Hi, everyone and welcome. Thank you for joining us for today's webinar scaling for commercialization Considerations for Large Scale API production. As your moderator, it's my role to make sure that we make the most of your time with us. My name is Jacqueline Ruff and I am a strategic marketing manager for our small molecules business. So as a CTTMO and to introduce our small molecules business, we are global integrated organization with development, manufacturing and testing services across a variety of critical modalities. Small molecule being one core component of our end to end offer. But to briefly Orient you to our overall global small molecule site network, you can see here that we have a very robust network of site locations in order to support your small molecule synthesis projects. From milligrams all the way to commercial quantities, we thrive on addressing the most difficult challenges and as a true partner here, we do offer a consultative approach to support your program. Our many years of expertise really shines through through several of our centers of excellence that you can see on the site map here. So for example, the Chef housing site is a center of excellence for custom activated pegs programs. Our Saint Louis site is the center of excellence for a BC and bioconjugation services and our Madison Verona site is a center of excellence for high potent API's. Our Sheboygan site that you see here offers non GMP supply of critical raw materials and intermediates to support a huge variety of our service programs. However, our conversation today on scaling for commercialization really focuses around the large scale API production capabilities that you can find at both our Verona and our Darmstadt sites. Our US based Verona, WI site has a number of years of experience in large scale API production and the site is home to two large scale production suites capable of supporting batch sizes from 50 to 350 kilos. This year we've expanded our available capacity for large scale API production programs recently bringing four additional production compartments online in the heart of Europe at our Darmstadt, Germany headquarters. We're so excited to share more about how our global footprint of large scale small molecule API production facilities can further support your journey to commercialization in today's presentation. So I'd like to go ahead and introduce our speakers here. I am here today with our speakers Doctor Bertram Suzan, Dr. Bertram Barnicle and Dr. Orr Reichardt. Bertram Suzan heads Process Development Synthesis and holds responsibility for the process, development and supply of API's from development until launch. Coming from a strong background of medicinal chemistry, merchant Barnicle heads the Valium Stream Management CDMO organization and is responsible for technical feasibility studies and technical project management of CDMO projects during implementation. And Org Reichard heads the Regulatory Management, CDMO and Bioprocess Materials organization and is responsible for registration of A P, I's and excipients with health authorities as well as preparation of CMC documents for customized modalities. So before I turn things over to our first presenter, I'm just going to cover a few housekeeping items. At the bottom of your screen are multiple application widgets that you can use. There you can also find a 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'll try to answer these during the webinar, but if a more detailed answer is needed or if we've run out of time, we'll definitely make sure it's answered later via e-mail. Please know we do capture all of your questions. You will also have the opportunity to participate in a in a quick poll question throughout the session. I encourage you to take part in this survey. If you're watching the webinar on demand, you can still submit poll responses and questions via the Q&A 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 as well as a copy of the slides of the webinar will be available afterwards and can be accessed using the same link that was sent to you earlier. So that's it from my side. And I'd like to turn it over to Dr. Over Breckhart. Yes, thank you, Jackie, for this kind introduction. Let me start with the agenda for today. So the first topic will be an introduction to the regulatory expectations on active substances, which increase over the course of clinical trials to the commercial drug product. And I want to give a brief overview about that before I hand over to Beth Cezanne and he will talk about production scalability from lab to plant. The third part is on process optimization and efficiencies at commercial scale and will be presented by Beth Barnicle and he will share his first hand experience from the production suites. And now I move to the next slide and talk about the regulatory expectation on APIs including clinical trial and moving later to commercialization for APIs for authorized drug products. I would like to start off with this figure and this figure illustrates the increase of the expected GNP level throughout clinical development. Starting from the left, I would like to indicate that early GNP expectation even start in research and development and this is even prior to the first in human studies. Since already at this stage appropriate documentation and quality expectations should be considered so that results of for example, toxicological studies are obtained with a material that is representative for the material that is used later in the clinical studies. So GP expectations are initiating definitely for the first in human clinical studies. These increase continuously over the clinical phases and the magnifying glasses on this figure so represent the review of dossiers to apply for the proper phase of clinical trial or even marketing authorization or even variation once the product has been approved. Of course hybrid approaches are possible as well As for example phases one and two may be