3D-PRINT OF ORALLY DISINTEGRATING TABLETS – HOW TO GET STARTED
Pdf
European Statement
Production and Compounding
Author(s)
K. Koch, The Pharmacy of the capital region of Denmark, Quality, Herlev, Denmark
R. Højmark, The Pharmacy of the capital region of Denmark, non-sterile production, Herlev, Denmark
L.R. Duckert, The Pharmacy of the capital region of Denmark, non-sterile production, Herlev, Denmark
T. Schnor, The Pharmacy of the capital region of Denmark, production, Herlev, Denmark
Why was it done?
There is an interest in implementing more safe, affordable, and sustainable treatment methods for patients for whom a personalized approach is beneficial. These treatments can be expensive and associated with patient safety and compliance issues. For the pediatric population, many medications are not available in appropriate form or dose and therefore is being manipulated before administration. Extemporaneous oral solutions often have a limited shelf life and bad physical properties or undesirable excipients.
Patients with impaired renal function or need for accurate dose adjustments are also expected to benefit from 3D-printed orally disintegrating tablets (OTDs).
What was done?
The initial steps necessary before implementing 3D-printing for manufacturing personalized ODTs has been identified and completed. The clinical advantages and barriers of the personalized treatment has been discussed interdisciplinary and the new dosage form has been risk evaluated in dialogue with the competent authority. As a result, the best suited technology has been identified.
How was it done?
The European marked has been searched for technologies suitable for extemporaneous personalized production in hospital pharmacies. 3D-printed OTDs was identified as most easily implemented both concerning technology, GMP and patient acceptance.
A dialogue about risks and benefits regarding 3D-ptinted ODTs was initiated with the hospital staff. Risks identified concerned the number of drugs available for 3D-printing, the need for stability testing and resistance from authorities. Benefits like flexibility, just-in-time preparation and patient safety was identified.
A meeting was held with the competent authority, to establish the level of validation, documentation and analysis needed on the final product and starting materials.
What has been achieved?
The necessary steps to get started have been identified and completed. Risks and benefits were assessed, and the decision about implementing 3D-printed ODTs was made. An equipment that is reliable and automated has been sourced.
An API for the initial manufacture was selected, combining clinical relevance and adequate physical properties.
Ink/matrix for the 3D-printer was evaluated and found safe for medicines for children. The matrix is manufactured according to GMP.
A regulatory framework has been agreed upon with the competent authority.
What next?
Validation of the equipment and printing of the first ODTs to be used in the clinic.
DEVELOPMENT OF PHARMACY CRRT SOLUTIONS SERVICE AT KING CHULALONGKORN MEMORIAL HOSPITAL, THE THAI RED CROSS SOCIETY
Pdf
European Statement
Production and Compounding
Author(s)
Phontep Wongkrasoe; Wongsathorn Padungsupalai
Why was it done?
Premixed customize CRRT solutions were compounded by sterile pharmacy.
What was done?
According to the medication management policy, CRRT solution was defined as
High Alert Drugs that require the independent double check throughout the
medication use system. Conventional methods (prepared by nurses) take many
risks and may affect the quality of ICU-patients care by spending more time
for preparing.
How was it done?
Nephrologists, nurses, and pharmacists made a consensus for standard
customized CRRT solution formulas and clarified the ordering (for physician),
dispensing (for pharmacist) and preparing (for nurse to add potassium)
instructions. The procedure for compounding CRRT solutions by sterile
pharmacy was established to optimize traceability aspects as a quality
assurance. With the large batch size compounding, we mockup the preliminary
batch to identify the risk and assure the consistency of compounding process.
Quality control was planned to measure electrolyte content and test sterility
at D0, D7 and D14 at room temperature and refrigerated storage. After the
preliminary batch test was accepted, we started a pilot service in one ward
and reached the maximum service capacity at only one patient per day. The
pharmacists redesigned the compounding process, and the repeater pump was
introduced to increase capacity. Because the product was changed in total
volume from one liter to 1.2 liter, we conducted the preliminary batch test
again. Teams revised the ordering, dispensing, and preparing instructions and
expanded the service to 7 ICU wards.
What has been achieved?
We formulated 2 CRRT solutions in the name of “Chulasol-22 1.2 liter” and
“Chulasol-35 1.2 liter” with BUD 14 days at room temperature storage. The
results were (1) we can provide the CRRT solution for maximum 5 patients per
day compared to only one patient per day in the initial period, (2) the cost
of pharmacy compounded solution was much lower than conventional method or
comparable commercial solution and (3) most nurses (91%) were satisfied in
product quality and had more time for patient care.
What next?
The success of this model was a multidisciplinary engagement that resulted in
improvement of patient care. We use this model in other services such as pain
preparations and eye preparations.
The European Paediatric Formulary: a reinforced approach for improved monographs
Pdf
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.
A risk-based choice of syringes and associated equipment for compounding and intravitreal administration of drugs for wet age-related macular degeneration
Pdf
European Statement
Production and Compounding
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.
