Hello everyone and welcome. Thank you for joining to us for today's webinar solving synthesis challenges, a small molecule CDMO services strategy. My name is John Stevens and I'll serve as your moderator today as your moderator. It's my role to ensure that we make the most of your time. Before I turn things over to our first presenter, let's go ahead and take a look. Quick look at our agenda while I 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 indicating indicated by the thumbs up emoji and this allows you to give immediate feedback on the presentations, topics or really 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 run out of time, it will be answered later via e-mail. Please know that we do capture all questions. You will also have the opportunity to participate in a couple. Of quick poll. Questions throughout the session. I encourage you to take part in these surveys. If you're watching this 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's no dial in number for the best audio quality. Please make sure that your computer speakers or headset are turned on and the volume is up so you can hear the presenter. An on demand version of the webinar will be available after and can be accessed using the same link that was sent to you earlier. So that's it. For housekeeping items, it's my pleasure to introduce Kyle Lehrer. Kyle has extensive cross functional expertise in science, operations and business development and is currently the Head of Sales of the ADC and Small molecule business. He started his career in 2001, applying his educational background in chemistry to various roles such as Manufacturing Supervisor, Senior Project manager, Senior business Development Manager, and his experience and background inform his work in his current role as part of the Synthesis and ABCCDMO business in Life Science Services. Kyle, go ahead and take it away. Thank you, John, and thank you everybody for joining here today. First of all, my apologies. I'm having some technical issues, so I will not be able to go live on screen. The first thing I would like to start out with it is taking just a broad overview of the services that we offer under our life science service division within the organization we support our we have a biologics division, small molecules, antibody drug, conjugates, mRNA and LMP formulation as well as viral vectors. Each of these services at their facilities have analytical components to support your programs on site but also underpinning this as needed. We have a contract testing service as a stand alone service that you could that you can utilize and we call that bio reliance. For today's symposium, our focus is going to be on the small molecule modality within the small molecule. Our global footprint or network really spreads between the US and Europe where we have facilities in Sheboygan, Madison and Verona, WI, St. Louis, MO, Darmstadt, Germany and Schothausen, Switzerland. We will dive deeper into these sites and slides coming up here yet. But broadly speaking, these are the sites that service our AP is our high potent AP is our activated pegs. Our next generation conjugates if there's a small molecule component, our targeted protein degradation, we provide linkers, we provide payloads, we also provide linker payloads combined as well as some drug development acceleration products. First area we're going to look at is, is really the the high potent API capabilities which are located in in Madison and Verona, WI. That's our center of excellence. Some Nuggets about this facility is they have newly expanded capacity with six high potent kilo labs which have just come online. They have state-of-the-art containment within within this facility down to single nanogram containment. It is truly state-of-the-art. They have flexibility, not only flexibility and capacity we have. We can start your programs today in our process and analytical development teams. We have capacity that we can start your programs immediately. So it's that flexibility but also we we have flexibility and what types of programs we take on. We are not just a commercial organization. We take on your programs that are that are starting in pre clinical, phase one, phase two all the way through through commercial as well as scale that ranges from grams to you know 35 kilos in more of this high potent areas up to 50 nanograms per cubic meter. And all of This site is really, really underpinned and has a really strong history. They have 30 years of experience and 26 commercial programs. Little more about those commercial programs is some of them were tech transfers at a later phase maybe a secondary supply. Some of them, we started right from right from scratch at the beginning with the customers and took them all the way up through through their launch. The next area we look at is how can we support you with large scale manufacturing, large outputs of AP is now we have 2 facilities that can support that and that's in Darmstadt in Germany as well as again here in Madison Verona. From a volumetrics perspective, we we say we can handle up about 400 kilos. Again, that depends on ratios and solvents. But generally speaking, we have the, we have the cattle capacity and the volumes as well as the isolation capacity and purification to handle up to 400 kilos with a potency up to 1 microgram per cubic meter. Some of the technologies, this is not all inclusive, but some to highlight here today are cryogenic capabilities down to -80 or even 100C as well as as well as large scale GMP hydrogenations up to 6 bar. And of course these technologies are within different materials of construction whether that be Castelloy, glassware, stainless steel. So we have the abilities to handle your different chemistries with these some of these unique capabilities. When you talk about supply chain, we can take your project and we can say launch out of Darmstadt in Germany and get you to your commercial program and let's say you maybe you wanted to launch out of the US we have, we have that capability in the Madison Verona. The other thing that these geographies offer is a secondary internal supply. So if you get to a point where maybe you want to de risk all, all of your programs out of or all of your material, I should say out of one facility we can provide, we can offer you a secondary internal supply right within our organization. And these technical teams can work very closely together transition it. So now you can operate within whichever region you want to make sure that you can cover all the materials and needs that you need. The other thing I would say here is they both of these facilities all have pilot scale equipment. So we're not just going to jump into 400 kilos. We could I guess if if the chemistry support that. But there is supporting pilot scale equipment to make sure that we de risk your programs and scale them properly and safely and and make sure we hit the quality that we need before we hit that large scale demand. The next site we should we're going to be talking about is and located in shop halls in Switzerland. The this is the site that specializes in our activated pegs. So the things that make this unique is the custom development. So when when I think of activated peg, sometimes they're bought off the shelf their portfolio and you start with them early in your early phases. But as that as your programs mature, you might need more process knowledge, more analytical, just more information and that's what this sites really, really is very good at is taking those programs, internalizing them and supporting you through your neck like the next bullet point, your regulatory support, what do you need for your filings. This also comes with very strong communication and really really on time delivery, This site is top notch for on time delivery you will have a project team. We don't, we prefer not to work in a transactional environment. I mean we're we're very flexible. We like to partner with you, we want to work with you, meet with you every however often we need to make sure that you're you are comfortable with how we are progressing with your program. We don't how do I want to say this, we would rather not just take your purchase order and deliver you final product at the back end. If you want that, that's great, but we would like to work with you all the way through to make sure everybody's on the same page as your programs mature and longevity. This site has also been there a very, very long time. It's a legacy site for the organization that's been in in there for quite some time and they do have a have a reputable history for taking these challenging PEG programs, internalizing them and delivery. The final site to hit on today is our site and it's another Wisconsin site, it's in Sheboygan. They work very closely with with Darmstadt as well as with the Madison Verona site. So what this site specializes in, they also have the Kilo scale equipment up through large scale equipment but they're they're non GMP. So if you're looking to secure your supply chain bringing it back to a western supply, it's a critical reagent or it's just a non non GMP step of a long synthetic step to your final product, we can pull in Sheboygan. These teams work together all the time. There's economics to using the Seboygan site and again from a from a capacity and handling standpoint, again very small kilo scale, very large, large equipment, multi materials or construction and they are used to handling some some chemistries that not not everybody can. You know if they have large scale phosgonations, they also have hydrogenations, ozanalysis and high pressure and air sensitive chemistries. That's what they that's what they specialize in. They also have their own internal development team. So a project comes in there, it goes through the process and analytical development team, hazard evaluation, all the things you would expect us to be doing that we need to do to make sure that you're when your project gets to a manufacturing stage, it's ready to go. And again it's it's this global supply chain benefit that that we really hang our hat on where when you need that intimate program some people, when some people think of non GMP steps or just reagents they you don't think let's just go by that that doesn't always happen. These these are complex, they can be and they can be very critical to the success of your program making sure impurities are monitored and overall quality of the of the material you need is hit with that. I thank you for the time today. Again, I apologize for not being online. Please reach out at any point and I will turn it back over to John Stevens. Thank you, Kyle. We really appreciate this introduction and for providing an overview of our small molecule services. And with that we have our first poll question of the day as we would like to learn more about you, the audience. The poll question is what areas of small molecules are you interested in and you can check any that apply. The options are high potent APIs or HPAPIS standard small molecule APIs, activated pegs, next generation conjugates, targeted protein degraders like payloads and advanced intermediates. So please go ahead and click all the all of these that are that are applicable to your work and that you're interested in. All right. We'll give this a couple more seconds. Getting some good responses coming in here. All right. Maybe 10 more seconds. Please finish up those responses. All right, Let's take a look at those results. All right. Very interesting, very interesting split amongst the replies here. Thank you all for taking the time to to complete this. This is very helpful to us. And next we will move on to our next speaker Jason Modest. Jason has been in the Pharmaceutical industry for 25 years and is the Director of Manufacturing Science and Technology Department at the Madison Verona, WI site. Here he leads the technical transfer and validation teams and provides life cycle management for commercial programs. Transitioning into technical operations positions in the brand generic and the CVMO space has allowed for comprehensive understanding of what is required to successfully move early phase development programs to commercial launch. Jason holds a Bachelor's degree in Biochemistry from Fort Lewis College. Jason, the floor is yours. All right. Thank