combined or phases 3 is completed after market approval. But I would like to illustrate this here for the traditional phase approach of clinical trials. So in date phase three the study results are used for marketing authorization application and for APIs used in this so-called pivotal study. So full GP requirements comparably to a commercial application are to be met. And in the line below the GP inspection practice is pictured. In Europe for example, the API manufacturer is required to notify each API production to the national competent authority and this triggers an inspection by the authority from APIs produced from early phase on. So after a successful inspection, the authority grants the GMP certificate including active substances which are mentioned for a commercial production and also a general information about clinical trial applications. And in the US typically the first inspection is to be expected as a pre approval inspection, so meaning later in the process. However in both territories you and the US is the GMP conformity is expected for the first clinical batch. So the GMP inspection expectations increase throughout the clinical development. As illustrated, the quality and regulatory requirements are similar in the regions. However, there are difference in the authority inspection practice process. Validation, by the way, shall establish evidence that a process consistently results in the product meeting its predetermined requirements and the knowledge about the API manufacturing process increases over time. Of course that means identification of process variations and introduction of a suitable control strategies and process monitoring increases over time. So accordingly, the expectation to conduct process validation is expected for a later stage, meaning for application for marketing authorization with the API production for the pivotal clinical study. Going to the next slide that should show proper registration of the site of API manufacturer is also important also to applications for clinical trials in different countries. Here are only a few examples. In the European Union, a GP certificate for the manufacturing side is a requirement and in addition the spore organizational data must be submitted as a prerequisite to start the clinical trial. Spore by the way, that stands for Substances, Products, Organizations and Referentials in the EU. Data management services in the US API manufacturing site require an FDA drug establishment registration and latest for commercial application. This ensures that FDA has the data and site information to start an inspection for the site and to check the relevant GP compliant manufacturing processes for application of drug products in China. The API site should demonstrate its capability to produce under GP as well. The suitable means is to demonstrate a GP certificate. In addition, there are registration requirements for imported APIs to submit CMC documents. This is required for APIs and commercial applications and already recommended also for phase three clinical trials in Japan. You need a foreign manufacturer accreditation to allow placing active substances of a manufacturing site which is outside Japan on the market. And this comes along with an extensive procedure in which details about the facility needs are to be provided. And this includes floor plans, list of manufacturing equipment, information about personnel or things like that. And this is usually followed by a so-called GMP paper inspection where detailed further information is requested. So it is particularly useful to have a partner who's experienced with these requirements. So back to the manufacturing side and points to consider for investigation of APIs. For manufacturing of an active substance which is used for drugs in clinical trials, it is important to have a partner who's familiar with the appropriate quality requirements in the relevant phase of clinical study. For investigational API's several points should be considered to meet appropriate quality expectations. This is also referred to as clinical phase appropriate quality and it's always a risk based approach. These points should be considered for investigational APIs which I have listed here on the slides from the first human trials on SO. Incoming raw materials should be responsibly managed and should be of appropriate quality. The selection of the API starting material should be well justified, since the introduction of the API starting material determines the start of the GMP process and the start of from which the detailed process description must be submitted to authorities and the start from which the process validation should start at a later stage. So choice of API starting materials has really a high impact. Process equipment and facilities should be calibrated and qualified, The manufacturing process should be appropriately managed. While the process validation is not required for early phases, full traceability must be given from early phase on and the master batch record must be approved by the quality unit. The quality unit is also responsible for reviewing the executed batch records for completeness and accuracy. Analytical methods need to be proven scientifically sound, qualified analytical equipment should be used and the message should be qualified through method qualification at a later stage. At a minimum, critical non compendial method should be validated according to the established method. Validation protocol, change control documentation requirements and rules of record keeping should be conducted across all activities and so I would like to demonstrate that here. The next picture. GP is always a risk based approach and based on the process there are quality and regulatory assessments to address all the risks. Risk management of several process related risks are addressed in this in specific guidelines and are applicable typically for marketed products. Nevertheless, it's useful to