Hi, everyone, and welcome. My name is Naima Sperun, and I will serve as your moderator today. Thank you for joining us for today's webinar. Little patience, big challenges developing patriotic formulations. As your moderator, it is my role to ensure that we make the most of your time with us. I'm here today with Ammut Vanderbrilli, Marcus Krolich and Lars Albemann. Aimut Fonaprili is a senior strategic Product manager for excipients solid application. As a food chemist by training, Aimut has gained more than 17 years of experience in the global B2B marketing for functional cosmetic food and pharmaceutical ingredients in highly regulated markets. In her current position as a strategic product manager, she is striving product innovations for solid dosage forms with the focus on the design of tablet film coatings and paste optimization. Marcus Koelich is a strategic product manager for Excipients liquid application. Marcus holds a PhD in pharmaceutical sciences from the University of Heidelberg in Germany. He joined the company in 2009 as Technical Product Support Manager, responsible for contract manufacturer management. In his current position, a strategic product Manager, he's driving innovations for liquid formulation. Marcus is responsible for a broad portfolio of pharmaceutical excipients for liquid application, with a focus on regulatory topics. Prior Marcus worked in formulation development at RP Shearer. Catalan Pharma Solutions Doctor Las Eberman is Head of Pharma Registration and Regulatory Projects as a molecular biolog biologist by training. Las has been working in several regulatory positions in Pharmaceutical industry for both truck products and pharmaceutical raw materials as well as contributing to a number of industry associations joining our company in 2012. Currently he is responsible for a team of regulatory experts in life science regulatory management. The team is working on regulatory topics mainly related to AP, IS and excipients supporting a number of manufacturing sites as well as global activities. Before I turn things over to our presenters, I'd like to cover a few housekeeping items. At the bottom of your screen are multiple application widgets you can use. There you can also find our reaction button, indicated by the thumbs up emoji, that allows you to give immediate feedback on the presentations, topics, or anything that stands out. All the widgets are resizable and movable, so feel free to move them around to get the most out of your desktop space. You can expand your slide area or maximize it to full screen by clicking on the arrows in the top right corner. If you have any questions during the webinar, you can submit them through the Q&A widget. We will try to answer these during the webinar, but if a more detailed answer is needed or if you run out of time, it will be answered later via e-mail. 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It's my pleasure to turn things over to Aymuth, Marcus, and Las. Thank you very much, Naima dear. All children are a sensitive patient target population that deserve special attention when it comes to the development of age appropriate and safe medicines. It has been well recognised that pediatric patients are not small adults but rather a different and heterogeneous group with regard to physiological needs. In this webinar, we like to provide you with an overview for the regulatory requirements in the EU and in the USA and share latest regulatory trends for pediatric formulations. In addition, we will discuss important aspects for the selection of suitable excipients used in oral, liquid and solid formulations for children. Medicines developed for infants and children present unique formulation challenges compared to those intended for adults. The term pediatric patients actually describes the subset of the population from birth to the age of 16 to 18, depending on the reference standard. In deciding on the appropriateness of the pharmaceutical design, the following aspects need to be considered in relation to age and developmental Physiology. A consistent quality supported by high quality excipients with good batch to batch consistency. The safety of formulation excipients. In general, well established exhibients are preferred under the consideration of a sound and scientific risk benefit assessment. The needed administration volumes play an important role also for the determination of the suitable dosage form. The ability to precisely administer a dose is essential, especially for therapies targeting neonates when very small volumes are needed. Finally, authorities are requesting a good acceptability by the little patients and caregivers, which includes a good swallow ability and taste, facilitating the patient's compliance. Yeah. With this we come already to our first park question and this is have you already gained an any experiences in the development of patriotic formulations? A yes. B, not yet, but considering to start with the development of patriotic formulations. C not yet, but I would be interested in your application service offering for oral solid formulations or D not at all. Yeah, so interesting, interesting fields. And while you still have some time to answer this, I would like to remind you if you're interested in a certificate after the webinar, that you need to answer three of those poll questions and stay a minimum of 30 