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Objectives To design and execute a comprehensive microbiological validation protocol to assess a brand-new sterile compounding robot in a hospital pharmacy environment, according to ISO and EU GMP standards. Methods Qualification of the Class-A inner environment of the robot was performed through microbial air and surface quality assessment utilising contact plates, swabs and particulate matter monitoring. To evaluate the effectiveness of the microbial decontamination process (UV rays) challenge test against Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis spores and Candida albicans was used. The challenge Media Fill test was used to validate the aseptic processing. Results After 3 hours, no microorganisms retained viability. Monitoring inside the equipment evidenced complete absence of microorganisms. The Media Fill test was always negative. Conclusions According to our results, the APOTECAunit meets the requirements for advanced aseptic processing in the hospital pharmacies and the pharmaceutical industry in general, providing advantages in terms of safety for patients compared with conventional procedures of parenteral preparation production. The protocol has demonstrated to be a comprehensive and valuable tool in validating, from a microbial point of view, a sterile-compounding technology. This study might represent an important benchmark in developing a contamination control strategy, as required, for example, in the Performance Qualification of the GMP in the case of drug manufacturing.

The automated aseptic preparation of ready-to-administer antineoplastic drug solutions with robotic systems reduces the risk of occupational exposure. However, the surfaces in the preparation area of the robot are to be cleaned by wiping with an appropriate cleaning solution. The aim of the study was to evaluate the cleaning efficacy of four cleaning solutions on four surface materials installed in the APOTECAchemo robot. Predefined amounts of cisplatin (Cis), 5-fluorouracil (5-FU), and cyclophosphamide (CP) were intentionally spread on test plates made of stainless steel, aluminium, polyoxymethylene, and polycarbonate just as installed in the robotic system APOTECAchemo. After drying, the plates were cleaned with 0.2% ethanolic NaOH, 0.23% isopropanolic sodium dodecylsulfate (SDS-2P), 0.5% sodium hypochlorite (NaOCl), and 0.1% benzalkonium chloride (BZK) solutions following a standardized wiping protocol. Residual contamination was recovered with wipe tests, Pt was quantified by voltammetry, and 5-FU and CP was quantified by gas chromatography-tandem mass spectrometry (GC-MSMS). The mean residual contamination after cleaning and the cleaning efficacy (CE) rates were calculated and aggregated on different levels. The CE rates varied between 81.5% and 100% and lay in the majority of cases above 90%. The lowest CE rates were registered for Pt contamination. Especially on aluminium surfaces the residual contamination was high. The overall CE rates of the three different drugs and four different surface types amounted to 98.3% for NaOCl, 97.9% for SDS-2P, 96.9% for ethanolic NaOH, and 96.5% for BZK. The tested cleaning solutions proved to be higher than 90% in most cases, but none of them was able to eliminate 100% of the intentional surface contamination of three antineoplastic drugs on the test plates. The cleaning efficacy varied according to the different surface types and antineoplastic drug. Results could be used in the daily clinical practice to develop and implement effective cleaning procedures.

Carbon dioxide constitutes one of the largest carbon feedstocks for fuel production. This work demonstrates that an environmental bacterial consortium grown on methane is able to directly and selectively reduce CO2 into formate. The conversion was carried out at 30°C and atmospheric pressure, without any the addition of organic molecules (such as cofactor), photons or H2 to the reaction medium. When exposed to a CO2:air (1:1 v/v) mixture, the consortium was able to produce 280 ± 10 mg·g dry cell−1 of formate in 15 days. A control experiment performed solely with air coupled to NMR analysis suggested that at least 17% of the formate was produced from direct CO2 reduction. The formate produced could be used as a precursor for methanol production from methane by methanotrophic bacteria or it could be acidified to feed Direct Formic Acid Fuel Cells.

Background The aseptic compounding of injectable antiblastic drugs is centralised in the oncology pharmacy and, since 2014, is performed by using a fully automated platform that enables control of the whole production process. The platform comprises a robotic system for fully automated preparation (APOTECAchemo), a supporting device for manual compounding (APOTECAps) and a workflow management software (APOTECAmanager). The production is mainly just-in-time (80% outpatient and 20% inpatient) and performed in a Class C cleanroom by seven pharmacy technicians and two pharmacists. The daily working time is from 8 am to 4 pm (Monday–Friday). Purpose The aim of this study was to analyse the performances of the fully automated oncology pharmacy production. Material and methods The performances were analysed by means of the statistical tool of the APOTECA platform over a period of 9 months (January–September 2018). Productivity, dosage accuracy, precision and turnaround time were measured and compared between automated preparation with APOTECAchemo and manual preparation supported by APOTECAps. Results Overall, 18 524 preparations (62.6% infusion bags, 26.3% syringes, 11.1% elastomeric pumps) were compounded with APOTECAchemo and 5272 preparations (52.3% infusion bags, 46.8% syringes, 0.9% elastomeric pumps) with APOTECAps. In total, 82 different active ingredients were processed. Regarding dosage accuracy, APOTECAchemo showed better performances, with 96.6% of preparation with a deviation of ±5% versus 93.0% of the manual compounding. Less than 1% of preparations presented a drug error exceeding 10%. The turnaround time, calculated from the prescription time to the delivery time, was similar for both procedures. The average output amounts to 13.2 preparations/hour for APOTECAchemo and 15.0 preparations/hour for APOTECAps. Conclusion The utilisation of the fully automated platform for managing the oncology pharmacy activities guarantees the possibility of measuring and controlling every single step of the whole production process. In-process controls, such as gravimetric control, barcode and photographic recognition, allow prompt corrective action in the case of deviations. References and/or acknowledgements No conflict of interest.

