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La mise sur le marché de biosimilaires requiert une démonstration stricte de la similarité avec l’anticorps de référence, au travers d’études précliniques et cliniques. Cet article synthétise l’ensemble des analyses physicochimiques et fonctionnelles mises en œuvre in vitro, préalables à la réalisation d’études cliniques. Pour chaque caractéristique critique de l’anticorps, nous avons détaillé les techniques analytiques communément employées, leur principe de fonctionnement, ainsi que le type d’informations que ces techniques permettent d’obtenir.

PURPOSE Chemotherapies are considered high-risk drugs for patient and staff safety. Considering the rising burden of cancer and the increasing use of chemotherapy drugs in low- and middle-income countries (LMICs), promoting continuous improvements in the safety and quality of practices in these settings is essential. This paper describes the development and proof of concept of a toolkit to audit chemotherapy handling practices in the health care facilities of LMICs. METHODS A steering committee defined the audit method and the toolkit content. Several checklists were developed to facilitate the audit and data collection. Items included in checklists were derived from key reference works on safe handling. Different tools were validated using Delphi surveys and expert reviews. Audits of pilot sites were performed to test the toolkit's applicability and relevance. RESULTS The toolkit contains a 134-item global assessment tool for the different processes at each step of the medication pathway and three step-specific observation checklists to assess different health workers' practices during the prescription, preparation, and administration of chemotherapies. The toolkit also proposes using a surface-wipe sampling method to measure any cytotoxic contamination of the immediate environment. The toolkit was tested in three teaching hospitals in Africa. CONCLUSION The toolkit developed was successfully implemented in a variety of LMIC settings, providing a comprehensive evaluation of the quality and safety of the chemotherapy drug handling practices in participating health care facilities. This toolkit can help facilities in LMICs to implement a new approach to continuously improving the quality and safety of their practices and ultimately ensure patient and staff safety., A toolkit for implementing safe chemotherapy handling practices to ensure patient and staff safety in LMICs

The validation and uncertainty assessment of the analytical method developed for the simultaneous determination of 25 anticancer drugs commonly handled in hospital pharmacy was reported. Selected compounds were 5-fluorouracil, cytarabine, fludarabine phosphate, ganciclovir, gemcitabine, dacarbazine, methotrexate, pemetrexed, busulfan, raltitrexed, etoposide phosphate, topotecan, ifosfamide, cyclophosphamide, irinotecan, doxorubicin, epirubicin, daunorubicin, idarubicin, vincristine, vinblastine, vinorelbine, docetaxel and paclitaxel. Accuracy and uncertainty profiles were obtained for all compounds. Quantitative performances were satisfactory in term of specificity, sensitivity, precision and accuracy. Repeatability (1.9–25.4%) and intermediate precision (2.7–29%) were determined for all target compounds. Lower limits of quantification between 1 and 25 ng/mL were obtained. Uncertainty associated to measurement of routine samples was evaluated. The multi-targeted method was specific and reliable and was successfully applied to wipe samples from hospital pharmacy chemotherapy compounding unit and to the determination of outside contamination of vials from pharmaceutical manufacturers.

Although considerable efforts have been made over the last 40 years, occupational exposure to antineoplastic drugs is still a daily concern, since eradicating such contamination from workplaces seems unattainable. Considerable data are currently available on the risks associated with their use at work. Hospital facilities are often cleaned with marketed antimicrobials whose chemical decontamination efficacy certainly differs but remains unknown. To keep compounding facilities sterile, alcohol-based solutions are frequently used but with very limited efficiency. It would be particularly useful if a decontamination method could be added to the means already available so that all conventional antineoplastic drug contamination could be removed. Several degradation methods or desorption methods have previously been experimented, with varying success. They have never been compared or discussed in terms either of efficiency or usability. This review aims to analyse and discuss the results of each degradation or decontamination procedure and to compare them. This should facilitate selection of the method to be implemented in daily practice.

In 2019, we celebrated the 40th anniversary of the famous article published by Falck et al , dealing with the mutagenicity of the urine of nurses who were in daily contact with conventional antineoplastic drugs.1 Since the publication of this article, highlighting the hazard of handling such drugs, extensive literature has flowed, in order to: All this knowledge has raised our level of vigilance on this issue and encouraged us to upgrade our practices constantly. Scientific data have been obtained through technological advances and in many different operating conditions, the latter making it difficult to define a fair protection level. Moreover, a lack of relevant clinical references and toxicological values has led to a continuous exploration for protective measures. Forty years after the first report of … Correspondence to Dr Nicolas Simon, GRITA Grp Rech Formes Injectables, LILLE Cedex 59006, France; nicolas.simon{at}univ-lille.fr

Purpose The stability of busulfan solution in 0.9% sodium chloride and stored in polypropylene syringes or infusion bags was evaluated. Methods Busulfan solutions (0.54 mg/mL) were prepared and transferred to 50-mL polypropylene syringes and 100- and 500-mL polypropylene infusion bags and stored at 2-8 and 23-27 °C. Chemical stability was measured using a stability-indicating, ultrahigh performance liquid chromatography coupled to mass spectrometry method. The stability of busulfan was assessed by measuring the percentage of the initial concentration remaining at the end of each time point of analysis. The initial busulfan concentration was defined as 100%. Stability was defined as retention of at least 90% of the initial busulfan concentration. A visual inspection of the samples for particulate matter, clarity, and color without instrumentation of magnification was conducted at each time point of analysis. Results The visual inspection demonstrated no influence of the storage container when busulfan infusions diluted in 0.9% sodium chloride injection were stored at 23-27 °C. No color change or precipitate was observed at this temperature; however, a rapid decrease of the busulfan content in all containers stored at room temperature was observed. Busulfan in syringes was chemically stable for 12 hours, while busulfan in infusion bags (100 and 500 mL) was stable only for 3 hours at 23-27 °C. Conclusion Busulfan 0.54-mg/mL solution in 0.9% sodium chloride injection was physically and chemically stable for 30 hours when stored in 50-mL polypropylene syringes at 2-8 °C and protected from light.

