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Author(s)

Mette Lethan, Marianne Lund Sørensen, Jakob Kronkvist Hoe, Heidi Waenerlund Poulsen, Louise Rasmussen Duckert

Why was it done?

On July 1st, 2016, an EU resolution caused a new national requirement to establish a PD for new as well as known EP’s produced by the hospital pharmacy. PD’s had to be established for 450 known products in our facilities.

What was done?

A Product Dossier (PD) for extemporaneous preparations (EP) was established in our hospital pharmacy. They contain a risk evaluation and information about the specific value of the preparations, a demonstration that the active pharmaceutical ingredient(s) (API), excipients and containers meet relevant requirements, an evaluation of the stability of the product, and a description of the preparation process and analysis.

How was it done?

To approach the task, an interdisciplinary project group was formed. It consisted of members from Quality Assurance/Control, Stability, Drug Information Center and Production. A formulation for a collaborative approach was established to ensure a high and uniform quality of the PDs. The information obtained included e.g. information and evaluation of API and excipients, ongoing stability studies, indication of the drug and alternative preparations. A few examples were concluded in the group to ensure a quality baseline of the PDs.

What has been achieved?

PDs for 150 products have been successfully implemented. In some cases the formulation regarding excipients was changed to better suit the patient group. In other cases, it was evaluated whether a drug registered in another country could better ensure patient safety. Based on stability data, storing of some products were changed. Collaboration across departments has enabled us to ensure compilations of PDs for our pharmaceutical stock preparations. Completing the PDs on existing products has ensured a pool of knowledge about our products collected in one document and accessible to all departments in the hospital pharmacy.

What next?

Through the interdisciplinary approach PDs ensure focus on the quality, safety and benefits for the patients. All existing EPs will be maintained and evaluated anytime there may be a change in production. For all new products a PD will be prepared according to the guidelines set up. Having the information in one document (PD) ensures that all departments can quickly obtain information needed to consistently maintain and evaluate product quality and thereby the specific value of our production.

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Author(s)

Maria Rautamo, Niina Laihanen , Laura Lehtola

Why was it done?

Erysipelas was the most commonly treated infectious disease at the home hospital unit in 2015. Previously the standard treatment was broad-spectrum antibiotic cefuroxime three times daily. The infectious disease specialist wanted to improve the antibiotic stewardship by shifting from cefuroxime to a continuous infusion of narrow spectrum benzylpenicillin. The aim of the initiative was also to improve patient care and reduce the number of treatment visits and thus overall treatment costs.

What was done?

The production unit at the hospital pharmacy began preparing elastomeric pumps containing benzylpenicillin for Helsinki city home hospital unit for the treatment of outpatients suffering from erysipelas. A pilot study was conducted in November 2018 before further implementation of the elastomeric pumps.

How was it done?

A benzylpenicillin 10 million IU infusion solution was prepared and transferred to elastomeric pumps (Folfusor LV10, Baxter) in the production unit at the hospital pharmacy. The production method was developed by pharmacists at the hospital pharmacy in cooperation with Baxter and the formulation as well as stability information was received from Baxter. The pilot study was planned and executed in cooperation with Helsinki city home hospital unit. The batch size of prepared elastomeric pumps was 7 pumps a week and the overall pilot period consisted of 5 weeks. A total of 8 patients were treated during this period. The opinions of nurses and patients about the use of elastomeric pumps were investigated through a questionnaire. The impact on treatment costs were also evaluated.

What has been achieved?

Elastomeric pumps containing benzylpenicillin have been implemented as a standard treatment for erysipelas at the home hospital unit. Cost savings from the pilot period of 5 weeks were 125 nurse visits corresponding to approximately 100 hours of work as well as 200 km of driving for nurses to patients’ homes. The patients were very pleased with the elastomeric pumps and the fact that the pump had to be changed only once daily.

What next?

Production and delivery of elastomeric pumps containing benzylpenicillin has expanded to other home hospital units. The implementation of elastomeric pumps containing other active ingredients is under investigation.

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Author(s)

Beatriz Sánchez Sanz, Iván González Barrios, Siria Pablos Bravo, Sara Ortiz Pérez, Cristian Rosas Espinoza, María Arrieta Loitegui, Francisco Martínez de La Torre, Dolores Canales Sigero, José Miguel Ferrari Piquero

Why was it done?

The objective is the elaboration of a formulation as a cost-effective alternative to the diazoxide oral suspension not commercialised in Spain, to treat patients with hyperinsulinaemic hypoglycaemia.

What was done?

Diazoxide is the first line therapy in infants with hypoglycaemia due to hyperinsulinism. A formulation to facilitate the dosage in newborns has been developed due to the increasing demand at our Hospital.