you, John. Thank you for that introduction. And as John stated, I've been in the industry for 25 years and a focus on right the first time is is always a topic regardless of the the, the phase of the program, but certainly at the start of of the process. So we're going to talk about right the first time and and and pressure testing your readiness to ensure success in GMP Batch #1. So let's go ahead and get started. So we always want to start with the the why. So we'll we'll go into that. We'll progressively make our way through the the start of the process, what we can do while we're in process and certainly as we're wrapping up production some factors that are critical to success write the first time success and then we'll we'll sum it up with some key points from throughout the process. So why does it matter? I think it's important that not only the project teams understand that but certainly folks who are performing the operations and so timing is a topic. So I think it's very clear that in an early phase effort you are you're up against the clock and so whether that's manufacturing an API, an API intermediate or even a custom raw material, there's generally A downstream process that is pending a tight schedule production of what you're you are delivering as a manufacturing site or a CDMO. And so that could lead to fill and finish it could be additional processing and that's certainly the start of another process at A at a an adjacent site. An example for us would be our site that we that that I'm a part of the is responsible for high potent linker payloads that ultimately support an ADC modality. So certainly downstream processing with antibody drug conjugation is, is it is an element that we have to be mindful of and the timing associated with that followed by feel unfinished. And so that only becomes more challenging when there's a a clinical trial that may occur at multiple sites. I think everyone is aware there's a significant amount of coordination that needs to occur. So being able to ensure that we hit that timing is is critical cost is a topic whether that those errors that could occur during the run or are lead to additional time to investigate challenges or in extreme cases it may may result in a a rejected batch. Those can obviously lead to cost cost constraints that may not be factored in within the original project. So that that can be a bit of a challenge and then certainly raw materials, raw materials are can a raw material supply can be mitigated by having additional material on hand. However, in early phase programs, custom raws may may not be available. So once again having a right, right the first time execution is critical there with respect to ensuring that we don't consume limited raw materials and then penalties and and delays that as I stated before clinical trials are some of the in factors associated with the the, the material that we're producing. There's a significant amount of coordination that needs to occur there. And so ensuring that we delivered on the the material that's been requested, ensuring that the that meets the schedule that for for that downstream processing is imperative. So penalties can be incurred based on not achieving target milestones for the project. And so those are factors that have to be have to be taken to account. I think the last part and this is this is important as there are already challenges associated with getting to market. And so the one thing we really focus on is being that preferred provider so that we can instill confidence and reliability and that translates into confidence and reliability and supply chain certainly want to ensure that you're getting a a quality material but ultimately confidence for future work as well. So once you've got that perverted preferred provider that has a track record of of success and reliability certainly want to you, you want to stay with that provider. So, so let's move on into the start of the process. So for us safety and and training is is important and I'll I'll maybe dive into it immediately. With respect to the, the site that I'm a part of, we handle high potent materials for majority of our programs. And so the safety element is, is critical in a lot of those requirements for handling those high potent materials are are built into the process itself. So we certainly want to make sure that our staff is well versed into in that handling and as well as as trained in the unit operations that have that safety, those safety elements integrated. So they're very important there. Our site also has the luxury of of having training spaces that allow us to perform simulations. So why is that important? But the very nature of a first time write, the first time badges, you've got limited runs and so being able to de risk a process by having a space where you can execute challenging unit operations is important. So I talk here I I list simulations and walkthroughs at our training space. We do have a have have a area where we can mock up complex unit operations. We can give the operator operations team an experience that allows them to execute and manipulate those operations whether that be fully gowned in CAT4, PPE or also in an in an isolator which many of those high potent materials need to be handled. So it creates confidence with the process. It allows us to optimize our handling so that we don't have unforeseen errors that occur during manufacturing. I think the the last element here at the start is to make sure you've got your your process teams lined up and so. That can look, that can. Look very different from one site to the next At at our location we do have a cross functional team that stays with the program from start to finish. And so that includes your product development, analytical development teams, your Ms. and T team or a technical operations team and then certainly project management QC there there is a, A, A, a dedicated resource from each of those disciplines support your first time GMP batch. I I will dive in a little bit more here too those, those those teams meet on a regular basis and when it's time to make your GMP batch that there's added schedules and tier one meetings to ensure that you've got the necessary support that would occur on on the the across the different shifts and and into the weekend. So our operators know those individuals they they have names and contacts to be able to reach out to those individuals. And so that allows a level of support to ensure that we don't run into challenges and if they do if we do run into challenges we can certainly address this quickly. Additionally strategic hold points are are are an important pieces things do occur during production. It could be a facility topic that might need to be addressed. There could be an equipment issue that that might rear its head. And so knowing where we can safely hold your your project or or program in advance is is vitally important at the start of the run. And so one that generally involves having some stability information to ensure that those strategic hold points don't impact the the program. But for for us at our site we we ensure that we know what those points are prior to the start of the so that we can leverage them as needed when it when events arise. So while the process starts, it's important to understand you know, is the plan still the plan? And when I say that things can occur at the beginning of a process and you've got a schedule, you know where your unit operations that you're challenging unit operations will occur. You've got oversight scheduled, but there may be some unforeseen delays. And so is there a topic around the staffing support, maybe maybe somebody who's been close to the program is unable to to support that execution? How does your plan change? Is this schedule change because of another unforeseen error? So being able to to one properly assess that and adjust accordingly is a necessary element to success. There's different mechanisms on how to do that. In our case at our site we have daily meetings that assess the tactical elements of the batch. So while there was an A great deal of planning coming into the batch, the tactical activities that have to occur when the batch is under execution are followed through on a daily basis and actually across shifts. So you've got real time support and and real time adjustments that can be made in the event that your original plan changes. We like to check our work as we go. I think that's a pretty common practice. But for us the big, the big, the big part associated with that is to ensure that one we can address errors quickly. There might be an opportunity if there's a similar unit operation downstream to take those same same actions and address them in advance. So we do encourage as we produce our our work through the process that we are. We are asking folks to make sure they're reviewing their work during hand offs, making sure that when we go from one shift to the next, not only are we accepting the state of the lab but we are also reviewing the record for one shift to the next to ensure that there are no issues from the previous execution and and people are aware of what's going to occur in the the future steps. And and I would say this last part really is a is a a carryovers from from the previous step here looking ahead in a multi shift environment we there a lot of hands, your program will change a lot of through a lot of hands. And so ensuring that there's a proper pass off, ensuring that you know if you're going into the weekend that that that is properly staffed that you've got necessary support in those off shifts is, is vitally important as things do happen generally that that can sometimes translate into less resources. But in a right the first time scenario we certainly go through great length to ensure that as we go into into the weekend that we've got support lined up. In many cases that support will come in on the weekend to to ensure that operations go smoothly. I think the the last part I, I really want to highlight here then we'll kind of sum it all up is that a lot of efforts at this point has gone into your, your batch production and as we close it out you want to you want to ensure that the documentation has been properly filled in and on. In addition to that you've got secondary support just for maintaining the lab space, maintaining your working area, the equipment. And so the the last thing you want to have to delay release of a batch or delay the schedule is to not have complete work. And so we've got metrics in place at our facility that allows for quick turn around of that work it by by having that it ensures that we have an expedited response in the event that that you know we do find incomplete incomplete documentation. But for for, for the objective of releasing this material, it's vitally important that you have controls in place so that you can continue to maintain that schedule and hit those milestones. I think the last part that's vitally important here as well as what we're talking about right the first time it, it's very common to to to need a batch immediately and so having another batch within the campaign and so having a mechanism to be able to take the information that you get from that first GMP run and and quickly turn that around and feed that into the next batches is very important. In our case, we've got a couple of mechanisms, some some are real time and then some are post batch review. Those mechanisms are process summary, summary reports and summary sheets. So that allows for real time feedback during the process. It allows us to to make notes and then additionally state that, Yep, here's an area that worked pretty well. I think we can make some changes. I think we can optimize this or here's something that we'll need to watch out or clarify. If we continue to progress this program along and that information is fed directly back into our technical teams to assess and then implement if if necessary. The last part of that would be a a campaign summary report which would actually some summarize the the, the whole process. It will summarize the performance of the batch and then also once again feedback, additional corrections or updates that that would benefit the program. Those get assessed, shared with the customer and then certainly implemented if if if it makes sense