Objectives Over the past 40 years, numerous actions have been undertaken to decrease the contamination of hospital facilities by intravenous conventional antineoplastic drugs (ICADs) such as centralizing compounding in pharmacies, using personal protective equipment, specific compounding, or infusion devices. As recently proposed in the monograph, an additional specific decontamination step must be envisaged. A recent literature review analysed and discussed the different solutions tested in terms of decontamination efficacy. This article aims to discuss the performance of these solutions in the framework of aseptic compounding. Methods The same dataset used in the previous literature review was reanalysed according to other parameters so as to select decontamination solutions: overall decontamination efficiency (EffQ), tested contaminants, and the risks of use in daily practice. Results Using an EffQ threshold of 90% resulted in discarding 26 out of the 59 solutions. Solutions were tested differently: 8 on 1 contaminant, 11 on 2 contaminants, and 14 solutions on between 3 and 11 contaminants. Three risks were identified to help make choices in routine practice: the mutagenicity of degradation products, the safety of operators and facilities, and respect for the aseptic environment. Conclusions From the results, performance is discussed according to specific situations: a one-time incident or the basic chemical contamination due to daily practice. Accordingly, the decontamination solution selected then required a risk analysis and an evaluation before implementing it in the daily practice of a compounding unit.

Background Several decontamination methods are currently available to reduce the occupational exposure of hospital facilities to conventional anti-neoplastic drugs. Alcohol-based microbicides are not sufficiently efficient in removing chemical contamination and data are lacking on many marketed biocides. Recent data confirm that using a specific chemical decontamination solution is helpful in removing traces of contaminants. Purpose To perform a literature review in order to help pharmacists in choosing a chemical decontamination solution to implement in their compounding unit. Material and methods Articles were searched on Pubmed using the following requests: ‘antineoplastic agents AND cleaning’ or ‘antineoplastic agents AND chemical degradation’ or ‘antineoplastic agents AND chemical decontamination’. Criteria used to classify the performance and usability of decontamination solutions were: decontamination efficiency, number and nature of tested contaminants, hazardousness of the decontamination solution, implementation difficulties and respect of the aseptic environment. Results Two-hundred and seventy-four articles were retrieved following the request application. Two-hundred and fifty-seven articles were discarded for different reasons leading to the analysis of 17 articles. Fifty-nine methods were tested as degradation (n=19) or desorption methods (n=40) with various decontamination efficiencies ranging from ≤10% to 100%. Applying the selection criteria, three decontamination solutions were chosen: sodium hypochlorite, admixture of 10-2 M sodium dodecyl sulfate (SDS) and 70% isopropanol (80/20), marketed two steps towelettes kit (1. Quaternary ammonium solution, 2. Isopropanol). Their inertness to facilities’ surfaces is different and sodium hypochlorite solutions oxide metals. Solutions involving tension-active agents such as SDS may form a film on the facilities surface, which may alter the sterility environment. Conclusion The applied selection criteria led to select only three decontamination solutions. Their application modalities are also to be discussed regarding the biological and chemical facilities’ monitoring. As the solutions were assessed with various methodologies, further studies are necessary to compare them in the same conditions. Because each solution has been tested with different contaminants, new studies are required to confirm their ability to decontaminate other conventional anti-neoplastic drugs. References and/or acknowledgements Vasseur, et al. EJHP 2017;24(Suppl 1):A218. doi:10.1136/ejhpharm-2017–000640.485 Vasseur, et al. PLos One 2018. No conflict of interest.

The wastewater contamination of a Swiss university hospital by active pharmaceutical ingredient (API) residues was evaluated with a three months monitoring campaign at the outlet of the main building. Flow-proportional samples were collected with an automatic refrigerated sampler and analyzed for 15 API, including antibiotics, analgesics, antiepileptic and anti-inflammatory drugs, by using a validated LC-MS/MS method. The metals Gd and Pt were also analyzed using ICP-MS. Measured concentrations were compared to the predicted ones calculated after the drug average consumption data obtained from the hospital pharmacy. The hospital contribution to the total urban load was calculated according to the consumption data obtained from city pharmacies. Lastly, the environmental hazard and risk quotients (RQ) related to the hospital fraction and the total urban consumption were calculated. Median concentrations of the 15 selected compounds were ranging from 0.04 to 675 μg/L, with a mean detection frequency of 84%. The ratio between predicted and measured environmental concentrations (PEC/MEC) has shown a good accuracy for 5 out of 15 compounds, revealing over- and under-estimations of the PEC model. Mean daily loads were ranging between 0.01 and 14.2g/d, with the exception of paracetamol (109.7 g/d). The hospital contribution to the total urban loads varied from 2.1 to 100% according to the compound. While taking into account dilution and removal efficiencies in wastewater treatment plant, only the hospital fraction of the antibiotics ciprofloxacin and sulfamethoxazole showed, respectively, a high (RQ>1) and moderate (RQ>0.1) risk for the aquatic ecosystems. Nevertheless, when considering the total urban consumption, 7 compounds showed potential deleterious effects on aquatic organisms (RQ>1): gabapentin, sulfamethoxazole, ciprofloxacin, piperacillin, ibuprofen, diclofenac and mefenamic acid. In order to reduce inputs of API residues originating from hospitals various solutions can be envisioned. With results of the present study, hospital managers can start handling this important issue.

