Author(s)

Alessandro D’Arpino, Fiorenza Enrico, Caterina Donati, Simone Leoni, Giorgia Longobardo, Marco Bellero, Alessandra Bianco, Giuseppe Zacchi, Anna Zaltieri, Stefano Monica, Nicolò Squartini, Matteo Federici

Why was it done?

In most of Italian healthcare organizations, the large majority of non-cytotoxic IV medications are prepared in clinical environment by nursing staff. This is recognized as a complex and labour-intensive process that entails various risks of potential medication errors (microbial contamination, wrong reconstitution/dosing). Centralizing the preparation from the clinical environment to the pharmacy in order to provide ready-to-administer IV medications represents a strategy to improve safety and prevent medication errors.

What was done?

The community of APOTECA technology users is committed to fostering co-de¬sign of technology based on the hospitals’ needs and sharing best practices for improving hospital pharmacy services. During a meeting taken place in September 2021, a panel of hospital pharmacists belonging to APOTECA community laid the groundwork for centralized preparation of non-cytotoxic intravenous (IV) drugs and establishment of Central Intravenous Additive Service (CIVAS) in Italian hospital pharmacies.

How was it done?

The following methodology was adopted to promote a standard profile of centralization: (1) definition of criteria for the selection of drugs suitable for centralized preparation, (2) identification of IV medication classes for which preparation should be centralized due to intrinsic risks and demand, (3) evaluation of potential benefits, (4) discussion on organizational challenges regarding the establishment of CIVAS, (5) assessment of the role of automated preparation with robotics.

What has been achieved?

Five selection criteria to centralize drugs were mentioned: long-term stability data, frequency of use, cost, complexity of preparation, microbial contamination risk. Continuous infusion of antibiotics, vasoactive drugs, anaesthetics, pain medications, intravitreal injections, and patient-individual doses for paediatric patients were chosen as eligible IV medication classes to implement centralized preparation. Major benefits of centralization were pointed out, i.e. proper aseptic preparation, perspective quality controls, process traceability, reduced drug wastage, and releasing nursing time to care. Logistics, inventory management, limited space, and inadequate quality control units were identified as main challenges to the CIVAS establishment. Participants agreed that robotics plays an important role to minimize repetitive manual activities, optimize working efficiency, and increase pharmacy production capacity, thereby streamlining the introduction of CIVAS.

What next?

A close collaboration between healthcare staff and hospital pharmacy will be essential to evaluate the feasibility of centralized preparation as well as its clinical and cost-effectiveness.

Author(s)

María Molinero, Virginia Puebla, Cristina González, Lidia Ybáñez, Gonzalo Hernando, Natalia Sánchez-Ocaña, Javier Corazón, María de la Torre, Jose Manuel Martínez

Why was it done?

This technique provides autonomy to the patient allowing to adjust the dose based on the intensity of pain. It has been demonstrated that small on-demand doses of analgesia provide a reduction in the final dose, thus reducing side effects. In addition, by minimizing the possible delay in the administration of analgesia, the anxiety associated with pain and exacerbations is reduced.

What was done?

Hospital Pharmacy Service in collaboration with Acute Pain Unit has developed a protocol for an analgesic mixture for intravenous administration in continuous infusion based on tramadol, dexketoprofen and haloperidol. It is a patient-controlled analgesia (PCA) administered by pump for the treatment of acute postoperative pain.

How was it done?

We performed a bibliographic search of stability studies in order to standardize the analgesic mixture, guaranteeing its physical-chemical and microbiological stability.

What has been achieved?

A mixture of 600mg tramadol, 300mg dexketoprofen and 5mg haloperidol was prepared and it was filtered through a 5-micron filter. It was diluted in 100mL of 0.9% sodium chloride, obtaining a mixture of 125mL. It was sealed and bagged in a photoprotective bag. After the bibliographic search on stability data and physical-chemical compatibility of the mixture, a stability of 14 days at 2-8 ºC was established. Once elaborated, quality control was performed by gravimetry. It was dispensed weekly by stock to the post-anesthesia resuscitation unit. The established perfusion rate is 1.3 mL/h or 1.7 mL/h for 48h. With each rescue, 8mg of tramadol and 4mg of dexketoprofen are released per hour or 4mg and 2mg every 30min, respectively. The maximum dose that can be administered is 400mg tramadol, 150mg dexketoprofen and 2mg haloperidol, except if the patient weighs less than 50kg: 8mg/kg tramadol. If renal insufficiency, dose adjustment was mandatory.