consider quality and regulatory aspects already from early phase on, for example here mutagenic impurities. They need to be evaluated through toxicological assessment. Besides actual impurities, also the potential impurities needs to be identified and the structures are to be listed. The toxicological assessment then is conducted by use of two quantitative structure activity relationship methods which are supported by databases which is 1 empiric and one is rule based. This will result in the prediction of multigenic potency of the impurities and requires further action if a concern has been identified as well as nitrosome means. So the risk of generation and presence of nitrosome means needs to be assessed considering the use of Nitros 18 agents and also the use of the OR the presence of vulnerable amines all through all the process and storage as well elemental impurities. They are usually also process related impurities depending on the raw materials used in the process, so meaning the catalyst and the reagents and elemental impurity screenings particularly useful to support this process. All materials should be assessed on their origin of course and even the contact with animal derived materials. Of course the TSE evaluation is required if animal derived materials are used and especially if room in materials are used, but the assessment is relevant actually for all materials and to control product related impurities. A suitable chromatographic separation technique must be developed and applied to control related substances. On the reporting limit forces to identify impurities at the identification limit which is typically 0.10% and then the identified impurities exceeding the qualification limit must be assessed. Regarding the toxicological profile here, it is recommendable to consider this already all these quality and regulatory aspects from early phase on. So fulfillment of all these requirements shall serve the goal to use the API for clinical trial or for commercial. But this needs application with the competent authority. The regulatory documents to describe product quality in authority submissions are called CMC documents. What stands for chemistry, manufacturing and control? CMC documents need to be prepared for investigational and commercial applications, meaning starting with a clinical trial application. CMC documents already need to be prepared and submitted. Overall, the process looks like this. So the contract giver qualifies a contract manufacturing organization to produce a substance. Then a process has been developed for manufacture. Test procedures have been implemented so that the product can be manufactured and released for CMC documents which are required for clinical trial applications already. It is the applicant's choice. Use their own regulatory organization, use a third party consultant or use the manufacturer's regulatory service to prepare CMC document. Then the CMC documents are embedded into the clinical trial application and the IM, PD or the Ind, yes contains the CMC documents. We as a contact manufacturing organization offer regulatory support to prepare CMC documents and this is part of our comprehensive range of manufacturing and testing services. As a one stop shop, we ensure a face appropriate content so that suitable submission documents and content details by aligning this with the face of the clinical trial. We make use from a global regulatory network having global reach with regional presence in the US, in Europe, in Asia Pacific region, in Latin America, Eastern Europe, Middle East region, even Africa. So we use access to registration pathways for our submissions and we keep regulatory surveillance and advocacy activity to be on the top of current regulatory developments. And we are used to have a regulatory collaborations by a the state-of-the-art electronic data management system also with you with our clients. And on the last side of my part of the talk, I would like to show the countries and regions where we obtained experience through active product. As you see, many countries are covered and showing the experience that we are happy to leverage and partnership with that. And I would like to hand over to my colleague Batram to let you know more about process scalability from that to plant. Thank you. Hi, Many thanks Ollie for this kind introduction to the regulatory part and welcome to our webinar. So in the next 15 minutes, I'm going to present you how we can support you with process and analytical development capabilities. Throughout the development cycle of your product, so from research to through development, up to launch commercial and commercial phase and later on even life cycle management. So who are we, what can we do and what are our capabilities? So on this slide, you will see that we are embedded in the process development unit in electronics and we are around more than 300 scientists, mainly chemists, engineers and data scientists with a broad experience in many, many development projects. We support process development in different for different business businesses like electronics, materials, healthcare and life science including of course API and let's say GMP manufactured intermediates. Process transfers into the manufacturing plant is something we are really used to and we have around about 50 transfers of chemical transformations every year and which which is I think keeping us really very busy and and and brings us a broad experience. What we also can exploit is our broad technology basis in our company with very different disciplines and of course the different chemistry capabilities from small molecules, even polymers and several intermediates. Our staff is GMP trained and well prepared for executing API products. On the bottom you will see the different phases of our projects. We usually start with roots counting and optimization. Later on we start with scale up trials and 1st supply from pilot plants and also kind of