for the process. So, so lastly we talked about a couple of things and I'll just kind of highlight some key points. We we we want our folks to be present but we certainly we certainly instill instill them to look ahead and so things happen by looking ahead you can predict the future in in, in a little bit of the in in that respect. So if you have an event that occurs in step one, Step 2 might have a similar unit operation by looking ahead this allows you to to mitigate that in advance know your support team. This is vitally important in a first time GMP run being able to have those folks available. As I stated we have a a cross functional team that supports your GMP activities that are are ready to jump in immediately to provide clarity and or support for the operations team once that batch is in production and then checking, checking your work. That's something we instill within our team once again trying to mitigate anything that could happen, address any issues that happen real time as they occur and then any anything that might occur in the future and then communication. So we have multiple levels of communication whether that's from a tactical day-to-day review when the batch is in process, communication between shifts and then certainly communication to across the the immediate teams that support the that support the batch. So with that I'll turn that back over to John. Thank you. Interesting talk. Thank you so much, Jason. Before we let you go, we actually have a couple of questions from our Q&A that I'd like to ask. Although before we do that I would like to remind everyone in the audience that it's not too late send us your questions using the Q&A widget. This also applies to our on demand viewers. Those questions that we won't get to today will be answered individually after the event. Jason, I've got, I've got two questions for you that that came up in particular, the first of which is in a multi shift environment, what activities or roles are essential to ensuring right first time success for your GMP batch? That's, that's a great question, John. Certainly as as work changes hands, the knowledge has to change hands. And so I think there's different ways to handle a scenario like this. For, for us at our site, we have a a fairly regimented hand off between shifts that can start with the the shift of meeting and then folks go to their individual labs and the the receiving team members will work with the team members that just completed their shift. The receiving team members will accept the lab and so that that basically is an inspection of the lab and then there's also acceptance of the documentation. So it really promotes a a review and acknowledgement they understand what is where the program is, what steps are in the near future and then it gives them the space and time to ask any questions that that are there. So like I said that that is baked into our process. I think there's probably different ways that folks can ensure a good hand off, but we've we've had a lot of success with that approach of lab acceptance, not only of the space but of the documentation. Great question. OK, thank you. Second question I have is what are some other ways to challenge production readiness and ensure first right first time success in the manufacturing process? Yep, another another very good question. So at the beginning of the program, as you're leading up to the start of the process, you're getting all your raw materials ready. Documentation is coming in play training the the operation spaces is is prepped, equipment is set up, you've got that space where you have time to really assess OK, what else is there. And so for lack of a better term, we know what a post mortem is. Sometimes there's a a pre mortem and that's what could go wrong. Where are single points of failure, Are there unit operations that we know are a challenge and then start working back and developing things that could de risk those. And so a good example that that as I mentioned earlier in our in the presentation I had just given is, have you done enough from a simulation perspective or do I really want to maybe bring some more support folks on to the site while we're executing this unit operation. So I think the part I'll emphasize here is once you get into that practice and you do that for every batch it becomes fairly routine and fairly regimented. That pre mortem of OK, we're ready to go what else is there And that that just becomes in in my mind a a very effective approach to really challenge and and and set set the the program up for success. Great question. And a very insightful answer. Thank you. And thank you everybody on online for taking the time to ask those questions. Jason, thank you for taking the time today to discuss your team's approach to a successful first GMP batch. Thanks, John. Next up in our agenda is Angela Messino. Angela has been in the pharmaceutical manufacturing industry for 18 years. She's currently the Head of Quality at our Madison Verona site. In this position, she's focused on leading process improvement initiatives with emphasis on quality, operational excellence, efficiency and productivity. Angela previously held quality positions supporting both large and startup companies. At Cell Script Mentor, and Johnson and Johnson, she strives to instill a quality, always mindset among all employees, regardless of position or role. Angela holds a bachelor's degree in chemistry from the University of Wisconsin Whitewater, and the title of Angela's talk is Strategic CMC Planning through a Phased, Appropriate Quality Approach. Angela, Take it away. Thank you so much, John. Today I'd like to explore how adopting a phase appropriate quality is, is a deliberate approach that really allows you to meet the GMP requirements through all the phases of your product's development process. By prioritizing your quality throughout your development process, your strategic planning is going to effectively integrate phase appropriate quality standards into your development, manufacturing, and control of your CGMP pharmaceutical materials. A phase appropriate approach is really emphasizing that quality, the scalability and sustainability at different stages of the development cycle. This balanced approach is going to help your company meet the overall development goals by integrating a risk based approach of late stage requirements into your overall quality program. The adherence to these quality standards during technical development assures the validity and integrity of the of the development development data which is used to support future GMP work and regulatory dossiers. Maintaining GMP standards even in a non commercial setting really demonstrates A commitment to quality that reflects the importance of patient safety. By installing quality into your development process, it's going to support a risk based approach to your products progress. Striking the right balance between product phase and supply speed to market is important in achieving the desired product performance. We want to focus on what's critical to patient safety, ensuring that we're meeting all the GMP requirements throughout all those clinical phases. This process is not about shortcuts, it's really about assessing the risk and taking a systematic approach that is based on sound science and quality risk management just to build that foundation into the products process. A phase appropriate approach really demonstrates throughout the product and process understanding that we recognize why each phase increases the increase of GM PS that are required and we can use this knowledge to incorporate critical late phase requirements into our early phase processes which then set that product up for overall success. When you're connecting with a trusted and experienced CDMO, both parties should really set clear expectations and requirements in your quality agreements and supporting documents so that you understand what support to the phase appropriate approach is going to be between the two companies when you're moving a product through the development phase. But regardless of the phase, the process should be demonstrative of that state of control and continuous improvement. This is going to establish a quality oversight that ensures the safety, efficacy and compliance of your products throughout the development process. The introduction of a strong quality presence early in your product's life cycle ensures that you've got basic safety and documentation standards and you're meeting those. By imbuing quality into your manufacturer and testing a phase one clinical trial material, it's setting up your entire life cycle of that product to continually build on that strong foundation. As you can see in the ICH Q10 diagram, GMPS really should be independent of your quality system elements and enablers. GMP is the base of what you build your entire process around and as your product progresses through the later phases of tech transfer and commercial manufacturing, those quality elements like performance process, performance, Kappa systems, you know management review those are applied appropriately and proportionally to each of those life cycle stages. Enablers like knowledge management and identifying quality risk management those support your overall quality system goals of achieving that product realization. It established and it maintains your state of control and it facilitates continuous improvement with looking at activities that are phase specific for the GMPS. The regulatory expectation is that the knowledge gained during your development phases is going to continue to grow in terms of your manufacturing process, understanding and your controls. So Quality's role is performing that quality evaluation based on process and product understanding and then utilizing A structured risk framework to evaluate how to instill quality as it moves from discovery all the way through commercial manufacturing. In phase one, it's important that critical quality attributes are identified that you're document that you're documenting that as part of your phase appropriate approach. In phase one, you're still accumulating knowledge, you're improving the process and you're also identifying controls for your analytical methods. When you move on to phase two, your process is maturing. You're identifying your production and your process controls. You've probably characterized your process which leads to setting acceptance criterias where your products, raw materials, you're identifying critical suppliers and you're qualifying your analytical methods. Once you get to phase three, your product should now have a validated process. You have got all of the controls for production and process in place. Your previously qualified analytical methods should now be validated and all those materials that you have previously qualified should have a qualified supplier as well. So as you can see, it's an increase in GMP expectation as the product moves through the phase life cycle, and understanding what the requirements are in the early phase ensures that you're consuming your resource appropriately. If your phase one is not successful, spending time and resources on criteria that isn't needed until phase or two, two or three is going to be consuming your resources that aren't really required at that point in this phase. Appropriate approach. Each successful phase triggers that next criteria of that next phase which really delivers cost effectiveness based on your success. Some examples of how to introduce a phase appropriate quality approach is by looking at what your GMP requirement is and evaluating how to use this phase Appropriate approach based on what phase your product is currently in. So for example, if you've got a phase one product, you might be evaluating how are you going to control the equipment that is used in your process. If you're using a phase appropriate approach instead, you might evaluate well instead of using a full blown quality approved SOP to control the operation of that equipment, instead the user manual that came with that equipment might provide sufficient instruction. So instead you'll just use that equipment manual for something like a calibration or a maintenance of a piece of equipment. You could identify that this piece of equipment has either a low, medium