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Author(s)

Clara Estaún-Martínez, Catalina Perelló-Alomar, Ángela Bueno, Naiara Tellería, Olga Delgado-Sánchez

Why was it done?

Automated compounding emerges as an alternative for manual compounding, making possible the centralisation of standardised compounded medications in hospital pharmacy aseptic services at a larger scale. This provides sterile, high-quality, safe, traceable ready to administer products to clinical units. Additionally, it could free up nursing time for patient care instead of performing pharmaceutical work.

What was done?

We evaluated productivity, dose accuracy and environmental monitoring of KIRO Fill®, a robotic compounding system (RCS). We also assessed the microbiological results of the sterility tests performed.

How was it done?

We implemented a RCS equipped with ISO 5 aseptic environment, horizontal airflow with HEPA filters and continuous monitoring of: air flow operation, non-viable particle counts (limits for ISO Class 5 are 0.5μm and larger size: not more than 3.520 particles/m3, and 5μm and larger size: not more than 20 particles/m3) and temperature (not more than 25°C). Two automated units work in parallel handling transfer syringes to withdraw solutions from source containers (SC) and fill final containers (syringes or infusion bags) via Luer Lock connections. This technology allows barcode/data matrix verification of source and final containers used and RFID for in-process tracking. An integrated scale is responsible for gravimetric control of the compounded preparations within an acceptable ± 5% error range. Gri-Fill® filling system was used for the preparation of SC.
Drug verification was assured through drug workflow management system and datamatrix verification in RCS.
We performed sterility test of all batches and physicochemical stability studies were developed when not available in the literature.

What has been achieved?

Between January 2022 and September 2022, we have prepared with RCS 2.813 syringes of norepinephrine (base) 0,2 mg/ml in normal saline for critical care unit syringe pumps and 395 morphine hydrochloride 1mg/ml normal saline 250 ml infusion bags for patient-controlled analgesia (PCA) administered in the surgical area.
The average dose accuracy errors for syringes and infusion bags were 0.23% and –0.09%, respectively. Environmental monitoring results and temperature controls met our standards at all times.
Results from sterility tests demonstrated the absence of microbial growth in all tested preparations

What next?

Overall satisfactory results when compounding sterile preparations using KIRO Fill and the positive feedback received from nurses in clinical units, have led us to incorporate new batches, such as morphine syringes for critical care unit syringe pumps, to the production with the RCS. Stability studies are currently being performed for this purpose.

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Author(s)

Louise Rasmussen Duckert, Marianne Kjettrup Jensen, Mette Lethan, Trine Schnor

Why was it done?

The hospital pharmacy wishes to support the implementation of OPAT and during the process the need for standardised kits with utensils was identified. The availability of kits with necessary utensils for aseptic handling of parenteral infusion would simplify and standardise the work for hospital and home nurses. Considerations regarding patient safety and sustainability were also in favour of the kits, as choice of utensils could secure compliance to regional guidelines considering use of closed systems and rinse of the line after infusion. Kits containing the exact needed utensils for an administration also reduces the possible waste.

What was done?

The hospital pharmacy has composed standard kits with utensils for outpatient parenteral antibiotic therapy (OPAT).

How was it done?

The kit is composed in collaboration between the pharmacy, hospital nurses and home nurses. The best suited infusion set was chosen – a closed system with two spikes for antibiotic mixing and infusion. Hereby nurses avoid direct contact with antibiotics and avoid antibiotic aerosols in the citizen’s home. The infusion set contains no PVC, phthalates or latex. When fully emptied the infusion set can be discarded as regular waste.
The kit also contains a sterile cover for the workstation, sterile ethanol swabs, gloves, pre-filled saline syringes for rinse of the line after infusion and a written manual. All is packed and labelled by the hospital pharmacy and lot numbers are registered for traceability.

What has been achieved?

The kits have been tested in selected municipalities and the content of the kit has been adjusted. As a result of the feedback a film has been recorded showing the handling of the infusion set. The video is used for training and a QR code on the written manual guides the home nurse to the video if needed. The kit is now used widely in the region and response is positive. With the set-up being identical in all municipalities in the region, handling antibiotics and utensils is simpler for the hospital nurse at discharge.