How was it done?

To evaluate the solubility, a research on Pubmed was executed including terms such as “diazoxide AND solubility” and “tiazides AND solubility”. To determine the stability, the agreement approved by the “Pharmacotechnics Group of the Spanish Society of Hospital Pharmacy” concerning the viability of the non-sterile oral formulations was reviewed. In terms of effectiveness, a retrospective observational study was conducted. Demographic and clinical (duration of the therapy and blood sugar levels 24 hours after first administration, sorted as “sensitive” if those levels were over 60mg/dL) variables were collected.

What has been achieved?

Carboxymethyl cellulose gel 1.5% (CMC) was evaluated as suspending agent, with adequate results. The steps to compounding the formulation of diazoxide 10mg/mL oral suspension were: 1. Four capsules of 25mg were opened and spread over a mortar. 2. 10ml of CMC was measured on a test tube. 3. CMC was added slowly over the powder while stirring the mixture to obtain a homogenized milky creamy. 4. Suspension was stored in an amber bottle. Following our stabilities studies and the lack of preservatives, an expiration date of seven days at ambient temperature was assigned. In our hospital, seven neonates (four males) aged 5.8±2.3 days have been treated with this oral suspension, for an average period of 28 days. Six of them were classified as “sensitive” with levels of 105±30mg/dL while one showed no improvement. Analysing the global expense, one pack of 100 capsules costs €21. Thus, 1 unit of our suspension 10mL cost €0.84 versus 1 bottle of 30mL (€473); the savings are remarkable.

What next?

The preparation constitutes a suitable alternative by using a simple and cheap technique since its introduction. In the future, full studies of stability must be designed to prolong its period of validity and monitor its security.

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Author(s)

Liisa Eesmaa, Katrin Sõnajalg, Ülle Helena Meren

Why was it done?

Intravitreal tissue plasminogen activator (tPA) injection is a guideline recommendation for patients with medium, large or thick submacular haemorrhage mainly due to exudative age-related macular degeneration (AMD). This treatment hasn´t been available: off-label use, rare demand, high price (generic unavailable, the cost uncovered by health insurance).

What was done?

Ophthalmologists contacted the pharmacy to work out a plan for emergent cases of patients with large submacular haemorrhage in the better seeing eye. The pharmacists worked out the logistically simplest, economical affordable solution to prepare the injection in a cleanroom setting.

How was it done?

The pharmacy came up with two models: 1. Compound intravitreal injection (50 μg/dose) from Actilyse 50mg vial (€375) containing substance for intravenous infusion. The rest of the vial would possibly be used in the neurology department during the next 24 hours. The costs would be shared based on microgram use. 2. Use unregistered Actilyse cathflo 2mg vial. Application for permission and delivery would take up to 6 weeks and drug shortages would be usual. The price for 50 μg would be €65. For the first two patients the first model was used. It was logistically complicated for the neurology department as they needed to change their everyday practice. The second model has now been introduced into practice and used for another two cases. It is accepted by the doctors and pharmacists.

What has been achieved?

Four patients have received new treatment with intravitreal tPA in addition to the common practice of pneumatic displacement of the haemorrhage with intravitreal anti-VEGF (vascular endothelial growth factor) injections or intravitreal anti-VEGF monotherapy. The treatment was well tolerated by the patients with some benefit to visual function. The pharmacy is ready to prepare tPA injections during working days. The price of the injection is acceptable.

What next?

The University hospital became interested to start the same treatment. The second model was presented to their hospital pharmacy. Our ophthalmology department is now equipped to inject tPA into the subretinal space during vitrectomy to increase the efficacy of the procedure and improve patients’ visual outcome.

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Author(s)

Jannik Almasi, Irene Krämer

Why was it done?

Aim of the study was to evaluate if the microbiological cleanliness of the working area of APOTECAchemo® is affected by extending the interval of intensive cleaning from biweekly to monthly cleaning intervals.

What was done?

Automated preparation of ready-to-administer chemotherapy products with the APOTECAchemo® robot is well established in a number of pharmacy departments. One of the few disadvantages is the time-consuming, intensive cleaning and disinfection of the working area (clean room class A) by wiping with cleaning and disinfection solutions.

How was it done?

