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Operational interventions to improve the performance of cytotoxic medicines compounding

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European Statement

Production and Compounding

Author(s)

Leila Costa, Rui Marques, Ana Castro, João Paulo Cruz

Why was it done?

Cytotoxic medicines are drugs used mainly in the treatment of neoplasms. Their preparation is a key activity of Hospital Pharmacy, carried out in a Class II Type B2 Vertical Flow Chamber (VFC). With the emergence of new cytotoxic drugs, the increase in the number of patients (2100 in 2010 to 3168 in 2021), and preparations (from 30000 in 2010 to 40000 in 2021), the time spent by Pharmacists in routine work and in the organisation and research of information also increased, and innovative approaches in terms of resources optimisation are deemed.

What was done?

Evaluate the performance of cytotoxic compounding after the implementation of relevant operational interventions designed to optimise drug preparation and delivery, between 2018 and 2021 in a University Hospital Centre.
Retrospective analysis of the average waiting times of patients for treatment delivery in some day hospitals (DH), after implementation of the operational interventions.

How was it done?

We began with the computerisation of the chemotherapy protocols, in order to standardise the prescribed treatments, which allows to reduce transcription and prescription time and associated errors. A comprehensive database was also created with the main characteristics of cytotoxic drugs and their physicochemical stability, in order to support pharmaceutical validation. In partnership with DH nursing team, every patient’s treatment schedule was determined beforehand, which allowed an enhanced organisational workflow, and the grouping of more complex drugs to prepare at the same time, and the preparation of drugs with adequate stability in the day before. This resulted in a reduction of average waiting times from 2 hours to only 30 minutes. The DH that benefited the most from these changes was Haematology, which adopted all proposed changes from the start after a multidisciplinary team meeting. Currently, about 45% of treatments are prepared the day before. Since the compounding unit is structured in rotating shifts, this practice allows to minimise drug wastage and to reduce preparation time, which improves the organisational capacity and agility in response to patient needs. When available, preference was given to ready-to-use drug solutions instead of powder formulations, e.g. pemetrexed and bortezomib, reducing preparation time and increasing operator safety. Also, in Gastroenterology DH, we promoted switch from original infliximab to its biosimilar by centrally preparing the biosimilar. We used two pharmacy technicians in the same cabinet instead of one, increasing the preparation yield. The last intervention was in the transportation of the compounded preparations, through the implementation of the delivery of treatments via a pneumatic tube system. This system ensures the integrity of the material and the conformity of the transport, thus allowing the safety and stability of the material transported, without bumps and avoiding changes in physical properties. It was possible to obtain a higher frequency of transportation and better workflow at peak times.

What has been achieved?

With the same human resources and the operational changes described, it was possible to improve the compounding unit performance, and to reduce patient waiting times in 75%, saving time and money.

What next?

With the increasing number of patients and cytotoxic preparations, it was necessary to reorganise the compounding unit in several key features.

Physicochemical and biological stability study of mogamulizumab in diluted solution

European Statement

Production and Compounding

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.

How to become a resilient chemotherapy preparation unit?

European Statement

Patient Safety and Quality Assurance

Author(s)

Victorine MOUCHEL, Romy LINOSSIER, Chloé FERCOCQ, Jean-Luc PONS, Lucie BAILLET

Why was it done?

Injectable anti-cancer drugs are critical drugs and production disruption would result in discontinuity of care. Moreover, 60% of the production is dedicated to external clients as part of outsourcing contracts. To strengthen client’s confidence, we achieved the ISO 9001 certification in 2019. Implementing a BCMS is part of the overall quality and resilience process.

What was done?

In our hospital centre, production of injectable anti-cancer drugs is centralised in a chemotherapy preparation unit. Within the unit, we decided to implement a business continuity management system (BCMS). Therefore, we established and validated a business continuity plan (BCP) to face a production disruption and continue the delivery of products.

How was it done?

