EVALUATION AND DECISION-MAKING RELATED TO QUALITY AND WORKLOAD ASSESSMENT OF PARENTERAL NUTRITION COMPOUNDING
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European Statement
Patient Safety and Quality Assurance
Author(s)
Jorge Esquivel Negrín, Amara Magdalena Pérez, Josephine Peña Hernández, Jenifer González Chávez, Carmen Lidia Díaz Díaz, Silvia González Suárez, Alba Domínguez Hernández, Jaime Muñoz Manrique, Esther González Carrillo, Pilar Díaz Ruiz
Why was it done?
PN is a high-risk preparation that carries a significant risk of iatrogenesis, making it essential for staff responsible for its prescription, validation, and preparation to be well-trained, and for a reliable quality assurance plan to be in place. Monthly quality indicators include errors by pharmacists during transcription to nutrition software, errors by technicians in tray preparation, and nursing errors during PN preparation. Acceptable monthly error thresholds were set at 2 for transcription, 25 for tray preparation, and 6 for sterile PN preparation. Additional activity indicators, such as the number of PN preparations per month, episode duration, and reasons for suspension, were also analyzed.
What was done?
A training program centered on audiovisual resources related to parenteral nutrition (PN) procedures was implemented in a tertiary hospital after a quality assessment within the PN department revealed a decline in certain indicators between 2020 and 2022. A shared folder with video tutorials covering various processes was made available to pharmacy staff, mainly intended for nursing staff and pharmacy technicians, who typically have high turnover rates between departments.
How was it done?
The indicators showed a steady increase in PN preparations, rising from 411±74 per month in 2020 to 475±51 in 2023, with a record of 634 preparations in March 2024. Notably, 18.1% of episodes in 2023 lasted over two weeks, partly due to the underutilization of home PN and a lack of hospital beds despite increased outpatient activity. Errors in tray preparation increased from 2020 to 2022, peaking in 2021. This coincided with high staff turnover and an increased workload. In response, the implementation of video tutorial training for rotating staff was introduced in 2022.
What has been achieved?
This initiative reduced tray preparation errors, which decreased to an average of 12±4.9 between January 2023 and March 2024.
What next?
These measures could be adapted and implemented in other departments within the pharmacy service. Regarding PN, we are now aiming to optimize the workload by promoting home PN, and implementing semi-automated systems such as barcodes and gravimetric control, which are also recommended to improve safety and traceability.
CIRCUIT FOR THE PREPARATION, CONTROL, AND DISPENSATION OF AUTOLOGOUS SERUM EYE DROPS IN A PHARMACY SERVICE
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European Statement
Production and Compounding
Author(s)
Eva Gómez-Costa; María Begoña Feal-Cortizas; María Mateos-Salvador; Sandra Rotea-Salvo; Andrea Luaces-Rodríguez; Laura Caeiro-Martínez; Clara Fernández-Diz; Andrés Torres-Pérez; Luis Margusino-Framiñán; María Isabel Martín-Herranz
Why was it done?
Implement a circuit for the preparation, microbiological control, analytical control of patients, and dispensation of autologous serum eye drops in the Pharmacy Service (PS) of a tertiary-level hospital.
What was done?
Autologous serum eye drops are classified as a special medication that must be prepared in authorized centers with an up-to-date patient registry. This initiative aims to ensure the safe use of autologous serum eye drops, guaranteeing quality and safety in their preparation and administration.
How was it done?
The circuit was established in the PS in 2015. After prescription by the Ophthalmology Service, pharmaceutical validation confirms that the treatment is optimal and complies with regulatory requirements. Blood samples are collected from patients under controlled conditions, and the serum is prepared in a vertical laminar flow hood. Once prepared, the eye drops are stored frozen in the PS until dispensation to the patient. The pharmacist reviews the microbiological control of each batch and the patient’s serological results. When collecting the eye drops, the pharmacist records batch traceability and provides the patient with necessary information on storage and administration.
What has been achieved?