Every two weeks (period 1: 07-12/2018) or every four weeks (period 2: 01-06/2019) all surfaces in the working area of APOTECAchemo® were wiped with ethanolic NaOH solution in order to inactivate or remove cytotoxic spillages. In a second work step all surfaces are disinfected by wiping with spore-free alcohol. The procedure lasts about one hour. The working area is at the end of each working session irradiated with UV light for 4 hours. Microbiological monitoring of the working area is done weekly in operation by passive air sampling (2 settle plates at predefined locations S1, S2) and surface sampling (3 contact plates at predefined locations O1, O2, O3) and colony-forming units (CFU) are counted after incubation. Results of the microbiological samples (CFU ± standard deviation) were compared for period 1 and 2. On average, 0 CFU (n=52) were detected (period 1) and 0.04±0.2 CFU (n=44) (period 2) on settle plates. During period 1 on average 0.04±0.19 CFU were found at O1, 0 CFU on O2, and 0.81 CFU±4.23 at O3 (n=27 each). During period 2, 0 CFU were detected at O1, O2 and 0.04±0.2 CFU at O3 (n=25 each). The extended interval for the intensive cleaning process did not affect the microbiological cleanliness. The CFU limits set for clean room class A were met.

What has been achieved?

Maintaining the daily cleaning procedure, the interval of intensive cleaning can be extended to one month without increasing the microbiological contamination risk and saving two hours of cleaning.

What next?

Monthly intensive cleaning will be attended by trending the microbiological results.

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Author(s)

MARGHERITA GALASSI, CHIARA DELLA COSTANZA, CLAUDIA TIRONE, ELENA ALIPRANDI, ERNESTO RUFFINO, SARA BERTOLI, ELEONORA FERRARI, ELISABETTA MARTINELLI, VITO LADISA

Why was it done?

Intravitreal bevacizumab is refunded by National Health System for AMD and diabetic macular oedema but the splitting process must be carried out only by authorised pharmacies. Recently the established regional refund price was lowered to €55/dose that covers the costs of intravitreal bevacizumab but not the other authorised drugs ranibizumab and aflibercept. Our Centralized Pharmacy operated the repackaging of intravitreal bevacizumab for internal patients but we implemented a new process and a new procedure in order to provide doses to hospitals not equipped in performing sterile preparations.

What was done?

We implemented a production process to repackage a drug to be used in treatments not covered by marketing authorisation. Bevacizumab was split into fractional doses for off-label intravitreal injections; the doses obtained were given to our hospitalised patients as therapy for uveal melanoma and provided to hospitals in our region as therapy for patients with age-related macular degeneration (AMD) and diabetic macular oedema.

How was it done?

The procedure for preparing intravitreal injections was reviewed to optimise traceability aspects of processing batches, individual doses of finished products and particularly to choose the most suitable packaging for transport to hospitals that will administer the drug. Further quality control to regional law was established on processes and finished product: environmental, instrumental, maintenance controls. All processes were validated in accordance with applicable regulations. Agreements related to prescription, purchase, conservation and transport of bevacizumab doses were signed with the hospitals that administer the drug.

What has been achieved?

The price refunded for a single intravitreal dose of an anti-VEGF (vascular endothelial growth factor) drug from August 1 2019 is €55, previously the price for each single dose of ranibizumab was €600. Considering that AMD therapy requires a monthly injection for about a year we can assume a standard average cost saving of €6540/patient.

What next?

AMD is the leading cause of blindness among populations over 50 years old. To provide treatments to all those affected by degenerative eye diseases in the next years, we must operate cost savings policies safeguarding patient security. The practice described is worthy of implementation in hospital realities.

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Author(s)

ADRIANA DURCANSKA

Why was it done?

The quality and safety standards of pharmacy preparations are not harmonised throughout Europe. They fall under the national competencies of individual European countries.

What was done?

The quantitative risk assessment of the pharmacy preparations for stock in hospital pharmacies (HPs) in accordance with Resolution EDQM CM / Res (2016) 1; to specify the decision criteria for the risk assessment; the risk management of the pharmacy preparations for stock in the country; to design a check list of the risk assessment for extempore preparations.

How was it done?

Out of the total number of 53 hospital pharmacies contacted, 5 pharmacies sent a suitable file.

What has been achieved?

A total of 170 types of medicines are being prepared in HPs. One HP  had the result of the risk ≥ 100 when preparing ophthalmic medicines. Annex A is a check list designed to assess the risk of extempore preparations.

What next?

The management is and will be forced to consider its introduction or to use another model: hospital – GMP / outsourcing / central pharmacy preparing and distributing. The aim of using the document in hospital pharmacies of the country.

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Author(s)

María Lourdes Recio Blázquez, José Manuel Martínez Sesmero, Lidia Ybáñez García, Gonzalo Hernando Llorente, María Molinero Muñoz

Why was it done?

The purpose is to control two environmental conditions to guarantee the comfort of the workforce and the quality of the finished product quality. 519,321 SODFs have been repackaged in unit doses last year. The 8% of the SODFs come from multidose containers that have been exposed to environmental temperature and humidity during this process. Employees have been exposed to identical conditions.

What was done?