A liquid chromatography separation with electrospray ionisation and tandem mass spectrometry detection method was developed for the simultaneous quantification of ten commonly handled cytotoxic drugs in a hospital pharmacy. These cytotoxic drugs are cytarabine, gemcitabine, methotrexate, etoposide phosphate, cyclophosphamide, ifosfamide, irinotecan, doxorubicin, epirubicin and vincristine. The chromatographic separation was carried out by RPLC in less than 21min, applying a gradient elution of water and acetonitrile in the presence of 0.1% formic acid. MS/MS was performed on a triple quadrupole in selected reaction monitoring mode. The analytical method was validated to determine the limit of quantification (LOQ) and quantitative performance: lowest LOQs were between 0.25 and 2ngmL−1 for the ten investigated cytotoxic drugs; trueness values (i.e. recovery) were between 85% and 110%, and relative standard deviations for both repeatability and intermediate precision were always inferior to 15%. The multi-compound method was successfully applied for the quality control of pharmaceutical formulations and for analyses of spiked samples on potentially contaminated surfaces. Figure Preparation of cytotoxic formulations at the Pharmacy of Geneva University Hospitals

Two capillary electrophoresis (CE) methods were developed for the analysis of 16 antineoplastic drugs contained in injectable pharmaceutical formulations. A capillary zone electrophoresis (CZE) method coupled to UV was developed with a background electrolyte (BGE) made of a 100 mM phosphate buffer at pH 2.5 containing 50% (v/v) of acetonitrile and dynamic coating of capillaries with Ceofix®. This method allowed the analysis of doxorubicin, epirubicin, idarubicin, daunorubicin, irinotecan, topotecan, vincristine, vindesine, vinblastine, and vinorelbine in less than 8 min. A micellar electrokinetic chromatography (MEKC) method coupled to UV was also developed for the determination of methotrexate, pemetrexed, etoposide, etoposide phosphate, fludarabine phosphate and 5-fluorouracil. A run time of 16 min was obtained with a BGE made of 50 mM borate buffer at pH 9.2 with 80 mM of sodium dodecyl sulfate (SDS) and 20% (v/v) of acetonitrile. For both methods, the applied voltage was 30 kV and the sample injection was performed in the hydrodynamic mode. All analyses were carried out in fused silica capillaries with an internal diameter of 50 µm and a total length of 64.5 cm. Both methods were validated and trueness values between 99.4% and 101.3% were obtained with repeatability and intermediate precision values of 0.5-1.8% for all drugs. These methods were found appropriate for controlling injectable pharmaceutical formulations containing antineoplastic drugs and successfully applied in quality control.

International audience; BACKGROUND: Despite the use of closed system drug transfer devices (CSTD), residual contamination from antineoplastic drugs is still detected inside isolators. The aim of this study was to compare the decontamination level obtained using a CSTD + standard cleaning procedure with a CSTD + standard cleaning procedure + specific decontamination procedure. METHODS AND FINDINGS: A comparative and prospective study was carried out in a newly opened compounding unit. Compounding was performed with a CSTD (BD-Phaseal, Becton-Dickinson). In the Control isolator (C), the cleaning process was completed daily with a standard biocide solution (AnioxysprayTM, Anios, France). In the Intervention isolator (I), weekly decontamination with a homemade admixture of sodium dodecyl sulfate 10-2 M/70% isopropanol (80/20, v/v) was added. Monitoring was performed via a validated LC-MS/MS method. Eight drugs (cyclophosphamide, cytarabine, dacarbazine, fluorouracile, gemcitabine, ifosfamide, irinotecan and methotrexate) were monitored daily over 14 consecutive weeks on three sites inside the isolators: gloves, workbench and window. Results are presented as the odds-ratio (OR) of contamination and as overall decontamination efficiency (EffQ, %). The proportion of EffQ ≥ 90% was assessed by a Fisher's exact test (p

Antibody Drug Conjugates (ADCs) are innovative biopharmaceuticals gaining increasing attention over the last two decades. The concept of ADCs lead to new therapy approaches in numerous oncological indications as well in infectious diseases. Currently, around 60 CECs are in clinical trials indicating the expanding importance of this class of protein therapeutics. ADCs show unprecedented intrinsic heterogeneity and address new quality attributes which have to be assessed. Liquid chromatography is one of the most frequently used analytical method for the characterization of ADCs. This review summarizes recent results in the chromatographic characterization of ADCs and supposed to provide a general overview on the possibilities and limitations of current approaches for the evaluation of drug load distribution, determination of average drug to antibody ratio (DARav), and for the analysis of process/storage related impurities. Hydrophobic interaction chromatography (HIC), reversed phase liquid chromatography (RPLC), size exclusion chromatography (SEC) and multidimensional separations are discussed focusing on the analysis of marketed ADCs. Fundamentals and aspects of method development are illustrated with applications for each technique. Future perspectives in hydrophilic interaction chromatography (HILIC), HIC, SEC and ion exchange chromatography (IEX) are also discussed.

Background Busulfan is an alkylating antineoplastic drug extensively used in myeloablative regimens prior to haematopoietic stem cell transplantation. Administration every 6 hours for 4 consecutive days and the low stability of this product induces organisational problems for cytotoxic preparation units in hospital pharmacies. A few studies have already been conducted to investigate the stability of diluted busulfan solutions but published results showed important variability. Purpose The purpose of this study was to evaluate the stability of busulfan solutions diluted to 0.54 mg/mL with 0.9% sodium chloride and stored in polypropylene (PP) syringes or PP infusion bags with a highly sensitive, specific and rapid ( Material and methods Busulfan solutions (0.54 mg/mL) were prepared from three Busilvex batch numbers and transferred into 50 mL PP syringes (n=12), or 100 mL (n=12) or 500 mL (n=4) PP infusion bags (stored at 2–8°C or 23–27°C). The chemical stability of busulfan was assessed by measuring in each container the percentage of the initial concentration remaining at each time point of analysis (max 100 hours) with an ultra high performance liquid chromatography coupled to mass spectrometry (UHPLC-MS) method. Busulfan and [ 2 H 8 ]-busulfan (internal standard) were detected in selected ion recording mode as ammonium adducts at m/z: 264.1 and 272.1, respectively. Stability was defined as retention of at least 90% of the initial busulfan concentration. Physical stability was assessed by visual inspection. Results Busulfan in PP syringes proved to be stable for 30 hours at 2–8°C and 12 hours at 23–27°C. A reduced stability of 12 hours and 9 hours were obtained at 2–8°C for 100 mL and 500 mL PP bags, respectively. At 23–27°C, all PP bags presented stability for 3 hours. The main effects observed were hydrolysis at 23–27°C and precipitation at 2–8°C. Conclusion This study demonstrated that the stability of busulfan diluted solutions depends on the container type and storage temperature. Stability for 30 hours in PP syringes stored at 2–8°C is a considerable improvement compared with the manufacturer’s recommendations (12 hours). The extended shelf life of busulfan infusion in syringes allows better organisation of the chemotherapy preparation unit by reducing the number of busulfan production to once a day. No conflict of interest

