy of their dosing is highly dependent on the formulation and quality of the administration device. For these reasons, the European Medicines Agency has issued stringent guidelines that must be fulfilled in order to receive approval as a biosimilar soluble insulin. Prescribers should therefore consider issues of manufacture, protein quality, formulation, reliability of supply, and other factors that might affect efficacy, safety and tolerability when making choices regarding the selection of biosimilar products.

Assessing the risk to health care staff from long-term exposure to anticancer drugs - the case of monoclonal antibodies

Today the occupational health and safety risk involved when handling most anticancer drugs is well recognized and, as a result of regulatory requirements, safety measures have been established. There is little knowledge about the occupational hazard posed by handling monoclonal antibodies assigned to ATC Class L01XC. The aim of our study was to evaluate the occupational risk of monoclonal antibodies. Using the information obtained in a systematic review of the literature, the potentially dangerous properties of the active drug substances were assessed using a specially devised algorithm. As a result, all monoclonal antibodies in question were categorized as substances with developmental toxicity. In addition, gemtuzumab ozogamicin was categorized as mutagenic. In view of the high molecular weights and the proteinogenic nature of monoclonal antibodies, the route of exposure for health care staff is limited to inhalation, unless there is an accident. Employers should implement the necessary administrative and engineering controls. Employees should adhere to the standards in order to avoid occupational exposure. The hazard assessment algorithm devised and the evaluation procedure may also be used for other drugs considered to be dangerous.

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

Viability of microorganisms in novel antineoplastic and antiviral drug solutions

Introduction. In determining the expiration-dates of ready-to-use antineoplastic and antiviral drug solu tions, microbiological aspects must be considered. This is especially true because many antineoplastic drugs introduced into the market are already known to lack antimicrobial activity. The purpose of this study is to evaluate the growth of four different microorganisms in ready-to-use solutions of 14 differ ent novel antineoplastic and antiviral drugs. Methods. The lowest concentrations of 14 dif ferent antineoplastic and antiviral drugs prescribed in our hospital were prepared in polyvinyl chloride bags or a polyethylene container (paclitaxel) containing 0.9% sodium chloride or 5% dextrose solution. Inoc ulations were performed by adding 9 mL of a freshly prepared drug solution to a 1 mL suspension of bacteria or fungi (Staphylococcus aureus, Enterococ cus faecium, Pseudomonas aeruginosa, Candida albicans). Resulting concentrations were about 104 microorganisms per milliliter. Pure 0.9% sodium chlo ride and 5% dextrose solutions served as positive controls. Inoculated solutions were stored at elevated temperatures (22°C or 37°C). Samples of each test solution were withdrawn at 0, 15, 30, and 60 minutes and at 2, 3, 4, 24, 48, and 120 hours after inoculation, transferred to tryptic soy agar, and incubated at 37°C. After 24 hours, colony-forming units were counted. Results. In the concentrations tested, no antimi crobial activity was registered with most of the drugs tested. There were only two cases of significant antibacterial activity, involving treosulfan and oxali platin against P. aeruginosa, respectively. Moderate antifungal activity was seen with foscarnet, ganciclo vir, pentostatin, and treosulfan. Conclusions. The lack of antimicrobial proper ties should be considered when assigning extended expiration dates to ready-to-use antineoplastic and antiviral drug solutions. Solutions should be kept under refrigeration whenever possible to minimize the growth of any contaminating microorganism. With the exception of treosulfan, end-product steril ity testing may be performed without further dilution or inactivation.

How to select a biosimilar

In the past few years biosimilars have penetrated the market following the expiry of patents of originator variants. This offers the opportunity to apply high-tech protein products at a lower cost. In contrast to small-molecule generics, clinicians and pharmacists have found it difficult to judge the efficacy and safety profiles of complex protein products. In recent years, the European Medicines Agency (EMA) has gained knowledge on assessing comparability between biosimilars and originator products in scientific and legal areas. This article provides an overview of an extensive set of 31 previously drawn biosimilar selection criteria and describes how several of these criteria are covered by EMA regulations and guidelines. A panel of experts (authors) reviewed the criteria and produced a shortlist of 10 criteria relevant for clinicians and pharmacists.

Physicochemical compatibility of mixtures of dornase alfa and tobramycin containing nebulizer solutions.

Patients suffering from cystic fibrosis (CF) often need to inhale multiple doses of different nebulizable drugs per day. Patients attempt to shorten the time consuming administration procedure by mixing drug solutions/suspensions for simultaneous inhalation. The objective of this experimental study was to determine whether mixtures of the nebulizer solution dornase alfa (Pulmozyme®) with tobramycin nebulizer solutions (TOBI® and GERNEBCIN® 80 mg) are physico‐chemically compatible. Drug combinations were prepared by mixing the content of one respule Pulmozyme® with either one respule TOBI® or one ampoule GERNEBCIN® 80 mg. Test solutions were stored at room temperature and exposed to light. Dornase alfa activity and tobramycin concentrations were determined by using a kinetic colorimetric DNase activity assay and a fluorescence immunoassay, respectively. Physical compatibility was determined by visual inspection and measurements of pH and osmolality. Tobramycin concentration was not affected by mixing the drug products. In spite of the high variability of the dornase alfa potency assay, it is obvious that activity is especially affected by sodium metabisulfite, used as excipient in GERNEBCIN®. Patients should be advised, not to mix Pulmozyme® with GERNEBCIN® because of the incompatibility reaction. Further analytical studies are needed in order to determine the integrity and activity of dornase alfa in mixtures of Pulmozyme® with TOBI®. Finally clinical studies are necessary in order to demonstrate equivalent efficacy and safety of simultaneous inhalation in comparison to consecutive inhalation of both drugs. Pediatr Pulmonol. 2009; 44:134–141.