A temperature (t) and relative humidity (RH) control system has been established in the enclosure where the solid oral dosage forms (SODFs) are packaged in unit doses.

How was it done?

Among the diversity of hygrometric sensors commercialised, a device equipped with a condenser was chosen. The operation is based on modifying the capacity when varying the dielectric constant of the medium, in this case, due to varying the amount of water contained in the air between the plates. – C = ε A / D – C: capacity value. – ε: dielectric constant. – A: area of the condenser plates. – D: distance between the condenser plates. The device also incorporates a temperature sensor. The t (ºC) and RH of each moment are shown, for visual inspection, on the device screen. The data obtained with certain time frequency can be stored on a Secure Digital memory card and be downloaded on a computer that has that program installed (on spreadsheet format) helping to obtain graphics as well.

What has been achieved?

The range of t (ºC) has remained stable between 26 and 24ºC for 6 months, with minimal variations from maximum 28.5ºC to minimum 23.4ºC. The UNE 100713: 2005 is met. RH has been below 45% during 68% of the days worked, which has favored the repackaging of the units affected by humidity but not the worker. The range of RH has varied between 56.3% and 23.6%, not complying with the UNE 100713: 2005 standard.

What next?

Metabolic rate, clothing insulation, air temperature, radiant temperature, air speed and humidity shall be addressed when defining conditions for acceptable thermal comfort. It would be helpful to regulate the commercialisation of multidose pharmaceutical specialties susceptible to deterioration when opening the package.

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Author(s)

Swantje Eisend, Herwig Heindl, Karen Tiede, Sven Jirschitzka

Why was it done?

Definition of an organisational structure for the best implementation of APOTECAchemo technology in the UKSH hospital pharmacy workflow

What was done?

The implementation of robotic systems for aseptic compounding cytotoxic drugs requires a specific workflow organisation in the hospital pharmacy to ensure an optimal combination of manual and automated production as well as the effective use of the technology. Since 2017, the APOTECAchemo robot has been installed in the hospital pharmacy and one of the first objectives was to create an organisational structure that would allow successful integration of the system into the existing workflow of the cytostatic department.

How was it done?

The pharmacy has carried out an analysis to identify the active substances that can best be transferred into automated production based on 4 main points: • Pharmaceutical form of the active ingredients: liquid or powder; • Average of vials needed for the compounding of one preparation for each active ingredient; • Average of ml of medication required for the compounding of a preparation associated with each specific active ingredient; • Robot compounding speed. In addition, the pharmacy has also tried to identify the optimal organisation of personnel and daily workflow for the automated compounding. The effectiveness of these measures and the work organisation defined have been evaluated through an intensive compounding week in April 2018.

What has been achieved?

The analysis of the active substances and the data collected during the “Robotic Intensive Week” showed the following results: • 42% of the total production was operated by APOTECAchemo; • 87% of active ingredients was handled by APOTECAchemo; • average of 60 preparations per day (with an actual working time of 5 hours); – average of 12 preparations per hour.

What next?

The study shows that the planning and organisation of the workflow plays a central role in the implementation of a robot solution in a hospital pharmacy. Through the work carried out, the hospital pharmacy has successfully integrated automated and manual production.

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Author(s)

Kirsten Lykke Vorbeck

Why was it done?

When preparing treatments for blinded clinical trials it is very important to make sure that it is not possible to distinguish between the active and the placebo dose, as this may lead to unblinding of the treatment and thus jeopardise the results of the trial.

What was done?

The purpose was to find solutions for how to handle active and placebo drugs in the production system CATO to ensure they would end up being identical when prepared.

How was it done?

Before preparing a drug using CATO the drug must be registered in the system with all of its data. It is not possible to have two different sets of data for one drug. CATO records detailed documentation of what is being done during preparation and it is not possible to pretend to pick one drug and then grab another instead. Also, the label is printed automatically so it will show exactly what was prepared. We decide on a common name for the active/placebo and register both of these in the system under that name so that they will be prepared in exactly the same way and appear identical on the label but are still distinguishable in the batch documentation. We name the drug ‘Protocol name Active substance/placebo’ and register the stock of both active drug and the sodium chloride solution that is used as placebo under that name. We will also stock vials of NaCl for this purpose next to the drug it is being placebo for, and NaCl can be prepared pretending it has the density of the drug. CATO will think they are the same drug but they have been registered with their very different batch numbers, maybe with a NaCl after the number of that, so it is always possible to see what was actually being prepared.

What has been achieved?

Our doses of active and placebo are indistinguishable. Labels are the same and, for example, withdrawal into a syringe and insertion of a needle into the port of the infusion bag will be done in the same way.

What next?

These very simple routines can be used anywhere for the preparation with CATO and possibly also with other systems.