Development of an oral ketamine: compounding and creation of a pharmaceutical care circuit for phantom limb syndrome
Pdf
European Statement
Clinical Pharmacy Services
Author(s)
Javier Corazón Villanueva, Natalia Sanchez-Ocaña MartínPast, Virginia Puebla García, Lidia Ybañez García, Maria De la Torre Ortíz, Paloma Pastor Vara, Maria Fernandez-Vazquez Crespo, José Manuel Martínez Sesmero
Why was it done?
The PLS is the perception of a non-existent limb that may occur in up to 80% of amputees. The management of this syndrome is complex and alternative drugs are sometimes used for the treatment. The absence of a marketed formulation, off-label use of drugs and the complex treatment of pain make the role of the pharmacist essential.
What was done?
Development and validation of an oral ketamine compound and a specific pharmaceutical care circuit (PCC) as a part of the treatment of phantom limb syndrome (PLS).
How was it done?
A literature search was carried out on the preparation of this compounding, as well as on the use of oral ketamine (bioavailability, dosage, adverse reactions).
An oral solution of 10mg/ml was prepared (final volume 50ml: 500 mg of injectable ketamine solution or raw material, 20 ml of simple syrup with a sufficient amount of purified water and 2 drops of lemon essence). To establish the expiration date recommendations of Good Manufacturing Practice Guideline were followed and the organoleptic characteristics were evaluated for quality control.
The PCC created consists of the following stages:
1. Setting up a first presential visit to provide pharmaceutical care during admission: to inform the storage conditions, most common adverse effects and recommendations about medication intake.
2. Dispensing at discharge and initially appointments every 7 days for a closer follow-up: control of adverse reactions (confusion, agitation, nausea, etc.), monitoring of the appropriate use of ketamine and other analgesic medication (avoiding possible abuse and addictive behaviour) and pain control. Pharmaceutical interventions are communicated to the pain management unit (PMU).
3. Spacing of visits fortnightly once the treatment is well-stablished and proposing a telepharmacy service.
What has been achieved?
The ketamine formulation developed has been used in our hospital in three patients with satisfactory results. The interventions carried out were: pain control problems, possible inappropriate use, reduction in the number or dosage of concomitant medication or ketamine itself.
What next?
The capacity to provide therapeutic alternatives and a more exhaustive pharmacological control of pain in collaboration with the PMU can improve the safety and effectiveness of these treatments.
COMPOUNDING AUTOMATION OF NON-STERILE EMULSIONS
European Statement
Production and Compounding
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.
PUBLICATION OF THE FIRST TEXTS IN THE EUROPEAN PAEDIATRIC FORMULARY (submitted in 2019)
Pdf
European Statement
Production and Compounding
Author(s)
Jane Francomb, Dirk Leutner
Why was it done?
Formularies for extemporaneous formulations of paediatric medicines of appropriate quality are currently available in some regions or countries, but no pan-European equivalent exists. Some formulations in use are not appropriate due to a lack of knowledge of best practices. The idea behind the new formulary is to collect, review and then select the most appropriate formulations currently used in Europe which meet today’s requirements.
What was done?
The European Paediatric Formulary was launched at the end of 2019. It is a freely available online publication for pharmacists and clinicians that is intended to provide guidance on the use and preparation of standardised paediatric medicines of an appropriate quality when a suitable licensed medicinal product is not available. The first two monographs and two explanatory texts of the European Paediatric Formulary have now been published by the European Directorate for the Quality of Medicines & HealthCare (EDQM).
How was it done?
Criteria for selection and evaluation of formulations were developed by 2015. Since then the current work is carried out by the European Paediatric Formulary Working Party under the supervision of the European Pharmacopoeia Commission and the European Committee on Pharmaceuticals and Pharmaceutical Care (CD-P-PH). The EDQM provides the scientific secretariat. Monographs for development were prioritised based on patient need. Many formulations currently described in national formularies and other well-established formulations have been gathered from stakeholders throughout Europe. The information available for the most appropriate formulation was transferred into a common format with full quantitative composition details, extemporaneous preparation instructions, validated test methods for quality control and storage conditions.
What has been achieved?
Monographs for hydrochlorothiazide 0.5mg/mL oral solution and sotalol hydrochloride 20mg/mL oral solution were published at the end of 2019. These were accompanied by an introduction and general principles which describe the purpose and content of the European Paediatric Formulary.
What next?
Monographs for Azathioprine oral suspension, Chloral hydrate oral solution, Furosemide oral solution, Isoniazid oral solution, Omeprazole oral suspension and Ranitidine oral solution and a monograph on an oral vehicle are currently under development. Further prioritised items will subsequently be added. Draft monographs for public consultation and final texts will be made available on https://paedform.edqm.eu.
PRODUCT DOSSIER AND RISK EVALUATION FOR EXTEMPORANEOUS PREPARATIONS KEEPS FOCUS ON PATIENTS (submitted in 2019)
Pdf
European Statement
Production and Compounding
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.