Hi, everyone, and welcome. My name is Shannon Hen and I will serve as your moderator today. Thank you for joining us for today's webinar envisioning new concepts for pharmaceutical 3D printing and solubility enhancement. As your moderator, it is my role to ensure that we make the most of your time with us. I'm here today with Dr. Thomas Kipping and Dr. Michelle Schilling. Dr. Thomas Kipping is a distinguished expert in the field of pharmaceutical technology and formulation development, is currently the Head of Drug Carriers in our company with more than 10 years of industrial experience spending across various sectors within the Pharmaceutical industry, including drug product development and CDMO services. He has consistently demonstrated a strong commitment to advancing pharmaceutical sciences and enhancing drug development processes. After obtaining his PhD in Pharmaceutical technology from the University of Bonn, Thomas has experienced a journey of continuous learning and growth within the industry including formulation development, solability enhancement, advanced manufacturing technologies, regulatory compliance, quality assurance and research and development. Dr. Michelle Schilling is currently Manager of Product Development at Appreciative Pharmaceuticals. With 14 years of pharmaceutical experience. She has been a technical leader of multiple cross functional product development teams which expertise and formulation and process design from early development through scale up of IR and modified release truck products. Her experience includes process development with 3D printing, binary jetting, subletting, fluid bed manufacturing, high share granulation, course servation, encapsulation and roller compaction. Michel is a chemist by training and holds a PhD in industrial and a physical pharmacy from Purdue University. Before I turn things over to our presenter, 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 a thumbs up emoji that allows you to give immediate feedback on the presentations, toppings and 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 a full screen by clicking on the arrows under top right corner. If you have any questions during the webinar, you can submit them through the QA widget. We will try to answer these during the webinar, but if you are more detailed answer is needed or if we run out of time, it will be answered later via e-mail. At least now we do capture all questions. You will also have the opportunity to participate in a couple of quick poll questions through the session. I encourage you to take part in this service. If you are watching this webinar on demand, you can still submit poll responses and questions via the QA widget. The webinar is being streamed through your computer, so there is no dial in number for the best audio quality. Please make sure your computer, speakers or headset are turned on and the volume is up so you can hear the presenters. An on demand version of the webinar will be available after and you can be accessed using the same link that we sent you earlier. So that's it from my side. It's my pleasure to turn things over to Michelle and Thomas. Thank you, Shannon, and welcome everybody to our joint webinar here on envisioning new concepts for pharmaceutical 3D printing and suitability enhancement. First, let's dive into the background of 3D printing for truck products and let's have a look at the potential advantages of 3D printing. We see a lot of movements in the sector of personalization. We see that diagnostic tools are evolving and also personalized medications are improving. So there we have a great impact here also matching here the 3D printing environment. We also see a good application for the acceleration of clinical development where we can then here simplify formulation development and also allow fast responses here to individual clinical demands. Another big pillar where we see a good application for 3D printing is the framework of sustainability. In order to then reduce the environmental footprint here on one hand by simplifying development processes but also moving more into a smart manufacturing approaches. That ultimately leads us then also to the concept of decentralized manufacturing that can also impact the entire supply chains and even a complete manufacturing lines or concepts that can be utilized for the production. So we see the key differentiators here for this technology are driven by flexibility, smart manufacturing and also the nature of the process itself as we are already entering highly digitalized processes. Let's start with our first poll question. What would be the main drivers for you to adopt 3D printing technologies? Select all that apply personalization, the speed up clinical development, see safe drug substances, the environmental aspects you keep waiting for a little bit. All right, thank you for your participation. So thank you for joining the poll questions. Let's now have a look into the 3D printing applications within Pharmaceutical industry and looking here first at the overview of available 3D printing technology that are already meanwhile quite well established and that are further explored and also for early development stages. And we are ranging here from powder based systems where we're looking on the drop on powder or binder jetting technologies or for example the selective laser centering technology. And here you have also different concepts on how you create your three-dimensional form, either by the liquid binder or by the energy of a laser for example. Then we see also evolving the liquid based systems. You can see them on the right side here, mainly driven by the drop and drop deposition or even more known currently the stereolitography, the SLA. Here we use energy of a UV or laser system or even a temperature system in order to allow polymerization and