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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.

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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.

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Author(s)

Lucija Tominović Gjivić, Gabrijela Kos, Anita Šimić

Why was it done?

In order to ensure correct use of voretigene neparvovec and minimise the risks associated with its administration, the product can be distributed only through treatment centres where qualified staff (vitreoretinal surgeons and pharmacists) have participated in the mandatory risk management plan (RMP) education program required by EMA.
Since voretigene neparvovec has to be transported and stored frozen at ≤-65 ºC, has short shelf life after dilution (4 hours), contains genetically modified organisms and must be handled according to local biosafety guidelines, there was a need for establishing standard operating procedures (SOPs) for each step of the treatment process.

What was done?

The University Eye Clinic, University Hospital Sveti Duh in Zagreb, Croatia, was designated as the world’s 6th gene therapy centre in 2020.
Hospital pharmacists, as part of a multidisciplinary team, play an important role in preparation and administration of the gene therapy product voretigene neparvovec which is indicated for the treatment of patients with vision loss due to inherited retinal dystrophy caused by biallelic RPE65 (retinal pigment epithelium-specific 65 kilodalton protein) mutations.

How was it done?

The multidisciplinary team consists of a paediatric ophthalmologist, an inherited retinal disease specialist, retinal surgeons, pharmacists and nurses.
SOPs were created for: ordering process, storage of the product, coordination between members of the multidisciplinary team, preparation of the product, administration and disposal of waste.
Preparation of voretigene neparvovec is performed under aseptic conditions in a Class II vertical laminar flow biological safety cabinet (BSC) according to Pharmacy Manual which was ensured by the manufacturer.

What has been achieved?

Since 2020. there had been 47 dose applications of voretigene neparvovec (26 patients, Croatian and nonCroatian citizens).
The prevalence of inherited retinal dystrophy associated with biallelic RPE65 mutation is 1:200 000 and it is expected that there are 19 individuals (population of 3,8, million) with biallelic RPE65 mutation in Croatia, and 13 of them were detected since 2020.
There were no registered side effects which could be associated with errors during the preparation or administration of voretigene neparvovec.

What next?

With the increasing number of gene and cell-based therapies, the need for continuous education of hospital pharmacists and exchange their experiences is greater than ever.

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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.

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Author(s)

Espen Gleditsch, Dag Fossum

Why was it done?

There are no available syringes with CE approval for intravitreal administration. The CE approval for sterile single use syringes covers dosage and sterility, but not the special needs associated with intravitreal administration. The choice of syringe and associated equipment therefore have to be based on a risk assessment. The intravitreal administration includes increased patient risk regarding sterility (infection), particles (inflammation), injection volume (ocular pressure), silicone oil (floaters in the vision) and technical performance (leakage and compatibility with needle). The aim of this work was to find the syringes, associated equipment and compounding process that present least risk to the patients.

What was done?

Oslo hospital pharmacy delivers ready to use syringes for intravitreal administration of drugs for wet age-related macular degeneration. The pharmacy has in cooperation with the eye department at Oslo university hospital done a risk assessment in 2023 to decide syringes and associated equipment for compounding and administration.

How was it done?

The syringes historically used for intravitreal administration in Norway are Insulin syringes with prefixed needles (BD), Inject F syringes (BBraun) and Zero Residual syringes (SJJ Solutions). The needles used are TSK Low Dead Space needles and Zero Residual needles. The compounding methods are filling of the ready to use syringe from a bulk syringe by a needle or use of a Zero Residual bubble adaptor. All ready to use syringes are compounded in isolators with grade A in the working chamber, delivered with needle or cap, and packed in sterile bags. The risks associated with each syringe, needle and compounding process were assessed with a Failure Mode Effects Analysis Method.

What has been achieved?

The risk assessment shows that the risk to the patients are lowest when administering drugs for wet age-related macular degeneration with Zero Residual syringes and needles, filling the syringes with bubble adaptor and deliver with cap. This will give the lowest risk score regarding sterility, particles, injection volume, silicone oil and technical performance.

What next?

This work is relevant for other pharmacists and prescribing practitioners when assuring that syringes and associated equipment are of appropriate quality and suitable for intended use.

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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.

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Author(s)

Isabel María Carrión Madroñal, Concepción Álvarez del Vayo Benito , Begoña Balboa Huguet , Santiago Lora Escobar , Paloma Barriga Rodríguez

Why was it done?

-Improve security, planning, and access to information for correct prescription, administration, and management.
-Guarantee the traceability of all processes.
-Improve the satisfaction of the services involved, preventing forgetfulness and therefore management of emergency calls, unjustified need for the prescribed preparations, and incorrect packaging.
-Improve communication and the work circuit from PD.

What was done?

To prepare a protocol with the processes of prescription, validation, preparation and dispensing of personalised sterile formulations in the Paediatric Surgery Department (PSD: Otorhinolaryngology, Ophthalmology and Neurosurgery) from the Pharmacy Department (PD).

