Hi, everyone, and thank you for joining today's webinar. My name is Veronica Feinberg and I'll serve as your moderator today. Thank you. As your moderator, it's my role to ensure that we make the most of your time with us. I'm here today with Sarah and Alejandro. One second before I turn things over to our presenters, I'd like to cover a few housekeeping items. At the bottom of your screen are multiple application, which is you can use. There. You can also find our reaction button indicated by the thumbs up emoji that also 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 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. 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And lastly, attendees who wish to receive a webinar certification will need to fulfill the criteria of minimum 30 minutes viewing time and completing one whole question within the duration of this webinar. And so that's it from my side and it's my pleasure to turn things over to our speakers. Thanks so much, Veronica. All right, thank you everyone for joining us for this webinar. Today. We have an exciting agenda planned for you today. We're going to start by introducing our speakers. Then we'll take a look at what's happening in the industry and some of the trends driving the need for single use closed systems. We're going to take a look at the value, drivers and benefits associated with adopting closed systems and closed processing. We'll take a look at how the biopharma facility has evolved over the last five years and how it looks as we move into the future towards the facility of the future. And then we'll look at some of the industry groups, tools and resources available today to help you implement closed systems. One specifically is the process closure playbook recently published by the Bio Forum Group. And then we'll leave the last 20 minutes or so for Q&A. So please jot down your questions as we go through the slides or use the Q&A widget that Veronica mentioned to enter your questions and we'll get them answered at the end. I'll start by giving a brief introduction of myself. My name is Sarah Bell. I'm a marketing manager. I've spent the last 19 years working in the biopharma and life sciences industry. I started my career out at Amgen, Rhode Island where I held positions in process development, in upstream manufacturing, in project management and in quality control. For the last eight years, I've been working in a variety of technical marketing leadership positions and I really have a passion for developing and bringing new products to market to help drive manufacturing efficiencies and flexibility, ultimately trying to speed up the time to market for life saving and life enhancing drugs for patients. In addition to my day job, I am also the sponsor for the Bio Forum Groups Drug Substance Closed Systems Work Stream and I'm also recently involved in the nimble of process intensification control strategy work Street. So with that I'll hand it over to my Co speaker, Alejandro Cutter. Hi guys, my name is Alejandro Kaiser. I'm a Senior process engineer at Kaiser Global Engineering. I have over 12 years of experience in the biopharma industry mostly doing facility design, construction and I'm a bunch of risk assessments, closure analysis, contamination improvements, regulatory inspections and in addition to that I'm quite involved in different societies within our industry. I'm a voting member of ASMBP and then I'm also a member of ASP Bio Forum group. I've I've public review of ASTM and author of several publications. Hope you like guys there, the presentation. Great. Thanks, Alejandro. All right, so let's start by looking at what is happening in the industry today. And if we look back 5 to 10 years, we saw a lot of drug manufacturers really focusing on blockbuster products. We saw huge facilities and large amounts of capacity being dedicated to single products. What we've seen happen now is a diversification in the product pipeline and product portfolio looking across multiple modalities even. And what that's done is driven A trend towards smaller batch sizes and the need for more flexible multi product facilities. Hand in hand with that, we see this need for speed. And when we say speed, we don't always mean just time to market, but also speed, cycle time and also changeover speed. And we want to get that increased speed without any quality compromises. And then lastly, we see this cost competitiveness and cost consciousness, one because of the rise of biosimilars, but also just this desire to get more out of facilities with less resources. And so the Bioform Group has defined these very lofty industry aspirations across these different categories. And when we look at how we achieve these things, it's really going to take a paradigm shift in the industry and there's no one single strategy that can help us achieve these aspirations. It's really going to be a multi pronged approach. So we look at single use, the benefits of single use are very well known. Now. We have a lot of historical data. Generally it's very well accepted in the industry. Now if we start to combine single use with say process intensification, that's where we can really capitalize on the cost savings, the footprint savings and some of the speed savings. With intensified processing, we're able to get more product with less, with less equipment, with less raw materials and with less footprint. Now if you add the use of closed systems on to that, you're going to see an increase in contamination control, which becomes even more important as we look at intensified and continuous processing where durations are being extended, right. Contamination control is going to be critical there. But also with closed systems, we're able to reduce some of the environmental controls, so changes the way that we design and build facilities. But even for existing facilities, we are able to reduce the amount of Downing environmental controls and things like that. So it's