minutes in the webinar, and then this certificate is automatically sent to you. We keep waiting a little bit longer to give everyone the opportunity to answer before we have a look on the results. Yeah, very interesting. Thank you very much for all your answers and I give back to our presenters. Let's look at current market trends and challenges in the development of paediatric formulations. Government driven rewards and incentives promote the development of paediatric formulations by providing, for example, an extension of a six month longer market. Exclusivity shortages of pediatric products have become an important issue in the last years. EU and USFDA regulations request to make age appropriate formulations that are more acceptable, easier, safer and more effective. Yet there's still a lack of drugs developed specifically for children. Prescribing or administering of medications outside the terms of the market authorisation is referred to as off label medications. From the total paediatric formulations, up to 60% are used in an off label manner. According to estimations. This may expose paediatric patients to potentially harmful excipients, which may lead to allergies or other adverse effects. The quality requirements have become stricter after several serious events with cough sylopes two years ago that were contaminated with toxic deethylene glycol and ethylene glycol. Advancements in kids friendly dosage forms and acceptability testing have been made in the last years. Dosage form innovations include mini tablets and orals and films which can overcome the difficult swallowing of standard sized tablets. What are the answers to these challenges? Our answers are as follows. Our AP is and excipients are multi companion, so meeting international quality standards. Our end to end business continuity and risk management program identify, plan and mitigate our response to supply risks. Our well established excipients are manufactured under IPAC, PQGGMP and our life impacting APIs including folates are manufactured under ICHQ 7 guidelines. We offer regulatory support throughout your journey and what's new here. Impurity declarations for D ethylene glycol and ethylene glycol are now available for the majority of our improve excipients. Our improved quality programme helps you to speed to market and on top contact us for extensive application services which we offer to support you in the development of age appropriate dosage farms. What is the today's agenda? In the 1st 2 chapters our regulatory expert Las Albemann will provide you with an overview of regulatory references in the EU and the USA and will provide you with information about our improved program. Marcus Coylic will continue with a lecture on kids friendly dosage forms with a focus on liquids, oral dispersible mini tablets and oral dispersible films. In the last chapter, we will have a closer look at proposed APIs, vitamins and excipients for both oral solid and liquid applications suitable for pediatric formulations. With this, I'd like to hand over to Las. Yeah. Thank you very much, Ammud. As Ammud already mentioned, I will briefly talk about two different topics here. On the one hand, on the general requirements for excipients used in pediatric formulations and then also about the USFDA guidance on ethylene glycol and the ethylene glycol, which has a specific importance for pediatric formulations because children by and large have been the victims of any reasons mass poisoning occurrences with ethylene glycol and the ethylene glycol. Just looking at the general considerations on the selection of excipients mainly from an from from a regulatory perspective here. So obviously the function of the excipient in the formulation is the overriding first consideration here and also potential alternatives should be considered where an excipient might not have a very well established safety profile or a very or a limited set of information available. The 2nd consideration also very important for pediatric formulations is to mitigate the risk by keeping both the number of excipients used and also the quantity of individual excipients to the minimum required for a well functioning formulation. Here then another very important consideration is the safety profile of the excipient, specifically what they view to the target age group of that formulation. And also then of course based on the on the dosage regime, both the size of the single dose dose and also the overall daily exposure coming with that dosing regime. Another consideration is the duration of the treatment. So obviously it makes a difference whether we're talking about the short term treatment here, maybe even just a single dose or a few doses over a limited number of days versus long term treatments which can be over weeks, months or in cases of some chronic diseases, maybe even lifelong. Also, of course, the severity of the condition that we want to treat with a with a formulation here has an impact also on the safety considerations here also taking into account here particular alternatives and the risks associated with these. A very important consideration also is the risk of adverse drug reactions that could be down to components of the drug product. This could be allergies or also sensitization caused by specific components and then leading to subsequent problems. So taking all of this into account, well