verification batches if needed. The next phase we transfer usually the products into the production plants for large scale supply, but also for validation and for subsequently for the commercial phase and the commercial supply. And then in the last phase or at least for us for the last phase, we have also some work on process robustness and lifecycle management. But this is of course very much also dependent on your needs and your requirements and we can be here very flexible in in utilizing our capabilities along that development route. On the next slides you see a little bit our capabilities with respect to let's say to vessels or to equipment on different scales. What you see on the left hand side is that we have a number of process development labs with very modern equipment, but we usually do the familyization with the chemistry with the chemical Rd. but also root selection and optimization of the process upstream Downstream, of course, we also start in the early phase already with process simulation activities in order to have a better prediction what's ongoing on the large scale in the pilot plant and subsequently in the production plant. Usually the sample size in our labs is in the range of 10 grams up to a kilo and which is usually sufficient in order to provide samples to the customer for their kind of trials. The next phase we usually enter the pilot plant, which is let's say a multipurpose plant with various reactors and downstream equipment as well as dryers. So we are in the range of 60 to 3500 liters. Here, different materials and let's say very flexible to support our ongoing projects. Here we usually talk about quantities of around 1K up to two 100K maximum, but this is dependent on the concentration we run and project specific. And then the next phase usually we hand over to our production facilities and you will hear later on in the next talk from Beth Harmonical how this looks like in our production facility. I will now show a little bit our, let's say broad capabilities and technology basis, which of course as a company with various different technologies in house, we can exploit and bring into our projects if there's a requirement. Central of course to the API projects is our experience in GDP, manufacturing, API development, which you see on the middle right part. But also our particle engineering group where we have a dedicated group and laboratory mainly developing crystallization processes in order to have full control of the impurity profile. But also if designed on the particle size, particle shape of your final products. But also various other capabilities would sometimes be very important for projects, for example our specific hydrogenation or high pressure capabilities or our catalyst screening and catalyst development group. I would also highlight our, let's say approach to assess the sustainability. With an in house develop tool we can calculate a key performance indicator of so-called process mass intensity in order to follow up the progress in terms of sustainability of our chemical processes. On the next slide you will see now the capabilities that are dedicated to our customer projects. We are around about 40 process development chemists or engineers and with around about 1/4 having a PhD level degree and usually are running the projects as project manager. We've executed or with our capabilities work on this kind of phase appropriate development approach to support your projects from the very early phase, let's say preclinical up to the commercial phase and the launch. Usually we start with root initial root scouting efforts and some formalization experiments. Early phase development and supply of material for the preclinic and the clinical studies are part of our services. In later phases, of course, we step into design of experiments and quality by design approaches for process for further process optimization and preparation for validation, but also then in collaboration with our manufacturing colleagues. With the process validation we are specialized in complex chemistry as I mentioned. For example, catalysis and hydrogenation is something where we have quite some broad experience, but also specific purification or isolation technologies we apply. We can develop of course multi step processes and have several platforms in order to get very deep insight into what's ongoing in the reactor with several probes and let's say capabilities in order to follow online also several reactions. We have available preparative chromatography for early phases and a very broad catalyst, screening platforms for homogeneous as well As for heterogeneous reactions. And finally also we have some capabilities to run reactions under pressure, in particular also with reactive gases like for example hydrogenation but also carbonylation. Reaction is something we can apply in synthesis. We have also internally capabilities and capacity for the chemical process safety evaluation with different setups for calorie metric experimentation, terminal analysis and also special equipment for safety characteristics is available. And in order to make sure that we prevent corrosion of our reactors, we have a laboratory which is dedicated to corrosion and material testing before we do larger batches. Now on the next slide, I will of course highlight also a bit our analytical capabilities and what we can do in order to develop the methods that are required for compound validation and characterization. Of course we have two independent labs dedicated to method development with a focus on chromatographic methods, for example UHPLC or GC, but also depending on the needs with other technologies available. They are responsible for the method implementation, development, optimization and in the let's say in the validation phase, of course with the validation of the analytical methods. They also follow this face appropriate or face appropriate development and transfer approach in order to, yeah, be