or high risk using a risk assessment and then based on that risk assessment figure out you're going to be calibrating per that risk assessment. So low risk, you maybe don't calibrate as much, high risk you're going to calibrate on a regular repeating basis. And then if we look at something like a raw material for an early phase product, if that material can be sourced from an existing qualified vendor, I mean that's great. But because this is early phase, when you're selecting that raw material vendor, you need to balance, you know, being able to get that material with a vendor that maybe they aren't qualified right now, but they possess the ability to be qualified in the future so they can support that GMP work for a later phase. So while you don't need to use a qualified vendor for an early phase, using a vendor that can like achieve qualifications. So either on a provisional basis or whatever your company deems the appropriate qualification status should be part of what your selection is for that role. And then really the partnership for a phase appropriate relationship is. It's like anything you want to find the right partner for this phase appropriate approach because it's really important when you're trying to strategically plan to include quality in your development. Our site strives for alignment with partnering customers on what is appropriate for their molecule during that development journey. We offer a risk based approach dependent on phase to ensure that the development goals are met without sacrificing the late stage requirements of the program. We understand the quick turn around times needed for ensuring adherence to timelines and how important that communication and alignment is between the CDMO and their partner. We possess the capabilities to support early and late phase development and really focus on harmonizing the knowledge transfer to reduce time spent on managing tasks. Partnering with an experienced CDMO ensures your molecule is prepared for scale up activities to keep schedules on track and to not have to rework a process when it reaches the next phase. We've explored the critical importance of strategic CMC planning within the pharmaceutical landscape, emphasizing the value of a phase appropriate quality approach as we navigate these complexities of drug development. It's clear that meticulous planning and adherence to quality standards are really essential to your success. Our site is committed to working with our partners to continue to innovate and elevate the standards of pharmaceutical development for the betterment of the patients worldwide. Thank you very much. Back to you, John. Wonderful talk. Thank you, Angela. We really appreciate your insights from a from a quality perspective. Before we let you go, we do have a couple of questions that came in from the the audience through the Q&A widget. The the first one I want to ask is how do you document your phase appropriate approach? That's a good question. So with all kinds of you know anything we document we always want to start with clearly you know defining your phases. So what does phase one, phase two, phase three mean for your company and then where is your product currently at. So you can use this in either like a development plan or a protocol and that's going to describe your overall approach to the quality management for each of those phases. So you'll be looking at what your quality objective is for as your product moves through the phases, what you think the acceptance criteria is going to be, any kind of sampling plans, testing methods, documentation, requirements. This is basically just going to be a document that shows you've got, you've established that robust quality management system that's going to make sure that every phase of your cycle is going to be supported from is appropriate approach. OK. And then we have one member of the audience who wanted to know what they should look for from a quality system perspective when evaluating Cdmos for their program. That's another good question. So I think a great CD MO partner is going to have a really strong track record of compliance with regulatory standards, whether that's the FDA in the US or EMA regulations in Europe. They're going to be knowledgeable about those regulatory requirements and those relevant markets. Basically, you want to look for an organization that really runs robust quality management systems that's going to show that you're not only having a consistent product output, but that you are looking, you know, for your innovation, for, you know, making sure you're at the gold standard of those different compliance regulations. And really, I mean, anybody who's looking for a good CD MO is going to look for someone who's continuously improving. You know, they're seeking opportunities to optimize processes, You know, look for efficiencies, implement best practices, and just be a really effective communicator so that they're delivering those quality outcomes for your project. All right. Excellent. Thanks for that reply and for participating with us today. Absolutely. Thank you so much, John. Next, we have a poll question for all of you in the audience and that poll question is very simply what phase is your program in? Are you in discovery, preclinical phase one, phase two, phase three or commercial? Getting this information really helps us to understand you know a little bit more about the audience and and where you are in your, you know, your commercialization journey. And while you're completing this poll. As a reminder, this webinar will be available on our website very shortly. All participants will receive an e-mail notification when it's available for viewing. And looks like we still have answers coming in. OK, replies are slowing down. I'll give it 10 more seconds. All right, let's review the results. OK. Very interesting. Although given the breadth of small molecule therapeutics in the various pipelines, I guess I'm not too surprised by this. Now we'll move on to our next presenter, Matt Dodge. Matt is the Head of Client Program, sorry, excuse me, Client Project Management for our Madison Verona as well as our Sheboygan sites. He has 14 years of experience in client facing roles within the pharmaceutical CDMO and CRO space. He obtained his PhD in Organic chemistry from the University of Wisconsin, Madison, and Matt will be presenting on the critical role played by project management team supporting our small molecule CTDMO service with a very poignantly named Talk Patients. Can't Wait. Matt. Thank you, John. Welcome everyone to our presentation today. As John said, really happy to be able to talk to you about the urgency. We understand in the work we do with our clients and and certainly patients can't wait for the the products that we are here to produce. With regards to the agenda for my talk today, we'll talk about the site history for Madison and Verona as well as the experience. I'll talk to you about the client experience that you you get when you work with our company, our standard approach, how it works, why it works for us and then we'll also talk about some customization case studies. Again, we understand how critical these projects are to you, our clients and ultimately our patients. And so understanding how we can customize our client experiences is going to be really, really important and we'll follow up with some Q&A. So as far as the site history of the Madison and Verona site, the site has approximately 35 years of experience working in the CDMO space, much of that customer facing really you know we have an understanding of what needs to be done for our clients and and how to work with you to make sure that we find the solutions that you need. So the Madison site was originally founded in the late 80s as a private CDMO really established to focus on complex and potent API synthesis and and scale up. In the early 2000s, two 1003 the site obtained its Safe Bridge certification for handling APIs. Safety is very, very important to us. We want to keep our operator site safe but also keep your product safe and so we take that very seriously. We've been certified by Safe Bridge since about 2003 and just a couple of years ago based on our continued focus on on safety with Safe Bridge earned our industry leader certification as well. So really proving that safety continues to be important. In approximately 2005, the site was acquired by Sigma Aldridge and an expansion of the Madison site was completed to double its capacity. Further expanding our capacity resulted because of the expansion and building of our Verona facility. We added large scale manufacturing and and several other capabilities at that site. In 2011, our site completed the first process validation for a commercial ADC toxin linker. We have lots of experience both in AD CS as well as commercial programs. In 2015, we were acquired by our company and became part of the life science business where we remain today. In 2019, we launched our DM1 payload and advanced intermediates to support ADC customers. And at the end of 2022, we opened the Verona site expansion and our sixth single nanogram OAL containment kilo labs. We're GMP ready and have been producing GMP batches ever since. And so with that experience we're able to work really well with our clients and make sure that we get these medicines to the patients as soon as we can. So let me talk about our customer experience for a little bit. So this diagram I I really like because it conveys the importance of how we operate with our clients and how our team members all bring something really, really important to the table. And so you can see here in this diagram that our project manager and our business manager on our side work very, very closely together and also work very, very closely with the project manager and business manager with our customers. This is a key portion, key part of any work that we we do to build that relationship on the business and the execution side of of things. But I think what really speaks to how our paradigm works in the strength of it and and how we work really, really well is the bottom half of that diagram. In many cases, project managers are asked to sort of filter or otherwise, you know, facilitate communication for technical experts at our facility and in our company, we want those experts to talk directly to the experts with our clients. We want the right message coming from the right voice. And so our project managers on our teams do not stand in the way of direct communication and in fact favorite and and foster that right. So if our development scientist has found something really critical, really important, they communicate directly with your development scientists. That's the same with the analytical scientists. Our manufacturing leads are intimately involved in communication with our clients and we have technical experts in quality EHS regulatory from beginning to end. Those technical experts are engaged with our clients and you can speak directly to the experts working on your projects. Again, that's a key part of our our project experience, our customer experience and and we really facilitate that. Our clients like it and we know that you will too. All right. Let me talk a little bit more about our standard approach before I move into the customization. So with our standard approach, you will get a dedicated project team from our company. For each project will include a project manager. It will include an SME from every critical area, again from process development, analytical development, all the way through to manufacturing, quality, regulatory. And if there are SM ES that aren't necessarily needed during every single stage, we will bring those in when they are needed. And so you are supported along the way completely by our SM ES throughout all of the key areas that are needed. Of course, the key part of project management is consistent communication and with our clients. And so you will receive very consistent proactive comprehensive communication. And so our PMS are having daily daily e-mail communication with our clients. We certainly have recurring project meetings. These are typically scheduled weekly or biweekly. We can certainly schedule more frequently if needed or if something comes up and I can talk more about that in our customization case