Between January and August 2024, 294 patients were treated, with 477 blood extractions performed and a 11,925 eye drops prepared. Autologous serum concentration: 20%(76.9%), 30%(11.5%), 50%(11.2%), and 100%(0.4%). Microbiological control of the eye drops: 98.1% negative and 1.9% false positives, confirmed by a second negative control. Infectious diseases were detected in the serology of 3 patients: hepatitis C(1), hepatitis B(1) and syphilis(1). These data reflect a high success rate in the preparation and quality control, as well as the effectiveness of the implemented circuit. Additionally, the system has allowed for the early detection of viral infections, reinforcing treatment safety.
What next?
The implementation of this circuit has proven effective in ensuring the safety and efficacy of autologous serum eye drops, providing rigorous control over treatments and the quality of dispensed products. Future steps will involve pharmacists requesting serological tests and developing protocols for managing patients with identified infections. Furthermore, patient surveys will evaluate treatment effectiveness and overall patient experience.
BRAIN DEATH: RADIOCHEMICAL PURITY OF THE RADIOPHARMACEUTICAL 99mTc-HMPAO STABILIZED WITH COBALT
Pdf
European Statement
Patient Safety and Quality Assurance
Author(s)
Diana Monteiro
Luísa Álvares
Sara Brandão Madureira
Patrocínia Rocha
Why was it done?
The confirmation of a clinical diagnosis of brain death requires the demonstration of the cessation of brainstem functions and their irreversibility. Therefore, when this evaluation is incomplete or unreliable, it is necessary to support this diagnosis using diagnostic tests such as brain perfusion SPECT. This is performed after the injection of the radiopharmaceutical technetium-99m hexamethylpropyleneamine oxime (99mTc-HMPAO) and by assessing the obtained images for the lack of cerebral perfusion to confirm the diagnosis.
Given the importance of reliable results, a high radiochemical purity of 99mTc-HMPAO is imperative in quality control to prevent false positives.
What was done?
Selection of a method to evaluate the radiochemical purity of 99mTc-HMPAO.
How was it done?
A literature review was conducted to select the most suitable method for the conditions existing in the institution. The research focused on the Summary of Product Characteristics (SmPC), the European Pharmacopoeia (Ph. Eur. 11.0), the United States Pharmacopeia (USP 42) and several published articles.
After selecting the method, three assays were performed to validate it.
What has been achieved?
For evaluating the radiochemical purity of 99mTc-HMPAO, both the SmPC and Ph.Eur. 11.0 recommend a combination of two thin-layer chromatography (TLC) methods with a high-dimension stationary phase, for which the institution does not have a chromatographic tank.
The USP 42 describes a combination of three TLC methods, using acetonitrile as the mobile phase, which is also unavailable at the institution.
In contrast, the miniaturized method by Fuente et al. uses two TLC methods, with a silica gel stationary phase and sodium chloride (0.9%) and methyl ethyl ketone as mobile phases. This method was selected given that the institution has the required phases, the stationary phase dimensions are suitable for the available chromatography tanks and the execution time for the assay is feasible.
For method validation, three assays were conducted, yielding values exceeding 80% (the reference value).
The selected method represents a rapid, reproducible and reliable alternative for evaluating the radiochemical purity of 99mTc-HMPAO. It was implemented in the institution in October 2022.
What next?
In the future, we aim to develop quality control methods for all radiopharmaceuticals in use at the institution, in order to guaranty the quality of all the exams performed.
The development of hospital manufactured ready-to-use cefazolin 100 mg/mL injections
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European Statement
Production and Compounding
Author(s)
Bojan Žagar, Matej Vehovc, Mateja Tršan, Blaž Vehar
Why was it done?
Cefazolin injection 100 mg/mL is a sterile pharmaceutical formulation comprising cefazolin sodium and water for injections. Traditionally, cefazolin injections were prepared on hospital wards by reconstituting cefazolin sodium powder for injections with water for injections and subsequent dilution before intravenous administration.
What was done?
Establish a semi-automatic aseptic preparation process, ensure the production of final products that meet quality standards, develop analytical methodologies for in-process and final product quality control, ensure the reliability and validity of test results, and conduct a stability study to confirm long-term storage.
How was it done?
Product materials include: Pharmacy Bulk Package of Cefazolin for Injection, USP, water for injections, Luer Lock 20 mL sterile polypropylene syringes, steribags. Product is prepared with aseptic technique within a laminar flow unit situated in a pharmaceutical cleanroom. Bulk package is connected to a dispensing device, followed by reconstitution with water for injections. In-process samples are collected and volume-adjusted based on density. Following the preparation and dispensing, syringes undergo labeling and packaging into steribags. They are then promptly stored at -30°C within 4 hours. Final product samples are obtained and analysed (pH value, cefazolin content, endotoxins, sterility) prior to product release.