How was it done?

1. Creation of a multidisciplinary team in which a circuit for the prescription, validation, preparation and dispensing of sterile preparations was agreed.
2. Analysis with the departments involved of the personalised sterile-medications prepared by PD for use in paediatric-surgical-rooms, and the most frequent doses used.
3. Bibliographic review: PubMed®, Cochrane®, Uptodate®, Stabilis® and other sources such as the Good Clinical Practices (GCP) and the book ‘Preparation of Drugs and Magistral Formulation for Ophthalmology (JM Alonso).
4. Creation of electronic prescription protocols in ATHOS-Prisma®, containing:
• help notes and preconditions for the prescription.
• information for the administration and management of waste.
• detailed brew sheet and custom label for the PD.
5. Review of the protocols created and the circuit proposed for the prescription, preparation and dispensing.
6. Start-up of the circuit: review and validation of prescriptions, preparation of sterile formulations centralised in PD through laminar flow hoods and dispensing directly to the surgical-room on the scheduled date.

What has been achieved?

Piloting began with sterile otorhinology formulations in 2021, expanding to ophthalmology and neurosurgery in 2022-2023.
– Creation of three groups of protocols that will contain those related to each specialty to facilitate location and prescription by surgeons:
*Paediatric ophthalmology:
• Mitomycin 0.2mg/ml intraoperative-solution-trabeculectomy
• Fluorouracil 5mg/0.1ml intraoperative-solution-trabeculectomy
• Intracameral-cefuroxime 2mg/0.2ml (antibiotic-prophylaxis)
*Paediatric otorhinology:
• Cidofovir 5mg/ml intralesional (laryngeal-papillomatosis)
• Bevacizumab 2.5mg/ml intralesional (laryngeal-papillomatosis)
• Mitomycin 0.5mg/ml (choanal-atresia)
*Paediatric neurosurgery:
• Interferon-alpha 3MIU/0.6ml intralesional (craniopharyngioma)
– Sixty-two preparations have been prepared and dispensed for a total of 30 children; average age of 4 years (1-10). No adverse events were reported in any patient after the administration of these sterile preparations.
– A study limitation was sample size. Circuit under development.

What next?

The protocol is applicable to any hospital with electronic-prescription and surgical-area.

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Author(s)

BELEN SANCHEZ PASCUAL, IRENE SALVADOR LLANA, ANA MARIA MARTIN DE ROSALES CABRERA, MONTSERRAT PEREZ ENCINAS

Why was it done?

Romiplostim should be administered once weekly as a subcutaneous injection. The initial dose is 1µg/kg. According to platelet response (PR) the dose should be increased until the patient achieves platelet count over 50,000 platelets/µL(maximum dose=10µg/kg). In order to maintain durable PR, weekly doses of romiplostim are prescribed and adjusted every 4-6weeks. Although patients could be trained for the injection preparation, many had reported difficulties to understand instructions and calculations of concentrations/volume. Romiplostim vials have a significant overdose to ensure the extraction of the declared amount. The actual content of the 250µg vial was found to be 360 µg (110µg excess). The 500µg vial contents 600µg. In addition, patients should discard the unused part. The aim is to centralise the preparation/distribution of individualised weekly doses of romiplostim for each patient in RtA syringes that allows them to receive the correct dose and to maximise the use of vials.

What was done?

We develop a procedure for the preparation and distribution of individualised weekly doses of romiplostim prepared in the sterile preparation area in prefilled syringes Ready to Administer (RtA) by the patient.

How was it done?

The Pharmacy service (PS) prepares the individualised doses in syringes RtA in a laminar-flow cabinet. The waste of the vial is kept to be reused.
The main obstacle is the increase in the volume of daily preparations in the PS due to dose individualisation. This obstacle is overcome with fluid communication with the Haematology service that reports prescriptions with a duration of up to 21 days (if the patient´s control is adequate).

What has been achieved?

From the past 3 years (2019-2021), we prepared individualised syringes for 36 patients. The centralised preparation reduces unused romiplostin waste allowing a cost saving of near 50% of drug spending. Specifically, in this 3-year period, €385,759.00 were saved.

What next?

Preparation of RtA syringes of romiplostim under sterile conditions in a laminar-flow cabinet helps patient’s auto-administration (since is an easier dispositive) and allows for greater use and significant economic savings. It is a process that can be easily extrapolated to any PS. Next step would be to carry out stability studies in order to be able to work further in advance and allow to space out hospital visits of well-controlled patients.