What next?

As the number of patients in home-based OPAT rises, experiences with the kits will probably result in wishes for adjustments. A new kit with utensils for changing PVK is under development.

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Author(s)

Chloé JADOUL, Audrey DURAND, Rémy TORDJEMAN, Isabelle MADELAINE, Romain de JORNA

Why was it done?

With the development of advanced therapy medicinal products (ATMPs), a specific pharmaceutical process is necessary to secure the handling of genetically modified organisms. Gene therapy includes Chimeric Antigen Receptor T (CAR-T) cell therapy as well as clinical trials with oncolytic viruses and nucleic acids. Limited experience on these new activities and high staff turnover based on resident pharmacist explain the need of additional training material to supplement written procedures. Multimedia support seems to be the most appropriate didactic tool.

What was done?

The objective of this work is to create pedagogical tools as short video clips. The final aim is to standardise hands-on training in order to improve ATMPs circuit safety.

How was it done?

All steps of each activity were listed and filmed in order to create a video database. Clinical trial mock preparations were performed to create the clinical trial tutorials whereas CAR-T cell activities were filmed in real conditions.
Clipchamp (Microsoft) video editing software is used to create tutorial videos. Repetitive parts were edited once and reused for other videos. They are part of the database videos.
As a validation, all staff members’ approbation was required.

What has been achieved?

Activities include, to this day, five gene therapy clinical trials and the CAR-T cell activities: reception, shipment to the pharmaceutical hub, thawing and distribution.
We filmed 55 step clips and edited six repetitive parts. Finally, eight tutorial videos were created: three for clinical trials and four for different CAR-T cell activities.

To make the training more meaningful, we made dynamic videos that last no more than 5 minutes. The average time of a tutorial was 2 minutes 17 seconds.

What next?

The tutorial videos bank is created to be dynamic and can be easily adjusted. Videos of repetitive parts will be reused for new clinical trials implementation. These video tutorials allow new resident, student or technicians to be trained faster and in a more innovative way. They also allow permanent teams to benefit from a quick refresh. In order to assess the efficiency of this new process, next operators will have to read the procedure, watch the videos and will be evaluated in practice.

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Author(s)

Peder Nygard, Helle-Brit Fiebrich-Westra, Elise Smolders

Why was it done?

The aim of this project was to reduce paclitaxel waste caused by cancellation of administrations. Standardised dose bands make interchangeability of already reconstituted paclitaxel bags easier, as more patients use the same dose. This could potentially save drug- and material waste and costs even as manpower.

What was done?

Paclitaxel fixed dose bands were created for patients treated with a weekly dose of 80 mg/m2.

How was it done?

In consultation with prescribers the dose bands for paclitaxel where created (see table). These dosages were implemented as a dose-rounding rules in the drug preparation software (Hix 6.2, ChipSoft BV). The maximum deviation for dose-rounding rules for paclitaxel in our hospital is 10% of the prescribed dose. Dosage ≤72mg or >200mg were rounded as normal.

Prescribed dose (mg) Dose-band (mg) m2 (dose 80 mg/m2
>72 ≤88 78 1.0
>88 ≤102 96 1.2
>102 ≤116 114 1.4
>116 ≤136 126 1.6
>136 ≤152 144 1.8
>152 ≤168 162 2.0
>168 ≤184 174 2.2
>184 ≤200 192 2.4

What has been achieved?

These rules were implemented in April 2022. Data from 1 May 2022 to 31 August 2022 is compared with the same time period in 2021. In 2022, a total of 729 infusions where prepared compared with 872 infusions in 2021.
In this 4 month time period in 2022 a total of 14 different dosages were prescribed, compared with 24 in the same time period in 2021. Additionally, interchangeability was improved as the top 3 dosages prepared by the pharmacy were: 144 mg (36%), 162 mg (22%), and 126 mg (19%) compared with 144 mg (17%), 138 mg (14%), and 126 mg (10%) in 2021.
Furthermore, in 2021 we discarded 33 prepared dosages of paclitaxel of which three infusions could be reused. Compared to 13 discarded dosages in 2022 of which eight were reused giving a reduction of 25 infusions less waste (83% reduction, savings ~2500 euros).