What has been achieved?
Preparation of cefazolin sodium injections in a controlled, aseptic environment utilizing pre-prepared bags containing the appropriate cefazolin concentration (100 mg/mL) has successfully addressed critical concerns surrounding the safety, efficacy, and quality of these pharmaceuticals when administered on hospital wards. Challenges related to stability and shelf life are being addressed with the storage approach at -30°C within the pharmacy, followed by a carefully monitored transition to ward storage at 5°C for up to 28 days, and subsequent patient administration at room temperature within 2 days.
What next?
This approach not only streamlines the process but also safeguards the well-being of patients, marking a significant advancement in pharmaceutical preparation within our healthcare setting. We are conducting an ICH-compliant stability study with the objective of establishing a combined shelf life of 90 days at -30°C, followed by 28 days at 5°C, and an additional 2 days at room temperature.
The European Paediatric Formulary: a reinforced approach for improved monographs
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European Statement
Production and Compounding
Author(s)
Théo Henriet, Jane Francomb, Dirk Leutner, Jörg Breitkreutz
Why was it done?
The PaedForm project was launched as a bibliographical exercise, with the aim of collecting age-appropriate formulations from existing formularies or from established sources in Europe and incorporating them into the PaedForm.
However, the data underpinning existing monographs were not as complete as expected and errors in the source data were observed. Adding an experimental verification step was therefore crucial to ensuring the reliability and the appropriate quality of the formulations described in PaedForm and demonstrating that the monographs could be used in practice.
What was done?
A decision to add an experimental verification to the elaboration process for monographs to be published in the European Paediatric Formulary (PaedForm) was recommended by the experts from the PaedF working party (PaedF WP) – assisted by the European Directorate for the Quality of Medicines & Healthcare (EDQM) – and supported by the European Committee on Pharmaceuticals and Pharmaceutical Care and the European Pharmacopoeia Commission.
This verification step involved checking the preparation against the description in the monograph and, where necessary, completing it. Samples prepared during this step were then tested to check that the quality control methods included in the monograph were suitable. The findings were used to determine whether the monograph could be completed.
Where necessary, this experimental verification would include tests such as the microbial challenge test as described in European Pharmacopoeia (Ph. Eur.) general chapter 5.1.3.
How was it done?
Experts from the PaedF WP support the need for practical verification and perform the experimental verification if needed. The EDQM supported this work by sourcing active substances and consumables and by organising analytical testing for techniques not available to the experts.
What has been achieved?
This approach enabled the enhancement of a furosemide oral formulation. The composition of this formulation as described in the source material did not meet the Ph. Eur. requirements for antimicrobial preservation, so it was changed to include a higher concentration of the preservative and comply with the Ph. Eur. requirements.
What next?
The PaedF WP will continue to expand PaedForm by elaborating new monographs covering unmet therapeutic needs. Users are invited to contribute to this process by commenting on texts published in the PaedForm Pharmeuropa public consultation platform.
Evaluation of tetracosactide peptide in galenic formulations for rapid adrenocorticotrophic hormone stimulation test
Pdf
European Statement
Production and Compounding
Author(s)
Aleksandra Bračko, Janez Ilaš
Why was it done?
The rapid adrenocorticotrophic hormone (ACTH) stimulation test is a commonly performed test in all hospital departments of the University Medical Centre Maribor. The reason for its widespread use lies in its simple execution using a pre-filled syringe containing precisely 1 µg of tetracosactide solution. Until the year 2016, we prepared a 5 ml solution with a concentration of 5 µg/ml in glass vials. Based on a literature data we set a shelf life of three months from the date of production for the solution filled in plastic syringe. The solution in glass vials has a shelf life of four months. We wanted to confirm this shelf-life with several analytical methods.
What was done?
The aim of our work was the qualitative and quantitative evaluation of tetracosactide peptide in a solution with a concentration of 5 µg/ml, filled in glass and plastic containers and stored under different conditions, using multiple methods. We stored the sample solution of tetracosactide for five months under various conditions. We performed the analysis using the Qubit 4 fluorometer, the Bradford method and method based on ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC–HRMS).