study. And we also provide detailed written updates. And so verbal communication through a meetings is is critical, meeting agendas and meeting notes are critical of course. But having those written updates from manufacturing or PAD is really, really helpful to make sure that everyone has all of the most relevant information, the most current status of the project at any given time and of course rapid communication for key project events, right. So if there is something critical that comes up, if we find something really fascinating in development that might be impactful to the the process or if we have a deviation during manufacturing for example, we will rapidly get on the phone with you or on a team's call with you and talk about the situation. And we can talk more about that as we talk about the customization. And again the customization is important because we know that not all projects are the same. We are not interested in fitting your project into some box that we have established. We want to work directly with you based on the needs of your clients and sorry of your patience and your projects and we will do so as needed. So let me talk about those customization case studies just a little bit. So we talked about our standard approach being you know, certainly regular communication, but perhaps a a meeting weekly or or bi weekly. Again, we understand that that doesn't work for all projects. It works for a vast majority of our projects and our clients are very satisfied with that. But sometimes a project is super critical or the timeline is really aggressive based on the needs of the client and the patients. And so we know that an increase of communication cadence is is going to be needed. And so we've worked with our clients in lots of different ways to make sure that the cadence of that communication, the involvement of everyone is appropriate and is matched to the criticality of the project. And so in the event that our clients requested, we have and and would certainly offer in the future daily management system style paradigm, so daily tier one meetings, Tier 2 meetings, certainly escalation pathways if they are needed. This has worked very well for us in a couple of different circumstances and the client has been very happy with that format and and we've been happy to offer that to make sure that everyone is on the same page with the details of what's going on on those critical projects. We also encourage and offer joint steering committees or executive and senior leadership meetings. We know that the project teams on our side and on the client side are executing the scopes of work and and doing the work. But we also know that engaging leadership on both sides is really, really important. And so that's been a good option for many of our clients and and again a key part of building good partnerships to be successful. We welcome people on site. We have beautiful facilities. Those new labs in Verona as I said are ready to to go and and are open for for business. And so we encourage people to come on site. If you are interested in a site visit to our locations, please reach out. And we can facilitate that. We also know that from a business review side, our clients have their own internal requirements in internal processes. And so if you have a requirement to do an annual or a semi annual business review, we are more than happy to facilitate that and meet with you or provide data or plans that you know for the future of the projects. Again, I think a key part of working and partnering with our clients, supporting you and your processes as well. And so if you need a business review, we are happy happy to help you with that. And the final point on this slide about tailoring our, our communication or our client experience customized program management is offered when when appropriate. And so we have projects that go across multiple sites within our company. Sheboygan, Madison, St. Louis is a a group of sites that works quite closely together on our side. And if a project warrants it, if the scopes of work will go from one site to the next and it really is going to be beneficial. We offer a program manager to those types of projects and that program manager supplements the local project management teams at those sites. And so does not replace those local PMS. We always have a local PM on our projects, but that program manager really works to provide another level of enhanced support to make sure that our sites are working closely together, that their work with working closely together with you as our clients and under the right circumstances and for the right projects. This works really, really well and we're happy to offer it next topic person's in plant. So again our company understands the criticality of the work that that we do for many of our clients, these assets that we're working on are their top asset or a critical asset of necessary for the success of their programs or for their companies. And so we understand that, we understand then that getting these new medicines to patients is going to really be on the forefront of both our clients minds and our minds within our company. And so that means that our clients want to be on site during critical stages. And so we host client persons and plant or Pips during critical stages of manufacturing or other activities as needed to make sure that things are going smoothly to make sure that that communication is even more focused and and and moving things forward. So those client Pips stay on site during requested portions of key operations. We can't have them be in lab, but they can certainly be near lab, near our labs and work with our staff, speak to our staff, observe and discuss critical activities and we find that this works really, really well. And we are hosting Pips right now actually as I speak. We have tips at our our site and are happy to do that to make sure that we are supporting our clients during critical operations. We also have video and remote viewing options that are possible. I think we all learned lots of things during COVID, and one of the things that we learned was how to set up and and offer video and remote viewing options. And so depending on the circumstances, we can offer remote viewing options in lab to individuals that are on our site. So maybe they're sitting in an office, but watching more detail that they could see, then they could see from a vestibule or under the right circumstances we can offer a video viewing options to individuals that are at their own locations at their sites and are able to see those operations. And so that's worked really well for us during COVID. It allowed us to offer engagement to our clients when they could not be on site for health restriction reasons. But we're really well versed at this now and it works really, really well for for our clients. The final customization case study I want to talk about perhaps is a bit more on the technical side, but I think it does speak to again our understanding of how critical this work is, but also how we really want to partner with our clients to make sure that this work gets done, it gets done to the best possible way and it gets done as quickly as possible. So like I said, we understand that time is out the essence during all phases of of our work. Pharmaceutical development is challenging and we need to work together with our clients and their third parties to do that. And we've done that with a couple different examples on this slide, But again really partnering with our clients to make sure that we're doing what needs to be done for the sake of the clients project and the clients patients. The first example I have here is parallel process and analytical development. And so our scientists at Madison and Verona and client scientists at their own facility worked together doing parallel process and analytical development that resulted in rapid development and optimization of a manufacturing process for a critical client asset ultimately shortening the timeline significantly. And I think really making a a very robust process as well as we had you know the the the top scientists from our side and from our client side working together to make sure that that was able to be achieved and it worked very well. And again that's the type of thing that that we're happy to facilitate. The final example I have on this slide is on the method development perhaps more of the analytical and the QC side. So our method development and method validation teams and Madison and Verona worked with multiple clients, selected third party CMOS to make sure that we could reduce the overall timeline on the development and validation of key methods. And by working together in this way where we we were able to significantly reduce the overall timeline during an extremely aggressive PPQ campaign and that ultimately resulted in one of the fastest commercial launches ever. We're happy and proud to work with our clients and there are other third parties in this way and we're certainly proud of the being part of that very fast commercial launch. And so these are just a few examples of how we work with our clients. But I think the key message for today is we are looking to partner with you as our client and we're willing and and looking forward to discussing whatever client experience that you need, whether that's our standard approach or whether you need some sort of customization like does that like I've described. We would like to have that discussion and we're looking to make sure that we offer the best client experience for you. All right, John, back to you all. Right. Thanks Matt for the case studies and for helping us understand more about the pivotal role of project management in CTDMO project. Our audience has been busy with the Q&A widget and a few questions have come in. The first thing I'd like to ask is how does your organization respond to challenges? Things like deviation out of spec, out of trend observations during project execution? That's a great, a great question, John. We know that not everything can or will go perfectly, right. We all want deviation free batches, but we also know that that's not something that you can plan for. And so when we face challenges like the ones that you describe, in short, we act with urgency and with focus. So our SM ES including PMPAD manufacturing quality and regulatory, they'll assemble quickly, John, perhaps a bit like The Avengers Assemble, our team will assemble quickly to communicate the issue to you to develop and propose a solution and then meet and work directly with you to to solve it as quickly as possible. You know as as you shared on the title of my talk, we understand that patients truly can't wait. We need to resolve these things and get those batches released so they can be formulated downstream. So our teams and practices are built to respond with urgency and and to deliver on what we need to deliver on. Excellent. Another question I'll ask is that came in is what is the best way for new clients to partner with your organization during project execution. Yeah. Thanks, John. I think another excellent question and really speaking to what we're looking for when we work with our clients, whether that's new clients or the returning clients that that we have. And I think the key part in the question there, we're looking to have our clients act as partners and so have both sides act as partners. And so how can we do that? I think the first thing that both sides need to do is agree to the scope of work, right? So a very clear understanding of that scope of work helps both sides set expectations. We can of course do scope changes. There's no issue with that. My team issues scope changes when necessary. But if we can establish that scope of work upfront, that makes sure that both sides have the correct expectations and a plan moving forward to execute. The next thing, John, I recommend is engaging SM ES throughout the process. So I talked about in the diagram early on that key part of our process direct SME to SME interaction. So when our development scientists talk with yours, for example, our regulatory team talks to yours, that's really the best way. So we're going to dedicate a full project team to your project and our clients who do the same and buy into our client experience paradigm really enjoy the most benefits