Background The aseptic preparation of oncologic drugs is performed in the centralised, pharmacy-based cytotoxic drugs preparation unit equipped with a biological safety cabinet and the robotic system APOTECAchemo (Loccioni, Italy), installed in 2012. Manual and fully automated preparations run in parallel are operated by two and one pharmacy technicians (PT), respectively. On average, the annual workload amounts to 35 000 preparations, two-thirds of which are prepared with the robotic system. Purpose The aim of this study was to evaluate the working efficiency of PT after implementing the robotic system and calculate the amount of preparations to be transferred from the manual to the automated process to optimize human resources’ utilisation. Material and methods Manual and automated preparation were analysed over three years (2014–2016). Full-time equivalents (FTE) required by both processes were calculated for each year. A FTE of 1.0 was equivalent to a PT working full-time 40 hours per week, 1,700 hours per year. The throughput in terms of annual preparations per FTE was calculated including direct activities (compounding) and indirect activities related to production (quality controls and standard operating procedures, e.g. cleaning and gowning). The calculation was performed for both manual and automated preparation processes. Results On average, the overall working time spent by PT on direct and indirect activities amounted to 4,670 hours/year for the manual process and to 2,441 hours/year for the automated process, resulting in 14 151 and 21 534 preparations, respectively. The annual amount of preparations per 1.0 FTE in the automated process (mean: 15,066) was three times higher than in the manual process (mean: 5,036). The production times were comparable, but the working time spent by PT on indirect activities was reduced by 85% by using the robotic system. Each 7600 preparation transferred from the manual process to the robotic system results in 1.0 FTE made available for different working activities. Conclusion Results of this study revealed that the automated process with the robotic system improves the working efficiency of PT, thereby allowing the reallocation of human resources and the optimisation of workload distribution in the daily pharmacy practice. Other indirect advantages related to cost and production quality are achieved. References and/or acknowledgements No conflict of interest.

Background In April 2016 the Central IntraVenous Additive Service (CIVAS) began to compound non-toxic injectable therapies with a robotic system.1 The production started with antiemetic therapies, followed by antibiotic therapies ready to infuse, as cefazoline 1 g in syringes and piperacillin-tazobactam 4.5 g in bags. Purpose The purpose of this study is to present the new drugs involved that led to production increasing and to describe how CIVAS guarantees the non-hazardous preparations’ supply to hospital departments. Material and methods An analysis concerning the actual hospital antibiotic treatment needs has been carried out through the electronic medical record (EMR). Drugs in ready-to-use injectable form were immediately excluded as well as those with a daily consumption under 20 units. Among the remaining amount of medications, only those with a sufficient physical and chemical stability,2 that allow batch production and at least 7 days of storage, were considered. For every new molecule, a testing production with five batchs of 10 preparations each were compounded through a robotic system, in order to evaluate the dosage accuracy. Results The new validated drugs included in the automated production result were: oxacillin 1 g, cefotaxime 2 g, azithromycin 500 mg, vancomycin 500 mg and ceftriaxone 1 g, all in 100 ml NaCl bags. The average dosage accuracy ranges from 93.43% of azithromycin to 99.64% of cefotaxime, always compliant with the 10% error limit set by the Official Pharmacopoeia. The annual workload, including piperacillin-tazobactam 4.5 g and cefazoline 1 g already compounded inside the automated system, is estimated as 80 000 bags. Conclusion Within 2017, the robotic system will cover the dispensing of antibiotic treatments of 50% of hospital departments, reaching 100% by the end of 2018. References and/or Acknowledgements 1. Bufarini C, et al. Centralised non-hazardous intravenous compounding: from theory to clinical practice. Eur J Hosp Pharm2017;24(1):A1–A288 PP-041. 2. ‘Stabilis 4.0’. www.stabilis.org No conflict of interest

Background The preparation of antiblastic chemotherapy drugs is an activity of high clinical risk because an error in the preparation phase can result in severe damage to the patient. The robotic system APOTECAchemo has been in use in our centre since 2014. The system is not only able to intercept potential errors in the stage of preparation of therapies but is also equipped with software that records any potential errors to ensure continuous monitoring inside the antiblastic medication unit. Purpose In order to improve the production process by getting the attention of the operators that work in the antiblastic medication unit every day, we carried out an analysis of the errors that represent the potential critical points in the preparation phase. Material and methods We analysed the medication errors intercepted by the robots in the period between November 2016 and May 2017. The software APOTECAm@a for the real-time monitoring of the performance records and reports all the stopped errors thanks to controls at different levels: expiry date control of the drugs, load of the right components through barcode reading, components weight control and drug label identification. Results The robotic system intercepted a total of 70 errors on 3090 preparations, which could have been dispatched if the equipment had not been computerised and robotised. Six types of errors were identified: preparations with expiry date prior to the delivery date (14%); incorrect residual vials loaded (9%); wrong format and/or solvent of the loaded bag (60%); incorrect weight of a loaded component (erroneous loading of residue vials/incorrect filling of infusion pump) (11%); reading a barcode already used for another preparation (infusion pump) (3%); and the loaded drug not corresponding to the prescription (3%). Conclusion The study showed that the incidence of medication errors associated with human distraction is significant (2.3%). The picking of a wrong bag format and the expiry date of the medication prior to infusion date are the most common mistakes. Despite intercepting and avoiding human errors, robotics allows real-time monitoring of different key performance indicators, like intercepted medication errors, which guarantees the continuous improvement of the production process. References and/or Acknowledgements Thanks to staff pharmacy and Loccioni Humancare No conflict of interest