really the three of these things combined can help us really change the paradigm and help us achieve these industry aspirations. And before we dive deeper into the value drivers and benefits of closed systems, I want to align everyone on definitions. So really when we talk about a closed system, we're talking about segregating the process and the process contact services from the external environment. So we're really making sure that nothing gets into the system, so preventing any risk of ingress. There are a couple different ways to achieve closed processing. One is functionally closed processing. So think about a traditional stainless steel system like a bioreactor. In that case, you're going to be making some open manipulations. You're going to be connecting filters, connecting jumpers, connecting things that you need to add into the bioreactor or sampling assemblies. Once everything is connected, you're going to render that system closed through the the use of a sanitization or a sterilization cycle. On the other hand we have what we call fully closed. So think about a single use bag assembly. That assembly is going to come pre assembled and pre sterilized to you as the end user and then you'll be able to make a connection to other parts of your process either with an aseptic connector or a tube welder. In that case, that system is never ever opened or exposed to the environment, so there is no need for sanitization or sterilization. You can simply make your connections and start to process. In both of these cases, once those systems are closed, everything added to or removed from the system must be done in a closed way. So again, this is really just to say that the more and more we talk about closed systems, the more we just closed is closed. It doesn't matter how you get there. But once that system is closed, it's closed. And before we move on, I I want to make a point that close does not automatically mean sterile system closure is really a function of bio burden, control, cleanliness and integrity. So don't just assume that if a system is closed that it means it's a sterile system. We can use closed systems for low bio burden applications and it provides the same level of contamination control benefit because we're really protecting the system to make sure there's no ingress, All right. So now we're going to dive into some of the value drivers and benefits this slide we're just going to touch upon at a high level and we're going to actually walk through a model that dives deeper into each of these areas in a few slides. Today, what we see as one of the biggest drivers is the contamination, risk mitigation, and this is contamination in the sense of we're protecting the process and the product, but also our operators and our environment. We see a significant cost reduction and energy savings with both new and existing facilities. Now that's going to look a little bit different if you're retrofitting an existing facility versus building a Greenfield facility, but there will be savings. In both cases, we see a reduction in time to market, cycle time and product changeover. We see reduced footprint especially clean room footprint as well as infrastructure requirements because we're not needing to sanitize or sterilize as much. And then lastly and one of the biggest benefits and drivers is this enablement of multi product and multi platform manufacturing within the same facility. So really allows you to optimize your facility utilization and get more out of your existing footprint, which is huge when capacity is at such a premium in the industry. All right, now we're going to pause here for our first poll question. We encourage everyone to participate and I'm going to hand it over to Veronica to walk through this. OK. Thank you, Sarah. So your first poll question here is what close processing value driver is the most compelling for you? Reduced energy consumption, reduced contamination risk, enables concurrent multi products manufacturing, reduced labor and costs. So gowning, changeover energy environmental monitoring or reduced cleaning room footprint and simplified facility design. We'll give you a few moments to answer before we close out the poll. OK. We're going to close out the poll and then I'll hand it back to the speakers to comment on the results. All right. So it looks like reduced contamination risk is leading the way at 55.6% and this is very much aligned with some of the the market studies and voice of customer that we've previously done. It'll be interesting to see if over the next several years that reduced contamination risk continues to be the top driver or if that evolves over time more towards say multi product manufacturing. So this is something we'll definitely be keeping an eye on. Thank you for your participation. All right. So as I talked about earlier, we said you know we're moving away from these blockbuster molecules and looking more at diversified and more complex product pipelines. And so it's interesting to look at the drivers for closed processing by modality. And what's great is closed systems. Closed processing is really modality agnostic, but there are unique benefits and drivers associated with each of the different therapeutic modalities. So I just wanted to give a few examples. So if we look at viral vector manufacturing and vaccine manufacturing, we see that biosafety is the main driver for those processes. And this is really critical because we want to make sure we're protecting our operators and the environment from the manufacturing process itself. In these cases also we see contamination control and sterility being a big driver. And this is because some of these process products cannot be sterile filtered, right. So that product quality aspect is important. When we look at MABS and recombinant proteins, we see contamination controls, risk mitigation being the primary driver with product quality and processing efficiency falling closely behind. And then when we look