of our strong relationship and communication plan. Bringing client leadership is needed, John. So again as I talked about, we'll offer JS, CS and business reviews whatever it might be Proactively involving the leadership on both sides can prevent escalations and make sure that everyone is is aware of the situation. And finally, John, we like when our clients share patience, stories and impact with our with our team members. So our dedicated experts on our team work in the Pharmaceutical industry because of the impact we can have on patients as a CDMO, most of our patient interaction comes from our clients. And so if you can share information about the patients and indications you are targeting, our teams find that very engaging and motivation and motivating stories about individuals, real individual patients are even better. Our clients have shared stories with us about cancer patients, Kathy and Lisa. And those stories have really motivated our teams to ensure that our teams understand the tangible and real impact of the work that we do. And so John, those are the, those are the ways that I think we can best partner with our new clients. Sure. And and the thing that you said throughout your your response here that really resonated with me is, is the word partnering right that that we're always partnering with them, we're moving together with them. Thanks for taking a detailed. Look at that. Thank you. John. All right. We will now be moving on to a talk by Doctor Ross Bamowski, our Associate Director of API R&D. Ross overseas the analytical development of new API products focused on supporting antibody drug conjugates at our site in Madison, WI. He is also the technical lead for Keto Sensar, a technology platform. Prior to this, he was an analytical development scientist supporting the CTDMO offering of our company. He studied synthetic organometallic chemistry and received his PhD from the University of Iowa. Ross, I turn it over to you. Thanks John. So as as we are well known, we have this wonderful small molecule CTDMO services which offer you know really world class service on on developing and you know some companies of technology but we've also wanted to in the past few years bring in our own technology to to supplement that as well. And then I'll look the most of that technology has been revolving around the ADC or antibody drug conjugate field. So we're kind of started focusing on that and we we started launching new products from there. So just just as a brief overview, so antibody drug conjugates for those who are not familiar as the name would apply, it starts with an antibody. This antibody is is well specifically target an antigen. Typically these are used for oncology or anti cancer purposes. So it's targeting an antigen on the surface of a cancer cell that is that is highly expressed there and the idea then is that this antibody will then shuttle the payload which is shown in purple here. This payload is typically a a highly cytotoxic small molecule we'll shuttle it specifically to the cancer cells and therefore killing the cancer cells and and the last part of of an of an ADC is is the linker and this this really facilitates a a very important role in not only doing the the obvious linking of the payload to the antibody but it's also usually responsible for the release mechanism of of the payload and when and how this payload of releases actually has a a very large impact on on efficacy. So that the linkers is is not to be overlooked. So these these payloads that I had mentioned are typically come from when you're talking about oncology indications typically come from one of four classes and and the first of these is the metanzines so these are microtubule inhibitors. So the microtubule microtubules are kind of the scaffolding of a cell. So the cells is growing and dividing it build, it builds the tubulin to to kind of support it and and the matansines will will inhibit that and that causes cell death and so that that's very effective for for most cancer cells because the cancer cells are are dividing rapidly And so this is this has kind of an extra layer of specificity because of it kind of is more effective against highly replicating cells. So this stuff was isolated originally from an African shrub in this, this represents about you know 13% of the current active clinical AEC trials. The next class is the dual statins. These are also tubulin inhibitors. So dual stents are also sometimes called or statins. These are originally derived from a a sea slug and these are by far the most common payloads currently used in the market using roughly around have 1/3 of all of all clinical AD CS. The next class is the Prolibenzodiazepine dimers or PVD dimers. So PVD's in their monomeric form were used as can be used as antibiotics or or and and anti tumor indications. But when you make a, when you dimerize them, they actually are very effective at interpolating to DNA and cross cross coupling the DNA or excuse me cross linking the DNA and this essentially stop kills the DNA immediately. So this is you know very effective, have very highly potent class of compounds and this has the advantage because it because it's DNA damaging it, it can target any cell and so even even cells are in stasis or cells that are not quickly replicating which is the case some cancers it can still can't still go out there and be be effective. These are a small a lesser class about 5% of clinical AD CS currently and and the last last group is the camptothesins. These again have a a slightly different mechanism of action. These are top of isomerase 1 inhibitors. So top of isomerase is is involved in the unwinding of DNA before replication and the and the camptothesins can inhibit that and therefore again stop replication and cause cell death. One of the campus thesis is called exoticanas has been very hot lately due to its use and and very useful and very very wildly successful in her two ADC and and so this is a really a growing class of of molecules in in the clinic. And that brings us to a poll question. And the question is, if you are involved in an ADC program, what classes of payloads are you most interested in? Go ahead and check all that, apply if you have multiple. But we're wondering if, if you see the same thing, are you interested in Maytan scenes, Dulostatin, PBD Dimers, Camptothecins or multiple? All right, answers are coming in. We'll wait for a couple more of our attendees to respond. Again, thank you very much for your responses. This information is very helpful to us. We're grateful for that input. I'll give it about 10 seconds more. All right. Let's check the responses. OK. So not too far from what we've seen from some of the clinical data. Thank you very much for those replies, Ross. Back to you. Thanks, John. So looking back at these, these various classes of molecules, one thing they all kind of have in common is that they are, you know very complicated, small though they are small molecules, they're still rather complicated. Usually it's very stereochemically rich. So this leads to usually long and complicated synthesis in order to to procure them or or you know synthesize them on scale. So the the, the synthetic route shown here on the left is the synthetic literature synthetic route of of MMA, very common payload used and it's 16 chemical steps and it's it's very complicated because of all these these stereochemical stereocenters and it's just it's very challenging molecule to make. And so you know we've we've been working with with clients in the past and you know it takes a very long time and a lot of money to to really bring these molecules you know for from concept and into the clinic. You know something along lines of two to four years and you know and over €5 million to to do so. And and we saw this as you know as as a real challenge to our clients you know thought you know is there a better way, is there something that that we could do to to really help that and that really brought us to our our AD core product line. And so it's this, these are a series of advanced intermediates and toxins that that are already off the shelf for for our clients to use. So the first three here may Core, Dulcor and PVD Core are advanced intermediates for their respective toxin classes. And then we have MMAE and and Exo T Cam which are just fully synthesized toxins to be used. And so for the first three these, these the May core, dual core and PVD core, we were kind of we wanted these to be very personal. We wanted these to be able to be used in a you know wide variety of of of molecules that our clients might want to use because even inside of these you know various classes that there's a significant structural diversity in them. And we we wanted these these advanced intermediates to be advanced as possible while still being as flexible as possible and and we we've designed them to to to do that. And really the the the biggest advantage here is is really the speed is that you know using you know any of these products is really cuts a lot of time off of both the development timelines and also the manufacturing timelines. And just because of the the dramatic dramatically reduced number of of synthetic steps that need to be both developed and then transferred into manufacturing. And this this reduced synthetic routes or smaller synthetic routes leads to a much smaller supply chain which is you know reduced is a reduced risks as everyone has been experienced lately. You know these supply chain is is a real real hassle these days. And so having that smaller synthetic route leads to a reduced risk and and then we keep all these molecules on the shelf, so we always keep them in stock. Another thing here is that when we developed all these products we really kept, we were really keeping an eye on, on quality both in in terms of you know making these you know very highly pure molecules but also keeping a very close eye on the process in in in that it eventually will be taken into you know commercial based GMP. So we did a lot of you know impurity origin and control and and really designed both the the develop the chemistry to synthesize it and also the analytical methods that support it or really designed what with that in mind. And leading you to that is also we also provide a you know a phase appropriate regulatory support of these of these molecules. So as we launch them they're phase one appropriate. So you know just starting out clinical phase but then as as our clients progress through the various phases we upgrade the the the quality as as as they go and these are available royalty free, free. So we don't charge any royalties for these who just sell them on a on a program basis. So it's pretty easy to get and then this really the shortened timelines really also leads to earlier time on the market. So it leads to earlier market exclusivity and really the biggest thing here is it's gets to patients faster. That's really the whole point of this is saving, saving as many patients as possible. So as an example of you know how this can be increased speed is that there's like Dokor is a very good example of this. Again on the left is, is the the literature route for MMAE and that is again 16 chemical steps. That same synthetic route can be accomplished using Dokor, but now it's only three chemical steps. So this is a really good example of just how much time can be saved by using these these advanced intermediates to to really allow for for you know truncated routes to these molecules looking again back at AT versatility and I think that our PPBD core is a really good example of this. So PBDS in particular are a very diverse class of molecules and so we wanted to build something that was you know that had a a a good way to get to many molecules and and to do that we we chose a protecting group strategy that allows us to selectively deprotect and couple each individual one independently of the others. So that really allows us to to really be flexible and and how you would put this into a synthesis. And we also we also have the ketone there as well which we can convert to the triflate again from more cross coupling chemistry downstream. And so this is really again really demonstrates the the versatility of of these molecules and and lastly we have you know Makor which is really shows off our you know