What next?

The centralization of the preparation of intravenous admixtures from the pharmacy service allow us to adjust the expiry date based on stability studies reported in the literature, to maintain the asepsis of the mixture as it is prepared in horizontal laminar flow cabinets, to increase the safety and to secure the traceability.

Author(s)

Rui Relvas, Rui Pedro Marques, Ana Castro, Sérgio Nobre, João Paulo Lopes da Cruz

Why was it done?

Medicines compounding by the HPS-staff is a primordial activity, and its centralisation allows several benefits in levels such as patient safety, quality, efficiency, and pharmacoeconomics. Despite this recognised importance, it is not always possible to quantify its added value. The fact that vaccines against SARS-CoV-2 are supplied in multi-dose vials and the need to prepare and assure enough doses to vaccinate a broad population presented itself as an excellent opportunity to analyse such indicators.

What was done?

A quantitative analysis of the importance and added value of centralised preparation and compounding of vaccines against SARS-CoV-2 at the Hospital Pharmaceutical Services’ (HPS) Compounding Unit from a Central Hospital in Portugal.

How was it done?

Between 27th December 2020 and 2nd August 2021, 13.030 doses were prepared (96.9% Pfizer/BioNTech; 3.1% AstraZeneca). At the first 3 vaccination sessions, multi-dose vials were diluted at the HPS, and each syringe measured by the nursing-staff previously to the administration.
After these initial sessions, each dose started to be individualised by the HPS-staff on pre-filled, ready-to-use syringes. Each vaccine dose was individualised on a horizontal laminar flow cabinet according to a previously approved operational procedure.
Reception, preparation, and dispensation records were retrospectively analysed. Key performance indicators were quantified.

What has been achieved?

During the first 3 sessions of vaccination, when nursing-staff measured each vaccine volume, a total of 1640 doses were administered. However, it would be possible to measure a total of 1932 doses (84,9%). The daily maximum of people vaccinated was 770.
In the following sessions was possible to prepare 11.390 doses, with a theoretical maximum of 10.892 (104,6%) and a daily maximum of 1.113.
This yield, over 100%, allowed an excess of 498 doses, which translated into the vaccination of 249 extra individuals fully vaccinated with the 2 doses. Factors like needle and syringe selection and preparation beyond an aseptic and validated environment contributed for the yield increase.

What next?

Series-production of compounded medicines in a sterile, validated, and controlled environment allows important benefits and this analysis shows the potentiation of every key performance indicator considered. These data should be considered for the future planning of population-wide activities involving the massive preparation of sterile medicines.

Author(s)

Lidia Ybañez, Virginia Puebla , Cristina Gonzalez, María Molinero, Estefanía Rosón, Gonzalo Hernando, Natalia Sanchez-Ocaña, María De la Torre, Javier Corazón, Jose Manuel Martinez-Sesmero

Why was it done?

In 2020, Compounding laboratory’s activity increased as a result of COVID-19 pandemic. In order to achieve new needs and requirements, we decided to introduce a mixing and emulsifying robot. Improvement in productivity would also allow us to elaborate formulas that were previously outsourced (such as selective digestive decontamination (SDD) solution and oropharyngeal paste), thus saving money. The effectiveness of this measures was evaluated from April 2020 to April 2021.

What was done?

An emulsifying-mixing device for non-sterile oral and topical formulation was introduced at the pharmacy’s compounding laboratory. A reorganization of laboratory workflows was implemented to ensure an optimal use of the device.

How was it done?

We performed a needs assesments plan to determine what needs to be accomplished to reach our project goals (Good Manufacturing Practices (GMP) compliant. Formulas suitable to be compounded in the robot were selected. A reorganization of the daily practice was performed to achieve an optimal workflow.

What has been achieved?

Seven product formulations and 3 excipient formulations were suitable for being produced by robot (SDD solution and oropharyngeal paste being two of them, (11536 single dose packages of SDD solution and 5977 of oropharyngeal paste have been prepared throughout the year ).
37202€ have been saved by producing the SDD solution and paste instead of outsourcing its production. The investment required to purchase and operate the robot was approximately 2600 euros.

What next?

