Aleksandra Opalska is a policy officer at the European Commission in the Directorate-General for Health and Food Safety in the unit responsible for medicines: policy, authorisation and monitoring. She works on antimicrobial resistance, COVID-19 pandemic and pharmacovigilance related activities. She is a pharmacist by training. She is a professional PhD candidate with the Utrecht Centre for Pharmaceutical Policy and Regulation.

Abstract:
European regulatory and policy aspects of preventing and combatting antimicrobial resistance (AMR)
Aleksandra Opalska
Directore General for Health and Food Safety, European Commission, Brussels, Belgium

Antimicrobial resistance (AMR) is an increasing threat to public health. It is responsible for more than 35.000 deaths every year in the EU. The fight against AMR has many layers and requires not only financial and behavioral changes, but also comprehensive legal and regulatory interventions. Urgent measures are required to boost development of antimicrobials and strengthen their prudent use. In response to this multifaceted challenge, EU regulators have recently taken several actions, including the recent Commission proposal to review the EU pharmaceutical legislation and a Council Recommendation on stepping up EU actions to combat AMR in a One Health approach.

Dr. András Süle is currently the Director of Pharmacy at the Péterfy Hospital located in Budapest, Hungary. He is a guest lecturer and lead developer of the Hospital Pharmacy Specialization Program at Semmelweis University, Budapest. He is the chief pharmacy advisor at Hungary’s largest private hospital, Duna Medical Center. In 2008, Dr Süle obtained a PhD from Semmelweis University and has since gone on to complete a PharmD Specialisation in Pharmaceutical Technology and a PharmD Specialisation in Clinical Pharmacy. He also holds a BSc in Healthcare Management.
Besides his service within the European Association of Hospital Pharmacists (EAHP), he serves as the President of the Hungarian Chamber of Hospital Pharmacists. At EAHP he held the positions of Director of Professional Development, Director of Finance and President-Elect. In June 2021 he started his 3-year term as EAHP’s President.

Abstract:
Challenges we face: being a hospital pharmacist in the 21st century
Andras Sule
European Association of Hospital Pharmacists, Brussels, Belgium

European hospital pharmacy workforce is evolving but an equally rapid adaptation from healthcare systems is also needed to facilitate the changing roles of hospital pharmacists and the increasing need for their involvement in clinical care teams to enhance patient safety. To better inform policy decisions at both European and national levels, the European Association of Hospital Pharmacists (EAHP) conducted an investigation of the hospital pharmacy profession in Europe and put forward a set of suggestions on how to move forward in these dimensions. 

Both the results from EAHP’s Investigation and exchanges with EAHP member associations on the workforce issues that they are facing showed how vital the engagement of hospital pharmacists is but how difficult it is for them to carry out all tasks with limited resources. Clinical, patient-facing services have not developed as much compared to the more traditional pharmacy services due to the lack of capacity (not having enough staff), other healthcare professionals offering these services and this not being a priority for hospital managers. The capacity problems are also confirmed by figures from EAHP’s Investigation which indicate that many hospitals employ low numbers of pharmacists and technicians in relation to the number of beds they contain. New developments are also not reaching all European countries equally. Pharmacist prescribing is established in some countries like the United Kingdom but is not legally permissible in the majority of Europe.

In light of the Investigation and the changing roles of hospital pharmacists, EAHP’s member associations signalled the need for further growth and adjustment by the profession. Pharmacy prescribing and lowering the impact that hospital pharmacists have on the environment were identified as future priorities. Concerning sustainability, EAHP has created a Working Group comprised of experts from different European countries that is developing a roadmap for the Association. In the context of EAHP’s changing roles initiative, the topic of pharmacy prescribing is being explored based on the experiences of EAHP’s member associations together with the possibility of issuing micro-credentials. An introduction of such a system would be especially beneficial for countries that do not yet have a specialisation programme in hospital pharmacy. In addition, it would also offer those countries with a specialisation programme the opportunity to enhance continuous education possibilities for its hospital pharmacists.

In conclusion, it can be said that the role of the hospital pharmacist and his/her visibility in the care team on wards need to significantly improve in all European countries. EAHP’s advocacy work on the hospital pharmacy workforce should ensure better long-term planning at the national level. Micro-credentials attesting certain skills could be a tool for boosting the professions’ attractiveness.

^{Abstract:
Challenges we face: being a hospital pharmacist in the 21st century
Anikó Borbás
1}Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary,

²HUN-REN Molecular Recognition and Interaction Research Group, University of Debrecen, Debrecen, Hungary

The rise of multidrug-resistant (MDR) bacteria and the emergence of deadly zoonotic human viruses pose a serious threat to world health. At the top of the list of pathogens that cause serious, often incurable infections are Gram-negative bacteria, which directly cause about 1.5 million deaths per year. Among Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae cause some 0.5 million deaths each year. [1] The COVID-19 pandemic has drawn attention to the limited supply of antiviral drugs, which, together with the growing problem of antiviral drug resistance, poses significant health, social and economic risks.

Glycopeptide antibiotics are a class of cell wall biosynthesis inhibitors used to treat drug-resistant Gram-positive bacterial infections. In addition to their well-known antibacterial activity, glycopeptide antibiotics have been shown to exert some activity against a variety of enveloped viruses. [2]

Over the past decade, our group has systematically modified the glycopeptide antibiotics vancomycin and teicoplanin to broaden their antibacterial activity toward vancomycin-resistant Gram-positive bacteria and even Gram-negative bacteria. [3-5] We have also developed semisynthetic glycopeptides that are highly effective against devastating viruses such as influenza, Zika, SARS-CoV-2, etc. [5-8]

In this lecture, synthetic design, antibacterial and antiviral evaluations and SAR analysis of our semisynthetic glycopeptide derivatives will be presented.

References

[1] E. van Groesen, P. Innocenti, N. I. Martin, ACS Infect. Dis. 2022, 8, 1381−1407.

[2] I. Bereczki, H. Papp, et al. Pharmaceuticals, 2021, 14, 1111.

[3] Z. Szűcs, I. Bereczki, E. Rőth, M. Márton, E. Ostorházi, G. Batta, L. Nagy, Z. Dombrádi, A. Borbás, P. Herczegh, J. Antibiotics, 2020, 73, 603–614.

[4] I. Bereczki, V. Vimberg, et al. Sci. Rep. 2022, 12, Article number: 16001.

[5].Z. Szűcs, I. Bereczki, F. Fenyvesi, P. Herczegh, E. Ostorházi, A. Borbás, Sci Reports, 2022, 12, 20921.

[6] Z. Szűcs, V. Kelemen, et al., Eur. J. Med. Chem. 2018, 157, 1017-1030.

[7] Z. Szűcs, L. Naesens, A. Stevaert, E. Ostorházi, G. Batta, P. Herczegh, A. Borbás, Pharmaceuticals, 2020, 13, 139.