fit for purpose. We have very strong capabilities for impurity identification and quantification with several methods and several, let's say interface partners which are embedded in this process. And on the last bullet point, we also of course provide stability testing according to the guidelines including forced degradation studies, but also software assisted accelerated stability modeling in order to be fast and save time and be capable of drawing conclusions very early on in the project. As our chemical process development. Also, the analytical development is embedded into our large network of analytical capabilities and analytical experts, which you see here on these slides, which are let's say, worldwide represented with more than 215 experts in 25 labs and a broad variety of different analytical methods available and of course with a broad experience in more than 100 projects over the last few years. With this, I will hand over now to my colleague who is now having a poll and Many thanks for listening. Thank you so much, Bertram and Ulrich for the presentation thus far. We're going to take a quick pause here. Now for a poll question to hear from you, the audience. Our question here today is you know we're certainly talking about a wide variety of very important factors when it comes to your large scale API programs. But to you, what is the most important factor when selecting a partner for your large scale API program? Is it the regulatory support filings, specialized technologies, expertise and process efficiencies, project management, communication or secure supply chain? We'll give you a few minutes to chat in your responses while you're answering the poll question. I did just want to remind the group that if you have any questions for the speakers so far, you can feel free to chat those into our Q&A as well, so we can answer those at the end of the webinar. Just give it a few more seconds for responses to trickle in here. All right, Well, let's take a look at our results. So thank you, everybody for your feedback. We really love hearing from you. Now, without further ado, we'll go ahead and move on to our next presenter. Here, I'll turn it over to Bertram. Bertram, I think you'll need to unmute yourself. Welcome everybody. Can you hear me now? Sound great. Thank you. So thank you, Jacqueline, for the introduction. So it's a pleasure to guide you through the next chapter of our talk. It's about process optimization and efficiencies at commercial scale. So here in that setup, I'm the representative of operations. So let me start here with a collaboration because now experience collaboration is a very, very valuable part in CDMO business and we believe that strong communication and transparency is the core to that. So we strive for really being transparent with you during our projects and be a true consultative partner to guide you through your project. And we do this with all our expertise. We get in scalability and like my colleague Bertram, Tony, also in process development. And with that we identify efficiencies in your processes and then use the economy of scales to get the best out of you as our customer. All of this is done with our quality first approach. This means we focus to be a first time right in execution of course, while being always absolutely drink and adhering to the GDP guidelines and always face appropriate like Ulrich also mentioned in this first regulatory part. All this is done with the reason of the risk mitigation approach. We give you advice on possible hazards. We analyze in your process independent if it's a lab scale process or it may be into the cable lab or to the pilot plan. In parallel, we establish a stable supply chain with reliable raw material providers. We know from our long term experience all this is done with a very flexible approach. We know every project might change in timeline and we support every timeline you have, whether it's long term demand planning or maybe it's short term adapting to your timelines. That's part of our business and we support you there. And finally, but last but not least, we have an eye on sustainability. We manage your environmental footprint through sustainable waste management and maybe optimizing your process wherever possible and as you wish. So when going to the next slide, we come to the GMP production here in our Downstadt site. We recently upgraded 4 compartments which are basically independent production trains to the newest GMP standard and the radius of August 2023. In general, the surrounding is a multipurpose production facility focused in on organic fine chemicals and with the capability to do real large scale API production. All this is done compliant to the global quality standards like ICH Q7. For GMP production, we have all the GMP certificates available like Eric mentioned in the beginning and as well we are compliant to ISO in 9001. All these lines have containment concepts to be able to run potent API production and there we are able to handle starting materials and also final products down to an operational exposure limit of 1 microgram that you made. The plan is run in a continuous, a fully continuous shift that means we operate 24/7. So without any delay we get the best out of our equipment. For your projects. When turning to the next slide, this give you a brief overview about the setup of the plant. So the plant was designed in the late 90s, early 2000 years and it is designed from Sketch like any organic chemist or chemical engineer would like to have its plant. So the process flow is basically following gravity. That means you start on the top level, what we call the logistics level, where all the raw materials are charged to the reactors below. They have the usual chemistry takes place and usually end up with a crystallization slurry you want to get separated. So there we get a separation level where we usually use a centrifuges or notch to separate the mother liquor from the crystals