established excipients with a proven safety track record are preferred for this type of formulations whenever possible. But of course there are sometimes cases where novel excipients will be considered because they really pose a big benefit in a specific formulation. But that of course needs to be evaluated against the risk associated with the use of an excipient with with the small data sets available only and also needs to be weighted against the use of established excipients with a well known safety profile that could may be used instead of that. And one last consideration in this set here, patient acceptability of course, and I would already mention that is an important consideration for children especially because obviously the best medicine doesn't help if patient compliance is low. And factors to be considered here, for example, are the smell specifically, then the taste of course, but also other factors like the after taste or also the texture of the drug product. Now a quick overview of the age groups we're talking about here in pediatric or for pediatric formulations. Obviously the tagged age group has a big influence on, on the pharmacokinetics of your drug product, the absorption, the distribution, but also the metabolism and the excretion of obviously the API. But also excipients does depend on the age group. And there is a broad consensus, yeah, that that we're talking about 5, maybe six age groups generally starting with preterm newborn infants, then going to term newborns from date of birth to 27 days, then infants and toddlers reaching from 28 days to 23 months. Then children, which are here given as a pretty broad age group from 2:00 to 11:00 years. But often they are also subdivided into the age group two to six and six to eleven years year. And then you have adolescents who reach generally from 11 to 16 or 18 years of age. I'm just looking briefly at the regulatory requirements for excipients in in pediatric formulations. The general thing to say is there's very little if any specific guidance for this. So you generally find information on this topic in coming or looking at it from two different angels. On the one hand, in guidances on general exception safety where pediatric populations are also considered to some extent. And then on the other hand, general considerations for pederatic formulations where excipients are considered also again only to some extent. And if we look at what the US, what the US guidances say, generally, as you can already see the guidances are pretty old. There's a guidance for industry on non clinical studies for the safety evaluation of pharmaceutical excipients. That's a very general one on excipient safety that has a very small part also addressing. Pediatric requirements, then there's guidance for industry on non clinical safety evaluation of pediatric drug products. So here coming from the drug product side, not from the exhibition side and also an addendum on clinical investigation of medicine products in the pediatric population again here coming from the drug product side of things. And if you extract what little information is in these guidances on excipients and padiatic formulations, what you'll find is that there are a few points that are specifically mentioned there. So on the one hand, a pretty obvious thing, the pediatric age group has to be taken into account when selecting excipients and the overall formulation for pediatric age groups, then the frequency of dozing is an important consideration. We already heard that also the intended duration of treatment also pretty obvious thing to to take into consideration. And again the FDA also says that the number of excipients and their quantity in the formulation should be kept to the minimum use to ensure product perform performance, stability, palatability, microbial control and those uniformity. And if we look at what guidance in the EU provides, it's pretty similar again. So there's the EU Regulation on Pediatric investigation plan, which addresses the whole thing again from the point of view of the drug product and the specific pediatric use of drug product and gives a bit of consideration to excipients again here saying that that the the quality, safety, efficacy of pediatric products has to be considered. I mean that that goes without saying any, any way and that excipients used here should, should enable that. What they bring specifically is again the acceptability topic. And here they describe that a testing of acceptability is required, which includes palatability, so the taste, texture, flavor, etcetera. And they give that as a specific requirement for Pedro electric formulations here. And then again, coming from the exhibitions perspective, there's the EMA or EM EE MEA as it was back then. The EMEA guideline on excipients in the dossier for application for marketing authorization of medicine program from 2007, again already 17 years old. And it's basically states that excipients to be used in formulations for the pediatric population should should be selected with special care. Possible sensitivities of the different age groups should be taken into consideration. As you can see, all of these are very general requirements and not very prescriptive. So you're still left with a lot of things to consider and make up your mind about yourself. There are a couple of initiatives that are trying to make this a bit