Purpose Ganciclovir is increasingly provided by hospital pharmacy production unit in a ready-to-use form, in order to improve the safety of healthcare workers and the efficiency of the organisation. The objective of this study was to develop a stability-indicating method to assay ganciclovir and determine the stability of ganciclovir in syringes (5 mg/mL) and infusion bags (0.25 and 5 mg/mL) at two different temperatures. Method Ganciclovir solutions (0.25 mg/mL and 5 mg/mL) in 0.9% sodium chloride were prepared in 50 mL polypropylene syringes or 100 mL polypropylene infusion bags and stored at 2–8℃ and 23–27℃. The chemical stability was measured using a stability-indicating Ultra High Performance Liquid Chromatography coupled to mass spectrometry method. Physical stability was assessed by visual inspection. Results No significant loss of ganciclovir under any of the tested conditions was observed in this study. All solutions remained clear through the study period. Conclusion All tested formulations remained stable for at least 185 days independently of container type, temperature or concentration studied.

A large amount of residues from active pharmaceutical ingredients (API) that are currently in use are known to reach aquatic ecosystems and have potentially adverse effects on living organisms. Prioritization methods are useful tools for both regulation and surveillance purposes in the environmental policy of APIs. Their use has largely increased over the last decade, and the different existing methodologies can lead to large discrepancies between the highlighted substances. This chapter aims at discussing studies conducted in the context of hospitals. Perhaps more important than the results themselves, the methodologies with the set of selected criteria are discussed, as well as their advantages and associated uncertainties. A case study of API prioritization applied to a Swiss university hospital is presented with two different approaches: a ranking-based OPBT approach (Occurrence, Persistence, Bioaccumulation, and Toxicity) and an environmental risk assessment (ERA), with the calculation of risk quotient (RQ). The ERA results combined with those of other studies dealing with ERA-based API prioritization in hospitals highlighted several compounds presenting high risks for the aquatic ecosystems (RQ > 1): antibiotics (ciprofloxacin, amoxicillin, piperacillin, azithromycin), anti-inflammatory drugs (diclofenac, mesalazine), as well as the hormone estradiol and the antidiabetic metformin. Nevertheless, only the antibiotic ciprofloxacin was commonly determined as problematic. Finally, the most critical issues for API prioritization in hospitals were identified from the literature overview and the results of the presented case study: handling of the consumption data, involvement of expert judgment, uncertainties linked with the predicted environmental concentration (PEC) calculation, and quality of the hazard evaluation. Although prioritization procedures applied to hospitals can be burdensome to apply in practice and many associated uncertainties remain, they represent essential tools to establish lists of priority molecules to follow via monitoring programs and allow their theoretical risk assessment.

The number of patients suffering from cancer is constantly increasing and, consequently, the number of different chemotherapy treatments administered is increasing. Given the high reactivity and toxicity of antineoplastic drugs, analytical methods are required in all pharmaceutical fields, from drug development to their elimination in wastewater; including formulation quality control, environment and human exposure and therapeutic drug monitoring. The aim of this paper is to provide an overview of the analytical methods available for the determination of antineoplastic drugs in different matrices such as pharmaceutical formulations, biological and environmental samples. The applicability and performance of the reported methods will be critically discussed, with focus on the most commonly used antineoplastic drugs. Only conventional compounds and small molecules for targeted therapy will be considered in the present review.

Objectives To improve the safety of the preparation and its availability in ophthalmology, a ready-to-use cefuroxime syringe prepared under aseptic conditions according to good manufacturing practice was developed by the hospital pharmacy. Methods The chemical stability of cefuroxime solution at 10 mg/mL in 0.9% sodium chloride in syringes (0.5 mL) was achieved at −18°C by a capillary electrophoresis method. Syringes of the last acceptable time were then stored at 4°C and the study was continued for one additional month. The pH was measured throughout the study and the presence of particle matter was controlled. Sterility testing was performed to test the integrity of the syringes. Results An optimal period of 4 months at −18°C was defined for storage of syringes of cefuroxime without significant loss in potency and an acceptable rate (4%) of degradation products. After thawing and storage at 4°C, degradation products progressively increased. As these derivatives can represent up to 10% of cefuroxime in terms of peak area after 1 month, it is recommended that the syringes are used within 1 h after thawing. The pH did not change appreciably during the study and the sterility testing results were negative. Moreover, in all cases the syringes fulfilled all the European Pharmacopoeia criteria with regard to non-visible particles. Conclusions The availability of cefuroxime for use in ophthalmology is improved as ready-to-use syringes can be stored in the ward freezer and administered immediately after thawing.

Introduction The external contamination and cross-contamination by cytotoxic drugs on the surface (outside and septum) of 133 vials from various manufacturers and available on the Swiss market were evaluated. All of the tested vials contained one of the following active ingredients: cyclophosphamide, cytarabine, doxorubicin, epirubicin, etoposide phosphate, gemcitabine, ifosfamide, irinotecan, methotrexate or vincristine. Methods and materials The validated wiping liquid chromatography-mass spectrometry method used in this study allowed for the simultaneous determination of these 10 cytotoxic drugs in less than 30 min. Results External contamination by cytotoxic drugs was detected on 63% of tested vials (outside and septum). The highest contamination level was observed on etoposide phosphate vials with 1896.66 ng of active ingredient on the outside of the vial. Approximately 20% of the contaminated vials had greater than 10 ng of cytotoxic drugs. Chemical contamination on the septum was detected on 38% of the vials. No contamination or very low levels of cytotoxic drugs, less than 1 ng per vial, were detected on the vials protected by plastic shrink-wrap. Traces of cytotoxic drugs different from the active ingredient were detected on 35% of the tested vials. Conclusion Handling cytotoxic vials with gloves and having a procedure for the decontamination of vials are of the utmost importance for reducing exposure to cytotoxic drugs. Moreover, manufacturers must improve their procedures to provide products free from any contamination.