What next?

Pharmacists need to be instructed to adapt these rounding rules, which must decrease the variation in dosages and thus waste. Secondly, this project will be monitored the upcoming year and evaluated together with prescribers. The aim is to implement dose bands for paclitaxel dosages 175 mg/m2 and other chemotherapeutic drugs (eg, oxaliplatin, docetaxel, cyclophosphamide).

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Author(s)

Caterina Donati, Giulia Moroni, Matteo Federici , Paolo Silimbani

Why was it done?

To evaluate the performances of automated preparation in the oncology pharmacy by assessing productivity, errors interception, and waste reduction achieved by managing vials overfill.

What was done?

Automated preparation, operated by two robots and one gravimetric-assisted workflow system, was introduced to improve productivity and working efficiency [1,2], while reducing the risk of human errors. Furthermore, to optimize resources utilization and reduce waste, a procedure for managing overfill of drug vials during automated preparations was implemented. Indeed, manufacturers fill injectable drug vials with a volume that slightly exceeds the nominal volume (overfill) to ensure proper withdrawing and patient dosing.

How was it done?

The annual throughput in terms of preparations was calculated for automated and manual preparation. Human errors intercepted during automated preparation were clustered into four groups: loading of wrong component (i.e. final container, solvent, drug product), multiple barcodes reading, failed manual reconstitution, wrong expiration date. Overfill was calculated for 17 high-cost drug vials by volumetric verifications performed by experienced pharmacy technicians. The annual number of vials used and the corresponding waste reduction due to the overfill management was determined. All data were taken from the production management software and examined over a two-year period (2019-2020).

What has been achieved?

In total, 82,216 preparations were compounded over two years, 72% of which with robotic systems and 28% manually prepared, either with gravimetric-assisted workflow (13%) or conventional volumetric technique (15%). Overall, automated preparation covered 85% of the total production. The human errors intercepted during automated preparation amounted to 701 in 2019 and 662 in 2020. Most errors were intercepted by robotic systems and were related to loading of wrong component (83%). Vials overfill ranged from 0.2mL (ramucirumab, eribulin, trastuzumab-emtansine, pembrolizumab, nivolumab) to 2.5mL (ipilimumab). The total waste reduction due to overfill management resulted in 1331 vials saved corresponding to 855,013€.

What next?

The study showed that automated preparation of oncology products represents a well-established practice in terms of productivity, and moreover ensuring interception of potential medication errors and waste reduction thanks to the overfill management

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Why was it done?

Different automated production systems (APS) are now available on the market. It is essential not to make a mistake due to the impact on the organization, investments and architecture. Comparative tables of each equipment are not enough to properly make a good choice.

What was done?

We determined a decision tree to choose the most suitable equipment for the cytotoxic drugs production unit.

How was it done?

Based on our experience of using APS and interviews or visits of other users of the equipment, we have compared the different systems by classifying them according to the items that are the most efficient: productivity, precision, diversity of preparations and drugs, installation constraints, autonomy, maintenance of sterility of preparations, chemical contamination. We also used a French calculator, published by the ARS IDF, to determine the cost of a preparation, taking into account the purchase price, personnel, consumables, maintenance, personnel equipment, and operating costs. Then we defined our present and future needs (dose banding, nominative advance preparation, type and quantity of preparation (infusers, syringes, bags), architectural and air treatment constraints. Then we classified the needs and constraints by importance and then determined for each one which equipment was the best answer.

What has been achieved?

We classified the needs and constraints by importance and for each one we determined which equipment was the best answer. From most important to least we had: headroom, floor load, air handling, dose banding, sterility maintenance, productivity, autonomy and calculated price of the preparation. The results for preparation price showed that the highest price per preparation is not the most expensive equipment but one of the cheapest because of the very expensive captive consumables. Unexpectedly, the most expensive equipment has an average price per preparation because it is very productive, autonomous and has few captive consumables. To validate this tree, we applied it to another cytotoxic production unit.

What next?

Using this decision tree, the choice of equipment will be the most suitably adapted for each hospital.

Author(s)

Emma Pinet, Lionel Barty, Anne Blandine Bouvrain, Françoise Le Cheviller, Nicolas Vaillant, Nathalie Jourdan, Hélène Sauvageon, Isabelle Madelaine

Why was it done?