at cell therapy, we're looking at contamination control and sterility being the top drivers. And this is really because in this case the process is the product and in some cases the product is being injected back into the patient before we are able to even have any sterility results. So making sure that you're controlling that process and maintaining closure is very critical. Again, some of these systems are being done bedside at point of use, right? So having the ability to have a small, fast and closed setup is important, especially if you need to be doing this outside of a clean room environment. And then lastly, just preventing cross contamination, both for the cell lines themselves but also for patient samples. So really the intent of the slide is just to show that the drivers may differ by modality, but the benefits are universally realized and this is what makes the use of closed systems so appealing to multi product facilities or CDMO manufacturing providers. All right. So what we're going to do is we're going to dive deeper into each of those benefit areas using a model that we developed and I just wanted to ground everyone on some of the assumptions that were made before we look at the results. So for this model what we did is we compared a traditional single use batch process to a single use fully closed batch process. We looked at the process from the inoculum scale up portion through to the end of formulation. We did exclude media and buffer preparation and final fill from the the model and now we're going to walk through the results for that. So what I'll do is I'll start from the inside this kind of teal line and work my way out because we saw that contamination risk mitigation is really the top driver and we we've reiterated that with our first poll question. So we see a 47% reduction in contamination risk with the implementation of closed systems. We see from an energy perspective energy savings of up to 48% in a separate room concept. And what I mean by separate room concept is this say is an existing facility that used different clean rooms for different parts of the process with airlocks in between. They're maintaining that same room structure, but they're declassifying those clean rooms or down grading those clean rooms. And then if we're looking at a new Greenfield facility, we could see up to a 65% reduction in energy with a ballroom concept. And just a little bit of a fun fact here, when it comes to energy, pharma facilities use 15 times the amount of energy of a traditional commercial office building and half of that energy comes from HVAC alone. And just to kind of equate this to something that we all can can think about, if we're able to move to close systems and downgrade clean room space, say from a Class C in ISO 7 to ACNC space, the amount of HVAC savings that can be realized would be equivalent to what it takes to power your home for 12 years. So you know in the grand scheme of cost, it may not seem like a huge difference because operating a pharma facility is just so costly. But when we really look at those energy savings and think about that from an environmental impact or if a sustainability impact, it can be very significant. Moving on to environmental monitoring, we saw A50 seat 53% reduction in environmental monitoring with the separate room concept and up to an 88% reduction with a ballroom concept. In terms of Labor, we saw overall 47% reduction in labor. The main drivers here are reduced gowning and cleaning of the rooms as well as sanitization cycle time for the process itself. And then lastly, we see reduction in gowning both from a time perspective. So 55% reduction in gowning time. If you work in a manufacturing facility, you know how many times you're gowning in and out of these spaces. You know, if it's just the start of your shift going to the bathroom, you're going to get materials taking a break, right? It can be significant when you add up how much time you've spent gowning overall in a day or a week. And then we saw an up to an 81% decrease in gowning costs. So some significant savings across a variety of different categories here. And then something that was very interesting at the end, out of all of these savings, we actually saw the biggest even 10 times the amount of some of these other changes would be as a result of concurrent manufacturing. So the more operations you can run in parallel because you're operating in a closed environment, the more you're going to produce from your facility. And that's only going to increase your profit margin for the products that you're manufacturing. So we saw between A1 and 4%. Margin increase for products being manufactured in a facility using closed systems that's able to do concurrent manufacturing and obviously that varies based on the amount of parallel operations, but that can be very significant savings for companies. All right, At this point, I'm going to hand it over to Alejandro and he's going to walk you through some of the facility changes that are happening as a result of closed systems. So take it away, Alejandro. Thank you, Sarah. So now the question is how do we build a facility, what are the drivers to do so And reality is the manufacturing process and and having a manufacturing process closed that impacts greatly the design of the manufacturing facility. So for instance, you can see here under the picture. In case one you see a typical facility where you have everything in the clean room, the TCU, the bioreactors, the DSC, the interlocks. When you start closing the system, you're like well first of all in case two you see that TCU is is not in process, it doesn't need to be there is closed and not clean process. So you go to unclassified space. You keep closing things and you say, well guess what the main way I may may not have to open it the connections, I may not have to open them. I can push that also out to unclassified space or CNC and just leaving the sampling this yellow dots as open