and then the crystals are finally dried in the dry level in the appropriate dryer. And this process flow gives us the best economy of scales to handle the projects. So what are the capabilities of the CDMO production lines? We had the capacity expansion here now fitting perfectly large scale GMP commonalization. So to bigger batch size is from 100 to 400 kilogram per batch. And like I mentioned before, we're able to handle materials down to an operational exposure limit of 1 microgram per cubic meter. And all this is done by completely closed handling systems. Each line consists of three to four reactors, usually from 1000 to 4000 liters of volume and we get the glass line, stainless steel and has to lower as well. So we can always find the right fit for the special chemistry needs to have in your projects. The downstream is usually horizontal discharge centrifuge and then we use paddle dryers in the volume from 600 to 1000 inches. After drying. All the downfilling is done in our endless liner completely closed and in a clean room environment. So when it comes to a special capabilities, we know that every multi step chemical synthesis can has quite a bit of complexity in the chemistry wise and we have specialized technologies at hand to support it here as well. So we get large scale hydrogenation available 2500 liters scale and 1000 liters scale in different materials and with the pressure up to six bar. Additionally, we can provide the cryogenic reactions in 1000 liter of 1600 or 2500 liters scale down to -100 degree C and in case of a special need of volume or for example like a very low temperature crystallization, we can provide 4000 liters scale erection at -80 degrees C as well. On top of that we get in a non GMP environment continuous flow manufacturing equipment which enables us for example to produce API study materials in a very efficient way. And this is also supported by another ISO 9001 production line which is also capable of quite big volumes and close handling for downfilling for example for non gene key intermediates. All this is supported by our quality control group. Roughly 90 quality control experts running about 200 devices are supporting us here. One hard piece here for sure is that our QC is working 20% as well. So we don't have any time loss in the production in the continuous shift. But on top of that we got technical teams being available for method development, troubleshooting and of course method validation in an QC environment. So all those colleagues support the projects and you get direct contact to our subject matter experts here. Additionally, we have the full power of our internal central analytics department where we have another 250 another experts at hand like Button also mentioned before. That's all from my side. Thank you for your attention and we're open for questions from your end. Thank you. Thank you, everyone. So we'll go ahead, really appreciate the the great presentation from all the speakers. We'll go ahead now and answer a few questions that have come in from the audience. Before we jump into the Q&A, I do want to remind you it's not too late to send in your questions. This also applies to on demand viewers. If you're watching this later, We'll try to get through all of these, but if we do run out of time, we will respond to you individually. As a last reminder, this webinar will be available on our website soon. All participants will receive an e-mail notification when it's available for viewing. But back to start answering some of the questions that have come in. So Ulrich, I have a couple questions that have come in for you. So maybe we'll start with some some regulatory topics. You did mention that a Pi sites in the EU will be inspected for manufacture of a PI's used already in early phase clinical studies. What impact does this have for the drug product manufacturer as a user of the API? Thank you for this question. Yes, it's absolutely correct. In the EU, the authority inspects the GP processes for APIs already from the first trial on. And yeah, the impact for the drug product manufacturer is actually that it. That means there is an elevated level of confidence that processes are GNP conform and under control and this is an confirmed by inspectors from the authority and this the impact is that this mitigates the risk to observe GNP deficiencies for the active substance. And already from the early phase on and this then we have also recurrent inspection. So there's also low risk of having unfavorable results for late phase and also for approval inspections makes sense. Thank you. I'm scrolling through the Q&A here. I do have one other question for you, Ulrich. When do you recommend conducting a study on mutagenic impurities and so mutagenic impurities? We recommend the assessment already in early in the process of as prior to the first in human studies and the development of mutagenic or the DNA reactive impurities. That depends on the chemical synthesis process, right? And hence the materials used for this process and the resulting impurities of this process should be assessed regarding mutagenicity. And also when process changes are conducted and new impurities can be introduced, for example, when scaling up the process then a revised assessment on mutagenic impurities should be conducted. So answer short as early as possible. Sure. Maybe one last question we'll take here on regulatory topics. Again, if you have more regulatory questions, feel free to keep chatting those in, but but or what is the difference of CMC documents for early phase clinical trial application to those that are submitted for marketing authorization application. Yes, thank you. Thank you for this question. Good question. So the extent actually is the difference, the extent of the content provided in the CMC documents to the regulatory authorities is different. There is limited knowledge in the early phase and so the data are based on available data available