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Author(s)

Katrine Bødker Rubach-Larsen, Anne Rungø, Anette Eskildsen, Lone Skovhauge

Why was it done?

A research team at the MR Centre (MRC2) wished to set up the production of Pharmacy Kits, but had no prior experience of, or licence to, manufacture drugs. Thus, the hospital pharmacy was asked to participate in the development of such production.

What was done?

A new MR-scanning technology, hyperpolarisation, for the quantification of metabolic processes with an extremely high sensitivity enables physicians early detection of treatment effects in, for example, cancer and diabetes. A so-called Pharmacy Kit is used in the hyperpolarisation process and consists of a specially designed packaging with tubes, vessels and filters containing the contrast agent and buffer solutions. The objective for the hospital pharmacy1 was to manufacture Pharmacy Kits complying with Good Manufacturing Practice (GMP), though neither packaging nor two of the raw materials conformed to European standards.

How was it done?

The MRC research team presented the hospital pharmacy with the desired combination of compounds and the packaging required for Pharmacy Kit production. The task for the hospital pharmacy was then to set up a manufacturing process that met these requirements and complied with the guidelines for GMP. A production complying with GMP was developed in close collaboration with the MRC and an ongoing contact with the Danish Medicines Agency. During the process the hospital pharmacy carried out its own microbiology test in order to determine if, and for how long, the non-CE-marked packaging could store the contrast agent and buffer solutions. Risk assessment of the raw materials not found in the European Pharmacopeia were conducted. The method investigated by the MRC already takes place at a few other places in and outside of Europe. Experiences from these production sites were implemented and expanded with process optimisation, and specially designed equipment for the production.

What has been achieved?

Due to a strong inter-professional collaboration between the MRC and the hospital pharmacy and due to qualified risk assessments, it was possible to set up a production of Pharmacy Kits according to GMP.

What next?

When researchers contact hospital pharmacies with new ideas, we have to be willing to work with GMP in a different way by applying knowhow and risk assessments in order to ensure developments within the healthcare system.
1. Hospital Pharmacy Central Region, Production, Aarhus, Denmark.
2. MR Centre, Aarhus University Hospital, 8200 Aarhus N, Denmark

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Author(s)

Jemos Costantino, Martina Milani, Mariantonietta Piccoli, Mara Provenzi, Paola Paochi, Ilaria Clerici, Cinzia Lucia Ursini, Claudio Colosio, Fabrizio Mastrilli, Emanuela Omodeo Salè

Why was it done?

In outpatient setting, WT between medical visits and administration is strongly conditioned by time needed for preparation. We needed to reduce our WT caused by the use of an automated system by ensuring the same standards of quality control checks and traceability, not achievable with manual preparation.

What was done?

We introduced an assisted system for chemotherapy preparation, with a gravimetric and barcode verification. We started to switch part of preparations previously prepared by an automated system to this assisted system. We performed an analysis to measure the impact of a different strategy in preparing chemotherapy on patients WT.

How was it done?

Time needed for preparation was monitored in the first trimester of 2016, where drugs were prepared using an automated system or manually, and compared to the first trimester in 2017, when we introduced the assisted system.
In the first period we used a “WT optimization” criteria in selecting the preparing technology, while in the second period we decide to use a “risk based” criteria.
Risk based criteria consists of selecting the automated system for cytotoxics, assisted system for antibodies and low risk drugs and manual procedure when no other options are available.
In order to evaluate bias introduced by the risk based selection of different drugs, we performed a contest comparing preparation times of a defined sequence of representative preparations typologies. Three technicians are involved in order to reduce human factor impact.

What has been achieved?

Average WT (AWT) in the first period was 1h36m and median WT (MWT) was 1h22m (sample = 2365 preparations in 3 months). AWT in the second period (sample = 3437 preparations in 3 months) was 1h17m (-19,79%) and MWT 1h1m (-25,61%). The percentage of therapies dispensed after 2 hours waiting decreased by 55,69%. WT was stratified by preparation technology (assisted system: AWT =50m; MWT=44m – automated system: AWT=1h26m; MWT=1h07m).
The contest results were (average of three series) : manual preparation 15m19s; assisted 26m42s; automated 1h14m3s.

What next?

Assisted systems are able to guarantee quality standards for patients similar to automated ones, but with an important reduction in WT when compared with an automated one and an improvement in traceability compared to the manual procedure.

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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.

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Why was it done?

Individual total parenteral nutrition (TPN) for neonates was originally compounded by nursing staff on the respective wards. This process of TPN compounding was error-prone. Documentation and traceability was inadequate. Clean room conditions were absent. By transferring the compounding of TPN from the ward to the pharmacy level, several aims were accomplished. Time of nursing staff was released and the highest quality standards for compounding were implemented. By doing so, several types of errors (e.g. overdosing, wrong additives) were eliminated.

What was done?

Development and implementation of nutrition support protocols by using an electronic prescribing and compounding software (catoPAN™) to address the special needs of neonates and ensure a high level of individualized care.

How was it done?

In cooperation with neonatologists, nutrition protocols were developed. Furthermore, a TPN compounding process was implemented and validated, including the validation of catoPAN™ software and compounding pumps. An integrated risk analysis was performed, stability data to allow TPN supply for weekends were generated and fail-safe procedures were determined. To finally succeed, various process and organizational changes concerning the wards, the production and the QC department of the hospital pharmacy were required.

What has been achieved?

Compounding of individualized nutrition solutions within defined standards, predetermined specifications and quality attributes is implemented. The production process is continuously monitored, including complete traceability. A strong interprofessional collaboration between physicians, nurses and pharmacists was established, ultimately leading to a high level of confidence among all members. Workload of nurses in terms of compounding medicines was dramatically reduced.
Currently, we provide nutrition bags for four wards (24 ICU- and 30 intermediate care beds), equaling an average production of 50 bags per day. In 2016, a total of 11.126 bags were supplied, implying an increase of 75% compared to 2015. We expect an increase of around 30% in 2017 due to rising demand.