process and then you move to case 3 and then you can see that you're still removing more things outside of your clean room. Your footprints getting smaller, but you can go even farther to a case 4, which is OK. What if I am able to close absolutely everything? What if I can close my sampling? Well then nothing requires to be on the clean room. Of course you're seeing there a BSc because BSc doesn't. It's an open process and we'll talk about that later. And that needs to be in a clean room and you see the the airlock to come in and to come out. But potentially for instance, you could also combine the airlocks and then you only have one airlock in and out. You could potentially use an isolator. So you can see there's an absolute trend to remove equipment for clean spaces and to remove or reduce the footprint. So the baseline rule is that all facilities should be designed to mitigate the risk of proto contamination and there's a synergy between the product, the process that you run it and the facility. So if you have a well defined process and you couple it with a proper QRM quality risk management that rate the facility to a much simpler design, OK. So here you can see an example from a facility built by CRB where you can, you can see the different generations on the layout of these cell engines facility, OK. It's a cell therapy one. You see on the generation zero, you have here several independent workstations, OK. And those are in a higher grade grade B and you to get in you know you have to go to typical right C&C to D to C to B and then it's an open process. But then you jump into well what if and you can go to generation one which is what if I can segregate within my work in a station I can segregate what is closed versus what is open and then what is closed. I might have it combined on a same on a same room and just live in an isolated silos. The operation that need to be done open. But then you go farther and you say, well what if I can close everything and and leave it inside the room with a for instance isolators and close processing and you leave it in a smaller big workstation separation by the type of different set lines. And then the future which is not happening just yet is what if I can get absolutely everything through closed and in a big ballroom. So then the question is when this journey started because we've been talking about closing system forever and it it only started in the 2000s when the International Council for Harmonization, the ACH published their quality guideline Q7 for good manufacturing practice for for AP is and you can see a quote there in the bottom left where the equipment itself provides adequate protection of the material. Such equipment can be located outdoors, which is a very strong statement to say right being located outdoors. Reality is already pushing us to to close our systems and lower down the the classification of our rooms. And even in the same document later on, it also talks about that equipment should be striving to be closed and if you will have to have it open, well you need to have appropriate precautions. But on top of that and they were more. And the beauty of this by the way is the ICHQ 7 is endorsed by the majority of biotech countries. So it really it strives for a high degree of harmonization on foreclosed systems. OK. And by the way, the peaks were involved as part of the of the development of this document. But after that you have ICHQ 9 which is what I was mentioned before the QRM one. We all know the quite risk management document that also couples is married quite well with the Q7 to strive for closed systems and then they are like a bunch of articles on these iconic ones of the challenge in a clean room paradigm, the death to the clean room. And then of course we had the amazing ASP baseline guideline in 2013 for for manufacturing facilities that that also talked about closed system fully closed and and then we have the annex to The Who annex to the Pics to be all of them are driving that direction. OK. And then lately the Annex One that just came in August, they came, it was written last year, but it came official this August. It also couples it with it to me the last piece of the parcel which is that it needs to be a company the closure by a risk assessment and the concept of contamination control strategy. So all of that puts us in a very good spot. And on top of that we have a SMEVPE, which what it does is it tells you how to design equipment to be closed. So the latest to come to the gang is the phenomenal bio forum closure playbook. And one could say, OK, so what's the point of this? Everybody and their Mama have been connected commenting on this already. So why do we need one more? Well, because we've always talked about what it means to be closed and then ISP took it over and talked about how to design A facility when it is closed and then BP came over and say how to design your equipment to be able to make it close. But if we've never talked about on how to close a process and people throughout these past years, this past 20 years have a struggle with some of the concepts on how to close your process. So this book is intended really to help in the decision making on how to design A facility or how to design your process. So in here when you read it, you'll see that these we are using a risk based approach to determine what facility aspects are important and what process attributes are important and controls in order to maintain the security of the patient. And this implies talking about room classification, viral segregation, counting EM, environmental monitoring, sampling, cleaning. OK, so Sarah was mentioning before for disclosure between functionally closed and fully closed. And that derives from the ISP baseline guideline 2013. In this book. We've tried to take it out an aspect farther, which we are calling it all of them closed system. Because as you said, close is closed. I really don't care how you arrived there. The point is