Background Setting up an automated compounder device (ACD) takes time and money. Daily production of paediatric parenteral nutrition (PN) solutions in our pharmacy decreased after implementing standard PN for neonatology. To keep the production of a limited number of PN bags cost effective, we wished to set up the ACD weekly rather than daily. Objectives This study aims to validate (operational and performance qualification (PQ)) use of an ACD (Baxa MM12) for once-a-day and once-a-week set up. Methods Accuracy and precision of the ACD were evaluated using water (operational qualification) on a daily basis, and using the products for preparing PN solutions (PQ) on a daily and a weekly basis. Nutrient dosage was measured for specific PN solutions after daily or weekly ACD set ups. Particle contamination of PN solutions produced were controlled throughout the week. To validate the aseptic process, media-fill tests of the once-a-week set ups were carried out over three consecutive weeks. Results Accuracy and precision of the ACD were validated for small (0.5 ml) and high (100 ml) volumes. Precision improved when pumped volumes increased. Nutrient dosage in PN solutions following daily and weekly set ups were always in conformity with specification limits. No particles or microbiological contaminations were detected following the week-long set ups. Conclusions Validation proved good accuracy, precision and aseptic conditions existed throughout each week. PN solutions can be produced safely all week long with one set up. A week-long set up saves technician time and money.

Purpose The results of a study of the accuracy of i.v. medication preparation by anesthesiologists are presented. Methods The accuracy of syringe preparation was assessed by analyzing the contents of 500 unused syringes collected after adult and pediatric surgery procedures. The collected syringes contained various i.v. medication formulations representative of different preparation techniques: atracurium 1, 2.5, and 5 μg/mL and fentanyl 10, 20, 25, and 50 μg/mL, which required serial dilution after withdrawal of the drugs from ampuls; thiopental 5, 25, and 50 mg/mL, prepared by diluting reconstituted powdered drug from vials; and lidocaine 10-mg/mL solution, which was withdrawn directly from the ampul into a syringe. Variances between actual and labeled drug concentrations were determined via a validated ultraviolet–visible light spectro-photometry method. Results Overall, 29% of the evaluated syringes were found to contain drug concentrations outside the designated range of acceptability (±10% of the targeted concentration); 18% of preparations deviated from the declared dose by ±20%, 8% deviated by ±50%, and 4% deviated by ±100%. In one instance, the actual drug concentration was at variance with the labeled concentration by >100%. In 4% of cases ( n = 20), discrepancies exceeded 100%, suggesting not just imprecision but errors in the preparation process, such as incorrect dilution calculations and selection of the wrong medication vial by the syringe preparer. Conclusion Analysis of different i.v. formulations of four medications prepared in syringes by anesthesiologists revealed a high rate of discrepancies between ordered and actual drug concentrations, suggesting a need for increased institutional efforts to prevent errors during the preparation process. Am J Health-Syst Pharm. 2013; 70:137–42

Background and objectives Centralized chemotherapy preparation units have established systematic strategies to avoid errors. Our work aimed to evaluate the accuracy of manual preparations associated with different control methods. Method A simulation study in an operational setting used phenylephrine and lidocaine as markers. Each operator prepared syringes that were controlled using a different method during each of three sessions (no control, visual double-checking, and gravimetric control). Eight reconstitutions and dilutions were prepared in each session, with variable doses and volumes, using different concentrations of stock solutions. Results were analyzed according to qualitative (choice of stock solution) and quantitative criteria (accurate, 30% deviation). Results Eleven operators carried out 19 sessions. No final preparation (n = 438) contained a wrong drug. The protocol involving no control failed to detect 1 of 3 dose errors made and double-checking failed to detect 3 of 7 dose errors. The gravimetric control method detected all 5 out of 5 dose errors. The accuracy of the doses measured was equivalent across the control methods ( p = 0.63 Kruskal–Wallis). The final preparations ranged from 58% to 60% accurate, 25% to 27% weakly accurate, 14% to 17% inaccurate and 0.9% wrong. A high variability was observed between operators. Discussion Gravimetric control was the only method able to detect all dose errors, but it did not improve dose accuracy. A dose accuracy with

In the last decades, the number of patients receiving chemotherapy has considerably increased. Given the toxicity of cytotoxic agents to humans (not only for patients but also for healthcare professionals), the development of reliable analytical methods to analyse these compounds became necessary. From the discovery of new substances to patient administration, all pharmaceutical fields are concerned with the analysis of cytotoxic drugs. In this review, the use of methods to analyse cytotoxic agents in various matrices, such as pharmaceutical formulations and biological and environmental samples, is discussed. Thus, an overview of reported analytical methods for the determination of the most commonly used anticancer drugs is given.

A simple method based on capillary electrophoresis with a capacitively coupled contactless conductivity detector (CE-C(4)D) was developed for the determination of potassium, sodium, calcium and magnesium in parenteral nutrition formulations. A hydro-organic mixture, consisting of 100 mM Tris-acetate buffer at pH 4.5 and acetonitrile (80:20, v/v), was selected as the background electrolyte. The applied voltage was 30 kV, and sample injection was performed in hydrodynamic mode. All analyses were carried out in a fused silica capillary with an internal diameter of 50 microm and a total length of 64.5 cm. Under these conditions, complete separation between all cations was achieved in less than 4 min. The CE-C(4)D method was validated, and trueness values between 98.6% and 101.8% were obtained with repeatability and intermediate precision values of 0.4-1.3% and 0.8-1.8%, respectively. Therefore, this method was found to be appropriate for controlling potassium, sodium, calcium and magnesium in parenteral nutrition formulations and successfully applied in daily quality control at the Geneva University Hospitals.