Compounding automation improves efficiency and productivity (as we have been able to produce formulas that were previously outsourced), saving costs. Robot has been successfully incorporated into daily practice in a Hospital Pharmacy compounding laboratory. Its implementation has allowed the optimization of available resources (especially during the pandemic) and significant financial savings for the Hospital.
By implementing this device, other hospitals will be able to improve their production processes for non-sterile medicines in compliance with GMP.

Author(s)

PILAR RANZ ORTEGA, MARÍA ARRIETA LOITEGUI, DANIEL GONZALEZ ANDRES, ANA MARÍA AGUI CALLEJAS, MARIA TERESA POZAS DEL RIO

Why was it done?

– Optimize the workflow:Nursing staff are independent in final product quality control.Dissapear the manual register of compounding sterile preparations.Fewer mixtures are discarded.Also in Pharmacy Service only elaborate the sterile preparations with an economic and safety impact.

– Improve the safety of drug administration in pediatric patients: there are ready-to-use commercial parenteral presentations, which can lead to errors when dosing per kilo,fe: enoxaparin…

– Optimize economic savings:all excess vials are reused

What was done?

Previously,some parenteral drugs were compounded at Pharmacy Service.The rest of the vials were discarded daily,so the pharmacist had to anticipated some elaborations not to throw,so then some were suspended.
Also, the pharmacists done the final product quality control,it could be delayed the dispensing and specially when it´s necessary to repeat the mixture.

The changes were:

– Re-selection of the parenteral drugs compounded at Pharmacy Service by:
• Economic criterio:the cost of drug has to be >20 euros/vial
• Safety for the pediatric patient:redose individually parenteral drugs “readytouse”

– Review the storage conditions:physicochemical (technical data sheet drug,Stabilis web) and microbiological stability (Good practices for preparation drugs in hospital pharmacy services publised by Spain Goverment) of all parenteral drugs previously selected.Although the physicochemical stability is higher,the final stability will be limited by the microbiological stability and the risk level microbial contamination(USP 2004).

– Standard Operating Procedures with structured and updated information

– Reuse of partially used multi dose vials:we reviewed the physicochemical and microbiological stability of open vial

– Final product quality control by nursing staff

– Save time to pharmacist:daily scheduling instead of anticipated elaboration of sterile preparations

How was it done?

– A nurse involved in the circuit change giving her feedback on the changes

– Traceability of the rests of the vials:stickers are affixed to the opened vials indicating the reconstitution data and the expiration date

– Final product quality control should be done by a diferente nurse to elaborated to detect potencial errors

What has been achieved?

The total cost savings for this year is 295.778€. After the circuit´s change, the savings have increased by 55% for liposomal amphotericin b, 51% defibrotide, 24% micafungin.

What next?

Compounding sterile preparations individualized in Pharmacy Service to patients hospitalized at home, transplanted of hematopoietic progenitors and immunocompromised

Author(s)

Mette Lethan, Tove Hansen, Trine Schnor, Louise Rasmussen Duckert

Why was it done?

Oral vancomycin 125 mg four times a day for 10 days, is the common treatment for antibiotic-associated clostridium difficile colitis. As solid oral formulations are unsuitable due to strong diarrhea, an i.v. formulation in a diluted form (10 mg/ml) is used. However, several issues with that use, required the need for creating a new formulation.
The product is used for treatment of kids and adults, often with nausea. The low strength requires large volumes of solution and with no flavoring the liquid is very bitter.
Furthermore, the current solution has a limited stability causing difficulties as it is often desired to treat the patients at home. Therefore, a wish arose for a new formulation with a higher concentration, better stability and improved organoleptic qualities.

What was done?

A new oral formulation of Vancomycin was developed to improve the treatment of antibiotic-associated clostridium difficile colitis. The new formulation consists of the active ingredient (API) Vancomycin as a powder with a solvency for dissolving prior to use.

How was it done?

To obtain the best stability it was selected to make a new formulation consisting of a premeasured API, with a solvency ready to mix before use, to obtain a final strength of 50 mg/ml and a volume equivalent to 48 hours of doses.
Vancomycin in pharmacopeia quality was acquired and analyzed. A solvency was formulated mostly consisting of water, conservation and orange flavoring. A test was conducted with a weighed-out API to ensure that it was dissolvable with the solvency in the selected packaging.

What has been achieved?