thereby create the three-dimensional forms. Another technology that is frequently applied is the extrusion based system technology where we are also looking into the classical fused deposition modeling that is one of the most applied technology especially in academia of first industrial settings And another technology here is the semi solid form 3D printing where you are creating the form by a pressure assisted syringes. So today we're focusing more in the powder bed systems looking especially here at the liquid binder check. Another important challenge that Pharmaceutical industry is facing lies in the solubility enhancement. We see there is a big challenge for further formulation development in the future because compounds are becoming less and less soluble, coming more and more lipophilic and we see that also presented here. You can see on the left side an overview about the different BCS classifications. So we have a biopharmaceutical classification system where these compounds are classified according to their permeability and solubility. And when you look now in the center here of the presentation, you can see we currently still have a high amount of PCs Class 1 compounds. They are good soluble and good permeable. So they don't pose a complex formulation development. They can be easily formulated with standard technologies, but if you look on the right side now, you can see a big shift. The amount of the PCs Class 1 compounds is expected to drastically reduce in the future and the amount here of PCs Class 2 compounds will be drastically increasing. And there with these compounds, we have a big issue concerning solvability and that's why bioavailability enhancement here is a very important topic for the future of formulation development. And we are now also looking into ways of combining these two important needs here. On the one hand, the flexible manufacturing now also with the solubility enhancement technologies, we also developed already successful platform technology based on the Partech SLC. And if we can explain how that works here, you can see the crystalline drug substance here on the left side. It's a very densely packed crystalline form of the truck substance. And yeah, for our solubilization technology, we then solubilize the truck substance in a respective solvent and add it together here as Departec SLC. So it's a silica based, very porous material that then creates a very high surface area. And these pores where this structure provides the entry point for the drug substances are very tiny. They are only about 6 nanometers here in diameter and they can really sterically stabilize the amorphous form. So the compound here is entrapped within the pores and is then sterically hindered in order to be not able to crystallize and therefore maintain the high solability layer. You can see now how that works. So we're loading here via the solvent removal process. You can see it in the center, you can see the silica particle and around it the solubilized API. Then we remove the solvent. So then the yeah truck substance enters the pores, the solvent is removed and all the pores are now filled with the amorphous form of the truck substance. And then later on when, yeah, when this kind of busage form is then released in for example, dissolution media or later on in the body, we can see it gives away all the compound again and we have a good dissolution in the relevant medium at the end. That is, in a nutshell the concept of our solabilization technology that we are applying with the parting SSC. And the benefits here include that we can enhance solability. We can thereby increase the dissolution and ultimately improve the absorption of the attract substance. We also have additional advantage that are very important especially for challenging compounds because we are avoiding here the formation of polymorphs. Usually these compounds with other technologies can also crystallize out in different polymorphous forms, and here this can be prevented by really entrapping the form in its amorphous form within the port. And another advantage here is the applicable also to poor glass formers would be otherwise maybe not even be able to be formulated within a classical amorphous solar dispersion approach. So now we want to really combine these two innovative concepts here in order to accelerate the developments by using and introducing here the solar print technology. How does it work? Let's look at it together. On the left hand, we can see the PARTEC SAC technology. So as just introduced before, we have the innovative solution here to mitigate suitability challenges and thereby we can provide new opportunities to maybe even formally nonaccessible compounds. Here again you can see it in a nutshell, how the system itself works. And now we try to combine this kind of technology concept with our 3D printing technology where we can then see we have a higher flexibility and even access to smaller batch sizes. And then that will drive here cost savings that are driven here by reduced development times and also by the lowered amount of requirements of API amounts. Well, let's have a look together on how that works, how does it work. Now we're looking into combining really the binder jetting and the use of the Partec SLC. In the first step, we are depositing here the Partec SLC on the print pad. You can see there is a powder dispenser involved dispensing here the powder on the building platform. Then we are seeing a print head that can then apply here the binder and drug substance fluid. So we have already pre prepared binder and the API fluid R can apply that in separate nozzles. You can see then the binder is solidifying the layer. You can see here on the bottom right already the first individual layers that are solidified here by the binder and then in the next step here you can already see