We followed the ISO 22301:2019 standard methodology. First, we performed the risk assessment as described by the ISO 22300: 2018 standard. A multidisciplinary working group (pharmacists, pharmacy technician, quality engineer) identified and analysed the risks likely to threaten the unit’s business continuity (BC). Risks were rated in term of criticality (Cr) from 1 to 4 and risks with Cr ≥ 3 were considered as priority risks. Then, a business impact analysis was led by the pharmacists and validated by the department chief. Strategies were set to face priority risks in accordance with the BC objectives. Finally, we documented the BCP and validated it thanks to tests followed by debriefing.

What has been achieved?

The risk assessment highlighted 23 risks and 13 of them (57%) were rated as priority risks. Most of the risks revolve around unavailability of production equipment or premises (fire, flood, natural disaster). The treatment of 7 of these risks was included in the action plan for 2021. Three strategies were documented to treat these risks: extended opening hours of the unit, closed system transfer device used in a contaminated isolator and production relocation in two other centres. Five tests were conducted to check necessary procedures and devices to use these strategies (closed system transfer device, remote access, transportation). Tests will be repeated yearly to maintain the BCP.

What next?

In conclusion, implementing a BCMS represents a continual improvement approach that will improve the unit’s ability to cope with a crisis in an appropriate way.

Standard Operating Procedures for urgent chemotherapy mixture preparation by non-experienced staff

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European Statement

Production and Compounding

Author(s)

Ana Marín-Romero , Inés Monge-Escartín , Esther Carcelero-San Martín , Gisela Riu-Viladoms , Rubén González-García, Jaume Planas-López , Dolores Merino-Calderón , Rodolfo Juncos-Pereira , Carolina Lesta-Domene , Carmen López-Cabezas, Dolors Soy

Why was it done?

Cytostatics are hazardous drugs that must be prepared under safe and sterile conditions. In some life-threatening situations, there is an urgent need to initiate chemotherapy immediately. However, not all hospitals have experienced personnel in safe-handling cytotoxic drugs for 24 hours and 7 days per week.
The objective is to create a consensual protocol to be used when immediate start of chemotherapy is required, and preparation must be done out of working hours of specialized pharmacy staff. A secondary objective is to confirm that non-experienced staff can prepare cytostatics safely and to guarantee their quality by following this protocol.

What was done?

The oncohematology pharmacy team created a visual guide aimed to pharmacy personnel who do not routinely work with intravenous mixture preparations. This guide includes instructions about parenteral cytotoxic drug preparation for chemotherapy regimens that should be immediately initiated.

How was it done?

Urgent regimens were agreed with clinicians. They are: (i) fixed-dose intrapericardial cisplatin, (ii) intravenous carboplatin and etoposide, (iii) intravenous cisplatin and etoposide, (iv) intravenous cyclophoshamide and (v) fixed-dose intravenous daunorubicin. For schemes with different possible doses, fixed banding doses were agreed with clinicians.
A visual guide with images of all the material and preparation steps (including labelling, packaging and protection measures), for each scheme, was developed and attached to a prescription form to be completed by the physician and associated with a material kit that contained personal protective equipment, expendable material, cytostatic vials and serum bags.
The guide was distributed to pharmacy personnel external to preparation area, accompanied by a training session. Selected trained workers were supervised while preparing the mentioned cytostatic drugs in a simulated-base patient scenario.

What has been achieved?

All the cytostatic drugs were prepared correctly reaching a maximum preparation time of 45 minutes since physician’s prescription. The personnel involved maintained all the specified protection measures and reported feeling confident while cytostatic manipulation.
The guide proved to be useful to cover a possible urgent chemotherapy treatment outside the stipulated work schedule.

What next?

Re-training in safe-handling of cytotoxic drugs should be ongoing with regular updates to ensure a proper follow-up of this guide. This work methodology could be extrapolated to other pharmacy areas with similar needs.

BEST PRACTICES FOR THE IMPLEMENTATION AND USE OF THE APOTECACHEMO TECHNOLOGY AGREED BY THE GERMAN HOSPITAL PHARMACY USER GROUP

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European Statement

Production and Compounding

Author(s)

Bastian Mende, Irene Krämer, Jannik Almasi, Christoph Klaas, Bernhard Rainer Kujau, Swantje Eisend, Herwig Heindl, Jacopo Raffaelli, Jochen Schnurrer

Why was it done?