A product achieving the wanted changes was tested and made. Making a formulation consisting of a premeasured powder creates the possibility of a higher durability. When mixed with the flavored solvency, the wanted strength is achieved.
The new formulation can be stored at room temperature before dissolving. It can be dissolved by the patient before use and kept refrigerated until the full volume is used. The product is easy for the patient to handle and therefore enables treatment in the patients own home.

What next?

A new product was made. Final use by patients will be tested for ease of use and potential home treatment.

Why was it done?

To solve a problem with a foot wound of a young man not responding on the standard secondary surgical healing intention wound treatments, that appeared at the General surgery department of our hospital.The wound was infected with 2 bacteria, S. aureus and Enterococcus species.The patient was quite long time treated with i.v. antibiotics without result.The wound infections are one of the biggest common nosocomial problems that demand special professional team engagement.

What was done?

Compounded an extemporaneous sterile vancomycine and gentamycine solution for secondary healing intention wound treatment.

How was it done?

A responsible pharmacist being alone on an afternoon duty, initiated a topical application of sterile antibiotic solution according to wound’s antibiogram.The surgeon demonstrate suspicion due to lack of that kind of experience/practice.So 100 ml solution was prepared under sterile conditions of the Department for infusion solutions production in our hospital, containing 50 mg/ml vancomycine and 1.2 mg/ml gentamycin in a 0.9% sodium chloride sterile and nonpyrogenic solution for i.v. administration.According to the SmPCs of the antibiotics manufacturers we determined 7 days expire after production, kept on room temperature.

What has been achieved?

A departmental surgeon has accepted the initiative and treated the wound twice daily at the surgery department.On the second day of applying, the wound edges held closely together and the wound has started epithelialisation.There were not any allergic reactions, significant tingling, itching and pain on the skin around the wound.On the third afternoon of introducing the solution use, the patient was discharged home and reassigned for an ambulatory treatment i.e. daily hospital, for once daily wound washing with the sterile solution.We prepared the second dose of the solution on the 7th treatment day and the wound was healed on the 13th day.

What next?

To incorporate this GPI into daily surgical standard procedures for bacterially infected wounds for a best patient issues.

Author(s)

Denise van der Nat, Anouk Lindemans, Laurens van Rijn, Wilfred Weijers, Elisabeth Ruijgrok

Why was it done?

COVID-19 is an ongoing worldwide pandemic which causes millions of deaths. To reduce COVID-19 mortality and morbidity, vaccines are developed. However, preparing COVID-19 vaccines before administration is a time consuming process. To accelerate this process and increase efficacy for health care workers, the Vaxtractor was designed in January 2021. We aimed to examine the quality of COVID-19 vaccines prepared with the Vaxtractor.

What was done?

Development and testing of a device (Vaxtractor) for semi-automatic large-scale preparation of COVID-19 vaccines.

How was it done?

With the Vaxtractor, the desired volume of vaccine is drawn up automatically in syringes from two vials of vaccine simultaneously. A sterility test, measurement of accuracy and uniformity of dosage units tests were performed in September and October 2021. For the sterility test, 22 syringes were filled with 0.5 ml Tryptic Soy Broth and these were incubated at 25°C for seven days followed by a seven day incubation period at 30°C. For the accuracy and uniformity of dosage units test, 60 syringes were filled with vaccine. Subsequently, the filled and emptied syringes were weighed. Furthermore, a time analysis was performed on manually and semi-automatically prepared COVID-19 vaccines.

What has been achieved?

The sterility test showed no visual sign of growth of micro-organisms. Furthermore, the weight of 60 prepared Spikevax® vaccines deviated less than 5% compared to the average weight of the vaccines. Also, the observed volume per vaccine deviated less than 5% compared to the declared volume. Besides that, preparing COVID-19 vaccines with the Vaxtractor was about three times faster compared to manually prepared vaccines and reduced the risk of needlestick injuries.

What next?

The Vaxtractor can be used to safely prepare Spikevax® vaccines. In the next months we will assess the quality of preparing Comirnaty® vaccines with the Vaxtractor. If these results are positive, the device can be implemented at large scale at the in- and out-of-hospital setting. This will contribute to effective upscaling of COVID-19 vaccination.