the first prototypes of the amorphous API here within the silica tablets. That's basically an overview about such a process where we also perform on the fly loading of the silica while then 3D printing the system later on. Now looking here at the advantages simplify and combine, that is yeah, our motivation to combine really multiple steps. You can see the standard steps here. On the top we would have a preparation step, loading step, then a tableting step, and optionally even coding steps later on. And now we can, yeah, narrow that down, reduce especially the time for loading and even, yeah, neglect the tabletting step as we can combine that here in one printing step together. So you can see, you can see this, yeah, this combination here and you can also see on the bottom line, you can see the impact on potential development times when you would consider that here as a classical pharmaceutical development. So for us here, the coupling of these innovative solutions here provides substantial time and resource savings especially during the formulation development times and also enables here are difficult to formulate formulations. That's an important message also because we have now new opportunities for compounds that may have been neglected otherwise. Let's look at the production concept. Yeah, one goal, two roots, what does that mean? You can see here on the top how such a layer individually looks here and centered together and you can then look at the 2 routes that we are looking into on the left side. Here we are performing an open bad printing where we have the combined loading and 3D printing process as we just looked at together before. So that is one opportunity to really combine these two steps. We also have another technology that we're currently jointly evaluating here is the in blister printing where we are then 3D printing already preloaded Partec SLC. That's also very interesting concept because then you can use use also a loading technology create very large amounts of already loaded amorphous truck substance and trapped within the Partec SLC and then produce that here on demand and create your three-dimensional forms or personalization here of the yeah optic compounds on demand based on preloaded city that are basically 2 routes that can be utilized. Now looking closer at a case study that we recently evaluated, you can see here now a case study for the in blister printing. What we did here is we had a model compound, the caromosapine classic BCS Class 2 model compound that is frequently used also especially in the area of stability enhancement. And we can see, yeah here the ingredients that we used the SLC, the binder liquid and the certain powder plant to then also adjust really the final target amount. You can see an image here of the first tablets here on the left side looking at the surface. And we also performed A deeper analyzers assessment here of the homogeneity within within such a 3D printed tablet. You can see that here on the right side, on the bottom you can see a cross section. And what we did here is we performed the SEM EDX image of the cross section. So we can really then also see how is the distribution for example here of the silica within the tablet. And we can confirm with this kind of technology that we have a very homogeneous distribution within the tablet that's very promising from our, yeah, looking now also at the performance for sure, one important goal is also looking at the solution performance. So for us it's very important here to create an amorphous form. So we characterize the solid-state characteristics on one hand by differential scanning calorimetry, on the other hand by PXID studies. And we then could confirm that the carbamazepine here is successfully transformed in its amorphous form by entrapping it. Yeah, in these cavities. You can see the PXD data here on the left. You can see the distinct peaks of carbamazepine at the bottom. So very crystalline distinct peaks. Then we can see the placebo tablet on top. Yeah, this scans are matching the multiple ingredient as we saw before. So there is a certain pattern for sure and the carbon massapine tablet here loaded at the top and you can see especially for the distinct peaks of carbon massapine year round for example like 14 degree 2 Teta, there is no peaks available anymore also here confirming that we reached the amorphous form then especially the performance, that is something we were very happy to see. You can see on the right side here the dissolution of carbon massapine here in water and you can see how that differentiates here. Yeah, compared to the standard classical coverment, you can see the increase of the dissolution time, dissolution performance and also the solubility enhancement that we can achieve with this model component. So both confirmed we transferred the API in its amorphous form and we also confirm the performance here of the final dosage. Coming to our next poll question, how would you access the capabilities of new technologies such as the 3D printing A we want to evaluate with an in house system and capabilities B, we would like to partner. C We would need a full turnkey CDMO service provider. D depends on the application. We'll wait a few seconds more. Thank you for taking the time to provide your feedback. Yeah. And with that, I hand it over to Michelle. Thank you, Thomas. OK, So what was presented just now is sort of a wonderful example of the flexibility and the advantages of 3D P binder jetting in a pharmaceutical application. The studies shown were sort of performed at bench scale. And if we want to adopt new approaches for manufacturing, we need to be able to transfer those initial studies into a commercially viable process. So how do does one move sort of a, a novel 3D B technology application into a commercial GMP space? Well, here at Apprecia, we