International audience; OBJECTIVE: This study aimed to evaluate two cleaning solutions for the chemical decontamination of antineoplastic agents on the surfaces of two biosafety cabinets routinely used for chemotherapy preparation in a hospital pharmacy. METHODS: For almost 1 year (49 weeks), two different solutions were used for the weekly cleaning of two biosafety cabinets in a hospital pharmacy's centralized cytotoxic preparation unit. The solutions evaluated were a commercial solution of isopropyl alcohol (IPA) and water (70:30, vol:vol), and a detergent solution constituted by 10(-2)M of sodium dodecyl sulfate (SDS) with 20% IPA. Seven areas in each biosafety cabinet were wiped 14 times throughout the year, before and after the weekly cleaning process, according to a validated procedure. Samples were analyzed using a validated method of high-performance liquid chromatography coupled to mass spectrometry. The decontamination efficacy of these two solutions was tested for 10 antineoplastic agents: cytarabine, gemcitabine, methotrexate, etoposide phosphate, irinotecan, cyclophosphamide, ifosfamide, doxorubicin, epirubicin, and vincristine. RESULTS: Overall decontamination efficacies observed were 82±6% and 49±11% for SDS solution and IPA, respectively. Higher contamination levels were distributed on areas frequently touched by the pharmacy technicians-such as sleeves and airlock handles-than on scale plates, gravimetric control hardware, and work benches. Detected contaminations of cyclophosphamide, ifosfamide, gemcitabine, and cytarabine were higher than those of the others agents. SDS solution was almost 20% more efficient than IPA on eight of the antineoplastic agents. CONCLUSION: Both cleaning solutions were able to reduce contamination levels in the biosafety cabinets. The efficacy of the solution containing an anionic detergent agent (SDS) was shown to be generally higher than that of IPA and, after the SDS cleaning procedure, biosafety cabinets demonstrated acceptable contamination levels.

The important number of active pharmaceutical ingredients (API) available on the market along with their potential adverse effects in the aquatic ecosystems, lead to the development of prioritization methods, which allow choosing priority molecules to monitor based on a set of selected criteria. Due to the large volumes of API used in hospitals, an increasing attention has been recently paid to their effluents as a source of environmental pollution. Based on the consumption data of a Swiss university hospital, about hundred of API has been prioritized following an OPBT approach (Occurrence, Persistence, Bioaccumulation and Toxicity). In addition, an Environmental Risk Assessment (ERA) allowed prioritizing API based on predicted concentrations and environmental toxicity data found in the literature for 71 compounds. Both prioritization approaches were compared. OPBT prioritization results highlight the high concern of some non steroidal anti-inflammatory drugs and antiviral drugs, whereas antibiotics are revealed by ERA as potentially problematic to the aquatic ecosystems. Nevertheless, according to the predicted risk quotient, only the hospital fraction of ciprofloxacin represents a risk to the aquatic organisms. Some compounds were highlighted as high-priority with both methods: ibuprofen, trimethoprim, sulfamethoxazole, ritonavir, gabapentin, amoxicillin, ciprofloxacin, raltegravir, propofol, etc. Analyzing consumption data and building prioritization lists helped choosing about 15 API to be monitored in hospital wastewaters. The API ranking approach adopted in this study can be easily transposed to any other hospitals, which have the will to look at the contamination of their effluents.

OBJECTIVES: The handling of antineoplastic agents results in chronic surface contamination that must be minimized and eliminated. This study was designed to assess the potential of several chemical solutions to decontaminate two types of work surfaces that were intentionally contaminated with antineoplastic drugs. METHODS: A range of solutions with variable physicochemical properties such as their hydrophilic/hydrophobic balance, oxidizing power, desorption, and solubilization were tested: ultrapure water, isopropyl alcohol, acetone, sodium hypochlorite, and surfactants such as dishwashing liquid (DWL), sodium dodecyl sulfate (SDS), Tween 40, and Span 80. These solutions were tested on 10 antineoplastic drugs: cytarabine, gemcitabine, methotrexate, etoposide phosphate, irinotecan, cyclophosphamide, ifosfamide, doxorubicin, epirubicin, and vincristine. To simulate contaminated surfaces, these molecules (200ng) were deliberately spread onto two types of work surfaces: stainless steel and glass. Recovered by wiping with a specific aqueous solvent (acetonitrile/HCOOH; 20/0.1%) and an absorbent wipe (Whatman 903®), the residual contamination was quantified using high-performance liquid chromatography (HPLC) coupled to mass spectrometry. To compare all tested cleaning solutions, a performance value of effectiveness was determined from contamination residues of the 10 drugs. RESULTS: Sodium hypochlorite showed the highest overall effectiveness with 98% contamination removed. Ultrapure water, isopropyl alcohol/water, and acetone were less effective with effectiveness values of 76.8, 80.7, and 40.4%, respectively. Ultrapure water was effective on most hydrophilic molecules (97.1% for cytarabine), while on the other hand, isopropyl alcohol/water (70/30, vol/vol) was effective on the least hydrophilic ones (85.2% for doxorubicin and 87.8% for epirubicin). Acetone had little effect, whatever the type of molecule. Among products containing surfactants, DWL was found effective (91.5%), but its formulation was unknown. Formulations with single surfactant non-ionics (tween 40 and span 80) or anionic (SDS) were also tested. Finally, solutions containing 10(-2) M anionic surfactants and 20% isopropyl alcohol had the highest global effectiveness at around 90%. More precisely, their efficacy was the highest (94.8%) for the most hydrophilic compounds such as cytarabine and around 80.0% for anthracyclines. Finally, the addition of isopropyl alcohol to surfactant solutions enhanced their decontamination efficiency on the least hydrophilic molecules. Measured values from the stainless steel surface were similar to those from the glass one. CONCLUSION: This study demonstrates that all decontamination agents reduce antineoplastic contamination on work surfaces, but none removes it totally. Although very effective, sodium hypochlorite cannot be used routinely on stainless steel surfaces. Solutions containing anionic surfactant such as SDS, with a high efficiency/safety ratio, proved most promising in terms of surface decontamination.