Background Due to the toxicity of drugs involved, chemotherapy represents an high-risk treatment, both for operators and patients. To improve the safety of the oncologic therapy admixture process, in 2007 the clinical pharmacy introduced an automated system for the compounding of toxic drugs. The system is integrated with the hospital electronic medical record (EMR) and assures high levels of quality controls and a total traceability of the entire process. Purpose Since the safety and high-quality standards of the re-engineered process have been assessed,1 the purpose of this study is to evaluate also its economic sustainability and the related production efficiency. Material and methods To assess the economic sustainability of the automation, a cost analysis has been performed. Fixed costs (equipment investment, maintenance, human resources, personal protective equipments) and variable costs (compounding disposables and administrative management of the process) have been calculated both for the manual and automated compounding model, and the consequent differential saving has been estimated. In addition, we have evaluated the possibility of also centralising the production by taking into consideration the need of other hospitals and healthcare facilities in the region. Results The re-engineering of the onco-haematology process led to an annual saving of €85.715, with a marginal saving of €5.49 per preparation, a break-even point of 4.1 therapies and a return on investment in 3.3 years (against 8 years’ life-time of the robotic system). Furthermore, the total automated production capacity is estimated in 24.865 preparations per year where the 79.3% is sufficient to cover the annual hospital (hub) needs. Therefore, the residual capacity, corresponding to 5.145 annual preparations, can be allocated to satisfy the requests coming from other compounding facilities (spokes). Conclusion Besides the minimisation of the risks related to the automated production and the benefits coming from the re-engineering of the process,1 the economic sustainability of the investment and the production centralisation feasibility have been demonstrated. Reference and/or Acknowledgements 1. Bufarini C, et al. Safe and integrated onco-haematology workflow, 19th EAHP Congress 2014. No conflict of interest

Background The accuracy, safety and feasibility of, the compounding robot APOTECAchemo were evaluated in the clinical practice of Japan. Methods Accuracy and precision of robotic preparations by APOTECAchemo was evaluated in 20 preparations of fluorouracil (FU) and cyclophosphamide (CPA) infusions by four pharmacists. Environmental and product contaminations with FU and CPA were evaluated by wipe testing. Robotic performance was compared with manual preparation in a biological safety cabinet. The number of robotic products, total compounding time and total pre-reconstitution time of lyophilized drugs between January 1, 2014 to December 31, 2015 were investigated. Results Robotic preparation resulted more accurate and precise (mean absolute dose error and coefficient of variation were 0.83 and 1.04% for FU and 0.52 and 0.59% for CPA) than those of manual preparation (respective values were 1.20 and 1.46% for FU and 1.70 and 2.20% for CPA). Drug residue was not detected from any of the prepared infusion bags with the robotic preparation, whereas FU was detected in two of four analyzed infusion bags with manual preparation. Average total time to make single anticancer drug preparation (compounding plus reconstitution of lyophilized drugs) was 6.11 min in the second half of 2015. During the study period, the highest percentage of production covered by APOTECAchemo was 70.4% of the total inpatient pharmacy activity. Conclusion Robotic preparation using APOTECAchemo should give substantial advantages in drug compounding for accuracy and safety and was able to be successfully worked in Mie university hospital.

Background Denmark is one of the European countries that requires the Good Manufacturing Practices (GMP) certification to hospital pharmacies for medication compounding and delivery. In 2012, the Region HovedstadensApotek, the largest hospital pharmacy in Denmark, decided to invest in IV robotics to guarantee EU-GMP and GAMP compliance through the highest standards of safety, quality and efficacy in the compounding process. The go-live of this technology was preceded by a tough qualification aimed at assessing that the new compounding process was GMP compliant. The GMP qualification consisted of several validation procedures in sequence: design qualification, factory acceptance test, operational qualification, installation qualification and performance qualification. Purpose Case study on how the technology can help the hospital pharmacy to be GMP compliant. Material and methods A dedicated multidisciplinary team thoroughly studied the reference documentation: EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. The analysis led to the definition of 89 user requirements specification (URS) associated with GMP requirements, for a total of 143 URS addressed in the tender. The GMP requirements covered several aspects, such as environmental conditions, equipment design, product safety and efficacy, documentations, alarm alerts and messages, user accessibility, training and maintenance, and data storage and recording. During the tender, the competing systems were challenged on each URS to verify their compliance. Results The system that scored best in the tender evaluation was APOTECAchemo. It fulfilled 74 of the 89 GMP requirements from the beginning, and the manufacturer developed and validated the additional 15 before the qualification process. In November 2013, the Danish Health and Medicines Authority certified that APOTECAchemo was totally compliant with the GMP regulations and authorised the go-live. Since September 2016, 4 additional inspections have been successfully passed, without any deviation. Moreover, they approved the use of this robotic system in a class C cleanroom, different from the manual compounding that now requires a class B cleanroom. Conclusion Installation of an IV compounding robot in full compliance with GMP regulations ensures benefits in terms of the highest level of preparation quality, operator safety, continuous monitoring of environmental conditions and reduction in human interventions in controls and reports. No conflict of interest