In order to make hospital preparations in advance and optimize costs, a physicochemical and biological stability study was conducted in the pharmaceutical control laboratory.

What was done?

Mogamulizumab is a monoclonal antibody used in the treatment of Sezary syndrome and mycosis fungoides. The dilution of the 4 mg/ml vial of Poteligeo® in the infusion bag is stable for 24 hours at room temperature between 0.1 to 3 mg/ml.

How was it done?

Four bags of mogamulizumab were prepared in 0.9% NaCl 250 ml (2 at 0.14 mg/ml, 2 at 0.34 mg/ml). Each dilution is evaluated at 20±5°C and at 5±3°C, protected from light for 28 days. Analyses are performed in triplicate by High Performance Liquid Chromatography (HPLC-UV) associated with Chromeleon™ software. Concentrations are measured by HPLC after Flow Injection Analysis (FIA). Physical stability is studied by searching for IgG aggregates by Steric Exclusion Chromatography (Biozen™SEC3 column, 1.8µm 300*4.6mm). Chemical stability is evaluated by assessing acidic and basic variants proportions of the antibody by Cation Exchange Chromatography (CEC) (Biozen™WCX column, 6µm 250*4.6mm). Biological activity is determined by evaluation of the different glycoforms, by affinity chromatography (FcyRIIIa column, 5µm 75*4.6mm Tosoh®). The microbiological stability is performed by seeding the diluted solution on chocolate agar and brain heart broth.

What has been achieved?

At D28, the quantitative determination of mogamulizumab by FIA showed a deviation of less than 10% compared to theoretical concentrations. No aggregates or antibody fragments were found. The proportion of acidic, basic variants and of the main peak did not deviate by more than 5% compared to D0. For all infusion-bags studied by CEC, the main peak rates were between 79.1% and 85.8%, the acidic variant rates between 6.7% and 9.9% and the basic variant rates between 7.8% and 11.2%. The proportion of each antibody species (low, medium, high affinity) did not deviate by 5% from D0. The low affinity rate is between 48.2% and 52.7%, medium between 39.6% and 44.8% and high between 6.9% and 7.9%. No colonies were found on chocolate agar and heart-brain broth.

What next?

Mogamulizumab is physically, chemically and biologically stable for 28 days in diluted solution between 0.14 mg/L and 0.41 mg/L at 5°C and 20°C.

Author(s)

Lucia Ricchi, Gregorio Medici, Porretta Serapiglia Carla, Marzia Bacchelli, Marianna Rivasi

Why was it done?

Hazardous drugs (HDs) may include antineoplastic or cytotoxic agents, biologic agents, antiviral agents, immunosuppressive agents, and drugs from other classes. Healthcare workers, especially nurses and pharmacy personnel, experience occupational exposure to these HDs.
Preparation and administration of ganciclovir should only be performed by health professionals who have been appropriately educated and trained and deemed competent in its use. Until now the preparation of ganciclovir was performed by the pharmacy’s antiblastic drugs unit. However, during closing times, kits for the self-preparation (antiblastic gloves and gowns, FFP3 masks, eye protections and brief instructions for reconstitution) were provided.
Many strategies have been deployed to reduce the risk of occupational exposure to HDs, including control devices designed to act as closed systems and preventing exposure through liquid or vapor leakage. These devices mechanically prohibit the escape of HDs from the system and can be used for preparing and administering these drugs.

What was done?

Some of the intensive care units of our hospital have been enabled to prepare their own ganciclovir bags by using a closed system drug transfer device (CSTDs).

How was it done?

Each nurse involved was instructed by hospital pharmacists on how to handle CSTDs. In addition to this they were also given a short video and an infographic showing the main operations to be carried out.
Ganciclovir bags are prepared using the Tevadaptor® (Simplivia), in a needleless technique, by combination of the Vial adaptor, the Syringe adaptor, the Spike port adaptor and a connector closed male (Spiros, ICU).

What has been achieved?

Use of CSTDs is a simple and effective way to reduce exposure to HDs, provide better protection, better aseptic technique and better containment of waste than the traditional method, as well as allows the preparation of HDs to be carried out outside the antineoplastic drug unit.