A simple wipe sampling procedure was developed for the surface contamination determination of ten cytotoxic drugs: cytarabine, gemcitabine, methotrexate, etoposide phosphate, cyclophosphamide, ifosfamide, irinotecan, doxorubicin, epirubicin and vincristine. Wiping was performed using Whatman filter paper on different surfaces such as stainless steel, polypropylene, polystyrol, glass, latex gloves, computer mouse and coated paperboard. Wiping and desorption procedures were investigated: The same solution containing 20% acetonitrile and 0.1% formic acid in water gave the best results. After ultrasonic desorption and then centrifugation, samples were analysed by a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in selected reaction monitoring mode. The whole analytical strategy from wipe sampling to LC-MS/MS analysis was evaluated to determine quantitative performance. The lowest limit of quantification of 10ng per wiping sample (i.e. 0.1ngcm−2) was determined for the ten investigated cytotoxic drugs. Relative standard deviation for intermediate precision was always inferior to 20%. As recovery was dependent on the tested surface for each drug, a correction factor was determined and applied for real samples. The method was then successfully applied at the cytotoxic production unit of the Geneva University Hospitals pharmacy. Figure Wipe sampling procedure for the determination of cytotoxic drugs

A micellar electrokinetic chromatography (MEKC) method was developed for the determination of cisplatin, carboplatin, and oxaliplatin in pharmaceutical formulations. The background electrolyte consisted of a phosphate buffer (pH 7.0; 25 mM) with sodium dodecyl sulfate (80 mM). The applied voltage was 30 kV and the sample injection was performed in the hydrodynamic mode. All analyses were carried out in a fused silica capillary with an internal diameter of 50 μm and a total length of 64.5 cm. The detection of target compounds was performed at 200 nm. Under these conditions, a complete separation of cisplatin, carboplatin and oxaliplatin was achieved in less than 10 min. The MEKC-UV method was validated and trueness values between 99.7% and 100.8% were obtained with repeatability and intermediate precision values of 0.7-1.4% and 1.1-1.7%, respectively for the three drugs. This method was found appropriate for controlling pharmaceutical formulations containing platinum complexes and successfully applied in quality control at the Geneva University Hospitals.

Matrix effects, which represent an important issue in liquid chromatography coupled to mass spectrometry or tandem mass spectrometry detection, should be closely assessed during method development. In the case of quantitative analysis, the use of stable isotope-labelled internal standard with physico-chemical properties and ionization behaviour similar to the analyte is recommended. In this paper, an example of the choice of a co-eluting deuterated internal standard to compensate for short-term and long-term matrix effect in the case of chiral (R,S)-methadone plasma quantification is reported. The method was fully validated over a concentration range of 5-800 ng/mL for each methadone enantiomer with satisfactory relative bias (-1.0 to 1.0%), repeatability (0.9-4.9%) and intermediate precision (1.4-12.0%). From the results obtained during validation, a control chart process during 52 series of routine analysis was established using both intermediate precision standard deviation and FDA acceptance criteria. The results of routine quality control samples were generally included in the +/-15% variability around the target value and mainly in the two standard deviation interval illustrating the long-term stability of the method. The intermediate precision variability estimated in method validation was found to be coherent with the routine use of the method. During this period, 257 trough concentration and 54 peak concentration plasma samples of patients undergoing (R,S)-methadone treatment were successfully analysed for routine therapeutic drug monitoring.

A multi-residue analytical method was developed and validated for the quantification of 11 selected active pharmaceutical ingredients (API) and 2 human metabolites in hospital effluents using solid-phase extraction followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Targeted analytes belong to different therapeutic classes: non steroidal anti-inflammatory drugs (NSAID), analgesics, antibiotics and psychiatric drugs. Solid-phase extraction recoveries ranged between 21 and 101% for the selected API. Calibration curves were built with 6 standard samples prepared in ultrapure water ranging from 0.05 to 10 ?g/L and showed regression coefficients above 0.994. The instrumental detection limits (IDL) varied between 0.05 and 5 ?g/L, and the method detection limits (MDL) between 0.1 and 100 ng/L. Precision of the method, evaluated with spiked water samples at four different concentrations, varied between 84 and 117% for all compounds and an overall variability below 20%, with the exception of carbamazepine (71–123%). Except for two compounds, recoveries of spiked hospital wastewaters at four different concentrations (0.1, 1, 10 and 100 ?g/L) varied between 44 and 133%, with relative standard deviation (RSD) between 0.6 and 28.5%. The evaluation of the matrix effects showed that diluted samples exhibit lower signal suppression. Analysis of effluent samples from a Swiss university hospital resulted in a mean detection frequency of 92% for the selected compounds, with concentrations up to 1535 ?g/L for the analgesic paracetamol.

Giant fennel (Ferula communis L.) from Sardinia is characterized by two chemotypes with different biological activities. One chemotype is poisonous, due to prenylcoumarins, and responsible for ferulosis, which mainly affects sheep and goats, cattle, and horses; the other chemotype is nonpoisonous and contains daucane esters. The two chemotypes cannot be distinguished botanically. High-performance liquid chromatography-diode array-ultraviolet detection-mass spectrometry (HPLC-DAD-UV-MS) analysis of the composition of the fractions containing the biologically active metabolites and of the volatile fractions, by gas chromatography-mass spectrometry (GC-MS), of both essential oil and headspace sampled by headspace solid-phase microextraction (HS-SPME) are here shown to be effective in discriminating the poisonous and nonpoisonous chemotypes. HS-SPME with CAR/PDMS/DVB in combination with GC-MS has also been found to be a successful, fully automated one-step method for rapid and unequivocal discrimination of the two chemotypes, using aristolene and allohedycaryol as markers of the poisonous and nonpoisonous chemotypes, respectively.