Objectives The aim of this study was to compare environmental contamination of cyclophosphamide (CP) during 1 week of drug compounding by conventional manual procedure in a biological safety cabinet (BSC) with laminar airflow and a new robotic drug preparation system (APOTECAchemo). Methods During four consecutive days, similar numbers of infusion bags with cyclophosphamide were prepared with both techniques in a cross-over design. Wipe samples (49 for BSC, 50 for APOTECAchemo) were taken at several locations (gloves, infusion bags, trays, BSC-benches, floor) in the pharmacy and analyzed for CP concentrations by GC-MSMS (LOD 0.2 ng/sample). Results The detection rate was 70% in the BSC versus 15% in APOTECAchemo. During manual preparation of admixtures using BSC contamination with CP was below 0.001 ng/cm2 at most locations, but significant on gloves (0.0004–0.0967 ng/cm2) and the majority (70%) of infusion bags (2). During robotic preparation by APOTECAchemo, gloves (1 of 8: 0.0007 ng/cm2) and infusion bags (3 of 20: 0.0005, 0.0019, 0.0094 ng/cm2) were considerably less contaminated. Residual contamination was found on the surfaces under the dosing device in the compounding area (0.0293–0.1603 ng/cm2) inside the robotic system. Conclusions Compared to outcomes of other studies, our results underline good manufacturing procedures in this pharmacy with low contamination for both techniques (BSC and APOTECAchemo). Comparison of both preparation procedures validated that contamination of infusion bags was much lower by using the robotic system.

Purpose The quality and economic implications of manual versus automated preparation of antineoplastic drugs were compared. Methods This four-week study evaluated 10 routinely used antineoplastic drugs (fluorouracil, cyclophosphamide, gemcitabine, trastuzumab, bevacizumab, oxaliplatin, cisplatin, paclitaxel, irinotecan, and etoposide) prepared by manual and automated procedures. The accuracy of the dose of the active ingredient was calculated in terms of percent relative error for the difference between the nominal value indicated on the prescription and the actual value of the drug in the finished product. A comparative economic analysis of the manual and automated preparation procedures was performed by calculating the mean unit cost for each preparation at different production levels. Participating pharmacists and technicians completed a survey rating each preparation method in terms of performance, operator satisfaction, technology, and safety. Results Of the 2500 i.v. antineoplastic preparations made in the pharmacy during the four-week study period, 681 were analyzed (348 using the automated procedure and 333 manually). Of these, 17 varied by more than 5% of the prescribed dose, and 1 varied by over 10%. Accuracy, calculated in terms of average percent relative error, was the highest and lowest during manual preparation. The preparation time for individual drugs was always higher when prepared using the automated procedure. A lower mean variable unit cost was observed for preparations made using the automated procedure. Questionnaire results revealed that operators preferred the automated procedure over the manual procedure. Conclusion Both the automated and manual procedures for preparing antineoplastic preparations proved to be accurate and precise. The automated procedure resulted in substantial advantages in terms of quality maintenance standards and risk lowering.

Purpose The development of recommendations for advancing automated i.v. medication compounding is described. Summary Managing the shift from manual to robotic compounding of i.v. therapies requires an awareness of how automation affects practice and how to best implement robotics into current practice. An international panel of pharmacy professionals, researchers, and technology leaders with experience in i.v. robotics collaborated during a two-day meeting in August 2014 to define a general set of principles to broaden the understanding of the fundamental elements of robotic compounding worldwide. Participants were divided into four working groups (technology and safety; drugs and products; personnel; and facilities and quality) to analyze specific aspects of robotic compounding practice. The four working groups produced an initial list of 92 statements. This list was condensed to 35 statements by consolidating similar and overlapping statements from the different work groups. Participants were surveyed again to assess agreement with the 35 statements and solicit additional clarification. Respondents expressed full agreement with 25 recommendations. Six statements received one or more “don’t know” responses, with all other respondents in agreement. Four statements had a combination of “don’t know” and “disagree” responses. A total of 32 comments were recorded in free-text fields, including requests for clarification and suggestions for rewording the statements. Conclusion An international panel of pharmacy professionals, researchers, and technology leaders with experience in i.v. robotics developed a set of 35 recommendations toward a better understanding of the role of automated i.v. compounding in hospital and health-system pharmacies worldwide.