[8] Bereczki, M. Csávás, Z. Szűcs, E. Rőth, G. Batta, E. Ostorházi, L. Naesens, A. Borbás, P. Herczegh, ChemMedChem, 2020. 15, 1661–1671.

Abstract:
Biosimilars and Next Generation Therapeutic Antibodies
Attila Hunyadi
Institute of Pharmacognosy, University of Szeged, Szeged, Hungary HUN-REN-SZTE Biologically Active Natural Products Research Group, Szeged, Hungary

The insect molting hormone, that is, 20-hydroxyecdysone (20E), inspired the chemical evolution of a very diverse group of natural products, phytoecdysteroids, which serve as a defence mechanism in plants and mushrooms. To date, 577 natural ecdysteroids are known. Interestingly, while they are toxic to insects, in vertebrates they have a highly beneficial bioactivity profile that includes nonhormonal anabolic and cytoprotective activity. 20E was recently found to activate the protective arm of the renin-angiotensin system through the Mas receptor [1], which is a highly relevant mechanism in cardiovascular and pulmonary diseases.

We have recently discovered that insects and caterpillars can surprisingly accumulate phytoecdysteroids in large enough amounts to reach up to several micromolar blood levels in insectivorous animals, such as songbirds and bats [2–4]. In birds, this phenomenon was also associated with a toxic effect on ticks that feed on ecdysteroid-containing blood [2, 3]. Phytoecdysteroid accumulation in insects may occur through reversible inactivation, i.e., ester formation with long-chain fatty acids.

This presentation will provide a brief overview of the food chain transfer of ecdysteroids from plants through insects to vertebrates, as well as our most recent studies of this phenomenon. Potential implications for human and animal health will be discussed in detail.

Acknowledgments

Financial support from the NRDIO, Hungary (K-146359 and TKP2021-EGA-32) is acknowledged.

References

1. Lafont R, Serova M, Didry-Barca B, Raynal S, Guibout L, Dinan L, Veillet S, Latil M, Dioh W, Dilda PJ, J Mol Endocrinol 2021, 68, 77-87.
2. Hornok S, Kováts D, Flaisz B, Csörgő T, Könczöl Á, Balogh GT, Csorba A, Hunyadi, A. Sci Rep 2016, 6, 23390.
3. Hornok S, Csorba A, Kováts D, Csörgő T, Hunyadi A. Sci. Rep. 2019, 9, 17002.
4. Hornok S, Berkecz R, Sós E, Sándor DA, Körmöczi T, Solymosi N, Kontschán J, Hunyadi A. Mammal Rev, 2022, 52, 317-321.

Dr. Tsoukalas is an experienced expert in nuclear medicine, specializing in radiopharmaceutical production, quality control, and research. He holds a Ph.D. in Radiopharmaceutical Chemistry and has extensive experience in designing state-of-the-art facilities for producing sterile PET radiopharmaceuticals. At BIOKOSMOS SA, he oversees PET Radiopharmaceuticals production, serves as the Qualified Person and leads the R&D team for novel radiopharmaceutical drugs He played a crucial role in developing Prostalumin ([18F]PSMA-1007), an innovative radiopharmaceutical for prostate cancer detection that was approved and launched in Greece in 2022. Dr. Tsoukalas is an Associate Researcher at the Institute of Nuclear and Radiological Sciences and Technology, Energy, and Safety (INRASTES). He has received national scholarships and awards for his contributions. As a Fellow of the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging, he actively contributes to scientific journals and reviews. His research focuses on radiolabeled compounds such as nanoparticles, peptides, and antibodies for cancer diagnosis and treatment, using SPECT/PET/CT, SPECT/PET/MRI, and isotopes for the emission of α, β and electron Auger particles.

Abstract:
Production and Quality Control of Radiopharmaceuticals in the everyday Clinical Practice
Babis Tsoukalas
Institute of Nuclear and Radiological Sciences and Technology, Energy, and Safety (INRASTES), Paraskevi, Greece

Radiopharmaceuticals, employing radioactive isotopes for diagnosis and treatment, are essential in modern medicine. Their production and quality control are crucial for patient safety and procedure efficacy. This lecture explores the intricate production process, emphasizing regulatory compliance and best practices. It highlights the need for rigorous quality control methodologies, to ensure the safety and effectiveness of radiopharmaceuticals. Real-world challenges encountered in clinical practice are discussed, highlighting the need for continuous improvement in production and quality control protocols to optimize patient outcomes and maintain the highest standards in nuclear medicine.

Hubert (Bert) G. Leufkens is emeritus professor of Pharmaceutical Policy and Regulatory Science at Utrecht University, the Netherlands. He is research and policy-wise active at several (inter)national platforms on regulatory science, innovation, drug safety, and pharmaceutical policy (e.g., past-member EMA Pharmacovigilance Working Party, chair of Dutch Medicines Evaluation Board (MEB), past-member of the EMA CHMP, past-President of ISPE, former Scientific Director of the Utrecht WHO Collaborating Centre for Pharmaceutical Policy and Regulation. He is vice-president of the European Federation for Pharmaceutical Sciences (EUFEPS), and (co) author of >600 papers in peer reviewed journals, book chapters and research reports.

Abstract:
What makes alike a like in generics and biosimilars? A regulatory lens
Hubert G. Leufkens
Utrecht University, The Netherlands

Since the introduction of generic medicinal products, since the 60s of the last century, and biosimilars, in Europe about 20 years ago, there have been many discussions about the requirements on the data an applicant (product developer) should submit for regulatory review and assessment. Essentially, these requirements are based on a scientific comparison between the product under the development and a reference product. A generic medicinal product should have the same qualitative and quantitative composition in active substance as the reference product and bioequivalence with the reference product should be demonstrated. A biosimilar is a not a generic version of a biological medicine, but should be highly similar to a reference product, and biosimilarity should be proven by a scientific comparison of the biological structure, quality attributes, biological activity, including immunogenicity, between the product under the development and a reference product. All to show that the product will perform the same in terms of safety and efficacy in the body as the reference product. For both generic product and biosimilar development and regulation the comparison, choice of the attributes for comparison, accepted variability, etc., are key. But all comparisons are a composite of what makes a difference a difference, or in other words, what makes alike alike? Science will virtually always see a difference, what does it mean? Is it really a refute of alikeness? The regulatory frameworks that have been built over the last decades, not only in Europe, are constent work in progress, also with the introduction of new and complex (nano)products. The frameworks are also the result of interactions between stakeholders who have an interest in how the alike comparisons are shaped and implemented in practice. From that perspective, like many regulatory processes, these comparisons are built on a lot of science, but are also signatures of a ‘social construct’.      