Background Although an effort is always made to reduce contamination, traces of cytotoxic drugs can be found in the environment. External surfaces of vials can be a source of contamination, but the operators themselves also contribute to this problem during manipulation. Purpose To quantify the chemical contamination generated by a large panel of operators during a standard preparation process, using a non-toxic tracer in a multi-site simulation. Materials and methods Preparation was simulated voluntarily by operators in Swiss hospital pharmacies. Each operator had to reconstitute 3 vials of quinine diHCl powder (200 mg) with 5 mL of water and dilute them in 3 saline solution infusion bags (50 mL). A standard procedure was used, using only one 10 and one 20 mL syringe, 2 needles and 15 gauze compresses, creating a worst-case scenario. Contamination on vials, bags, gloves and compresses was analysed by a validated fluorimetric method (λ ex =345 nm, λ em =448 nm, LOD (limit of detection) =0.3 ng/mL or 15 nL and LOQ (limit of quantification) =1 ng/mL or 50 nL at pH 3.0). Results Sixty-two operators in 24 hospitals (1 to 5 per hospital) participated in the study. 95% of operators contaminated at least one object. Mean total contamination was 78 µL (0 to 596 µL). Compresses were the most contaminated items (mean 72 µL, 0 to 592 µL). Contamination also occurred on gloves (0.2 µL, 0 to 59 µL), bags (0.7 µL, 0 to 24 µL), quinine vials (0.2 µL, 0 to 16 µL) and water vials (0.02 µL, 0 to 0.8 µL). Conclusions A simple validation protocol for chemical contamination, using a non-toxic tracer, enables the ability of operators to avoid spillage to be checked. It demonstrated wide variability between operators in a multi-site survey. Such a simulation tool is of the utmost importance in the context of the operator9s initial and continuing training and qualification.

Background Preparation of capsules is common in hospital pharmacy when an adapted dosage is not available on the market. According to the Good Manufacturing Practices, validation of processes and operators are essential to ensure the quality of preparations. Purpose To evaluate and validate the operator9s accuracy during the manual process of capsules preparation. Materials and Methods Operators had to manually prepare, without using mannitol carmine, 3 batches of 100 capsules. Each 250 mg capsule (size 2) contained 6 mg of phenylephrine used as a tracer. Ten capsules in critical points of the capsule filler (2 in every corner and 2 in the centre) were analysed according to the European Pharmacopeia (uniformity of mass and content). Phenylephrine was determined by a validated capillary electrophoresis-UV method. Results were analysed considering the operator9s experience based on the years of experience and the frequency of execution (low, medium and high). Results Forty-two batches were produced by 14 operators (11 technicians and 3 pharmacists). Mass uniformity: all batches were conform. The mean mass (±SD) was 247.5 mg (±3.8). The mean mass obtained by the operators with low (n=6), medium (n=4) and high (n=4) experience were 244.6 (±2.4), 247.9 (±2.3) and 251.6 mg (±2.7), respectively (r 2 =0.60). Content uniformity: 6 batches (14%) were not conform. 9/14 operators (64%) passed the test for 3/3 batches, 4/14 (29%) for 2/3, and 1/14 (7%) for 1/3. The mean content for low, medium and high experience was 95.6 (±3.0), 96.9 (±2.1) and 97.0% (±2.5) of the target concentration, respectively (r 2 =0.06). Conclusions All operators displayed adequate skills to uniformly fill capsules, with a trend to a better performance by experienced operators. However, insufficient homogenisation of the mixture was observed, independently of the experience. Further studies are needed to evaluate different systems from producing consistent mixtures.

Background Exposure to cytotoxic drugs is a risk to healthcare professionals. To improve safety, most hospitals have introduced centralised preparation of cytotoxics, but the infrastructure and protective measures can vary between places. To determine the performance of confinement methods, it is important to benchmark the contamination levels between similar structures. Purpose To establish an overview of chemical surface contamination by cytotoxic drugs in a large panel of Swiss hospital pharmacies. Materials and methods A sampling campaign was conducted voluntarily in Swiss hospital pharmacies. At each site, wipe samples were collected in the preparation and logistics areas (most collection spots were common to all pharmacies, but each site could choose a few points of interest to itself). Chemical surface contamination of 10 cytotoxic agents (cyclophosphamide, ifosfamide, gemcitabine, doxorubicin, epirubicin, irinotecan, methotrexate, etoposide phosphate, cytarabine and vincristine) was determined by a validated wiping procedure and LC-MS/MS analysis. Results Twenty-four hospital pharmacies (out of 46 contacted, 52%) participated in the study: 12 to 29 wiping samples were collected in each site. The surface contamination was generally lower than 100 ng per 100 cm2, with wide variability between sites. In 2 pharmacies, no contamination at all was detected. The heaviest contamination (> 30 µg) was found on a CATO keyboard. Preparation areas (especially work benches, objects inside the safety cabinets and cleanroom floors) were more contaminated than logistics areas. Ifosfamide, cyclophosphamide and cytarabine were the drugs detected in the highest quantities. Conclusions Despite recommended safe handling practices, workplace surface contamination was observed. Most contamination was confined to manipulation areas, reducing the risk of exposure for operators. Possible correlations between structural and/or organisational characteristics and the level of contamination will be evaluated.

Purpose To evaluate the chemical contamination of surfaces by cytotoxic agents during preparation of injectable chemotherapies in hospital pharmacies. Methods 526 wipe samples collected in 24 Swiss hospital pharmacies were analysed using a validated liquid chromatography–mass spectrometry/mass spectrometry method able to quantify 10 cytotoxic agents: cytarabine, gemcitabine, cyclophosphamide, ifosfamide, methotrexate, etoposide phosphate, irinotecan, doxorubicin, epirubicin and vincristine. Information on chemotherapies produced, equipment and production processes used were collected from all the hospital pharmacies on a voluntary basis in order to investigate their association with contamination rates. Results In two pharmacies, no trace of the 10 cytotoxic agents was detected. Chemical contamination was found in the other 22 hospital pharmacies, with combined total contamination of the 10 cytotoxic agents ranging from 8 ng to more than 41 000 ng per sample. Most contaminated samples came from inside biosafety cabinets, but some came from other clean room areas and logistics rooms. Statistically significant associations were observed between contamination rates and sampling locations, the number of chemotherapies prepared per year and types of cleaning solutions used. Conclusions This study demonstrated that most of the hospital pharmacies tested had some contamination of surfaces by different cytotoxic agents. Even if highest levels of contamination were mainly detected inside biosafety cabinets, technicians were also exposed to cytotoxic agents detected in logistical and storage areas. Protective measures should therefore be maintained or even reinforced in these areas in order to limit technicians' risks of exposure when handling cytotoxic products.