During a two-day meeting in September 2018, the German community of APOTECAchemo users and technology experts developed Best Practices for the optimal implementation and subsequent application of APOTECAchemo technology in pharmacy based aseptic preparation of ready-to-administer antineoplastic medicinal products.

What was done?

Robotic systems, designed for the aseptic preparation of ready-to-administer parenterals in hospital pharmacies, should facilitate a fully integrated workflow and a process organization interconnecting the automated and manual preparation. Despite some differences between the hospital pharmacies, the definition of standards and Best Practices for the automated compounding of cytotoxic preparations facilitates the implementation of the technology in different hospital pharmacies.

How was it done?

Prior to the meeting of the user group a survey with 24 statements for the implementation and use of the APOTECAchemo technology was sent to the German APOTECAchemo users. The 24 Best Practices were assigned to 4 categories: Workflow & Organization, Production, Roles & Responsibilities and Quality & Process Control. The survey participants evaluated the proposed Best Practices in view of the practicability in German hospital pharmacies. During the meeting, results of the survey were consented or adapted and additional best practices were defined.

What has been achieved?

The German user group defined the Best practices for the implementation and use of APOTECAchemo technology. The most relevant result for each of the four categories is:
• Workflow and Organisation: The automated preparation should reduce the daily workload of manual preparation and minimize potential errors.
• Production: Optimum interconnection between technicians and the robot will increase the efficiency.
• Role and responsibilities: Pharmacists are responsible for the design of the automated production workflow, while technicians become the manager of the automated compounding process
• Quality & Process Control: Microbiological controls must be performed during manual and automated production

What next?

The best practices defined by the German APOTECAchemo Community support experienced users and are especially useful for hospital pharmacies newly implementing the technology.

ALGORITHM OF SAFE AND CORRECT PREPARATION OF CHEMOTHERAPY (submitted in 2019)

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European Statement

Patient Safety and Quality Assurance

Author(s)

Marijana Fortuna, Petra Tavčar, Jure Dolenc, Monika Sonc

Why was it done?

To support us in understanding our role in the preparation of chemotherapy products. To prevent the risk of harm to patients. Recognise prescribed error in pre-documented chemotherapy protocols

What was done?

Cytostatics are carcinogenic, mutagenic and teratogenic drugs. Handling requires a number of organisational and technical systems. All products should be safely and accurately prepared with special care to ensure the highest possible product quality, correct dose, the right patient, the right medicine, the right carrier solutions and right administration, without microbiological and particle contamination. The prescription and preparation of cytostatic drugs must be closely monitored. The most important factor in achieving this is the constant training of pharmacists in pharmaceutical techniques.

How was it done?

This year started with monthly reviews and training in the following subjects by using a written algorithm. Risk to product: Drugs reconstitution negative pressure isolators, leakage/damage or defects of vials, particles, transport and storage. Risk to patient: Incorrect calculations, microbiological contamination, incorrect administration, extravasation, incorrect administration route, incorrect labelling. Risk to operators: Contamination, toxicity, equipment, gloves, cleaning, occupational exposure. All checks have been made throughout the whole of preparation process, adhering to standard operating procedures (SOP-s).

What has been achieved?

We concluded that continuing education by using a writhen algorithm is useful practice. It helps prevent automatic work, remind us to check each step in process and know how to recognise errors in chemotherapy prescriptions and preparation. In 25 cases of prescribed chemotherapy, intervention of a pharmacist was required. In 5 cases of chemotherapy preparation, pharmaceutical techniques have detected a discrepancy in the prescribed therapy.

What next?

Regardless of experience at work, it is necessary to constantly repeat how to work properly, and awareness why we are doing this.