easier for formulators and are trying to address at least some of those topics a bit more specific and also specific for substances or substance groups. The one that stands out in this area is the STEP database. That's UFIE, the European Patriotic Formulation Initiative initiative has created. UFIE is, it's a group founded by stakeholders in Pediatrics in 2007. It has members from industry, from important children's hospitals and also from academia. So it's, it's a pretty broad, broad initiative. And the objective of this initiative is resolving scientific, regulatory and technological issues associated with pediatric formulation developments. They do this by providing a platform for discussions. They have yearly congresses, they conduct trainings and what they also have, and that's probably the most important, most helpful of all of their tools is what they call the STEP database, the database of safety and toxicity of excipients for Pediatrics. The link is down here. And this is a tool where they have tried to put together all the scientific information that's available for a number of important excipients that are used in pediatric formulations. You can see the list in the the lower half of the slide here. We have highlighted this our focus excipients that we will discuss later on here in In Pink. So you can already see which ones we talk about later on. And this database is really nice because it basically brings together all the information on pediatric use of excipients that's well distributed over a huge number of publications that otherwise you'd have to try and find for yourself. Good. And coming to the second point, I wanted to briefly talk about the risk of the ethylene glycol, ethylene glycol contamination in excipients and well subsequently in pediatric formulations. So this is a really tragic story with a very long history. The first cases of contamination with ethylene glycol and, or, and, or deethylene glycol occurred in the first half of the 20th century in the 1930s. And so far they've almost exclusively happened in oral liquid formulations. And these of course have the, the, the risk of being very popular for the pediatric population. So the pediatric population is the main, the main victim really here of of these contaminations. As I said, this started in the 1930s, but unfortunately it still isn't over. So there have been quite a few cases in 20/22/20, 2023 with a high number of of affected children and very unfortunately also quite a number of fatalities. So this is a pretty burning issue and this has led to a number of WHO alerts which which are visible on their website. And what it has also done, it has triggered the FDA to issue a guidance for industry on this topic and on how to minimize the risk of these contaminations occurring in the future. And what the FDA stipulate in their guidance is that manufacturers of drug products have to increase the activities to prevent such contaminations. They have introduced additional testing requirements for ethylene glycol, the ethylene glycol contaminations in a number of excipients and also in the drug products. And they also urged manufacturers to have a very close look at their supply chains and to make sure that they understand where their product is coming from and how it is controlled across the supply chain. What we have done as a company to to also work into that direction is as you know, we have a broad excipient portfolio which we market under the M Proof brand, which comes with a very extensive quality and regulatory support giving a lot of information that is required for the management of the DGEG contamination risk. We have a very extensive quality management system that covers the activities to ensure that such contaminations are not introduced through the raw materials that we use. We have a very extensive supplier qualification process including on site audits for all the improved branded ex excipients. We provide transparency by providing supply chain information to our customers and we also have developed an online tool that allows to track the origin manufacturer for each and every batch of improved excipients that you might buy from us. Specifically in terms of controlling the deck risk here, what we've done is we've conducted a risk assessment exercise for our entire improve excipients and API portfolio. This is almost finished and will be available as a complete set in the near future, but the majority of statements or of risk assessments has already been conducted and the resulting statements are available on requests. What we've also done of course is we've looked into the guidance in more detail and have decided where we might be required to introduce additional testing for high risk products. Yeah. With this, we come to our sorry last. Thank you. Yeah. With this, we come to our next part questions. Question, Have you already heard of the USFDA guidance on the control of ethylene liquol or diethylene liquol in high risk excipients? Yes, not yet or I would be interested in an impurity declaration in accordance with the guidance. Yeah. While I give you a bit more time also to answer this question, I would like to remind you if you have any upcoming questions right now, please feel free to use our QA widget to enter your question and so that we can consider it, consider it during the QA session later on. And there's still answers coming