have done just that. We are the first company to develop and gain FD approval for a drug product utilizing 3D P advanced manufacturing and that's really a significant milestone for advanced manufacturing. We see ourselves as a global leader in new technologies on particularly as a CDMO capable of transitioning novel 3D P applications into a GMP manufacturing space. And we do that because we have two different production systems at the GMP scale. We have a Z free open bed sort of forming system and then we have a Z form which utilizes sort of our new in blister binder Jenning equipment and this really forms the dosage form within the intended finished packaging configuration. So it's sort of a next step and further it seems capabilities of 3D PGMP manufacturing here at appreciative next slide, our Z3 production system is available at three different scales to accommodate GMP manufacturing throughout the development likes life cycle. Our first equipment the Z3 Pro is is represented in in this image with purple around it and this works sort of in a racetrack like design. This is the equipment that we used currently to manufacture our commercial equipment, our, sorry, our commercial product. So really it's a verified piece of equipment. We have continuous powder feeding being an auger and a vibration curtain that then spreads the powder onto trays. We have a stationary high resolution print head that then applies the print image onto that powder bed. And then we have some recirculation and harvesting of powder that's unprinted throughout the process. Tablets that are formed or sent through a low humidity drying oven where we remove the plates or harvest the powder, recirculate it. And by implementing this, we really have the capacity to produce up to 800 million tablets per year on this specific piece of equipment. We do have additional manufacturing capabilities in the Z free production system. We have a Z Free Flex, It's a smaller scale piece of equipment. It's it's in the light blue color. This is really for small to midsize manufacturing. We might use this to optimize formulations during development, but really it's going to produce clinical trial and low volume sort of marketed material. It works a little different in that it mimics the straightaway sections of the racetrack and I'm going to explain the racetrack in the next step. And then we have our Z free lab and this is really for very small prototype developing sort of at a rapid scale where we have limited material whether it be a Pi or just blend. And it really is great for giving us some feasibility in early formulation development platform. So as I mentioned, we have our Z3 Pro equipment and this utilizes a horse trap type design. There is no tooling, dye, compression activities associated with the manufacturer here. The powder is spread to a thin sort of defined layer thickness upon base plates and it's leveled by a counter rotating roll. This track moves around the Oval. The level powder passes underneath the print head and the print fluid liquid is selectively deposited on that level powder surface and the track circles back around and the process is repeated. And we do this layer by layer until we build up this three-dimensional dosage form powder. As I mentioned that it's not printed upon, it's these regions in white is recaptured and it's circulated back into the process. But really this equipment design is optimized for scale up and volume flexibility and ultimately production at large scale. Our other production system, the Z Form Flex is our newest sort of production system. And as I mentioned it, it's manufacturing the 3D dosage form within a cavity of a blister card. Printing in the 3D construction of the dosage form is the same fundamentally as a Z3. However, it's different in that we do not have sort of the powder or to say it's different in the powders dosed individually into the blister cavities and it's eliminating that need to recirculate material. Powder is added to each blister well via powder feeder system and it's very similar to that of a conventional tablet press. And then the powder is level, it's passed under a print head and just like in the other system that process is repeated layer by layer to build the dosage form. As part of this process, the tablets do undergo a sort of a gentle tap sort of to create a smooth external surface So. So we we do get a better appearance out of this technology or platform versus our open bed systems. And we also have some advantages in that this equipment is is really a modular design. So it's providing some added flexibility in formulation design compared to the Z free system. We have the ability to dose two different powder blends or say a combination of blend with a multi particulate and we also have the ability to utilize multiple print fluids and all of this within the same manufacturing operation. The Z Form equipment is also linking sort of 3D manufacturing with the shift to integrated process analytical technology. The Z form Flex, it has multiple PAT technologies integrated into the equipment. So we have near IR for blend uniformity from the dosing wheel we have smear which is a shortwave IR for assessing the quality of the print fluid. From the application side we have 3D laser displacement cameras for volume assessments and that will tie into weight and we also have two D cameras for assessing for a visual assessment. I should say that provides feedback with regards to the final surface appearance of the dosage form. So when we talk about transferring or scaling a 3D P formulation, we we have to consider more than just the equipment. We have materials, we have a powder blend and we have a print fluid that interact with each other and we have a printing process and these materials and this printing process really combined is what's producing