Author(s)

CARMEN MARÍA VALENCIA SOTO , ADELA GARCÍA-AVELLO FERNÁNDEZ-CUETO, SARA BARBADILLO VILLANUEVA, MARÍA OCHAGAVÍA SUFRATEGUI, MARÍA VICTORIA VILLACAÑAS PALOMARES, VIRGINIA MARTÍNEZ CALLEJO , MARÍA MARTÍN LÓPEZ, MARÍA RIOJA CARRERA, PAULA DEL RIO ORTEGA, MARTA VALERO DOMÍNGUEZ

Why was it done?

This project aimed to optimize security in the production workflow through automation of anti-cancer drugs compounding.
The use of recognition systems and gravimetric control guarantee traceability and accuracy in the compounding process, therefore improving patient safety.
Robotic systems avoid exposure to cytotoxic drugs, promoting healthcare operator safety. Moreover, once loaded, it runs automatically, liberating the operator for more complex preparations.

What was done?

In 2021, our hospital pharmacy implemented APOTECA platform, including management software (APOTECAmanager), two guided preparation systems for semiautomatic compounding (APOTECAps) and a robotic system for aseptic preparation of antineoplastic drugs (APOTECAchemo).

How was it done?

We configured each drug in the management software: dimensions, density, stability and expiration data, solvent, bags and transfer set information, QR code, etc.
A 3-phases process was scheduled:
– Integration between APOTECA and the hospital’s Electronic Prescribing Software (EPS). Carried out between November and December 2020.
– Training period: 8 weeks between May and July 2021, including pharmacists and technicians with progressively incorporation to real compounding.
– Real production analysis: 8 weeks between July-September 2021 (38 days, excluding weekends and bank holidays). Previously trained staff gradually trained the rest of the personnel.

What has been achieved?

During the 8 weeks considered, 4629 doses were elaborated, excluding clinical trials preparations.
APOTECA production supposed 85% (3944) of our daily compounding: 62,8% (2475) with the 2 semiautomatic systems and 37,2% (1469) with the robot. 99% of the doses prepared in APOTECAchemo were infusion bags and 1% syringes. In APOTECAps, 85% were infusion bags and 15% syringes.
Average dosage error for all preparations was 0,95% (±1,13) for APOTECAchemo and 1,57% (±1,31) for APOTECAps.
Up to data collection, 67 substances that fulfilled the criteria had been processed in APOTECA system and 41 of these in APOTECAchemo.
The top five ingredients compounded in APOTECA were: paclitaxel, carboplatin, pembrolizumab, etoposide and fuorouracil.

What next?

The implementation of this technology has improved patient and operator safety, as well as our daily workflow.
To ensure an optimal use we need to increase robot production by optimizing its operating hours and promoting more preparations in advance.

Why was it done?

The pharmacy received a request for reconstitution of an ATMP Luxturna. The pharmacy or hospital did not have a suitable aseptic facility that could perform the reconstitution in a way that allowed the ATMP to be administered to patients before the expiry after reconstitution (max. 4 hours).

What was done?

Development of a single use isolator for advanced therapy medical products (ATMP) or gene therapy drug preparation was undertaken. The single use isolator had to be mobile to enable pharmacy staff to preform reconstitution directly on ward or in OP-theatre. It had to comply with Health and Safety regulations and at the same time make it possible for pharmacy staff to use aseptic technique to be able to reconstitute ATMP.

How was it done?

A review of isolator technology was performed, and a suitable solution identified. The set-up was further developed in a team with representatives from pharmacy, the eye department at Rigshospitalet-Glostrup. A manufacturer of the equipment was selected, and development performed. The set-up for ATMP preparation was presented to The Danish Health and Safety (DHS) department responsible for handling this type of treatment. The approval was granted after a standard 90-day period. Pharmacy staff were trained in working with the set-up and a dry run made in the eye theatre with the full surgical team.

What has been achieved?

10 patients (19 eyes) have been treated, 4 male and 6 female patients with age span 12-39 years. After having performed the procedure twice there was enough routine to treat 2 patients per theatre day hence reducing the cost of preparation and increasing efficiency of the team.
The pharmacy and surgical team have established a great working relationship and now consider the set-up as routine.
In spring 2021 the set-up was approved by (DHS) for reconstitution of Zolgensma. On July 1 a pediatric patient was treated with Zolgensma using the method.

What next?

Plan to develop the method further and make it available for coming preparations of ATMPs and share knowledge of the method with other hospital pharmacy organizations.