What next?

In the future their use could also be extended to the preparation of monoclonal antibodies and antibiotics considering that there is not enough definitive research on the effects of occupational exposure to these agents. And, to date, there is no known safe maximum level of exposure to these drugs.

Author(s)

Quentin Misandeau, Romain Bosc, Muriel Paul, Valérie Archer, Lionel Tortolano

Why was it done?

The plastic surgery department bought two 3D printers in order to design and create custom-made medical devices. The main objective was to decrease the delay between mandibular cancer diagnosis and the surgery. The delays of production in the medical device manufacturers may exceed 2 weeks. Those delays are considered as a lost of chance for the patients.

What was done?

We helped our surgeons to secured the production procedure and reduce the risks for patients. We create a management quality system for supply, production, sterilization and using of our homemade personalized 3D printed guides.

How was it done?

First, we created a task force of pharmacist and surgeons.
The main work was a risk analysis with the FMECA method for all the steps in the procedure (software, tools, actors and materials).

What has been achieved?

Some correctives actions were taken. The riskier points were the plastic materials toxicity risk, the sterilization procedure that has been validated and the production traceability. A biocompatibility evaluation was performed. A clinical evaluation has been initiated in the same period.

What next?

Since the new medical device regulatory (2017 /745 CE) was published in 2017, the article five, that regulate the 3D printing in hospital, changes the possibilities. In fact, as personalized 3D printed guides are available on the EU market, homemade personalized 3D printed guides for mandibular reconstruction could be not authorized anymore. The only way would be for the hospital to obtain the regulatory statut of manufacturer and comply with the essential requirements.

Author(s)

Alessandro D’Arpino, Fiorenza Enrico, Caterina Donati, Simone Leoni, Giorgia Longobardo, Marco Bellero, Alessandra Bianco, Giuseppe Zacchi, Anna Zaltieri, Stefano Monica, Nicolò Squartini, Matteo Federici

Why was it done?

In most of Italian healthcare organizations, the large majority of non-cytotoxic IV medications are prepared in clinical environment by nursing staff. This is recognized as a complex and labour-intensive process that entails various risks of potential medication errors (microbial contamination, wrong reconstitution/dosing). Centralizing the preparation from the clinical environment to the pharmacy in order to provide ready-to-administer IV medications represents a strategy to improve safety and prevent medication errors.

What was done?

The community of APOTECA technology users is committed to fostering co-de¬sign of technology based on the hospitals’ needs and sharing best practices for improving hospital pharmacy services. During a meeting taken place in September 2021, a panel of hospital pharmacists belonging to APOTECA community laid the groundwork for centralized preparation of non-cytotoxic intravenous (IV) drugs and establishment of Central Intravenous Additive Service (CIVAS) in Italian hospital pharmacies.

How was it done?

The following methodology was adopted to promote a standard profile of centralization: (1) definition of criteria for the selection of drugs suitable for centralized preparation, (2) identification of IV medication classes for which preparation should be centralized due to intrinsic risks and demand, (3) evaluation of potential benefits, (4) discussion on organizational challenges regarding the establishment of CIVAS, (5) assessment of the role of automated preparation with robotics.

What has been achieved?

Five selection criteria to centralize drugs were mentioned: long-term stability data, frequency of use, cost, complexity of preparation, microbial contamination risk. Continuous infusion of antibiotics, vasoactive drugs, anaesthetics, pain medications, intravitreal injections, and patient-individual doses for paediatric patients were chosen as eligible IV medication classes to implement centralized preparation. Major benefits of centralization were pointed out, i.e. proper aseptic preparation, perspective quality controls, process traceability, reduced drug wastage, and releasing nursing time to care. Logistics, inventory management, limited space, and inadequate quality control units were identified as main challenges to the CIVAS establishment. Participants agreed that robotics plays an important role to minimize repetitive manual activities, optimize working efficiency, and increase pharmacy production capacity, thereby streamlining the introduction of CIVAS.

What next?

A close collaboration between healthcare staff and hospital pharmacy will be essential to evaluate the feasibility of centralized preparation as well as its clinical and cost-effectiveness.