Dr. Erika Cecchin is a PharmD, PhD at the Clinical and Experimental Pharmacology Unit of the National Cancer Institute in Aviano, Italy, where she leads the Pharmacogenomics and TDM Group. She works in the field of research and clinical application of anticancer drug pharmacogenomics, pharmacokinetics and genotype-driven phase I clinical trials.
She graduated in Medicinal Chemistry from the University of Padua in 2000 and received her PhD in Pharmaceutical Sciences in 2005 as well as a Specialization in Clinical Pharmacology and Toxicology at the University of Milan. During her training, she worked as a visiting student at the Department of Chemistry, University of Wales-Bangor and at the Department of Pharmacy, University of Padua. She also worked as a postdoctoral researcher at the National Cancer Center in Milan before moving to the Department of Clinical Pharmacology at the National Cancer Institute in Aviano.
Since 2016, she has been a member of the Academic Council of the Doctoral School in Biomedical Sciences and Biotechnology at the University of Udine. She is a member of several editorial boards of scientific journals. She is the author of more than 100 peer-reviewed publications. She is vice-chair of the pharmacogenetic working group of IATDMCT, she is a member of the pharmacogenetic working groups of the Italian Society of Pharmacology and the International Union of Basic and Clinical Pharmacology (IUPHAR). Since 2019, she has been an external evaluator for the certification of EMQN pharmacogenomics laboratories throughout Europe (www.emqn.org).

Abstract:
Clinical implementation of pharmacogenetics for routine drug prescription in oncology: state of the art and future directions
Erika Cecchin, PharmD, PhD
Experimental and Clinical Pharmacology Unit, CRO-Centro di Riferimento Oncologico di Aviano- IRCCS, Aviano, Italy

In the era of precision medicine, the dose and schedule of anticancer drugs are poorly personalized on individual features, with dose adjustments driven by the occurrence of toxicity or lack of efficacy. The analysis of germline genetic polymorphisms can be useful for the early identification of patients at risk of toxicity. We contributed to the clinical development of pre-therapy tests of UGT1A1 and DPYD polymorphisms to increase the safety of the chemotherapeutic agents irinotecan (IRI) and fluoropyrimidines (FL). More recently, drug regulatory agencies across Europe have recommended frontline genotyping to prevent adverse events associated with FL and that was demonstrated to definitely change the clinical practice guidelines of FL prescription. The result of large implementation studies such as Ubiquitous Pharmacogenomics could provide definitive proof of the utility of applying germline panel genotyping in cancer to prevent adverse drug reactions. Among the still existing limitations of the application of DPYD genotyping is the low specificity of the test which leaves many toxic events unexplained by known variants. We demonstrated that an NGS approach coupled with an in silico functional assay could be applied to detect rare and novel genetic variants in DPYD significantly related to a higher risk of toxicity.
For other anticancer agents more recently introduced in the clinical practice such as imatinib, sunitinib, palbociclib, ribociclib, etc. pharmacogenetic guidelines are still not available, but enormous inter-individual variability in plasma exposure has been reported, with an impact on the clinical outcome. The pharmacogenetic profile of the patient, concomitant medications or food intake, comorbidities (e.g. obesity, Covid-19) and lifestyle habits (e.g. smoking) could contribute to this variability. Frontline use of pharmacogenetics may be effective in lowering interindividual variability in both plasma exposure and patient clinical outcome. We are evaluating the clinical benefits of an intensified pharmacological care integrating pharmacogenetics, therapeutic drug monitoring and co-medication management, especially for oral anticancer drugs chronically administered at a fixed dose.

Abstract:
SST4 somatostatin receptor as a potential novel target in the treatment of neuropathic pain: from early discoveries to clinical trials

Erika Pintér^1,2, Rita Börzsei¹, Éva Borbély¹, Zsófia Hajna¹, Valéria Tékus¹, Lina Hudhud¹,
Ádám Horváth¹, Éva Szőke^1,2, Csaba Hetényi^1,2, Zsuzsanna Helyes^1,2

¹Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary; ²National Laboratory for Drug Research and Development, Budapest, Hungary

The neuropathic and chronic inflammatory pain cannot be adequately eliminated by the marketed conventional or adjuvant analgesics, therefore new potential target molecules need to be identified. Somatostatin (SS) regulates endocrine, vascular, immune and neuronal functions and cell proliferation via to Gi protein-coupled receptors (SST1-SST5). According to the early discoveries of our research group, SS released from the capsaicin-sensitive peptidergic sensory nerves mediates anti-inflammatory and antinociceptive effects via SST4 (Pintér et al. 2023). Therapeutic importance of the native SS is limited by its broad-range actions and short plasma elimination half-life. Therefore, SST4 selective ligands could be promising analgesic and anti-inflammatory drug candidates which work in a different mode of action from clinically applied compounds.

The presentation describes the early experiments that led to the discovery of the anti-inflammatory, analgesic effects of somatostatin, Demonstrates the effects of sst4 receptor ligands in animal models of various inflammatory and neuropathic conditions. We also report in silico SST4 receptor binding mechanism (Börzsei et al. 2022) in vitro binding (competition assay) and cAMP- decreasing effect of the potential SST4 ligands in human SST4-expressing CHO cells, as well as the analgesic and anti-inflammatory effects in chronic neuropathic pain and arthritis models using wildtype and SST4-deficient mice.

After a summary of the preclinical results, the second half of the presentation will present potential clinical trial data that seem to confirm that selective SST4 receptor agonists can sufficiently alleviate pain in various neuropathic conditions such as diabetic neuropathy or low back pain.

The presented preclinical and human data strongly support that SST4 could be a promising therapeutic target in the therapy of neuropathic and inflammatory chronic pain. The results of subsequent phase 3 clinical trials will determine whether a new type of SST4 receptor-selective, analgesic, anti-inflammatory drug will be added to the pharmacotherapeutic palette.

Supported by NKFIH K-134214, National Laboratory for Drug Research and Development, HUNREN.

References

Pintér E, Helyes Z, Szőke É, Bölcskei K, Kecskés A, Pethő G. (2023) The triple function of the capsaicin-sensitive sensory neurons: In memoriam János Szolcsányi. Temperature (Austin). 2022 Nov 21;10(1):13-34. doi:10.1080/23328940.2022.2147388.

Börzsei R, Zsidó BZ, Bálint M, et al. (2022) Exploration of Somatostatin Binding Mechanism to Somatostatin Receptor Subtype 4. Int J Mol Sci. 23(13):6878. doi: 10.3390/ijms23136878.