Plasticizer extraction of Taxol®-infusion solution from various infusion devices

Taxol® solution extracts the plasticizer DEHP (di(2-ethylhexyl)phthalate) from polyvinyl chloride (PVC) materials. In order to minimize patient exposure to DEHP, Taxol® solutions should be prepared and administered in PVC-free materials. Particulate matter may form in Taxol® infusion solution over time, so that in-line filtration with microporous membranes not greater than 0.22 μm is advisable. The purpose of this study was to evaluate the suitability of various administration- and in-line filter-sets for Taxol® application. The extent of leached DEHP was determined using a Reversed Phase HPLC assay specific for DEHP.The four tested administration-sets labeled as PVC-free, were all found to be suitable for Taxol® application. The tested standard PVC-lined administration-set should not be used for Taxol® application. Baxter Intermate® LV 250 can be recommended as a disposable infusion device for ambulatory Taxol® application. It can be connected with all the tested filter sets.

Physicochemical compatibility and stability of nebulizable drug admixtures containing Dornase alfa and tobramycin.

The objective of this in-vitro study was to determine whether admixtures of the inhalation solutions Pulmozyme(®) (Dornase alfa) and either Bramitob(®) or Tobi(®) (both containing Tobramycin) are physicochemically compatible and to analyze the aerodynamic parameters of these admixtures. After mixing, test solutions were stored at room temperature and under ambient light conditions over a period of 24 h. Tobramycin concentrations were determined by using a fluorescence immunoassay. Stability of dornase alfa was determined by size-exclusion high performance liquid chromatography, ultraviolet spectroscopy, sodium dodecyl sulfate polyacrylamide gel electrophoresis and tentacle strong cation-exchange chromatography. In addition, pH values and osmolality of the admixtures were measured and test solutions were visually examined for any changes up to 24 h. Aerosols of Pulmozyme(®)/Bramitob(®) or Pulmozyme(®)/TOBI(®) admixtures were generated with the PARI eFlow(®) rapid and aerodynamic particle sizing was performed via cascade impaction with the Next Generation Pharmaceutical Impactor. The stability tests revealed that neither the stability of tobramycin nor the stability of dornase alfa was affected by mixing the inhalation products. Cascade impaction showed no relevant changes in particle size distribution, Mass Median Aerodynamic Diameter, Geometric Standard Deviation and Fine Particle Fraction in comparison to aerodynamic parameters of the unmixed solutions. Thus, admixtures of Pulmozyme(®) and either Bramitob(®) or TOBI(®) can be designated as compatible for a 24 h period and simultaneous inhalation is feasible.

Long-term stability study of clofarabine injection concentrate and diluted clofarabine infusion solutions

Purpose: The aim of this study was to investigate the physicochemical stability of clofarabine (CAFdA) injection concentrate and ready-to-use CAFdA infusion solutions over a prolonged period of 28 days. Methods: To determine the stability of CAFdA infusion solutions, the injection concentrate (Evoltra®, 1 mg/mL, Genzyme) was diluted either with 0.9% sodium chloride or 5% glucose infusion solution. The resulting concentrations of 0.2 mg/mL or 0.6 mg/mL, respectively, were chosen to represent the lower and upper limit of the ordinary concentration range. Test solutions were stored under refrigeration (2–8°C) or at room temperature either light protected or exposed to light. CAFdA concentrations and pH values were determined at different time intervals throughout a 28-day storage period. Compatibility of diluted CAFdA infusion solutions (0.1–0.4 mg/mL) with different container materials (polyvinyl chloride (PVC), glass, and polypropylene/polyethylene (PP/PE)) was tested over a 48-h storage period. CAFdA concentrations were measured by a stability-indicating reversed phase high-performance liquid chromatography (HPLC) assay with ultraviolet detection. Results: CAFdA injection concentrate and CAFdA infusion solutions remained physicochemically stable (>90% CAFdA) for 4 weeks. Results are independent of storage conditions, drug concentrations (0.2, 0.6, and 1.0 mg/mL) and diluents (0.9% sodium chloride, 5% glucose infusion solution). Adsorption of CAFdA to container material can be excluded. Conclusions: CAFdA injection concentrate and diluted infusion solutions in commonly used vehicles are stable for at least 28 days either refrigerated or at room temperature. Physicochemical stability favors pharmacy-based centralized preparation. Due to microbiological reasons, strict aseptic handling and storage of the products under refrigeration is recommended.