a finished product with a defined product quality attribute. The material properties and printing process are very interactive with each other. So when we transfer within scale or to a new scale, we need to account for differences. And this is kind of particular case with print heads. There are many different inkjet print head unit print heads on the market and each one has particular capabilities. Material properties of the print fluid need to be aligned with those print head capabilities because they ultimately go into defining sort of that suitable jetting recipe that goes into the equipment. And this is where Appreciative really has an advantage because as a CDMO we have that 3D P expertise and experiencing scaling sort of a robust formulation process. So when we look at the application as presented by Thomas, utilizing the Partec SLC for amorphous API loading within a 3D P manufacturing space, one of the challenges we encountered was with regards to the suitability of the print fluid on the jetting assembly. All print heads have an optimized printing window and it's defined by the Reynolds number and the onus large number. And sometimes you'll see this graph as the Reynolds number with the Weber number. But essentially what we're looking at here are the fluid properties aligned with the print head properties and we need to follow into this sort of jetted window. So this window is going to be different depending on the print head and the application that you saw presented. Our companies utilize two different inkjet print heads. So that's where the the challenge came in. We need to align the print fluid that they had and bring it into the Jettable space of our print heads. And so when in this is going to be applicable to any type of scale up situation. So the first thing someone has to consider is that print fluid and what is the viscosity, what is the surface tension, what is the density and how do I need to change those and modify those to align them with the process that you have internally or that you're trying to scale into. Once you do that, it's really a fundamental step moving forward from there. So one of the key things to scale is a print saturation. So you're going to have a combination of a drop volume resolution or a drop per inch and a layer thickness that all combines free to saturation. And you want to maintain that when you scale because that's going to impact your end quality attributes on your dosage form. We want to target these print fluids targets to be the same into our print head. But in order to do this you may have to modify your waveform. You might have to modify the print frequency, you might have to modify your amplitude. But these are all things that can easily be screened as part of scale up. The easiest part is actually the materials. So really materials are very accommodating in the process. So binder jetting can really accommodate a wide range of traditional pharmaceutical excipients. There are some considerations to align flow properties, the particle size, the density. Again, you can account for that within your print process or your print recipe. But ultimately when we look at accommodating the materials such as part tech, SLC into a technology, it's really done very easily. So as a case example here, when we looked at taking this sort of approach, we were able to modify the print fluid that Merck KG, a Darmstadt, Germany had produced, made it acceptable for our jetting assembles, US jetting assembly. And then with some changes in the printing parameters to sort of target that print saturation, we're very easily able to manufacture a pure part tech SLC tablet. Again, there's some contributions from the binder fluid, but what you see here in image wise is us having transferred the process from that Thomas had presented into our equipment. And this is a direct print of that SLC part pack and you can see that we got a very nice pretty 3 dimensional printed tablet. And I think I will transfer or we have a cold question next. Our final poll question is for which applications are you most likely to use a platform driven CDM or when considering 3D printing technologies, select all that apply a when implementing lifecycle management strategies, B when enabling formulation of a challenging NCE, C to accelerate cynical development and D to optimize commercial success. We still keep waiting a little bit. We appreciate your responses to the poll. Yeah, thank you all. And yeah, thank you for the questions. And they are now looking at the summary and looking here also at the current state and future potential of the technology. First, the concept of 3D printing. So we see a great potential in this kind of concept really creating 3D object here by layer by layer deposition approach, especially here as we have a good link with the digital design that will be very important especially in the future also for Farmer 4.0 applications. And also we see great potential here in enhancing the functionality of this concept here by combining the high flexibility with the solubility enhancement technology really providing thereby an added value to formulators and later on for sure to manufacturers. Another important point that we need to consider here is the high process flexibility. So we can really enable those customization, customized design approaches and as mentioned, advanced functionalities that will become more and more important especially for critical development. Another important application that we see is the acceleration of truck product development also by reducing the number of unit operations. And in our case here, for example, combining the silica loading steps directly with the additive manufacturing, so really integrating different production steps into one process. Yeah. Another important topic here is the evolution of 3D printing technology. And