Florence Delie is currently a researcher and lecturer at the School of Pharmaceutical Sciences of the University of Geneva (CH) in the Laboratory of Pharmaceutical Technology.
Florence Delie is a pharmacist and received her Ph.D. degree in 1992 from the Paris Sud University (Pr. Patrick Couvreur’s lab). Her Ph.D. work focused on oral administration of a peptide as a prodrug. She then spent 5 years working in the industry (BYK France, Le Mée sur Seine and the Department of Pharmaceutical R & D – Drug Delivery Group at Genentech, Inc., USA).
She is a group leader at the University of Geneva since 2002. Her research interests focus on the development of drug delivery systems mostly based on polymeric nanoparticles for the encapsulation of different therapeutic compounds for customized site delivery and tailoring release kinetic profiles. Recently, she worked on delivery systems for targeting ovarian cancer or the prevention of preterm birth.  She is also involved in the development of new gel systems and particularly a biphasic drug delivery system associating a gel and polymeric microparticles for the prevention of arterio-venous graft failure.
She supervised master students from Geneva University as well as universities abroad, she co-supervised several PhD thesis and post-doctoral fellows. She has scientific collaborations in Switzerland as well as abroad (Italy, Greece, France, Spain, and Cameroun).

Abstract:
Drug-eluting biphasic delivery system to prevent vascular graft failure.
Florence Delie ^1,2, Pharm.D, PhD.
1. School of Pharmaceutical Sciences, University of Geneva
2. Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva

Vascular surgical intervention such as by-pass surgery or arterio-veinous fistula have a high rate of failure (20 to 50 % of stenosis in the 2 to 5 years following the surgery). The failure is related to a narrowing of the lumen due to intimal hyperplasia development. This complication leads to dramatic consequences for the patient such as reintervention, limb loss, increased morbidity and mortality.

The occlusion of the operated vessel is the result of two processes: a) intimal hyperplasia which is the thickening of the tunica intima due to vascular smooth muscle cells proliferation and extracellular matrix secretion; and b) wall remodeling which results in a change of the vessel’s structure. Currently, this collateral effect is prevented by the repetitive systemic administration of anticoagulant and/or statins with the known adverse effects related to these drugs. For a more effective prevention, we are developing a statin-eluting biphasic delivery system to be applied directly on site during the surgery. This perivascular system has been designed for a local release over 6 to 8 weeks to meet the development of intimal hyperplasia schedule. This is achieved by combining atorvastatin-loaded polymer microparticles incorporated in a hydrogel. In a first part of the study, the particles were produced by an l-evaporation technique and the gel was a commercially available hyaluronic acid. This allowed to demonstrate that both the gel and the particles should be loaded with drug in order to be efficient on a mouse model. However, this study showed that particles needed to be highly loaded and that in a largr animal model, the gel was not found 4 weeks after application. Therefore, the second part of the study was dedicated to increase the loading of the particles using a spray-drying method and tune the hydrogel with DOPA radicals to have a more adhesive formulation to stay longer at the site of action.

Abstract:
Multimorbidity and polypharmacy from the point of view of depression
Gabriella Juhász^1,2, Tamás Nagy^1,2,3, Gábor Hullám^1,3, Nóra Eszlári^1,2, András Gézsi³, Péter Antal³

¹Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
²NAP3.0-SE Neuropsychopharmacology Research Group, Hungarian Brain Research Program, Semmelweis University, ³Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary

The aim of the TRAJECTOME project was to identify depression-related multimorbidity subgroups based on temporal disease profiles to better understand the pathophysiology of this highly heterogeneous mental illness. We used data from healthcare systems and biobanks and applied machine learning approaches to identify depression-related multimorbidity trajectories and characterise these subgroups from multiple aspects, including genetic variants, lifestyle, and environmental factors. The project also attempted to analyse the pharmacological profile of the depression-related multimorbidity trajectories, which will be summarised during the presentation. Based on the project’s results we provided foundation to prioritize molecular drug candidates matching the multimorbidity pathways, which would potentially offer personalised treatment approaches for depression-related multimorbidities and simultaneously minimise polypharmacy and related side effects.

Acknowledgement

This study was supported by the Hungarian National Research, Development, and Innovation Office 2019-2.1.7-ERA-NET-2020-00005 under the frame of ERA PerMed (ERAPERMED2019-108); the Hungarian National Research, Development, and Innovation Office (K 143391, K 139330 and PD 134449 grants); the Hungarian Brain Research Program 3.0 (NAP2022-I-4/2022); and the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, under the TKP2021-EGA funding scheme (TKP2021-EGA-25 and TKP2021-EGA-02). Supported by the European Union project RRF-2.3.1-21-2022-00004 within the framework of the Artificial Intelligence National Laboratory. This research has been conducted using the UK Biobank Resource under Application Number 1602. Linked health data Copyright © 2019, NHS England. Re-used with the permission of the UK Biobank. All rights reserved.

Dr. Hülya Ayar Kayalı graduated from Dokuz Eylül University Chemistry Department (1997) and has completed her master’s degree (2001) and doctoral studies (2005) in the field of Biochemistry. She then conducted her postdoctoral studies in the McGill University-Canada on cellular biology.
She was appointed as an associate professor in Dokuz Eylül University Faculty of Science in the year 2008, and achieved the rank of a full professor in 2014. She has been working as the leader of the Biopharmaceutical Technologies and Bioanalysis Research Group at the Izmir Biomedicine and Genome Center since 2015. Ayar-Kayalı has around 50 publications in international journals indexed in the SCI database and has presented numerous papers at both national and international conferences.
Dr. Hülya Ayar Kayalı has participated as both project coordinator and researcher in nearly 20 national and international projects in total. In these, she particularly focuses on cancer signaling pathways as well as the production, purification, and characterization of biotherapeutic drugs.
At the Izmir Biomedicine and Genome Center, two biosimilar drug production projects were completed, with Ayar Kayalı serving as coordinator in one and as a researcher in the other. Technology transfers to pharmaceutical industry partners were successfully carried out as a result of these efforts.

Abstract:
Biosimilars and Next Generation Therapeutic Antibodies
Prof. Dr. Hulya Ayar Kayalı
Izmir International Biomedicine and Genome Institute, Dokuz Eylul University; Izmir Biomedicine and Genome Center; Department of Chemistry, Faculty of Science, Dokuz Eylul University; Izmir International Biomedicine and Genome Center, Izmir, Turkey

Monoclonal antibodies (mAbs) have become widely recognized as a well-established and rapidly expanding form of drug therapy for various human diseases, such as cancer. This is primarily due to their exceptional specificity towards targets and favorable safety profiles. However, mAbs are very costly, with annual treatments costing up to tens of thousands of dollars. Given that the patents of some best- selling mAbs have expired, biosimilars, which are designed as biologically similar alternatives that are similar in quality, safety, and efficacy to the approved reference products, have led to significant expansion of biopharmaceutical industry.

The mAb production process involves various steps including host CHO cell maintenance, cellular engineering, transfection, clonal selection, culture, cell harvesting, purification, and characterization. There are many factors influence the yield of a production process, such as culter media, feeding strategy,  process duration, and the specific productivity. Among the quality attributes of therapeutic antibodies, FcRn binding and related structures are well known to affect the pharmacokinetic profile of the product. Other quality attributes such as antigen binding, glycan structure, and isoelectric point are considered to have a potential impact on the pharmacokinetic profile of the product.