in. So I give it a little bit more time. Yeah, let's have a look at the results. That is very interesting. Thank you everyone for replying on this one. A look. And with this, I give back to our presenters. Thank you very much, Naima. I've just got one additional slide on the M proof program here. Most of you will probably be aware of it and may be familiar with it. It's it's a tool or a tool set that gives you an excellent set of regulatory and quality information in a very easy to handle online tool. And I don't really want to go into the details here because we don't have the time to do that. The link at the bottom right, bottom right corner of the slide will bring you to the improve information page on the web. So you can just click there and find out for yourself. And with that, I will hand over to Marcus for the next slide. Thank you, Lars. I would like to give you now an overview on kids friendly dosage forms. So for example, liquid or liquid formulations, but also orally dispersible tablets like mini tablets or dispersible films. And I would like to start with, I know, sorry. Where's another part question right? Yeah, I take this over Marcos. What are your preferred age appropriate dosage forms of paediatric medications? A oral liquid dosage forms. B conventional tablets. C Oral dispersible tablets, ODTSD oral dispersible films, ODFS or parenteral formulations. Yeah. And again, while I give you some time to answer those questions, if you would like, I wanted to remind you that you will be able to download our webinars presentation right after the webinar. There is a corresponding widget on your screen and then this will be available. And we still give it a little bit more time. A lot of answers are coming in. This is really nice to see. And then we have a look at the results. And then Marcos will start with the third agenda point. Yeah. All right. Have a look. OK. So here are your answers. This is a nice spread. OK. Thank you very much for all of this. And now I give back to Marcus, starting with this topic. Yeah, I would like to start first with oral liquid dosage forms. So they really have several advantages, especially suitable for pediatric formulation. So they are easy to swallow, especially important for younger children. Then also the volume can be adjusted, which enables really precise dosing depending on age, weight or surface area of the child. And it's a relatively easy administration, but there's also formulation challenges. I will go to this a bit on the next slide. But in the end, if you want to solve all those challenges, you end up very often with a formulation which has a lot of several different in excipients in the formulation. And it's last mentioned, it's actually the goal to have a small number of excipients. So that's sometimes challenging to achieve. And therefore it's very important that you really have the very strict eye on the excipient you use to control the quality of the final product. And overall, it's the most commonly used dosage forms for paediatrics. So historically, it's been basically the only option or the most preferred option. And I would like to now show you some formulation challenges you have to address. So the API normally is in the solution or my sometimes in the suspension or in emulsion. And the first aspect is really the solubility. So a lot of small molecule AP is are weak acids or bases. So by the selecting the correct pH for your API with APH adjustmentation or buffer you can increase the solubility. So this can be phosphate, citrates or really a wide range of different excipients. 1 aspects are also solvents and Co solvents which can be used to increase the solubility like glycerol or propylene glycol and you can also use surfactants which have a positive effect on the solubility, for example like polysorbates. Another challenge you have to consider is the microbial stability because normally in oral liquid formulations you always have water present and when you have water there's always a risk of microbial growth especially in those formulations because they are used in multi dose containers so they are opened by the patient and closed again. So you have to have normally to add a preservative like sodium benzoate or parabens for example. Another aspect is the chemical stability. So in a liquid formulation the reactivity of the API normally is higher than in a dry formulation. So you might also add an antioxidant for example, sulphites for example. And physical stability is also concerned, for example in suspensions. You have to have an even distribution of the API throughout the formulation when you take out the dose of your container and therefore the viscosity is especially important. For example you control this with PEG and Pvas as viscosity increasing agents. And last but not least, the taste is very important because in the end the child decides if your formulation development was successful because as last mentioned, if the kid doesn't take the medication it can't work. So it's a very critical aspect for paediatric formulation. You can use for example sorbet hall solutions or also sweeteners like sucralose and neotane. Another aspect are solid dosage forms. So they sometimes now have also some advantages or which you previously had for liquid formulations also in solid formulation because they are very small in size like 2 to 3mm, which also enables