How was it done?
The first two relatively simple methods, Qubit 4 fluorometer, the Bradford method, did not provide the desired results. We assume that these methods were not sensitive enough for our sample with a concentration of 5 µg/ml. In the end, we used the UHPLC-HRMS analysis, which proved to be sensitive and highly selective.
What has been achieved?
The peptide molecule has eight basic centers in its structure, so both tetracosactide and each impurity were differently charged in an acidic medium, specifically +3, +4, +5, +6, +7, and +8. The distribution of charge of tetracosactide and impurities among the samples is very similar, with the highest proportion represented by molecules with a charge of +6. We have identified 11 impurities. The highest proportion was represented by impurity with the increased mass of 16 Da (tetracosactide sulfoxide). HPLC-HRMS method is highly selective and allows identification of each impurity
What next?
Based on the findings we will validate a method for quantification of the selected impurities which will allow us to perform the stability study of according to the ICH guidelines.
Evaluation of microbiological shelf-life of preparations of cytotoxic agents in infusion bags combined with medical devices
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European Statement
Production and Compounding
Author(s)
Timea Botházi, Lone Madsen
Why was it done?
The purpose was to find data for an increased microbiological shelf-life of preparations of cytotoxic agents in infusion bags combined with medical devices. The aim was to increase microbiological shelf-life from 24 hours to 7 days. Existing data were studied to find evidence to support the prolonged shelf-life.
What was done?
The purpose was to find data for an increased microbiological shelf life of preparations of cytotoxic agents in infusion bags combined with medical devices. The aim was to increase microbiological shelf life from 24 hours to 7 days. Existing data was studied to find evidence to support the prolonged shelf life.
How was it done?
A team from the production and quality assurance departments worked together on writing a report that could provide the rationale for the change of shelf-life.
We collected data from
– supplier qualification of the medical devices
– aseptic process simulations (APS)
– process validations
Data were evaluated and risk assessment was performed.
Six medical devices were included.
All suppliers were qualified as low risk.
APS for the specific production process showed no growth.
Process validation data for two types of medical devices showed no concern regarding sterility of preparations.
What has been achieved?
The increase of shelf life was accepted. First product was Blincyto® in infusion bag with Take Set Swan-Lock ® with shelf life increased to 4 days. Patients now visit the oncology clinic only twice a week instead of daily thus saving time and transportation.
What next?
The result means that new product implementation is quick because the only things to evaluate are the stability of the substance and the compatibility of this with materials in contact with it.
Implementation of a Ph. Eur. compliant recombinant method for testing of bacterial endotoxins in sterile pharmaceuticals
Pdf
European Statement
Production and Compounding
Author(s)
Randi Hamre Svendsen, Vilde Pettersen, Theo Dogbeten
Why was it done?
Endotoxin testing by the gel-clot method is a limit test and relies on the operator’s subjective evaluation of the results. The procedure itself contains several steps and dilutions, and it is time and resource consuming. The availability of the amoebocyte lysate reagent can also vary since it is harvested from the endangered horseshoe crab. The recombinant factor C method (rFC) is a fluorimetric method based on the gene sequence of the horseshoe crab, providing quantitative results with no interpretation by an operator. The rFC method consists of less handling and is less susceptible to human error.
What was done?
The hospital pharmacy implemented a modern system for testing of bacterial endotoxins as a part of the quality control of raw materials (i.e. water for injection (WFI)) and sterile pharmaceuticals manufactured at the pharmacy, replacing the old gel-clot test.
How was it done?
All sterile pharmaceuticals manufactured at the hospital pharmacy were evaluated for maximum valid dilution (MVD) and endotoxin limit. Firstly, the optimal dilution of the products was established, and then tested with three different batches to ensure valid results regardless of any batch-to-batch variation. WFI was validated undiluted with batches from three separate days. Validation started with the most frequently manufactured products, and subsequently continued over the next year with the rest. To expedite the full validation of some products, expired batches were used simultaneously with at least one recently produced batch due to infrequent production times, otherwise a full transfer of method would not be achieved for up to six years.
What has been achieved?