New generation treatments refer to a class of medications that have been developed using innovative approaches and technologies. Drug delivery systems, which enable the use of chemotherapeutic agents in treatment by reducing the side effects of traditional treatment, have taken its place in the literature as new generation treatment method. Exosomes, which are natural microvesicles, and synthetic nanoparticles are one of the most important components of drug delivery systems, enabling the transport of therapeutic cargo. Another component of these systems is mAbs, which provide specific targeting and are used in stand-alone therapy. In this way, the elimination of difficulties encountered in traditional treatments and the implementation of successful treatment methods with next-generation therapies created by functionalizing the surfaces of drug-loaded vesicles with specific targeting agents are of great importance.

Abstract:
Patient centered drug formulation
István Antal
Semmelweis University Institute of Pharmaceutics, Budapest, Hungary

Today, the development of new dosage forms is of particular importance as they create new opportunities to improve the safety and efficacy of drug therapy. A well-constructed formulation with advanced excipients is also a drug delivery system that can increase efficacy and/or reduce side effects through innovative technological solutions. While the active substance is the essential ingredient of a pharmaceutical formulation, it is the dosage form that functions as a carrier system, that delivers the content to the site of action.\\r\\nThe release profile and physiological environment behavior, as a functional objective, appropriate to the therapeutic objective, is based on the structure, and in many cases also the integrity, of the dosage form, which determines the conditions of administration (e.g. disintegration). The specific formulation or manufacturing technology may result in more uniform efficacy and/or better tolerability, as well as other properties that aid adherence and reduce medication error.\\r\\nThe pharmaceutical formulation is expected to provide the appropriate level of activity, onset, and duration of action, but there are also challenges about special considerations for certain patient groups (e.g. elderly or children) and for people with certain medical conditions (e.g. difficulty swallowing, mental or physical conditions). Innovative pharmaceutical technologies can ensure the desired pharmacokinetic profile, appropriate bioavailability, and improved dosing regimens.\\r\\nIn addition to traditional dosage forms, several multiparticulate systems have gained therapeutic and diagnostic relevance in recent decades. Microparticles, microspheres, and microcapsules show various therapeutic advantages for patient-centric drug delivery based on their structural and functional capabilities. The different structures allow the possibility of tailored drug release mechanisms and modulating optimized pharmacokinetic profiles.\\r\\nThere is an increased interest in the use of 3D printing in drug delivery for personalized medicine. 3D printing can result in the creation of unique spatial structures, even Lego®-like assembling, by stacking or varying layers of pharmaceutical substances. Biodegradability is challenging, but the printing technique and parameter settings, as well as the variation of excipient composition, offer a wide range of possibilities to control the drug release of drug delivery systems or even to provide a specific and unique property.\\r\\nIt is now clear that the right dosage form is an important prerequisite for successful therapy and that patient-centered drug therapy, which is already underway, requires a paradigm shift in the field of pharmaceutical technology. Drug Delivery Systems aim to allow for a reduction in the frequency of doses and the introduction of a more favorable dosing regimen, and flexible use, while at the same time promoting patient cooperation and thus the effectiveness of treatment in many ways.\\r\\n

Abstract:
Continuous-flow solid-phase peptide synthesis in the field of cell-membrane penetrating peptides

István M. Mándity^1,2, Nikolett Varró^1,2, Beáta Mándityné Huszka², Balogh Balázs¹, Márton Ivánczi¹, Dóra Bogdán^1,2,
Péter Nagy³, Gyula Batta³, Florina Zákány³,

¹Semmelweis University Institute of Organic Chemitry, Budapest, Hungary; ²HUN-REN Research Centre for Natural Sciences, Institute of Materials and Environmental Chemistry, Budapest, Hungary, ³University of Debrecen, Institute of Biophysics and Cell Biology, Debrecen, Hungary

The importance of synthesis of peptides is warranted by the need for peptide-based medicines, the roles of peptides in drug discovery, etc. Since its introduction by Merrifield, peptide synthesis was performed almost exclusively on solid supports. The solid-phase peptide synthesis (SPPS) technique has subsequently been progressively developed. However, still a general property of these methodologies are the high number of amino acid equivalents required for total coupling. [1]

Continuous-flow (CF) approaches have recently gained in significance among synthetic techniques. [2] We show here that the number of amino acid equivalents used for SPPS can be lowered drastically to around 1.5 equivalents through the application of a CF technique and by complete reaction parameter optimization.

Under the optimized conditions the couplings of all 20 proteinogenic amino acids with 1.5 amino acid equivalents proceeded with excellent conversions. To demonstrate the efficiency of the CF-SPPS methodology, known difficult sequences were synthetized in automated way. The purities of the resulting crude peptides were comparable with literature result, but the CF-SPPS methodology requires much less amino acid and solvent. As further evidence of the effectiveness, β-peptide foldamers with alicyclic side-chains, were synthetized in excellent yields. Nonetheless the direct synthesis of N-methylated peptides was carried out by the utilization of Fmoc-protected N-methylated amino acids too. Predominantly, the fast synthesis of protected sequences was carried out too. Importantly, exotic and expensive artificial amino acids were incorporated into sequences by an automated way through the use of exceptionally low numbers of amino acid equivalents at low costs. [3]

This technology has been utilized for the synthesis of various cell-membrane penetrating peptides and conjugates thereof. In the case of penetratin we have shown that a decreased, positive membrane dipole potential significantly increases both the total cellular uptake and endocytic escape of penetratin depending on what kind of treatment is used for modifying the dipole potential. As a result, both medically relevant (atorvastatin) and irrelevant (phloretin) treatments decreasing the dipole potential enhance the concentration of penetratin in the cytoplasm, the compartment most relevant for its therapeutic action. Although the applied treatments do modify other membrane properties, the dipole potential was the strongest predictor of penetratin uptake. The experiments identify the biophysical properties of the membrane in general and the dipole potential in particular, as apotential target for enhancing the delivery of drugs and drug candidates exhibiting low or no transmembrane permeability into cells in animal experiments, human trials or in the clinical setting after further studies clarify the cell type dependence and the in vivo potential of such treatments.

References

[1] Sewald, N.; Jakubke, H. D. Pepides: Chemistry and Biology, Wiley-VCH Weinheim, 2002.

[2] Orsy, G.; Fülöp, F.; Mándity, I. M. Green Chem 2019, 21, 956.

[3] Mándity, I. M.; Ötvös, S. B.; Fülöp, F. ChemSusChem 2014, 7, 3172.

[4] Batta, G.; Kárpáti, L.; Henrique, G. F.; Tóth, G.; Tarapcsák, S.; Kovács, T.; Zákány, F.; Mándity, I. M.; Nagy, P. Br. J. Pharm. 2021, 178, 3667.