an accurate dosing of the medication. Then you need preserve don't need preservatives in those kind of formulations. And normally also the number of different excipients is a bit smaller. They are well accepted and it's actually a suitable alternative to oral dosage forms. One challenge might be the drug load because of the small size of the mini tablets. It might be challenging if you require a very high dose of API, but nevertheless very interesting alternative considering development. Another aspect is or dispersible films. They are fastest thing disintegrating in the mouth so they dissolve without water and they also enable an accurate dosing because you can control the size of the film. It's also potential to have this as a personalized H tailored medicine because you can really tailor the API doses and that's also other aspects or other formulations you might be able to consider for your drug development. So you can also have oblong tablets which might be easier to swallow, chewable tablets, semi solid formulations for example gums and also 3D printed applications. So previously we only had liquid formulations, but now the, let's say variety of formulations which are let's say relevant or can be considered for pediatric formulations is really wider. So one size does not fit all. So you can really choose from what might be the best suitable formulation for your API. And an interesting aspect is also that sometimes the problems of the geriatric population like swallowing also is similar to the pediatric formulation. So you can bind those age groups or let's say patient groups in for your formulation development. And with this, I would like to hand over to Almoud with more technical information. Thank you very much, Marcos. Yeah. What if you could take medicine that melts in your mouth? In the following, I like to share two case studies on kids friendly dosage forms, starting with Oro dispersible mini tablets containing Amlodipine as the active pharmaceutical ingredient which is used in the treatment of hypertension in adults and children. For the age of 6 to 17 years, a daily dosage of 2.5 to 5 milligram is recommended. Let's have a look at the formulation here on the left side, the galenical parameters. On the right corner you can see pictures of the mini tablets which were produced by our application service team in the size of two millimetres and five millimetres by using our Partake ODT. This is a Co processed excipient system based on Money tool which is used here as a filler and sodium cross camelose as the disintegrant. In the formulation. The measured disintegration times were two and in the case of the larger tablets 25 to 37 seconds, fulfilling the limits of the European Pharmacopoeia for oral dispersible tablets with disintegration times of 180 seconds and partly even fulfilling the FDA limit of 30 seconds. Here you see the dissolution profiles of both tablets in 0.1 molar hydrochloric acid. And as a conclusion, it can be stated here that the developed mini tablets show a fast release of the API. Before we come to the next case study. A short introduction to oral dispersible films. Short ODFS and hot melt extrusion technology. OD FS are single or multilayer sheets containing appropriate ingredients that rapidly disperse when placed in the mouth. In our case study, we used hot melt extrusion for the production of the OD FS in this solvent free process, which through heating and mixing disperses the API with a matrix polymer, helping to increase the dissolution rate and improving the solubility of poorly soluble APIs. As a matrix and film forming polymer Poly vinyl alcohol short PVA is widely used. In our case study, we used the API Loratadine, which is widely used as an antihistamine agent because of its efficacy in the treatment of allergic disorders. It is classified as a Class 2 drug based on the biopharmaceutical classification system. Due to its low water solubility, Lora Tardine's high thermal stability makes it suitable for films produced by hot melt extrusion. To increase the low solubility, the recommended dose is 5 milligram per day for children up to 12 years with a body weight of 30 kilograms or even below 30 kilograms. As a polymer, we used our Apartek MXP 488. This is based on the Poly vinyl alcohol grade 488 which has been specifically developed for hot melt extrusion processes to destabilize the drug molecule in its amorphous form, hereby increasing the solubility of the API. And as lauritardine is known for its intensively bitter taste, our neotame was added as a sweetener for taste optimization. Its advantage is that it does not add significant bulk to the mini tablets or films due to its high sweetening potential. Neotame is around 8000 times sweeter than sucrose. You see the process parameters at the right side. Two films with a thickness of 60 to 70 micrometers and 70 to 80 micrometers were produced at an extruding temperature of 190°C. Overall, we could recognize a smooth processability and obtained homogeneous and fast integrating films. As you will see on the next slide, the film was cut in three different shapes in a hard in a balloon and rectangle of different sizes. As stated here, the rectangle had the largest size with a dimension of 1.9 by 2.9 centimeters. This is in line with films successfully tested in others acceptability studies with children, which can be found in