What next?

With the expansion of TPN compounding to further pediatric wards, new nutrition protocols addressing other requirements have to be developed. Process changes are likely to follow. Further support can be provided by pharmacy-based IV admixture service. Additionally, due to current software updates, the prescribing and compounding software catoPAN™ must continually be revalidated.

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Author(s)

María Lourdes Recio Blázquez, Alberto Pérez Morales

Why was it done?

It was necessary to establish a quality control of this pharmaceutical process.

What was done?

A computer method of gravimetric quality control of the tablet splitting process was designed.

How was it done?

The procedure consists on a precision scale connected to a computer in which, according to the uniformity of mass assay of the European Pharmacopoeia, the weights of 20% of a batch of whole tablets destined to be split are automatically recorded in a spreadsheet, carrying out the following formulas:
=AVERAGE: provides the average weight of the sample of whole tablets.
=MAX and =MIN: selects respectively the largest and the smallest of the weights.
=STDEV: calculates the standard deviation of the sample weights.
With the average weight of the whole tablets, the theoretical weight of the half-tablets is calculated, establishing a maximum and a minimum admissible limit with the following formulas:
=AVERAGE(whole tablets)/2: determines the theoretical average weight of each half-tablet.
=AVERAGE(whole tablets)/2 ± 7.5%: establishes upper and lower gravimetric limits that cannot be exceeded by any half-tablet.
All the half-tablets need to be weighted, as the tablet-splitting process is carried out tablet-by-tablet and this modus operandi is not reproducible enough. In case of non-compliance with maximum and minimum weight criteria, the half-tablet must be discarded.
Conditional functions were established such that the spreadsheet itself reflects the half-tablet acceptance/rejection decision.
Basic technical computer skills, training in the technique of tablet splitting, appropriate clothing and environmental measures to avoid risks to the operator and the medications are required.

What has been achieved?

Since 2015, two different medicinal products were subjected to the tablet splitting technique. A total of 10,536 halves of suitable tablets were obtained, which permitted safe dosing at lower doses than commercialized, and also generated a financial asset of 101,724 Euros. 566 halves were discarded. The splitting efficiency was of 94.9%.

What next?

This quality control procedure is applicable to all divisible solid oral dosage forms. The standardization of the technique and the quality controls will allow to extend it to other medicinal products with dosing and economic purposes.

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Why was it done?

The preparation of cytotoxic drugs perfusions can be accompanied by errors that can be fatal to some patients. Several methods were tested to minimise the risk of errors associated with reconstitution of cytotoxic perfusions (camera, HPLC, analytical balance, the presence of a second technician to monitor his colleague). All of these methods can be expensive and are not available to all hospital pharmacists.

What was done?

We present a simple and effective method that we have developed in our hospital to solve the problem of reconstitution errors.

How was it done?

Errors of cytotoxic drugs reconstitution can have catastrophic consequences for patients. Some studies have found that the incidence of major and minor errors were, respectively, 0.19% and 0.26%. Reconstitution control methods are numerous but not always accessible to all hospital pharmacists and preparers, particularly in developing countries.

This work involves the development of a computer application developed from an Open Source voice recognition software. The daily chemotherapy protocols are entered in the application that dictates to a technician the protocol prescribed by the physician, product by product, for all patients. The technician performs the cytotoxic preparations in the order in the centralised pharmaceutical unit for the preparation of cytotoxic drugs and he communicates with the application manually or by speaking.

The application begins with the patient’s ID, name and surname, the first drug, the dosage, the dilution solution and the volume of this solution. Then, it passes to the second product and so on. In the case of an observation, the application warns the technician to take this observation into account.

What has been achieved?

This application has helped provide better assistance to the technicians and pharmacists in the reconstitution of cytotoxic drugs, and no event or error has been detected to date.

What next?

To make a large number of reconstructions using this application to assess its effectiveness and install it in other hospitals who handle cytotoxic drugs.

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Why was it done?

Chemotherapies are generally prescribed and produced as a function of Body Surface Area (BSA). The most recent literature recommends that marketed drugs continue to use BSA-based dosing supported by clinical evidence. If not, it recommends DB with adjustments for other important parameters.

What was done?

Determine which of the drugs compounded in our centralised chemotherapy production unit were potential candidates for dose banding (DB) for adults, whilst guaranteeing patient safety and meeting the needs of physicians, pharmacists and nurses.

How was it done?

The database of chemotherapy doses produced between 2010 and 2013 was analysed to define a Top 10 chart of the most common protocols and compounds. Dosage patterns were analysed and new bands were modelled using exponential calculus in order to aid in DB decision-making. Discussions with interdisciplinary teams and senior physicians took place in order to promote acceptance of the project and its deployment.

What has been achieved?

Oncology professionals requested an integration of bands into the electronic prescription system, the possibility to prescribe doses above those suggested using BSA and a maximum 5% margin of difference to the usual prescribed dose. They highlighted the necessity of maintaining “ready for administration” doses. For example, in 2013, 613 infusion bags of gemcitabine were produced in 111 different doses, ranging from 266 to 2900 mg. Following the new specifications, just two bands (2000 mg and 1805 mg) already fulfil 50% of annual production needs; producing five band doses streamlines 90% of annual production needs.

What next?

Chemotherapeutic doses can now be prepared in bands and the pharmacy activity can be rationalised by producing doses in batches. The imminent introduction of automation should ensure accuracy of the doses delivered. Future studies should examine product stability so that chemotherapy production planning becomes highly efficient.

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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.