here we can say that we confirmed the new concept already really on evaluations that are already based on a GMP printer design. That is very important that we can also directly utilize such a technology on a larger scale and in the pharmaceutical environment. And we also saw we have a high scalability of the process providing a large manufacturing capacity and even yeah good scale out potentials also for example in the framework of on demand production. Thank you Thomas and Michelle for this great presentation. Now it's 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 light to send us your questions now using the QA widget. This is also applied to the 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 way we know it will be available on our website soon. All participants will receive an e-mail notification when it's available for viewing. Now back to Thomas and Michelle who will start answering questions that have come in. Thank you. So we see, yeah, a lot of interest in the technology and in our presentation. You can see that in the big interest here coming from the questions. And we have major, let's say, major 2 clusters that people are mainly interested in. And there is a lot of questions first on the drug load, maximum drug load and another topic is around commercialization. And yeah, we'll just pick the first questions that we can answer them. One very interesting one, what truck loadings can be reached, what a typical moisture content in each layer after dropping binder and API, Are there drying challenges for example? Yeah. And yeah, maybe I can start with the truck content. So if we are looking for example at the silica loading, usually for sure depending on the truck substance, we can reach loadings up to around 50%. So that is achievable with the technology. When we look into truck loading of the, yeah, pure silica and then if you consider for example that we can use as presented already the pure silica printing, we just use a tiny amount of binder liquid, a certain percentage of binder liquid. So you can imagine we have very high truck concentrations here going up to maybe even 40% or 50% in the final tablet for sure depending on the on the truck substance a little bit. And maybe also I can, yeah, ask me shed also maybe to comment on the drying and and how we can assure that the system is trying well or maybe giving some insights into how we can facilitate that at a larger scale. Yes. So drying is already integral to binder jetting. Any challenges associated with fully sort of drying this as we manufacture it in situ is something that can be accommodated as part of the process. Again, there might have to be some modifications associated with the specifics of the printing recipe and the quantity of liquid being applied, but it would be within scope again of already the process train associated with the technology. Thank you, Mitchell. OK, that is was one important question and a lot of people were asking in this direction. Let me just have a look. We have another interesting questions here. In what way this technology can be advantages over traditional technologies including HME spray drying or doubleting. Yeah, so that question is also directly targeted to the area of solubility enhancement. So that is something where our technology now is differentiating because we are really using the drug loading here of the silica and therefore entrapping the drug substance in the nano pores really preventing a certain crystallization. And that is then especially interesting, as we shortly mentioned in the introduction for, yeah, poor glass formers that wouldn't be too stable in an amorphous solidus version for a long time. So here they would be entrapped and stay in its amorphous state. That is 1 interesting aspect where we can differentiate. And then also certainly especially if you look into tabletting, you always need to optimize your formulation according to the substance that you want to use within. So you would need to modify the formulation also looking into different release kinetics, but especially the compaction behavior for example is they are highly affected by for example changes in the crystalline form of the API or even modifications of the API. So by really using the additive manufacturing approach, we can create these forms here independent of the compact ability behavior of the material. So that is also and definitely an advantage when it comes to your early formulation development, especially for the timelines because you don't need to optimize then your compaction behavior for dedicated formulations and also you can streamline your development processes by utilizing this kind of technology. Just to mention this kind of advantages another question we see incoming, did you assess the long term stability of SSE loaded particles? Yes, we developed the SSE technology is already a longer time developed from us and this really a big part of the yeah so ability enhancement platform. So we have, yeah, a lot of knowledge on this technology for extended time period and we also assessed already long term stability studies with the technology and we can yeah, confirm that if you apply the right processes there is a very good long term stability for this type of technology. Look what we can do next that we have some questions like what are some examples for example for Binder Liquid that we can use in the general binder jetting technology. Maybe for Michelle that's maybe something you're very familiar with. What kind of binder, liquid or binder systems? You can in general use them as soon as I mentioned your print fluid needs to align with your print head. Generally all of the print heads on the market are going to be at least the inkjet print heads on that are applicable to find your jetting are going to have some viscosity considerations around them as the