literature. In these studies, ODFS with the size of three by 2cm were used for children in the age of 1 year and older. The rectangle contained 5 milligram API, the heart and balloon 2.5 milligram each. The measured disintegration times were ranging from 33 to 45 seconds in the case of the rectangle, meeting the requirements of the European Pharmacopeia for oral dispersible tablets. Let's have a look at the dissolution profiles of the films into strengths of the API represented by the upper profiles on the left side in magenta, on the right side in in red. You can see here The OD FS showed even a faster solubility of the API in simulated cell lever with the pH of 6.7 faster than the pure API shown here by the green profiles. So we can conclude that Odfs of this drug give better therapeutics benefits for children. And it's worth to explore Odfs further due to their potential for age tailored API doses as they offer an interesting potential for personalized dosages. The acceptability of Odfs was also compared compared to xyrobes in neonates and infants by Doctor Klingman and others in 2020. According to their results, Odfs are both a safe and effective dosage form for this population. In the last chapter of our presentation, we will have a brief look at proposed AP is vitamins and excipients, which are well established for pediatric medications and suitable for oral and liquid solid applications. Yeah. But first we have another poor question. So coming to this, what are your main challenges in the development of patriotic formulations? And with this question, you can select all that apply taste modification for enhanced palliability, high loads of APIs in oral dosage forms, physical and or microbial stability of oral liquid formulations, availability of safety and quality data or control of impurities. Yeah, this is a very interesting field and I look forward to the results. And while we give it a a bit more time for all of you to answer the poll question if you like, I wanted to remind you if you've still questions that came up during the webinar, lots of informations from a regulatory side and also from a technical side etcetera. So please feel free to use our Q&A widgets and we tried to cover those in the Q&A session. And if not, as mentioned earlier in the in the introduction, our presenters come back to you later person personally. Yeah, yeah, still, still answers coming in. It's really nice to see. You had a few more moments. Yeah, let's have a look. All right. Yeah, nice trends to see. Thank you very much. And with this, I give back to our presenter. Thank you, Naima. Yeah, let's have a brief look at proposed products of our portfolio for paediatric formulations, starting with folates, which are essential for cell replication and cell growth. As shown in our dedicated webinars, no other manufacturer has explicit approvals for infants in the EU and in the USA. In addition, I like to highlight that stability data are available in liquid formulations. Discover our range of mineral salts under the improved program. We provide full regulatory support and documentation for the use in oral, solid and liquid application as well as parental applications. Here you find an overview of our offering of widely used vitamins suitable for paediatric formulations. I'd like to highlight the launch of our newcomer Pyridoxine hydrochloride improve expert vitamin B6 hydrochloride ensuring growth development, which is also suitable for parental use. Palatability is a key element of the patient acceptability for the taste optimization of formulations with a bitter API, sweeteners are usually the formulator's first choice. Our high intensity sweetener, sucralose and neotame are widely used food additives and restrictions for the use in pediatric formulations are not known. Extensive data on sucralose can be found in the Sepp database. Partec. TA, Calcium carbonate. This is our titanium dioxide alternative. You will know that titanium dioxide is extensively used as a no pacifier in solid applications. Currently it's used in pharmaceuticals, is under evaluation by the EU Commission after it's been as a food additive in foods and nutritional supplements in the EU in 2022. This ban was related to safety concerns as genotoxic effects could not be ruled out, according to an assessment which was provided by the European Food Safety Authority. It is our calcium carbonate with a unique homogeneous particle morphology specifically developed for enhanced opacity in tablet film coatings. The EFSA recently assessed the food additive calcium carbonate as a product of no concern at reported use levels in all age groups of the population, including infants below 16 weeks of age. Then let's have a brief look at our Partek M products. Partek M-102 hundred. We offer two money tool grades here of different particle sizes. The Sugar Alcohol Money Tool is a well known filler and binder which is widely used in pediatric formulations as it enables high tablet strength, good flow and fast disintegration. According to US regulations, it has gross status, meaning it is assessed as generally recognized as safe. Now I like to hand over to Marcos. Yeah. Thanks Almud. So we also have a glycerol and propylene glycol which are mainly used in liquid formulations and those are the specific two excipients which are really related to most of the poisoning or contamination incidence