Dr. Jelena Djuris is a full professor at the Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, where she participates in teaching in the fields of Pharmaceutical Technology and Industrial Pharmacy. She is engaged at various levels of studies, including integrated academic, specialist, doctoral, and master’s studies. She is the editor of an international scientific monograph, and co-author of 8 chapters in international books and 64 papers in journals from the SCI list with 1310 citations. Dr. Djuris is a reviewer for a number of international scientific journals. She has been actively engaged in a number of scientific projects and her research interests include data science, machine learning, quality by design, modified drug release, drug delivery, and process optimization.

Abstract:
AI-empowered QbD and PAT: a new era for pharmaceutical manufacturing
Jelena Djuris
Department of Pharmaceutical Technology and Cosmetology, University of Belgrade – Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia

The fusion of quality by design (QbD) and process analytical technologies (PAT) represents a critical turning point in pharmaceutical manufacturing, leading to unparalleled efficiency and quality assurance. QbD principles lay the foundation for superior product quality in various formulations and delivery systems by determining critical process parameters and material properties. Complementary modeling and simulation tools, including hybrid models that combine mechanistic insights with empirical data, enable a nuanced understanding of design spaces and establishment of the precise control strategies. In this changing landscape, artificial intelligence (AI) is proving to be a cornerstone, offering a versatile approach to optimization and innovation. Through the use of machine learning (ML) algorithms, AI techniques can overcome regression, classification and data processing challenges across diverse data types—numerical, textual, and images, driving efficiency and insight at every stage of pharmaceutical development. In particular, artificial neural networks (ANNs) are demonstrating their effectiveness from the initial formulation stages through to validation of bioequivalence in production batches. Furthermore, the integration of AI goes beyond traditional processes to include the design and optimization of complex biotechnological and continuous production systems. The emergence of explainable AI and generative AI further enriches this landscape. Explainable AI sheds light on decision-making processes and improves interpretability and compliance, which is of utmost importance in the PAT context. Generative AI offers promising opportunities to optimize the synthesis of active pharmaceutical ingredients, accelerate development times and reduce resource expenditure. The integration of AI into pharmaceutical production is leading to a re-evaluation of modeling standards and guidelines as the regulatory framework adapts to technological advances. The anticipated revisions to the regulatory framework will establish robust practices for the application of AI techniques, support the implementation of real-time release testing (RTRT) strategies and ensure compliance with evolving standards. In summary, the confluence of QbD, PAT and AI embodies a holistic approach to pharmaceutical manufacturing characterized by increased efficiency, quality assurance and regulatory compliance. As researchers, manufacturers and regulators navigate this dynamic terrain, harnessing the potential of explainable AI and generative AI promises to unlock new frontiers of optimization and innovation, leading the industry into a new era of quality excellence.

Abstract:
Possibilities of Using Health Care Data to Improve and Develop Care
Judit Bidló
Ministry of Interior, Budapest, Hungary

To be determined…

In the eighties, Klaus studied veterinary medicine followed by a thesis in applied biochemistry in boar reproduction at the Veterinary School in Hannover, Germany.
From 1991 to 1994 Klaus worked at Pfizer Animal Health in Germany on technical, marketing, regulatory requirements including quality, safety and efficacy of VMPs. Since 1995, Klaus is consulting the animal health industry on the development and registration of animal health products and plans, supervises and conducts safety and efficacy studies testing veterinary medicinal products in various animal species. From 1997, as founder, he has been the General Manager of the contract research organisation and regulatory consultancy KLIFOVET, Munich, Germany, one of the leading organisations providing dedicated services to support new product development and registration for animal health products. Since May 2022, he is the Chief Veterinary Officer of KLIFOVET, which is now part of the Argenta Group. He has extensive experience consulting all, multinationals, family businesses and start-ups how to develop animal health products and has led various organisations to successful granting of marketing authorisations for vaccines, biologicals and pharmaceuticals. He also has been responsible on various aspects to maintain marketing authorisations including acting as qualified person and,head of quality control within GMP and qualified person for pharmacovigilance (QPPV) for veterinary medicinal products.
Klaus is active in various animal health and veterinary organisations including the Association of Veterinary Consultants (AVC), the European College for Veterinary Pharmacology and Toxicology, the European Board of Veterinary Specialisation (EBVS) for many years, at the same time he has been a member of the American Association of Veterinary Parasitology, American Association of Veterinary Pharmacology and Thereapeutics, European Association of veterinary Pharmacology and Toxicology and World Association of the Advancement of Veterinary Parasitology and selected member of organisation committees of Antimicrobial Agents in Veterinary Medicines since 2014. He has also organised and hosted multiple international conferences and workshops.
Multiple scientific publications on antiparasitics, antimicrobials, vaccines, and novel therapies in various animal species, but also on various topics of the regulation, quality and legal requirements on animal health products show his broad spectrum of expertise (www.klifovet.com).

Abstract:
The Challenges Registering Human Medicinal Products for Animal Use: general aspects, orphan drugs, limited markets
Hellmann, Klaus; Cornelia Huettinger
Argenta, Business Development, Munich, Germany

Within the One Health Initiative, the use of data generated on animals and humans are discussed to be valuable to support the registration of either human (HMP) or veterinary medicinal products (VMP). Registrations for animal use are mainly done for major species, (dogs, cats, chicken, pigs, cattle and sheep for meat production); other species are legally defined as minor species being of minor commercial interest. For development of human medicines, studies are typically done in mice, rats, (rabbits,) dogs and monkeys. There is little overlap. During the early development of a VMP, studies are conducted in mice, rats, sometimes guinea pigs or rabbits. Only if a HMP is intended to be registered as VMP for dogs, further studies are required in dogs and therefore such study may be of value; other legally required studies for a VMP need to be done in the target species.

Active ingredients of HMPs intended to be used in humans are frequently used to treat animals. In general, the registration of VMPs follows similar, but different rules than those for HMPs: for both, quality, safety and efficacy need to be confirmed. For both, the requirements for registration follow the identical stringent rules for manufacturing, defining the quality of the product: these are regulated in the same legal act in the EU (EudraLex Volume 4), based on Directive 91/356/EEC as amended. While in theory, formulations used as HMP can be used in animals, practically this often has limited value, as animals have different weight ranges, require different route of administration and other formulations due to the specific needs of the animal species; and to be competitive in the market.

While user and environmental safety requirements are based on the standard toxicological studies and are very similar, safety in the target animal species is different. Nevertheless, safety studies performed as part of the safety evaluation of an active ingredient for human use maybe valuable, especially the toxicity studies in the dog. The other toxicity studies maybe used, if not protected by the owner of such data; such studies often need to be repeated, which is little acceptable from a 3R perspective. A major difference exists in the case of registering VMPs for food producing animals, as consumer safety is priority: this is a major limitation for many projects, as the maximum residue level (MRL) requires to be established for each active ingredient to define the safety margin acceptable for the consumer. An MRL must be set before the registration of a VMP containing such active

Efficacy in animals needs to be proven per indication in each species, which is a relevant investment and always mandatory. Beyond a pharmacokinetic study in the target species, the effective dose has to be justified and confirmed under field conditions for the final formulation.