primary driver. So you're probably not going to be able to print something with a viscosity higher than maybe $0.20 of boys and at the low end maybe something around 8 Cinnaboys. So usually we can accommodate any polymer system, but we need to fall within that range of viscosity and again aligning it more particularly to the jetting assembly that you're utilizing. You know as far as other components, usually you want something that's in solution. Suspensions probably wouldn't be a good idea, but traditional cross covidones, covidones, interior polymers, again, as long as you're making sure that you are using a solvent that maintains viscosity, that's agreeable and you considerably use great. Thanks, Michelle. There's another interesting question here coming up directly also for Michelle. Is the powder for the powder bed just blended API and excipients or is there another powder processing step necessary like wet or dry granulation? How is your experience with the powders? I think the this is gonna be very similar to what you're gonna see in other pharmaceutical manufacturing processes. It's really gonna depend whether or not you have a blend that's primed segregation or other considerations, medium low API concentration where you're trying to make sure you get homogeneity throughout the process, but you can do direct blends. Certainly a lot of our development is in direct blends. Again, you want to make sure you look at flow properties and you look at particle size as it relates to your print process, so your layer thickness. But if you need to do a wet or a dry granulation, that can certainly be incorporated into find your jetting without any issues. But if you don't need that and you're able to formulate a direct one appropriately, you can certainly go that way. Pretty clear, Yeah. Thank you. Another interesting questions. Yeah around the QC technologies and maybe even PIT technologies. How far has QC techniques been developed for 3D printing of personalized medicine? Are there only products in small quantities? And as there will be a need for non destructive methods for SA and dissolutions, where do we stand in the validity of these methods replacing chromatography and dissolution? So very broad question, but I think Michelle, maybe you can give some insights about the PIT or IPC controls that you established and maybe how you think that may look in the future maybe. Yeah, this is a pretty broad question. I think right now whether or not it's for personalized medicine for for a more traditional sized commercial batch on production scale. I think the requirements right now are pretty much the same as far as expectations around what you're going to need to validate any model that's used in PAT. And I think it's probably something that will have to be discussed. But you know, I, I don't know right now again FDA kind of opens up the door towards some discussions around novel technologies. That might be something that we can start bringing up the discussion as to what requirements do you need to validate that model and what sort of could there be a more general model utilized with the various pieces of equipment that are brought on sort of to allow that real time release. So I don't know about as good as I could get on that one. Yeah, tricky question. Yeah, a lot of things ongoing in the direction, a lot of movements that we see there. But I think so far no ultimate solution yet, but I think I'm going very fast. Yeah, yeah, another question we see here, what is the advantage here with loading API into Silica as part of the printing process compared to the preloading? Yeah, that is also a good question because that is what we demonstrated. We have these two ways of getting to the final form. So especially with the loading via 3D printing, then we can really narrow down the entire development times and look for example very broad and early screenings and be very flexible. Also when it comes for example to early clinical supply where you also might need to modify a lot of details of your formulation, looking at those but also release kinetics and looking also then at the preloaded, that can be pretty interesting. Also if you envision for example like a more decentralized production where you could then have the preloaded particles already there with a certain long term stability and then you manufacture them for example on demand and really then produce for example larger amounts at a certain dose those strengths or with a certain release kinetic that you that you then need locally. That could be two major drivers for the concept. Yeah. Now coming maybe to one of to the last question, what differentiates your technology from classical 3D printing concepts? Yeah, I think, yeah, I mean as mentioned in introduction there is various 3D printing concepts out there ranging from the melt based technologies and over to the liquid base. And then also now here especially focusing at the powder binder systems especially the technology we presented today. The aim is really to combine the solvability enhancement part of this technology with the flexibility manufacturing here of this 3D printing itself. So that is an important differentiation to classical concepts where we're really focusing on combining here these advantages and that gives us here high flexibility and especially later on also the potential for decentralization of the manufacturing. All right, Thank you very much for all your questions. If we did not get to your question, please feel free to e-mail our presenters directly To register for future webinars or to access our achieved webinar library, please visit our website. I would like to thank Thomas and Michelle for today's presentation and thank you to our audience for joining us. Have a great day. Thank you. _1732521182219

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