you were able to close the system. And closing the system means two real things here. It's not just making. Well, number one is you need to prevent any ingress of contamination from your environment. But to start with, you need to maintain a low bio burden inside your equipment as well. So two of them are quite, quite important, OK. And and then we also were brushing up some of the definitions as open, open processing or briefly exposed, which was a little bit hard to understand some points. So and we here we do our road map and in this road map one of the of the Cornerstone is doing what we call a Clara and we'll talk about it in a little bit, which is a risk assessment on closure, OK. Closure is being accepted as the most effective contamination control, risk mitigation strategy. OK. And then of course we took our validation, A continuous validation and how the Clara can help you on that. And here on the picture you can see a little index of what is on the book currently. So far we've publicly published and by the way, it's for free. So you can, I would have really encouraged everyone to download it because there's a lot of goodies in here. It will not tell you exactly what to do, but it will definitely hand hold you on what aspects, what things you need to consider in order to close your process. We've already published the introduction and the regulatory considerations and we're about to publish the grocery probably in the next few days and every month or so we'll be publishing one more chapter. They're in legal and they'll be coming up soon. OK, so then what is in the process protection strategy? One of the things that we need to understand is that there are different layers of protection as you can see here in these different concentric rings. All of them are available to prevent the anger of contaminant of contaminant your process. But The thing is also they are not all at the same level and they are not all as effective. So these rings are all part of the so-called contamination control strategy that as I was mentioning before, you can see in Annex One. So the first thing here is defining your process. You know you want to produce a map, let's say, but what process is it going through? And the process really is your your first layer of protection and the process includes the solutions that the product is in and any other aspect of the product is involving because if your solution is impervious to the environment, if nothing can grow on that solution where the product is in that already effectively is protecting the product from bioburden proliferation on it. Other conditions such as very high, if it's been producing at very high temperatures, a very high pH, low PHS, things like that. Oligonucleotide is a great example for their for, for, for solvents that they don't allow any bio burden to grow in. So that is your first layer of protection. But let's say you're on typical map, you are developing Wi-Fi and you don't have any of those luxuries. Well then you jump into your next layer of protection, which is equipment, and equipment can be used in a closed process to prevent the ingress, it can be used in an open way. So the first question you trust yourself is can your operation be closed and if if if the the equipment has the potential to be closed, even if it doesn't, we we have to perform a risk assessment to make sure that we are taking all the precautions to make sure that the process is closed. And if it's not able to close that process, well then I will see later you have to rely on your environment. So when you're able to close that process is when you jump into the next layer of of protection which is the operational procedures is what are, what are the steps I'm taking to make sure that the equipment is closed. And there are a myriad of them and and all of us have used one or the other with single use. And so I was talking about gamma radiation. X-ray is becoming popular these days too, right in in stainless steel you have more and more CIP because again closure does not mean a sterile. So CIP is a means of closing your equipment. Also SIPVHP for your isolators. Here the the intention is to get a high lookup image reduction of your bio burden. OK And all the procedures would be the installation of your single use. Make sure you're installing in a way that you're not going to tear it up the back for instance. OK. And of course if all those fail, you go to the manufacturing suite, then which manufacturing suite is just means the the, the, the area where your process is taking place. It doesn't mean necessarily a clean room. It can be the greatest space where your pure water generation system is at, OK. So what ends up happening is if the equipment and the operational procedures are properly selected, they will isolate your process and you can kick that manufacturing suite out of your latest protection because the environment surrounding a process will not influenciate that process. OK. Will not contribute to the quality of the product, but if you are not able to close it then of course as we've done many times throughout the this past decades, the manufacturing suite has to be part of the process. So then gowning, air changes, pressurization, environmental monitoring, all the stuff. So to give you an example of what is closed versus what is not, first thing we need to talk about is process zone. And the process zone is the area that includes all the elements that may contact the process or the product. So you can imagine in particular, let's say top or left this speaker and you think about it, it's like, OK, well, what can influentiate this speaker, the content inside? Well, it could be a crossover of an operator just touching without with a dirty glove. It can be a carryover as well. It can be influential by raw materials, by the personal environmental contaminants. So all of these things that they're exogenous to your beaker and affecting what is inside your beaker. Hence it is an open