Objective Ultraviolet (UV) irradiation efficacy in the intravenous compounding robot APOTECAchemo was evaluated to define the best operative conditions in terms of sterility and time optimization. Design The challenge test was used against Pseudomonas aeruginosa , Escherichia coli , Staphylococcus aureus , Bacillus subtilis spores and Candida albicans . Inoculated plates were placed inside the robot and irradiated for different times. Microbial air and surface quality inside the equipment were monitored utilizing settle and contact plates, swabs. Results After 4 h, no microorganisms were viable with killing rates ranging from 5- to 7-log for different microorganisms after 1 h of exposition. In confirmation of the efficacy of the UV irradiation program adopted, the microbial monitoring inside the equipment always gave negative results. Conclusions This is the first exhaustive investigation of UV irradiation efficacy in the aseptic pharmaceutical production. We demonstrated that UV irradiation plays an essential role in maintaining the sterility condition of the workplace inside the APOTECAchemo and assuring the standards for aseptic manufacturing of medicinal drugs, as required for Class A clean areas. A 4-h UV irradiation also ensures sterility in the case of very resistant microorganisms and in the presence of high microbial charge (108 CFU/ml), but a killing rate of 5 or more is already recorded after the first hour of exposition. The results provide useful information for the best operative conditions in terms of both sterility and time optimization, not only for the automated compounding, but also for the traditional aseptic manufacturing processes.

SummaryReactive oxygen species (ROS) are potent inducers of oxidative damage and have been implicated in the regulation of specific cellular functions, including apoptosis. Mitochondrial ROS increase markedly after proapoptotic signals, though the biological significance and the underlying molecular mechanisms remain undetermined. P66Shc is a genetic determinant of life span in mammals, which regulates ROS metabolism and apoptosis. We report here that p66Shc is a redox enzyme that generates mitochondrial ROS (hydrogen peroxide) as signaling molecules for apoptosis. For this function, p66Shc utilizes reducing equivalents of the mitochondrial electron transfer chain through the oxidation of cytochrome c. Redox-defective mutants of p66Shc are unable to induce mitochondrial ROS generation and swelling in vitro or to mediate mitochondrial apoptosis in vivo. These data demonstrate the existence of alternative redox reactions of the mitochondrial electron transfer chain, which evolved to generate proapoptotic ROS in response to specific stress signals.

The enzymatic membrane reactor (EMR) consists on a coupling of a membrane separation process with an enzymatic reaction. The selective membrane aims to separate the biocatalyst from the reaction products. The main objective of EMR is to ensure the complete rejection of the enzyme in order to maintain the full activity inside the reacting volume. Depending on the case, enzyme molecules may be freely circulating on the retentate side or immobilised onto the membrane surface or inside its porous structure. This article intends to report some significant information showing the last progress realised in the knowledge of the phenomena which limit the performances of EMR, and to mention openings towards new and more efficient systems. A special attention is also paid to new catalytic membrane devices that could result in improved enzyme stability and high performance particularly in non-conventional solvents. © 2004 Elsevier B.V. All rights reserved.

Results from the gas gain monitoring (GGM) system for the muon detector using RPC in the CMS experiment at the LHC is presented. The system is designed to provide fast and accurate determination of any shift in the working point of the chambers due to gas mixture changes., Comment: 8 pages, 7 figures, uses lnfprepCMS.sty, presented by S. Colafranceschi at IEEE 08 Dresden (Germany) November 2008

Membrane bioreactors (MBRs) and their potential uses in food processing and food ingredients production are discussed, where ‘membrane bioreactor’ applies to any system constituted from a reactor working with enzymes or whole cells as the catalyst and from a membrane for separation and/or contacting purposes. The various types of MBR are presented and their advantages as well as their drawbacks are discussed. Several applications of MBRs in different food areas are then presented.

Performances of the Gas Gain Monitoring system of the CMS RPC muon detectors after one year of operation at the scaled down closed loop recirculation gas system are presented. The GGM is made of 12 single-gap RPC's arranged in a cosmic ray telescope, with charge readout for online monitoring of working point. Preliminary results on sensitivity to gas changes and to environmental variables will be reported on.

Results from the gas gain monitoring (GGM) system for the muon detector using RPC in the CMS experiment at the LHC is presented. The system is designed to provide fast and accurate determination of any shift in the working point of the chambers due to gas mixture changes.

Background In 2007, the University Hospital of Ancona started the journey in automating IV compounding. At the end of 2009, the clinical validation process and workflow reorganisation ended, the second robot was introduced to set up a fully automated IV oncology pharmacy. The laboratory is composed of two APOTECAchemo systems and a laminar airflow cabinet which work from 8 am to 4 pm. There are 3 technicians from 8 am to 2 pm and 1 technician from 10 am to 4 pm. We work in a just-in-time production (80% for outpatients and 20% inpatients) and the rush hours go from 9 am to 1 pm. Two systems are used until 2 pm and one system works for the entire day. Purpose To take stock of 7 years of experience in automated IV compounding. Material and methods The production data were analysed in terms of doses and type of preparations delivered, by means of the statistical tools of APOTECAchemo. Results Before 2010 10,400 treatments were produced automatically in a year and in 2010 this increased to 16,300 (80% of our annual production). In the following years, production increased with 19,300, 19,600 and 20,300 treatments in 2011, 2012 and 2013 respectively. In August 2014, we passed the threshold of 100,000 treatments compounded with APOTECAchemo, representing 95% of the treatments compounded. The annual production consists of 85% in bags, 10% in syringes and 5% in elastomeric pumps. 56 different active ingredients are used. Conclusion Automation ensures the highest quality standards because every step of the compounding process is controlled and traced Automation can cover more than 90% of daily preparations even in a just-in-time system. Automation allows a more intelligent and efficient management of human resources: for every 10,000 treatments automated, one FTE technician can be elevated to higher value-added tasks To take advantage of automation, the workflow should be redesigned (i.e. introduce multi-dose vials and drug days). References and/or acknowledgements No conflict of interest.