IMPLEMENTING NEW CHEMOTHERAPY COMPOUNDING WORKFLOW USING SEQUENTIAL PDSA CYCLES TO INCREASE PRODUCTION CAPACITY, REDUCE WAITING TIME, IMPROVE RESOURCES UTILIZATION, AND MINIMIZE THE RISK OF ERRORS

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European Statement

Production and Compounding

Author(s)

A Elsheashaey, A Elshishiny, A Orabi, A Almutairi, A Aboulwafa, H Alobaid, F Dashti, D Saeed, R Yassin, M Salama

Why was it done?

Kuwait Cancer Control Center (KCCC) is the only oncology hospital in Kuwait. Chemotherapy Preparation Unit (CTPU) was unable to meet the increased orders; causing delivery delay and more patients’ waiting time. Moreover; rework and more waste due to defective and faulty processes of current workflow resulting in frequent incident reports of wrong final products dispatched.

What was done?

Shifting to a systematic multi-step production workflow to increase compounding capacity, minimize risk of errors, reduce processing time, and maximize utilization of integrated technological resources.

How was it done?

Using multiple PDSA cycles, a comprehensive educational and practical training was conducted, proceeded by staff rotation with newly trained team. Every three weeks a new pharmacist trained and assigned to CTPU. Raw materials stores were rearranged for better accessibility and diminishing unnecessary staff movement. A staging step as the first independent double-check before the start of compounding, and for assembly of raw materials and supplies required for compounding. A verification Step as the second independent double-check upon compounding, using bar-code scanners, touchscreens and cross-checking with the chemotherapy order to assure the quality and integrity of the finished product. Production workload were restructured over three parallel line of manual stations and one automated preparation unit. Pharmacy Information System (PIS) screens were customized to give a first and second audio-visual alarms after 30 and 45 minutes of transcription time respectively. Chemotherapy sessions appointment system were established to assess the daily chemotherapy compounding needs from CTPU in advance with an incremental increase of production capacity to reach 100~120 patients/day or 180~200 preparations/day.

What has been achieved?

Number of preparation compounded by CTPU was increase by 8%, where more than 43% of preparations were validated to release in less than 30 minutes and approximately 88% of preparations were delivered in less than 45 minutes. Number of preparation by automation was increased by 82%, Furthermore, all production incidences has been completely eliminated after full implementation of final verification and validation step.

What next?

The new workflow has increase the workload capacity with less production errors and zero incident reports. Patient experience was improved by comparable preparation time to other international Pharmacy Workload Unit and average time required per patient visit.

IMPROVING STAFF TRAINING IN A CYTOTOXICS PREPARATION UNIT

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European Statement

Production and Compounding

Author(s)

S. Sernache, H. Goncalves, A. Gouveia

Why was it done?

Improved processes were required due to new CPU facilities, PIC & acute requirements and workplace safety legislation. The training program started in 2013. Our aim was to change from an informal training to a program where minimal qualification standards were achieved despite heavy workload and budget constraints.

What was done?

Implementation of a training program for the Cytotoxics Preparation Unit (CPU) focusing on product and staff safety. Key steps were hand washing with fluorescent gel, media fill and simulated preparations with fluorescent dye. Wipe sampling of cytotoxic contamination and microbiological control were performed.

How was it done?

Absence of national experience required literature review and support from other hospital in Europe. Lack of commercial products and budget constraints led to adoption of more affordable solutions like in-place compounding of fluorescein vials, and use of standard sodium chloride IV bags for media fill. Other resources were procured externally and adapted.

We enhanced motivation with involvement of staff in the goals and open discussion of results.

What has been achieved?

All relevant staff went through the training and reached the qualification thresholds. All technicians successfully performed media fill test (no microbial growth), and fluorescein test (no dye spots counted). Hand wash results had median of 5 spots of inadequate washing. Results were discussed with staff and new session implemented afterwards. Only 9% of staff (n=33) did not improve, median of results was 1 spot . Regular microbiological monitoring results meet GMP criteria for the laminar flow cabinets, and cytotoxic contamination (8 drugs tested in 5 locations) is in line with reference values except for 5-FU storage shelf.

What next?

Training program is to be repeated yearly, as well as the monitoring processes. Despite budgetary and staff constraints, a sustainable training program can be implemented with adaptation of published sources, resulting in adhesion to good practice.

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