process and the manufacturing suite is part of the process zone. Hence, it is part of your risk assessment. You need to be controlling to the possible extent because you can never control really your environment to the NTH degree. But then you go to the top right and you see, OK, well let me protect it a little bit. I'm gonna put it in a BST. But guess what? BST has a sash and the operator goes on the sash. OK. And he's flying around with his arms and creating disturbances on the unidirectional flow or operator is passing by him behind him and the same thing happens. So what ends up happening is that you cannot be fully certain that you are segregating your grade A environment within the BSc from the surrounding. So what ends up happening is BSc is an open process and your surrounding environment on the street is still part of your process zone. But then you go you to bottom left, OK, And you say, OK, well, I'm going to go into an isolator and I'm going to make sure that isolator is closed because I'm going to VHP and before I put my my bickering side. And then nothing that happens surrounding that. If you have, you can have 15 people looking around on that isolator, what the operator is doing and nothing will influenciate that beaker. So that process is closed because your process zone is really the inner limits of that isolator. But you can live in fans here and you can go for instance the bottom right and you can go to a beaker where you have one of those my cab or the likes where this cap has a point to Micron filter and has a still connectors and then you know that it is breathing pure. And if you are connected in for transferring her out and you're doing a close way, you are just fine. You are not influentiated by the environment surrounding you. So these are the very big distinctions that need to be made when we are deciding on, am I doing right closure or not in here. So let's jump into a next poll question, Veronica. Thank you, Alejandro. So we have our next poll question, Sorry. So outside of bioreactors and final fill operations, which unit operation provides the most value to close A harvest call clarification, B column packing, C chromatography, D virus filtration, EUF or DF and F media buffer prep. I'll give you a few moments here. And for this one we're just asking that you select your top choice. OK. I think we can close out the poll now and back to the speakers to comment on the results. All right. Boy, either you're already aligned or they weren't that many participants. OK, so column packing, of course, everybody talks about it. Virus filtration. Yep. Well, the good news I have for you too, there's the one second option is that there's a lot of things being developed these days to close those ones. Now the good or bad news for people that selected medium buffer prep is that you don't have to close it. That was a tricky one there because there's no point on closing on closing media buffer prep. And the reason is because again, closure means I want to protect it from ingress of environmental contamination but also reduce the the bio burden inside before putting my protein. Well, guess what, when you're putting your, your dry powders and buffer or your dry powders and media, those have more contamination on the environment itself. So you don't really have to close them and you cannot. But in any case you can do it in a very in a great D environment, reason being because you don't want to do environmental monitoring actively in operation because you'll definitely get hit. So you can be not worried about that one, let's say. So I was talking about the closure risk assessment was what we call Clara on the book and in in the risk assessment we focus on defining the several steps associated with it and the first one would be risk identification. OK. Then in the risk identification what you will do is once you have mapped out your process you are going to check every single point that can affect your process and we mark it out there with a number as you see what the all the inlets, all the ints and all the outs and everything counts. Gases count, liquids count, sampling counts, utilities count. So you need to check every single connection to see is that in any shape, way or form affecting my process? Can I potentially put here ingress any contaminant? And of course you need to know as well is my presence to be a sterile needs to be low by a burden. That makes a huge difference as well. In our case, you're presented it's a single by your reactor, so yeah, it has to be axanic. You cannot put any contaminant in there. So once you have mapped out all the potential risks to your process, you have to check what due to our risk assessment what are now with the points mapped out where the potential circumstances where I might be introducing some contaminant and potentially those risks are quite low and they are what we call all R as low as reasonably possible or potentially there is chances probability of that happening. In that case you have to make do mitigations mitigation strategies in order to lower the risk of that taking place of any potential English contaminant coming from your environment. So all that is your Clara, your closure risk assessment, you identify, you assess and if need be you mitigate and then this. All these will ensure that viable contaminants are removed from the process contact surfaces. OK, And then of course all the all the insurance and outs need to be in this case again is sterile or integral with welding gamma radiated because they need to come sterile. OK, so all these forms part of your Clara. And by the way, this is not just a one time activity. They can serve as a continuous validation of your process. Every time you change something, you can revisit it and it counts as a, as a core part of your CCS, as Annex 1 asks, OK. So then the question is, OK, well, now I know what closure means. Now I know how to do it. But then the question is what about my facility? And The thing