Resulting options for the registration of HMPs under the orphan drug’s regulation and of VMPs for limited markets according to Art. 23 or Art. 8 of Regulation 2019/6 will be explained.

Abstract:
Data-Driven Health as System Capability
Miklós Szócska
Faculty of Health and Public Administration, Semmelweis University, Budapest, Hungary

To be determined…

Abstract:
Steps towards data-driven clinical neurology – introduction to the National Laboratory of Translational Neuroscience
Dóczi Tamás
University of Pécs; HUN-REN Institute for Computer Science and Control; HUN-REN Institute of Experimental Medicine; HUN-REN Research Centre for Natural Sciences; Richter Gedeon Plc.; Semmelweis University; University of Szeged. 

The presentation introduces the NATIONAL LABORATORY OF TRANSLATIONAL NEUROSCIENCE (TINL in Hungarian). The mission of TINL is to implement the methods of digital medicine and data-driven health care to methodologically improve the prevention and treatment of central nervous system (CNS) diseases, with a unique research spectrum covering nervous system developmental disorders and diseases from childhood to adulthood. It concentrates on understanding the disease mechanisms underlying pathological changes in the nervous system that occur in the early stages of life, resulting from the multifaceted interaction of genetic and environmental factors, thereby developing new diagnostic and intervention options. The laboratory utilizes structured clinical data assets in the therapy of nervous system pathologies through the development of online structured patient data forms and analytical programs through direct integration of real-life data.

MAIN RESEARCH AREAS:

Clinical: Stroke; Head injury; Movement disorders (Parkinson’s disease); Epilepsy; Multiple sclerosis; Myasthenia gravis; Internet-addiction; Schizophrenia;

Preclinical: Autism spectrum disorder; Pathomechanisms of perinatal insults (preterm birth, asphyxia, hypoxic-ischemic encephalopathy); Disturbances in childhood social environment; Inflammatory mechanisms in early nervous system disorders; endocrine factors (abnormal changes in hormone levels, endocrine disruptor compounds, microbiome metabolites)

Abstract:
AMU and AMR in the One-Health Context: Why We Need AMS?
Ria Benkő
Institute of Clinical Pharmacy, University of Szeged, University of Szeged, Albert Szent-Györgyi Health Centre, University Pharmacy Hungary, University of Szeged, Szeged, Hungary

To be determined..

Abstract:
Extracellular vesicles as potential drug delivery bases and their stabilization in nanofibers

Romána Zelkó¹, Edit Buzás², Krisztina Németh², Adrienn Kazsoki¹

¹University Pharmacy Department of Pharmacy Administration, Semmelweis University, Budapest, Hungary

²Department of Genetics Cell and Immunobiology, Semmelweis University, Budapest, Hungary

Extracellular vesicles (EVs) are naturally released particles from cells, encapsulated in phospholipid bilayers, and carry functionally active biological molecules. They have a physiological role in cellular communication and are used to transport active substances. EVs are produced autologously from patient cells or blood, so they do not trigger an unwanted immune response when returned to the body. EVs can fuse directly with the targeted plasma membrane, allowing for more efficient internalization of the active substances encapsulated in the vesicle. Several approaches for exogenous incorporation of active substances into isolated extracellular vesicles have been reported in the literature, such as incubation, active loading techniques of lipophilic molecules or hydrophobic compounds, repeated freeze-thaw, and permeabilization with saponin, extrusion, ultrasonic treatment, and electroporation. However, the drug-carrying extracellular vesicles should be stored at -80 °C, which may be limited by cost and transport challenges. An alternative is lyophilization, which is costly, and its reproducibility raises questions. To improve the storage stability of vesicles, electrostatic fiber formation offers an alternative solution as a fast, cost-effective, scalable, room-temperature technology for complex nanofibre structures and platform technology, making it a viable tool for the formulation of sensitive active ingredients. The production of nanofibrous materials from a wide range of feedstocks is feasible, and fibrous systems have gained ground in many areas of medicine, including drug delivery vehicles, hemostatic devices, dressings, wound dressings, skin analogs, and spatial scaffolds. Our work’s primary objective was to investigate the stability of extracellular vesicles in nanofibrous systems. This study sought to embed medium-sized extracellular vesicles (mEVs) within rapidly dissolving electrospun nanofibers based on water-soluble polymers to investigate the relationship between storage conditions and the structural integrity of the resulting nanofibrous formulations. The electrospinning process utilized aqueous precursor solutions containing polyvinylpyrrolidone and polyvinyl alcohol. The presence of EVs in the electrospun samples was confirmed through various techniques such as transmission electron microscopy, flow cytometry, and confocal laser scanning microscopy. Results demonstrated that the fibrous structure of the samples remained intact throughout the storage period. Notably, both nanofibers and EV-loaded nanofibers were retained regardless of whether they were stored at 4°C or room temperature over the experimental duration. By integrating EVs into a stable solid polymeric delivery matrix, their stability can be preserved, and leveraging the properties of the polymer allows for targeted and controlled release of these therapeutic entities.

Abstract:
In search of key drivers behind changes in natural product pattern in medicinal plants: Case studies in quality-controlled plant metabolomics

Sándor Gonda

^{University of Debrecen, Debrecen, Hungary}

Plants generate chemically diverse natural products to cope with biotic and abiotic challenges. Therefore, studying the chemical patterns of medicinal plants as a function of some environmental, agrotechnological or any experimentally set parameter enables us to gain insights on the interconnectivity of plant chemical features with the quantified environmental parameters. In addition to gaining a further understanding on how the plant uses its array of metabolites, these data are a prerequisite of producing more reproducible medicinal plant materials.
Metabolomics (high-throughput chemical analysis) has now become an important technique in phytochemical analysis. As this technique is capable of the estimation of the relative abundances of literally hundreds of metabolic features, the usage of alternative validation protocols is paramount. Also, the individual evaluation of changes is rendered extremely challenging. Instead, bioinformatics approaches including network analysis, pathway analysis as well as attractive visualization techniques are used to identify major differences across the plant metabolome and find biomarkers. Herein, a few of our recent and current studies using untargeted LC-MS plant metabolomics as the core technique are presented.
Work on Tilia spp. (linden) has shown that the bracts contain a wide array of possibly useful bioactive compounds also outside the typical gathering period. Tissue cultures from Tilia spp. were shown to have a chemical pattern similar to that of the young tissues and to be excellent sources of a few bioactive constituents including catechin, flavonoids and coumarins. The similarity of the chemical pattern of Eurasian species to that of T. americana warrants further studies in anxiolytic activity.
The key conlusions from the research of Trigonella foenum-graecum (fenugreek) seedlings were that sprouts are extremely similar to the ungerminated seeds in overall chemical pattern, but an increased amount of most constituents including key bioactives 4-hydroxyisoleucine, trigonelline, steroidal saponins as well as flavonoid glycosides can be observed. This suggests possible therapeutic applications when there is a low tolerance for the galactomannan fraction of the seeds.
In studies on metabolome – microbiome interactions in Armoracia rusticana (horseradish), network analysis was used as the core bioinformatics approach. It was shown that the soil type heavily influences glucosinolate and isothiocyanate contents and year-to-year reproducibility. This renders different bioactivities to roots grown in various soil types. In addition, it was shown that the impact of soil chemical variability on the plant metabolome is rather indirect, with soil microbiome playing a key role.