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Author(s)

VIRGINIA PUEBLA GARCIA, MARIA MOLINERO MUÑOZ, ANA ANDREA GARCIA SACRISTAN, JAVIER CORAZON VILLANUEVA, LIDIA YBAÑEZ GARCIA, NATALIA SANCHEZ-OCAÑA MARTIN, PALOMA PASTOR VARA, MARIA FERNANDEZ-VAZQUEZ CRESPO, JOSE MANUEL MARTINEZ SESMERO

Why was it done?

Calciphylaxis is a vascular disorder characterised by the accumulation of calcium in the small blood vessels of the skin and adipose tissue. There is an imbalance in calcium metabolism which causes calcium to be deposited in the arterioles favouring thrombosis in the residual lumen of these vessels. It presents with severe painful skin lesions which progress to ulcers. It mostly affects patients on renal replacement therapy.

What was done?

To describe the making process of a 25% sodium thiosulphate ointment (ST25%) requested by the Nephrology Department as an off-label use for the topical treatment of calciphylaxis in a patient who was unable to use intravenous sodium thiosulphate (ST) due to haemodynamic instability.

How was it done?

We initially performed an online literature search of databases related to raw materials and excipients, experience of use with formulas prepared by other hospitals as well as articles related to calciphylaxis.
For the production and quality control, the Standard Operating Procedure (SOP) for ointments described in the National Formulary was followed. To establish the risk level of the preparation and the expiry date, a risk matrix was used according to the Guide to Good Pharmacy Preparation Practice (GBPP).

What has been achieved?

It was decided to make a ST25% ointment. Composition for 100 g: ST 25 g (active ingredient), glycerine 10 g (humectant, cosolvent), pure lanolin 32.5 g and white filmy petrolatum 32.5 g (vehicles).
Production: the ST crystals were pulverised in a mortar. Glycerine was gradually added on top of the ST until a uniform whitish paste free of crystals was formed. At the same time, lanolin and filmy petrolatum was mixed in the final container with the help of an emulsifier. Finally, the paste formed with ST and glycerine was added to the lanolin-Vaseline mixture and stirred in the emulsifier until a homogeneous ointment was obtained.
A yellowish ointment with a homogeneous appearance, oily texture and no crystals was obtained.
Expiry date: 30 days after opening. Low-risk preparation.

What next?

Calciphylaxis could be treated after intolerance to intravenous sodium thiosulphate by developing an ointment. The pharmacist through magistral formulation can provide pharmaceutical alternatives in situations where the use of commercially available medicines is not possible.

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Author(s)

Aidan Morris, Louise Byrne

Why was it done?

• mAbs were considered hazardous if handled by staff – prepared in a dedicated isolator in the PAU in TUH.
• No widely accepted standards for safe handling of mAbs, although more recent guidance allows preparation of some mAbs outside of PAUs once risks appropriately assessed.
• Significant reduction in production capacity in the PAU in early 2022 for planned repair work. Benchtop preparation of mAbs implemented to maintain patients’ treatment regimens and to reduce costs associated with outsourcing.

What was done?

• Preparation of monoclonal antibodies (mAbs) on the pharmacy benchtop temporarily introduced in the Pharmacy Aseptic Unit (PAU) of Tallaght University Hospital (TUH).
• Guidance from Ireland’s National Cancer Control Programme (NCCP) on Pharmacy Benchtop Preparation of mAbs reviewed and implemented.
• Risk assessment carried out for individual mAbs. List of mAbs suitable for benchtop preparation prepared.

How was it done?

• Implementation of the NCCP guidance on Pharmacy Benchtop Preparation of mAbs. Advice on risk assessments and safety, equipment and facilities, and staffing and training when preparing mAbs on the benchtop.
• Literature review of the hazards associated with handling mAbs – toxicity, immunogenicity, risk reduction measures. Individual mAbs assessed for suitability for benchtop preparation using Health Service Executive (HSE) risk assessment tool. This considered toxicity, immunogenicity and closed system transfer device (CSTD)-compatibility of mAbs, and personal protective equipment required.
• CSTD vial adaptor based on air cleaning (filter) technology replaced with vial adaptor with physical barrier (balloon) – additional safety measure. Dedicated area assigned for benchtop preparation – well-ventilated, clutter-free and easy-to-clean.
• Additional training on new vial adaptor provided to pharmacy technicians already experienced in aseptic compounding.

What has been achieved?

• List of mAbs suitable for benchtop preparation prepared. Conjugated antibody-drug complexes, mAbs of fully murine origin and mAbs not CSTD-compatible deemed unsuitable.
• mAbs prepared on the benchtop during period of reduced capacity, maintaining patients’ treatment regimens and reducing outsourcing costs, wastage.
• Facilitated by risk assessment and risk reduction using PPE, training and CSTDs.

What next?

• Although safety and handling requirements of mAbs not fully known, prudent to handle them with more care than most drugs but less than for cytotoxics.
• Contingency plan for benchtop preparation of mAbs in case of future reduced PAU capacity.
• Can be applied to other organisations experiencing periods of reduced capacity.