In total, 25 sterile pharmaceuticals and raw materials were successfully validated for endotoxin testing by rFC during 2021 and 2022. The gel-clot method is no longer in use at the hospital pharmacy, reducing the negative impact on the horseshoe crab population. The rFC method streamlined the testing for endotoxins, reducing the time spent on performing the analysis by 50% with less handling and increased capacity. Results are quantitative and objective, not relying on observations by the operator, thereby improving the quality.
What next?
The rFC method increases both quality and capacity of testing, opening up for expanded testing in pharmacy, and of samples from other departments or hospitals.
INTRODUCTION OF REGULATORY AND HEALTH WATCH IN THE CLINICAL TRIALS AREA
Pdf
European Statement
Patient Safety and Quality Assurance
Why was it done?
When the case for a study sponsored by the hospital has been filed a few months ago, the national agency authorizing trials raised the issue of health waltch, particularly the management of drug recalls. With the research department, which alerted us on the lack of resources for health alerts, and at the same time facing an international cease of some drugs, we set up a health alert and a regulatory watch system, to improve the quality of product and the patient’s safety.
What was done?
We set up a daily health and regulatory watch to stay abreast of any news. Regarding health watch, we included : studies for which the hospital is the sponsor ; studies for which the experimental treatments are not provided by the sponsor ; treatments used for adverse events and authorized by the sponsor.
How was it done?
Daily regulatory watch is carried out on the national legislation website with daily updates of national texts. If a new rule applies, it is written in a table to alert everyone.
Daily health watch is also carried out on the site of the national agency of drugs. Four types of information are recorded: drug shortages, alerts, recalls and releases.
What has been achieved?
Tables collecting those information are available on the pharmacy’s network so that anyone can read them, and can be shared with clinical research officers. To that day, some information has been collected due to a european legislation update on the clinical trials and has allowed us to anticipate what will change next year. We have not yet faced a drug recall but what has been done will allow us to react in the best way when this will happen.
What next?
The aim for carrying out regulatory and health watch is to allow us to quickly react and anticipate future problems, while keeping in mind the patient’s safety and the pharmacy practices improvement. This work was therefore completed with success, demonstrating the ability to react and the desire to deploy continuous improvement initiatives to strive for operational excellence and pharmaceutical. We now want to implement this work in the daily activity and extend it to other sectors.
Which analytical method for parenteral nutrition mixtures dosing to choose? A regional comparative study
European Statement
Production and Compounding
Author(s)
Joan-Candy MABIN , Aïssé DIALLO, Hortense LANNELUC-BEAUJARD, Xavier DEVIOT
Why was it done?
The aim of this work is to find a cheaper alternative, reducing the analysis duration and allowing the pharmacy to be laboratory independent.
What was done?
The opening of the production unit (PU) leads to reorganize the parenteral nutrition mixtures (PNM) dosing. Primarily carried out in the biochemistry laboratory of our hospital, potentiometry and colorimetry analysis were long (more than an hour) and costly. PNM composition accelerates the aging of one of the device components that costs 1400 euros and have to be changed every 3 weeks, raising the total around 24300 euros per year only for this component.
How was it done?
Hospitals producing PNM in the region were identified and approached. They were asked about the type of dosed elements, the analysis method and the equipment used, about the analysis duration and localization (laboratory or pharmacy departments) and their overall cost estimation.
What has been achieved?
Five hospitals with different dosing equipment answered. Four of them analyze cations: calcium, magnesium, sodium and potassium by capillary electrophoresis, potentiometry or spectrometry, three of them analyze glucose by chromatography or colorimetry, and two of them determine osmolarity of the PNM mixtures. Dosages are performed by the pharmacy department in three PU where technician are required. Results are provided in about an hour when the activity depends on the laboratory and around five to ten minutes when it is managed by the pharmacy department. The average cost to purchase the equipment for each hospital was around 50000 euros (without the associated materials and the labour cost).
What next?
To conclude, no hospital interviewed can be a model because of either the high costs or the unadapted equipment size to the scale of the room of our PU. Nevertheless, during discussions, an equipment that might answer our needs was suggested, because no technician is needed for analysis, and it is described simple and easy to use. The manufacturer has been reached out asking for demonstration and information before any purchase. If accepted, the device will be qualified before going into production.