Sofia Tranza is a pharmacist, specialized in Pharmaceutical Technology and Pharmacovigilance and is certified in the field of Medical Affairs. She is currently a student in the CAS Advanced Studies for Radiopharmacy degree at ETH University of Zurich, Switzerland. He has over 7 years of experience as a Qualified Person for Pharmacovigilance in the Pharmaceutical Industry and at the same time is certified according to ISO 9001: 2008, 2015 and ISO 13485. It has entered the National Medicines Agency in 2016, serving as an employee in the Undesirables Department of Energies and as a substitute member of the European Commission Pharmacovigilance (PRAC) for Greece. She currently holds the position of member of the PRAC, representing Greece in the European Medicines Agency (EMA), she is an Evaluator in the Department of Drug Evaluation of products for human use and responsible pharmacist in the Cosmetics department and in the European Standing Committee for Cosmetics and in the relevant working groups.

Abstract:
“The legislation of radiopharmaceuticals at national and European level”
Trantza Sophia
Pharmacist, MSc, MSc PV, CAS, President of the Panhellenic Association of Pharmacists (PEF)

The pharmaceutical legislation of the European Union has consistently pursued the twin objectives: the protection of public health and the free movement of medicinal products. The framework of pharmaceutical legislation originated over 50 years ago, 1n 1965, with the publication of Directive 65/65/EEC, known as the first Directive.¹  Currently, the requirements and procedures for the marketing authorization of medicinal products for human use, as well as the rules for the constant supervision of products after they have been authorized, are primarily laid down in Directive 2001/83/EC and in Regulation (EC) No 726/2004.^2,3 Directive 89/343/EU is dedicated to radiopharmaceuticals and provides an overview of definitions for kits and generators and also defines the special nature of radiopharmaceuticals for testing, the specific indications for labelling, the specific format of the Summary of Product Characteristics (SmPC), especially for dosimetry and preparation, and takes  account the need for radiation protection for patients and workers.⁴  Additionally, Directive 2017/1572/EC includes the principles of GMP requirements for medicinal products and also for investigational radiopharmaceuticals.⁵ Also, EudraLex Volume 4 and especially Annex 3 is devoted to quality assurance of radiopharmaceuticals and regulates the production facilities and the trained personnel on radiation protection issues.⁶ Considering clinical trials, the new Legislation 536/2014 sets the rules and requirements for therapeutic radiopharmaceuticals and the labelling for diagnostic ones.⁷ But also small scale radiopharmaceuticals are a different regulated area with national legislation in different Member States. This presentation will explore the legal framework of radiopharmaceuticals in clinical trials, GMP, labelling and SmPC and will investigate the differences between the Member States on small scale radiopharmaceuticals.

References

1. Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by Law, Regulation or Administrative Action relating to proprietary medicinal products, OJ 22, 9.2.1965, p. 369–373
2. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67–128
3. Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, OJ L 136, 30.4.2004, p. 1–33
4. Council Directive 89/343/EEC of 3 May 1989 extending the scope of Directives 65/65/EEC and 75/319/EEC and laying down additional provisions for radiopharmaceuticals, OJ L 142, 25.5.1989, p. 16–18
5. Commission Directive (EU) 2017/1572 of 15 September 2017 supplementing Directive 2001/83/EC of the European Parliament and of the Council as regards the principles and guidelines of good manufacturing practice for medicinal products for human use (Text with EEA relevance., C/2017/6127, OJ L 238, 16.9.201
6. Volume 4 of „The rules governing medicinal products in the European Union” contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use laid down in Commission Directives 91/356/EEC, as amended by Directive 2003/94/EC, and 91/412/EEC respectively
7. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance, OJ L 158, 27.5.2014, p. 1–76

Teresa Simon-Yarza earned her degree in Pharmacy and later pursued her Master’s degree in Pharmaceutical Technology at the University of Navarra. In 2013, she defended her Ph.D. in Pharmacy, with a thesis centered on the development of drug delivery systems for cardiac repair. Then, she joined the Institut Lavoisier and the Institut Galien (University Paris-Saclay) where she focused on the synthesis and application of metal-organic frameworks in the biomedical field. Since 2018, she has held a permanent position as a researcher at the Laboratory for Vascular Translational Science INSERM U1148 in Paris. Currently, she leads the Tissue Engineering Team, leveraging her diverse expertise to advance the engineering of vascularized tissues for therapeutic interventions and disease modeling.

Abstract:
Physiologically relevant 3D models based on polysaccharide scaffolds
Teresa Simon-Yarza
Inserm U1148, Laboratory for Vascular Translational Science, Paris

Three decades ago, tissue engineering emerged as a dynamic and transdisciplinary field, uniting biochemists, cell biologists, materials chemists, engineers, and surgeons. Since its inception, the field has experienced exponential growth propelled by advancements in biomaterials, the discovery of induced pluripotent stem cells (iPSCs), and the innovation of processing technologies like bioprinting, among others. Beyond its therapeutic applications, recent years have seen a surge of interest in leveraging tissue engineering for the creation of intricate in vitro models. This interest is driven by the desire to accelerate drug development, circumventing the limitations inherent in traditional simplistic in vitro models and addressing the ethical and scientific concerns associated with animal experimentation.

Porous polysaccharide biomaterials stand out as particularly promising tools for constructing complex 3D in vitro models. Their appeal lies in their resemblance to the extracellular matrix in terms of composition, as well as physical, chemical, and mechanical properties. Over the past years, our research has demonstrated the tunability of these scaffolds to match the properties of soft tissues. Through the adaptation of co-culture protocols, we have successfully generated functional micro-tissues resembling the liver, retina, and cancerous tissues, among others.

Addressing a critical hurdle in tissue engineering, we have also explored strategies to facilitate vascularization within these polysaccharide scaffolds. Utilizing various prevascularization techniques and incorporating microfluidic systems, our current goal is the creation of dynamic and high-throughput perfusable devices.

However, a pivotal question remains unresolved: How should these innovative multiscale models be validated to establish their reliability as tools for drug testing?