signs at this stage. But in later clinical stage we obtain more and increased knowledge about the criteria which are based on the advanced manufacturing data. And when the production then is changed to a larger scale, then the sponsorship should submit information appropriate to the expanded scope of this production. But for all phases, the data are submitted based on risk. And so the format, the format overall is the same for clinical studies and for later it's the CMC documents follows always the structure of the common technical documents which is called the CTD. Perfect. Thank you. Looking through the Q&A questions that are continuing to come in here, Bertram, Suzanne, I have a couple questions for you pertaining to process development topics. Can you tell us a little bit about what the typical number of synthetic steps are for your ongoing and completed projects? Sure. Thanks for the questions. So let's say we have quite a number of projects in the range of three to five chemical steps. But to be honest, what we see is that we're just getting more complex and synthesis and longer sequences. And in some cases we do have really up to more than 10 chemical steps for a customer product that we are currently developing. And I think based on our broad technology basis, we feel well prepared also to take up this more complex chemistry, of course. Perfect. Thank you, Bertrand. One other question that's come in that's a really interesting one here is pertaining to sustainability. So how do you assess sustainability of your chemical processes that you develop? Yeah, thanks in particular for the question about sustainability because this is something that everybody is now somehow affected by. And then this thinking about how can we improve sustainability. What we do is we calculate for our chemical processes, we calculated a key performance indicator which is called the process mass intensity and which is well established in let's say in the Pharmaceutical industry. And by calculating the process mass intensity index at various stages of our processes during the course of the process development, we have a good insight into improvements and then we can really follow up the improvements we see in terms of the sustainability KPI. We use an internally developed software tool which is called Greenspeed and we can automate automatically calculate these values right from our lab journals or protocols and we can even predict values for let's say proposed synthesis. Perfect. Thank you. I think we'll jump to some of the production questions that have come in now for Bertram Barnicle. But again, if you as the audience have further process development questions, feel free to keep chatting those into the Q&A here. So, so this next question is for you Bertram then and it's about the reagents that are typically handled in our in our production plants here. What would be some of those special chemistry or or reagents that you guys are able to handle? Yeah, thanks for the question checking. So like I mentioned in in the talk before, we are able to handle hydrogen on the plant but not only hydrogenation, but we are also able to handle regions producing hydrogen on usage. For example, sodium origin hydride is a quite common region we are capable to handle and like I mentioned also with the cryogenic temperatures we are able to handle on the plant. This gives us the opportunity to handle a lot of the typical metal organic regions like the lithium or LDA. We have a broad and long experience handling those, which are obviously helpful in typical chemical citizen steps. And there's a quite special thing. For example, we have the capability to use elemental bromine, which is I would say suddenly available in other plans. That's great. One other question here, just looking through the chat, how do you concretely optimize the waste stream of your processes? I think one of the most important things Bertram already mentioned, you start in process development and of course you look for efficiencies there, reducing solvent waste or replacing let's say toxic solvents by others. But what we do since years and which is really one hard piece of our voice stream optimization is the recycling of precious metals, especially when it comes to origination. You get the Palladium, platinum and others. And we got established recycling streams here, of course reducing the carbon dioxide footprint of the process and as well the production cost for the customer. Perfect, Right. I'm taking a quick look at the time here. I think we have time for one more question. But again, please don't stop entering things into the chat. We'll make sure we get back to you after the webinar if we're not able to tackle it here. The last question is, is for you still Bertram, how do you realize handling of potent substance with OEL's between 1:00 and 10:00 micrograms per cubic meter? We believe in a fully technical solution there. So we got a lot of state-of-the-art technical systems like isolators, endless liner downfilling and this enables us to get a really handling of these materials without the usage of personal protective equipment in the routine operation which is obviously state-of-the-art. And additional big bonus on the containment handling of the materials for the quality as well. Great. Well, thank you so much for for all the questions. Folks, if we did not get to your question, please feel free to e-mail our presenters directly. I will jump here to the the contact information. To register for any of our future webinars or to access our archived webinar library, please do visit our website. The slides will also be available after the webinar for you. I'd like to take the time here to thank all of our speakers for today's presentation. We really appreciate it. And thank you to our audience for joining us. Thanks again and have a wonderful day. Thank you. Bye, bye. Thank you. Bye. _1732357294529

 
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