is that there's a intrinsic relationship between the product, the process with the latest I was telling you guys and the facility and this synergy must be reflected on the design of the facility. So if we are, we have a defined process and protected and we have done as well an identification of and management of risks, then that needs to resolve on a design solution for that facility. We cannot do businesses using the facility if we went so many extra miles on protecting our process. So when you do a closed processing, reality is you typically work on a great deal or CNC environment because that's for close because again you don't have to do environmental monitoring among other things. OK. But the problem is CNC characteristics of the space are not defined anywhere by regulators and grade D are just you know just the limits for viable and unbibles are determined. But other than that if you go through around the world let's say, or even around your own facilities and your own corporation, you see that the, the, the, the how the grade D and the CNC have been designed are completely different. They they differ from each other and some of them are super clean that you can't even distinguish them from a great C for instance. So what we're training here we selected a lot of different criteria the design materials operational within the bio forum. We put a survey throughout the world mostly Europe and the US and we were telling him, OK, people anonymously tell me exactly all the different characteristics of your CNC space and your grade D space and we were trying to do in here was to create the minimum requirement and recommendations for these spaces. What can we all agree in and some other stuff that we don't agree in And we were analyzing them. It may be because they are discretionary upgrades, they're extra mile that companies went, but we cannot ask everybody to go that extra mile because it doesn't make sense. OK. So we're trying to tell the industry shake them up a little bit and say hey great D and great and CNC don't make it the new great C make it to what it used to be great D and CNC to what is important and necessary. And the rest the extra the cherry on top I'm sorry that is because of specifics characteristics of the facility or because corporate specifications of your of your company or because discretionary upgrade you wanted to do, but it's not needed. So it's important to distinguish that. So as a conclusion here with Sarah, we've seen that the market trends are driving us to go towards close processing, especially with having to put so much production out there and Atmps. We are seeing how the industry with the regulatory agencies we're talking about mitigating the risk and that deriving to reduce clean room footprint and you maximize also facility utilization giving away from airlocks for instance. OK. The facility of the future needs to be quite flexible because pandemics come and new products come and short campaigns come. So it needs to be reactive to what is coming to it and and then there's a huge push to harmonize, harmonize guidances throughout the industry and everybody's aligned BPE, peaks, bio, forum, ISP, everybody's going to align on this. So the all the all the stars are aligned for us to move towards this direction. And again, last thing, again, close processing. It is not synonymously sterile, it's just protecting you from ingress and and by a burden inside. OK. And anyway, with that, we thank you a lot and here are our addresses in case you have any question now or in the future. And we absolutely welcome any questions you guys may have. Thank you very much for listening. Thank you, Sarah and Alejandro for this great presentation. Now it's time to answer a few questions that have come in from our audience. But before we do, I'd like to remind you that it's not too late to send us your questions now using the Q&A widget. This also applies to on demand viewers. We'll try to get through all of them, but if we run out of time, we'll respond to you individually. And as a reminder, this webinar will be available on our website soon and all participants will receive an e-mail notification when it's available for viewing. So now back to Sarah and Alejandro, who will start answering questions that have come in. Great. Thanks you. Thank you, Veronica. And before we get into Q and AI, just want to mention that in the webinar resources section, there should be a few things that you can download. One of them is the link to download the process closure playbook that Alejandro mentioned. So I just wanted to point that out. And with that, I guess I'll kick us off with our first question and it looks like question is what do you see as being the biggest challenge associated with closed processing adoption. So maybe Alejandro, do you want to take that first? Sure, sure. And I have to apologize, I've been having an internal chat, apparently I'm a little muffle, might be I'm in a construction site, so it's the wonders of being live sometimes anyway, So hopefully you can hear me fine. So challenges on post processing, well one of the things I would say is it depends on which market are we talking about because if we talk about traditional markets such as could be the the antibodies, mammal antibodies, it is very well accepted the move towards close processing. We've have been talking about it for 1520 years. So people are familiar with it. Sometimes what ends up being the the the handicap. Here the obstacle is I see wrong sops or using wrong connectors. Very old sampling practices at the corporate standards that nobody has brushed up in 15 years and prevents you to take all the advantages on grading of the room or or closing all the systems as you would like to, especially sampling again. So and they claim well I'll take too much effort to to to do any of these changes and live as it is which I think is a is a big shame now on the newcomers the the CGT or the ATM PS the industry is still quite