We have developed a process to deposit a thin uniform layer of diamond-like film onto optical fibers. This UV-transparent film protects the fiber during the fiber grating inscription and maintains the geometry of the fiber so long length gratings can be fabricated.

This work deals with cross-flow ultrafiltration of highly viscous liquids. Several years ago a few attempts were made to decrease viscosity by either using high temperatures or adding chemicals. But these alternatives present significant drawbacks: high additional costs in terms of equipment or energetic consumption and destruction of thermosensitive compounds for the first, or additional separation to preserve environment for the second one. The new idea that we have developed is to reduce liquid viscosity at ordinary temperature by injecting a gas (CO 2 ) in supercritical conditions before ultrafiltration. At the end of the membrane process, the gas may be freely eliminated without environmental damage by a simple pressure reduction, which constitutes a main advantage. Based on this idea, very promising experiments were recently conducted at temperature conditions ranging from 40 to 80°C. The mixture viscosity is reduced and ultrafiltration performed with suitable inorganic membranes gives significant transmembrane fluxes. The process is tested on model oil. We recently observed membrane fouling when working below the critical pressure of CO 2 . Mechanism has been proposed to give an account of these results.

Background Paclitaxel albumin is indicated for the treatment of metastatic carcinoma of breast after failure of anthracycline therapy. It is notoriously a delicate drug to handle because it is a suspension with high tendency to foam. According to the information sheet, the drug reconstitution requires particularly attention during solvent injection. Furthermore, the vial needs to stand for 5 and 15 min, respectively before and after shaking, to reduce the foam. As a consequence, the therapy compounding appears laborious and demanding for technicians. Purpose To automate the compounding of Abraxane with APOTECAchemo and analyse the related performances. Materials and methods The manual procedure was deeply analysed to evaluate the feasibility to robotize the compounding of Abraxane. 10 preparations are compounded manually, according to the data sheet. Afterwards, 10 preparations of Abraxane were carried out with APOTECAchemo, following the standard procedure of the system. However, the vials were left to rest for 10 min after reconstitution, before going on with the compounding. The preparations are analysed in terms of dosage accuracy and compounding time. Results The preparations compounded manually showed an average dosage error of 1.5% and a compounding time of 30 min. The dosage accuracy of preparations done automatically was -0.5%. The total compounding time resulted in 22 min for preparation: 7 min for reconstitution of 2 vials, 10 min for vial standing and 5 min for compounding. The 10-minute rest time resulted enough to significantly reduce the foam. Dosage accuracy of the automatic procedure resulted similar or better than the manual compounding. In contrast, the use of APOTECAchemo implied a notable reduction of compounding time of 26%. Conclusions The automation of Abraxane preparation resulted feasible and sustainable. Because the dosage accuracy of APOTECAchemo is comparable with manual activity and compounding time is even shorter, the automatic compounding represents an easy and convenient alternative to the traditional practice. No conflict of interest.

Kinetic properties of Termamyl(R) 120L were investigated with respect to starch hydrolysis in a batch reactor at substrate concentrations of 50-270 g. dm(-3) and enzyme concentrations of 0. 17-1 cm(3). dm(-3) (i.e., cm(3) of Novo Nordisk enzymatic solution per dm(3) of raw cassava starch suspension). A general kinetic expression giving product concentration as a function of time was first developed; an equation relating the reaction rate of each product to the sum of the concentrations of oligosaccharides with a higher degree of polymerisation was then derived. The empirical model satisfactorily fits experimental data for oligosaccharides with a degree of polymerization ranging from 1 to 7.

Background Ultraviolet (UV) light irradiation is used in a variety of applications, such as food, air and water purification. The mechanism of UV disinfection differs considerably from chemical disinfectants: UV is mutagenic to bacteria, viruses and other microorganisms by damaging nucleic acids and preventing replication. However, the effectiveness of UV disinfection depends on a number of factors: time of UV exposure; power of the UV source; presence of UV barriers like airborne particles; microorganism resistance. Purpose To study the effectiveness of UV disinfection inside APOTECAchemo, the robot for preparing antitumour drugs in use at the University Hospital of Ancona. The Killing Rate (KR) and optimal exposure time were determined. Materials and Methods 5 different microorganisms were chosen for the study in order to cover all the most common families of microbes: Candida albicans; Escherichia coli; Bacillus subtilis; Staphylococcus aureus; Pseudomonas aeruginosa. Different concentrations of each organism (from 107 CFU/ml to 0.5 CFU/ml) were subjected to UV radiation for different exposure times. The plates were located inside the APOTECAchemo compounding room, using the robot’s UV equipment. The KR (logarithmic ratio of the concentration of microorganisms after and before irradiation) was plotted against the exposure time in order to chart the inactivation curves. Results With a four-hour exposure, the UV irradiation kills all microorganisms at the highest concentrations. The location of the plates inside the system showed only a slight effect on the killing rate, probably thanks to the mirror effect of the stainless steel surfaces. Bacillus subtilis confirmed the strongest UV resistance, indeed 4-hour exposure was necessary to kill 107 CFU/ml. The least resistant microorganism was Escherichia coli, which required 2 hours of UV irradiation. Conclusions UV radiation is a fundamental step in the sterilisation of workplaces. In fact, 4-hour exposure showed an effective sterilisation (KR No conflict of interest.