our focus on quality. So matansines on this case you know ones that that that have this this alanine attached to it is that the so the the stereo center shown there's circled in pink it it really likes to scramble as as you are synthesizing this molecule and the literature routes lead to a very significant amount of of the D isomer and this is the very bad because the DE isomer of this molecule is 100 times less potent than than the L isomer which is the the desired isomer. And so you obviously want to have as as little of that in there as possible. And so we developed new chemistries that are able to to accomplish the same synthetic route but at a much lower D content now and does this really we've seen this being very beneficial as you know keeping a higher quality material switching gears a bit to to a different technology that we have and that is mostly around solubility of of AD CS. So, so solubility has been a kind of a hot topic in in AD CS for quite a while now because of of trends in in the ADC community of of using higher, more hydrophobic payloads. So there's a you know, greasier payloads and then you're using higher amounts of them. So going to a higher drug antibody or DAR ratio, both of these things lead to less solubility in the ADC and that that can lead to a number of bad things, bad, bad effects. So if if you if you have an ADC and you're you're struggling with solubility, typically one of the first things that you might do is is reduce the DAR. So take it take away some of that payload and that can help with the solubility. But that that then you typically see a a subsequent loss of of efficacy and this leads to a a narrower therapeutic window and often then you also have to usually increase your dosage of your ADC and this can lead to to unwanted side effects. So really as as best as possible that's that's to try to be avoided and you know all the things you do other than than reducing dye you can change, you might want to change your payload entirely or change your formulation. But all these things require you know additional investment both in terms of time and money and this leads to to increased risk and if and if this is unable to be to be you know figured out then that leads to to project termination. And so we saw this you know out in the ADC community and and we wanted to do something to to kind of help that and and that led us to our keto sensor technology. So, so our keto sensor technology is is shown here in orange. It is a kaidoholicosaccharide and it is able to be attached to the drug linker and then this will significantly increase the the solubility. So in the example shown here we have an MMAE containing drug linker and we have attached the keto sensor at the PABC portion and then this really increases the solubility. And so a good test of this is looking at hydrophobic interaction chromatography. So as the name would apply it it measures the hydrophobicity and so on the top trace that we have we just did you know kind of a control which is we had we used an antibody which is the the peak and and blue there in this case it's Tmab and then we made a DAR 4 dot ADC using VCMM AE so pretty pretty standard dot ADC and and that that's a peak shown in red and as you can see it has shifted to the right and that is indicating it is more hydrophobic as one and would expect after you've added your drug linker. And then on the bottom we did the same thing except this time we used an MMA containing drug linker that had keto sensor attached and you can see that the shift now is much less in fact it is almost colluding with our bare antibody which is really what we wanted to see. So this is a good proof of concept that indeed Ketosynthar does dramatically reduce the the hydrophobicity and but from here you know like a Darfur MMAE containing ADC isn't isn't really new and so we wanted to you know how far can we push us what what what really is the limit of of what this can soluble eyes and and to that we went to our doricomycins. So Doricomycins are are a different class of of toxin, they're particularly troublesome one when it comes to to solubility because they're they're very hydrophobic. And so again we did the same thing here. So at the top trace is just tmap itself. So it's just the bare antibody, the the middle trace is we made a a DAR 8 with using just a standard drug linker with with Doricomycin and as you can see the the peak looks particularly terrible and that's because it's about 50% aggregated. So that that that ADC would have no clinical use. So it is it's too aggregated to be to be used. Compare that then with the the bottom trace which is the drug linker containing keto sensor and doricomycin and now we see you know a very nice peak and we can see it is again only slightly shifted from the bare antibody itself. Additionally we we measured the the aggregation on this and it was the aggregation of the ADC was no more than the bare antibody itself. So again really, really showing a a really good good solubility increase with using Ketosensor. So from there we wanted to see you know what what does Ketosensor compatible with, what kinds of chemistries can we use with Ketosensor. And from there we tested a wide variety of blinkers, payloads, antibodies and conjugation technologies and and you can see here from this you know this laundry list of of things that we tried. You can see that you know it was it's widely compatible with with many chemistries and this leads to to be able to design drug linkers in a you know in a piece meal sort of way. You can you can choose the linker or the payload that you want and the antibody and the conjugation technology that you want and you can just add in keto sensor and so that really allows allows for a lot of flexibility and and drug maker development. So while all that you know data is good you know really how does this stack up in vivo how does this really work in in you know in in in vivo studies. So we from here we did a test using Skov 3 xenograft. So this is a human ovarian cancer xenograft and on this graph here you can see what the the the line in in purple which is just the the control which is no treatment. You can see that the tumor tumor volume increases you know unchecked and and then we had in the middle we have a a standard ADCI guess I would say. So it's a Darfur BCMMAE based ADC and you can see that there is some reduction in tumor volume. So it's some efficacy but but still the the tumor, the tumor grows well in in in spite of that. And at the very bottom you can see the line in pink which is the the MMAE containing drug linker with keto sensor again Darfur and now we can see complete tumor regression. And so this is you know really demonstrating now a really good increase in efficacy using keto sensor which is which is really, really happy for us to see. And so this really got us very excited now because not now not not only are we seeing you know we can make these new you know drug linkers or previously kind of unusable, but now we also are seeing you know an increased efficacy and already known drug linkers. So that that really you know it is it was very exciting for us to see. Another note here that that's not really shown here is that you know at 1/3 of the dose that is in this case would be at 2 megs per keg, you see about the same response as the standard drug linker. So that was good, good to see as well. So while all this was very exciting, this is you know one point does not make a trend. So we wanted to to try this again and for that we partnered with our colleagues in healthcare and and for here we were this is using a going after a proprietary target but in this case the the target is a medium expression target. So it is a little bit harder to hit and is using a a proprietary doricomycin based payload. So again the counseling it's a little more, a little more hard to to soluble eyes. But even though the drug linker is different than the last last example and the antibodies different last example the the trend is the same. So we can see that the, the standard standard ADC and and Blue kind of you know is not terribly efficacious, but the the standard with the, the ADC with keto sensor, you know shows you know immediate or not not immediate but very quick tumor regression. And and in this case there was eight of the 10 animals ended up being tumor free with no regrowth observed which was once again very, very exciting to see. So now we can see that. Yeah, again like we we can see this over 2 completely different systems. We see the kind of the the same result which this is again very exciting to see. So that brings us to to kind of access of Ketosensor. So for one, we have free samples of various already made drug linkers containing Ketosensor. So if if there's something you're interested in, please, please reach out and we can get in contact. And then beyond that we also have our our CDMO network for our AD CS shown here. So we have the comeback kind of starts in in Martiak, France with our cell line development, so we can and then that leads to our MAP production up to GMP quality. There we also have our shuffles in site for pegs and then our again our Sepoygan site which can do our registered starting materials and then our medicine Verono site which is where I am I can do the highly potent AP is and with payloads and linkers. And then finally we have our our Saint Louis site which is our our ADC and bioconjugation Center of excellence to bring everything together and and make that final ADC. So to in conclusion you know we have shown that Ketosensor allows for for new hydrophobic payloads and higher DAR AD C's and this has also led to you know demonstrated a higher efficacy for across multiple AD C's and you know accelerated manufacturing of of Ketosensor enabled AD C's can be accessed to our our Mellapore CTDML services using our AD core intermediates. And with that, I'll turn it back to you, John. Very, very interesting technologies, Ross. Based on the questions in the Q&A, our audience thinks so as well. We have enough time for just a few. So I'm going to take one question from each of the two technologies. Can you can you please elaborate on what phase appropriate support means for the ad core product? Yes, so, so as I mentioned as we launch them they're they're phase one appropriate. So we we still file a dossier or DMF as you know as as is necessary. And then as our you know we're we're constantly communicating with the customer saying you know where are you at in your clinical trials. And so as our customers are getting closer and closer to to commercialization, we will start doing things like process validation, you know analytical validation, getting everything necessary to make sure that we are there to support them as they go to to file, you know get into phase three and commercial. And so it's just one of those things that you know we don't want to do that right away. We want to get these products that you know out into the into the you know community as as fast as we can, but at the same time we want to be able to to support them throughout their life cycle of of their medicines. I see. And then switching gears to A to a keto sensor topic question rather excuse me, the question that came in is, does keto sensor affect the binding affinity of the antibody? So yes, this is something that we have been paid close attention to and we have measured quite a few Times Now with a number of of customers both internal and external people we've been working with and we've never seen a, a, a reduction in binding affinity of of the antibodies, which again is this great to see. Great. Thank you for those answers, Ross. Thank you all of you in the audience very much for all those questions. If we did not get to your question, please feel free to e-mail our presenter directly, although you can expect an answer to your question in your e-mail shortly. To register for future webinars or to access our archived webinar library, please visit our website. We offer a breadth of thought leadership on small molecule as well as ABC topic. I would like to thank our symposia speakers, Kyle Lair, Jason Modest, Angela Messino, Matt Dodge and Ross Bamowski for today's presentation. And I would like to thank you, our audience for joining us today. Have a great rest of the day and thank you. _1732500385515