related to the Etilen Etilen glycol impurities. And therefore let's say you have to take special care to get the right quality of those products. We also have them in our portfolio and also we have sorbitol. This is really for sugar free syrups, also a widely used ingredient in liquid formulation, which also is relevant related to the impurity guidelines which just spoke about. So also very widely used and also now coming to the end. So as you have seen one size that's not fit all, there's now really a wide range of different formulation approaches you can take to come up, come to a final of kids friendly dosage form. So this can be liquid, solid and even more. And we can provide you and support you by providing you with the relevant excipients for all kinds of dosage forms and also the necessary information to help you to control the quality of your final product. And if you are specifically interested in Technical Support, we also offer extensive application services for our dispersible mini tablets or films. Please contact us here if you need dedicated formulation development support. Yeah, that's now the end of our formulation now. Naima. Yeah. Thank you. Thank you very much. I'm sorry. Thank you very much, Marcus and I would and last for this great presentation. Now it is time to answer a few questions that have come in from our audience. But before we do, I would like to remind you that it's not too late to send us your questions now using the Q&A widget. This also applies to on demand viewers. We will try to get through all of them, but if we run out of time, we will respond to you individually. As a reminder, this VB Now will be available on our website soon. All participants will receive an e-mail notification when it is available for viewing. Now back to Elmwood, Marcus and Glass, who will start answering questions that have come in. Thank you. Na e-mail. Yeah. I found here one question. I like here to ask last to answer this as this is related to your part of the presentation. The question here is what steps are taken by your company to ensure the compliance with the USFDA guidance on the control of D ethylene glycol and ethylene glycol contaminations? Yeah. Thanks Anne for bringing up that question. What we've done is we've done a risk assessment individually of all our excipients, the whole portfolio to figure out if they are high risk excipients, A in the sense of the FDA guidance and also B, in our own opinion. So what we've done is we've gone through them, we've looked at at their manufacturing processes at the raw, raw materials and then decided if they are high risk and if if they are high risk, we've looked into the possible risks and have decided if we need to do additional testing. And in case we need to do additional testing, we have brought the ethylene glycol and the ethylene glycol specifications onto the specification. Thank you very much. Last, another question I will take. How does the regulatory landscape impact the interest in the development of pediatric formulations? Yeah, the answer is, in fact, the authorities in the US and in the EU are rewarding companies for developing new and suitable dosage forms for children. Yeah, an example from the EU, medicines authorized across the EU with results of studies from a paediatric investigation plan included in the product information are eligible for an extension of their market exclusivity by 6 months. This is the case even when the study results are negative. And another example for often medicines in the EU, the incentive is an additional 2 years of market exclusivity. So really beneficial for companies being pediatric formulations. Yeah, for time reasons. Coming to the last question, what are the recent advancements in testing the patient's adherence and acceptability? Yeah. Here I like to refer to a proposal of a public private partnership. In 2022, they sent a request to the European Medicine Agency for a qualification opinion on a new developed composite endpoint method for acceptability evaluation of oral drug formulations in pediatric populations from the age range up to 18 years. And they received a really positive response. In its letter of support, the European Medicine Agency confirmed the need for a broadly accepted and sound methodology. I'd like to hand over to you. Yeah, you have. Another question I saw, I saw a question from the audience here which I can briefly address. The question was if we will provide a general risk assessment for our whole portfolio or product specific statements and we will provide product specific statements. We are through with most of our portfolio by now. So the chances are good if and when you ask that you can already get the product specific statement. If it's not there yet, it'll be available in the next couple of weeks. Yeah, thank you very much for all the questions. If you have any additional questions, please feel free to e-mail our presenters directly. To register for future webinars or to access our archive webinar library, please visit our website. You can also download the presentation slides in the Take Action field that will pop up on your screen once the webcast has finished. I would like to thank Elmwood, Marcos and Lars for today's presentation and thank you to our audience for joining us. Have a great day. _1732162110874

  
    
 
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