Background Errors in cytotoxic drug compounding can cause serious harm to patients due to the low therapeutic ratio. Robots are intended to decrease the risk of medication errors through 100% verification and traceability of the entire production process. Purpose This work is aimed at assessing the risk of medication errors in manual and automated compounding, taking into consideration the procedures and controls applied in both cases. Materials and Methods The FMECA technique was applied to the procedures for the manual compounding defined in the Recommendations of the Italian Ministry of Health and to the compounding procedures of the APOTECAchemo robot. The analysis involved two Oncology Pharmacies working with automation in the daily routine since 2007 and 2011 respectively. 5 macro-failure modes for the compounding process were identified and the corresponding Priority Risk Indexes (PRIs) were calculated. Results The failure modes that show higher benefits in risk mitigation are the wrong drug and wrong dosage with a PRI decrease of 80% (from 50 to 10). Indeed the redundant controls (vision system, scale, photocells) on the loaded vials guarantee the compounding of the right drug. In addition, the drug is dosed with a calibrated syringe pump and independently verified with the scale. The other failure modes reported a risk reduction of 50% and on the whole the total PRI passes from 186 in case of the manual activity to 63 for the robotic one. Conclusions The FMECA analysis shows an overall reduction of the PRIs of over 66% with the robotic compounding with respect to the manual production. Automation not only decreases the occurrence of dangerous events thanks to the complete control of every single step of the compounding process, but also develops an error detection system through independent verification processes. No conflict of interest.

Background The pharmacy laboratory of oncology drugs compounding of the University Hospital of Ancona runs about 20000 preparations per year. Thanks to the collaboration with Loccioni Group, the process of work automatisation started in 2007 with the introduction of a first robot for chemotherapy compounding. The following years were devoted to develop and validate the system, increase the number of drugs handled and enlarge the productivity. At the end of 2009 a new generation of robotised system was introduced into the Pharmacy with the objective of setting the first totally automated laboratory by the end of 2010. Purpose To evaluate the work of the last four years. Materials and methods The 2007-2009 data are analysing by combining the APOTECAchemo database with the clinical database of the Pharmacy. Since 2010, the two database were merged into the same platform in order to make the data mining much simpler. Results The authors starting with 5 active ingredients in September 2007 and now APOTECAchemo handles 56 oncology molecules, which correspond to more than 160 different vials. The production rate of the system passed from 3400 in 2008 to 6600 in 2009 and 16300 in 2010. In the first 9 months of 2011 The authors already produced 14200 units and The authors expect to overcome 19000 preparations delivered by the end of 2011. Conclusions The automated production of the cancer therapies is a matter of fact: the percentage of work daily covered by automation was around 80% in 2010 and is about 95% at the moment (Oct 11). 100% of the therapies compounded with the robot are certified and each compounding step is fully traced. This represents also an important protection of the work under the pharmacist9s responsibility.

Background The collaboration established in 2007 between the Oncology Pharmacy of the University Hospital of Ancona and the Loccioni Group was aimed at implementing, validating and integrating the robotised system for the chemotherapic drugs compounding in the day-to-day pharmacy activity. Currently the Oncology Pharmacy is almost totally automated (95%) and Loccioni has its clinical site for the continuous engineering. During this 4-year period, the constant implementation gave rise to three generations of robot with the final version ApotecaChemo released late in 2009. The authors had the chance to experience all three generations and to validate the tough work done to increase efficiency, ergonomics and user-friendliness. Purpose The objective of this work is to analyse the performance of the third generation robot and to compare it with the previous ones. Materials and methods Data were obtained from the robot database. An other advantage of automation is related to the data mining. Every step is measured and traced, providing a huge amount of information helpful for both performance statistics and process re-organisation. In this case, The authors compared production rate and the preparation time of specific drugs in standard protocols along the years. Results The average preparation time of a fluorouracil bag of a CMF protocol halved from 303 to 156 s with the 3 rd generation robot. Similar trend is recorded for a methotrexate bag (CMF) and an epirubicin bag (FEC), whose preparation time passed from 276 to 127 s and from 565 to 253 s respectively. The improvement is even more significant for other drugs like gemcitabine, which is about 80%. Conclusions This technology has developed rapidly reaching high production rate. Nowadays, ApotecaChemo performances are comparable to those of the manual activity, with the added values of a quali-quantitative certification of each preparation compounded.