Summary

An on-demand version of this webinar will be available after the live event using the same link. Register now and access the webinar at your convenience.

 

Agenda

Time (EST/CET)	Topic	Speaker
10:30 AM EST   4:30 PM CET	Welcome, Housekeeping and Introduction by the Chair	John Stevens
10:35 AM EST   4:35 PM CET	Introduction to Small Molecules	Kyle Loehr
10:50 AM EST   4:50 PM CET	Right the First Time: Pressure testing your readiness to ensure the success of GMP batch #1	Jason Modest
11:10 AM EST   5:10 PM CET	Strategic CMC Planning Through a Phase Appropriate Quality Approach	Angela Masino
11:35 AM EST   5:35 PM CET	Patients Can’t Wait: A Case Study for Overcoming Obstacles on the Journey to Commercialization	Matt Dodge
11:55 AM EST   5:55 PM CET	Accelerating and Enhancing ADC Therapies	Ross Bemowski
12:15 PM EST   6:15 PM CET	Closing Remarks	John Stevens
12:20 PM EST   6:20 PM CET	End

Abstracts

Right the First Time:   Pressure testing your readiness to ensure the success of GMP batch #1

Jason Modest, Director of Manufacturing, Science and Technology

In many cases, readiness can be consolidated into a list of tasks, which need to be completed prior to starting your first GMP batch.  Once the checklist is complete, it’s time to ensure success, by challenging your readiness, through confirmation of assumptions, walking/talking through the execution, and lining up your support cast.

Strategic CMC Planning Through a Phase Appropriate Quality Approach

Angela Masino, Head of Quality

A phase-appropriate quality approach emphasizes the quality, scalability, and sustainability at different stages of the development cycle. With an emphasis on quality in development, the strategic planning for the application of phase appropriate quality requirements in the development, manufacture and control of cGMP pharmaceutical material can balance multiple functions to meet the overall development goals without sacrificing the late-stage requirements of the program.

Patients Can’t Wait:  A Case Study for Overcoming Obstacles on the Journey to Commercialization

Matt Dodge, Head of Client Project Management

Over the last 30 years, our Madison/Verona site has provided CDMO services, and partnered with their clients to develop and execute manufacturing processes aimed at getting clinical and commercial APIs to patients faster. This talk focuses on the client experience when partnering with our Madison/Verona site and will discuss creative solutions developed to overcome obstacles faced when bringing new medicines to patients.

Accelerating and Enhancing ADC Therapies 

Ross Bemowski, Associate Director, API R&D

Discover how payloads and advanced payload intermediates can accelerate drug development efforts and enhance ADC therapies. From ADC payloads such as MMAE and Exatecan, to ADCore payload intermediates which provide rapid access to the most sought-after ADC payloads classes (dolastatins, maytansinoids, and PBDs) and the solubility-enhancing ChetoSensar™ technology. .

       

_1732500385743