The tetrafluoborates of the primary, secondary, and tertiary ferrocenylmethyl carbenium ions have been prepared from the corresponding carbinols in ethyl ether, tetrahydrofuran and t-butyl methyl ether by adding HBF 4 . The NMR spectra of these salts, which dissolve in CDCl 3 , are characterized by the presence of very strong signals attributed to the ether used in the preparation, the solubility depending upon the structure of the cation and that of the ether. The NMR data suggest that α-ferrocenylcarbenium ions undergo two distinct types of solvation with ether-like donor molecules: one involves a much stronger interaction than the other.

ACTH and beta-endorphin have been evaluated by means of a specific and sensitive radioimmunoassay in athletes reaching a status of physical stress. A concomitant marked increase of these 2 peptides has been recorded. The implications of this finding lead to the conclusion that stress stimulates the synthesis of the common precursor (31 K) in the pituitary.

The influence on plasma ACTH and cortisol and on blood sugar have been evaluated in seven volunteers after single oral doses of prednisone 4 mg and 8 mg and deflazacort 5 mg and 10 mg. Drugs were administered at midnight to achieve a maximum inhibitory effect on the hypothalamic-pituitary-adrenal axis. No difference was detected in the majority of cases between the high and the low dose of each drug. In particular, the results obtained with the higher doses show a significant effect of both drugs on ACTH (at hour 4 after drug administration) and on cortisol (at hours 4, 8, 12 and 16). As for blood sugar, the hyperglycemic activity of deflazacort appears to be lower than prednisone at hours 12 and 16. On the whole, the potency of deflazacort appears similar to that of prednisone.

Metabolic Clearance Rate (MCR) and half life of 125I Human Growth Hormone (HGH) have been studied in hepatopathic patients. A clear reduction of MCR and a prolongation of HGH half life have been found in all patients examined. After a 30 day therapy with crude liver extract (F.U. VIII ed.) both MCR and HGH half life have shown a tendency towards normalization. These findings are in agreement with the marked improvement of the clinical state of the patients and with the normalization of the laboratory indexes.

In a man with a pituitary prolactin-secreting adenoma almost only double spermatozoa were produced. These cells were almost completely enveloped in a unique membrane, a common bilocular acrosome capped two paired nuclei, and all the other organelles were double. After 120 days of treatment with 2-brom-α-ergocryptine the prolactin level was corrected, and only normal, single spermatozoa were produced. The authors suggest that a high prolactin level inhibits cell division.

The case of a 23-year-old man with a pituitary prolactin secreting adenoma is described. With the exception of prolactin all endocrinological parameters were normal. This finding provided an ideal opportunity to assess the role of prolactin on spermatogenesis. Sperm analysis and light microscopy examination of testicular biopsy showed normal spermatogenesis. Electron microscopic studies of the testicular specimen revealed the presence of undivided spermatids, containing two or more nuclei, partially embedded in a developing common acrosome. Morphological studies demonstrated a constant “paired” situation. In most instances two sperms were contained in a single membrane; no single sperm was detected. Following treatment with 5 mg/day bromocriptine prolactin levels decreased and this peculiar abnormality disappeared. In fact, after 2 months of treatment the sperm abnormalities were markedly reduced, whereas no change was found after a period of 120 days. Since this was the only alteration found in the patient with high prolactin levels, a correlation was sought between prolactin levels and cell division. Considering the similarities between prolactin and growth hormone, it might be possible to attribute to prolactin a growth hormone role in the germinal epithelium. This action could be either direct or indirect via an intermediate growth factor.

The problem of the generation of growth factors (somatomedins) (SM) is at present a matter of investigation. The liver has been proposed as the primary site of production of SM. In order to verify this hypothesis, SM activity has been assayed in patients with impairment of liver function. The subjects have been divided into three groups according to the severity of the hepatic damage, assessed with conventional diagnostic tests. In every group, somatomedin A (ASM) has been assayed by means of a biological procedure, in basal conditions and after treatment with a liver extract. The results show that the ASM activity is reduced in proportion to the degree of hepatic damage. The administration of liver extract restores the production of the ASM in the first two groups of patients, i.e. in those with mild and moderate hepatic involvement.

Dispersible single-walled carbon nanotubes grafted with poly(4-vinylpyr- idine), SWNT-PVP, were tested in coordination assays with zinc tetraphenylpor- phyrin (ZnP). Kinetic and spectroscopic evidence corroborates the successful for- mation of a SWNT-PVP·ZnP nanohybrid. Within this SWNT-PVP·ZnP nanohy- brid, static electron-transfer quenching (2.0 � 0.1) = 10 9 s � 1 converts the photoexcit- ed-ZnP chromophore into a radical-ion-pair state with a microsecond lifetime, namely one-electron oxidized-ZnP and reduced-SWNT.

The electronic properties of functionalised single and multi wall carbon nanotubes (SWNTs and MWNTs, respectively) were investigated in depth by conventional electrochemical techniques in solution. Significant differences were observed between these two classes of carbon nanotubes. In fact, despite functionalisation strongly modified the electronic properties of carbon nanotubes, the enrichment of the density of states of MWNTs with respect to SWNTs, due to larger tube diameters, is still appreciated. In addition, the redox behaviour of the MWNTs shows a series of discrete single electron-transfer events (a coulomb staircase), which are undetected in the case of SWNTs. This quantised capacitance charging phenomena is analogous to that observed for other nanosystems which is attributed to the discrete charging of conducting core, coated with a dielectric film in an electrolyte solution.