fresh quite green on these. And to me there are two factors preventing from all the full close processing. One of them is the fear of making the first move. And I don't mean for your first move on closing the process because of course everybody would like to do that. But taking the advantages of having done that, degrading these rooms, degrading the spaces, combining spaces in more ballroom like because it's a fear of the regulator of what they would say, what they will think about if they are too liberal on their design. OK. And then the other one is unfortunately it's so green and the the volumes are so small and the equipment is so new that the step operations are so new that a lot of the technology is not always there. It's been technology that was used for R&D, for labs that we just kidnap for our for our manufacturing facilities that is not possible to fully close. And they are working very fast, very hard enclose them, but not all of them are. It's the same thing with the Gump, the the, the, the automation is not there in a lot of these pieces of equipment. But let me tell you in the past two years we made tremendous advance and and we'll continue with that. Sarah, anything to add or great, Thank you. Yeah. Yeah, I have a few things to add. So I think one of the biggest challenges is really internal alignment. I think using closed systems in CNC is really a paradigm shift in the industry and I think changes like this can be very uncomfortable for some people, especially people that have been in the industry, especially in in working in the quality areas for quite some time, right. Clean rooms are just so ingrained in in biopharma facilities as we know it today and it's difficult to change people's perception. So I think just having an open mind, no pun intended, but right if a if a system is never opened or exposed to the external environment then why really is there need to control the environment environment at all. And I think we have to push the boundaries a little bit. And then I think another another challenge that customers will face is you know I think it's great that we have the tools available in the process closure playbook to walk people through the risk assessment. But I think still we need to understand like what does closure mean and how do we qualify closure, right, What data set do we need to kind of justify internally as well as to regulatory agencies that you know to demonstrate that closure, whether that's media whole challenges or bacterial challenges. Just thinking a little bit more broadly to see if we can kind of standardize in the industry of what testing really demonstrates closure. So those are two areas where I think we have some work to do. So and those are things that the manufacturers of equipment you guys are helping a lot to provide those tests and bridge build a gap in between you guys and the end users to make sure that those tests are in there to assure that you have closure. So, so things are happening every front, yeah exactly. And I and I think you know thinking about that from the very initial design and the raw materials that we're using, the manufacturing that process that we're using to manufacture the products themselves and then being able to arm the end users with the documentation package to support the Clara, right, or the risk assessment I think is going to be very helpful. All right. Looks like we did have another question come in. Oh, did you want to ask? No, you go, I don't care. You can you can read it. OK. This one came in from the audience. Does scaling down and scaling up impact clothes processing differently You want to go start or Sure, go take that one. Sure. I can go. I can start. I I oh, you got yours. Go, go ahead. That's right. I think when we look at especially single use technologies, right, I don't necessarily think about scaling up and scaling down more scaling out, right. So if you can just multiply your process trains, then you can replicate the setup. It makes it very easy to implement and expand. If you really are looking at scaling up or scaling down in the traditional sense in terms of processing scale, there may be unique challenges at different scales to close the process just because of the technologies available today. There may be scale limitations, but I don't think it necessarily changes anything. Yeah, I agree. No, I agree. The one thing I can think of is the scaling down. There's limitation in the in the smaller sizes of tubing that you cannot get a septic connectors. For the longest time it was 1/2 inch. I think we're now in the quarter, but he wanted one eighth. I maybe sort of correct me, but I don't believe we have one for that for instance, because that was always lab scale. Now you want to go up. Typically there's no much limitation. Well, there was limitation up to two inches as well on the septic connectors we used to have for the longest time 1 1/2. This year we a bunch of manufacturers came up with a 2 inch. But also if Sarah was mentioning, you can scale out but if for whatever reason your process is no, no, no, we scale up well, you can always also go to to stainless steel which is also you close it by CIP or SAP and there's some companies that try not also going to very big single use volumes. But overall there is no intrinsic difference on closing smaller scale versus higher scale larger scale other than making sure that you have apparatus to Weld your tubing for those sizes or to do a septic, connectors, things of that nature. But it should be pretty universal. Great. Thank you. And maybe we probably have time for, for one more question. So maybe Alejandro, I'll, I'll toss this one to you since you're kind of at the forefront of facility design, but in your experience, are most of the new facilities being designed and constructed today utilizing class D&C&C space only? Yes, I would say so. I mean on you can all throw a blanket statement saying yes, but they do it everything DNC and C the audience was seeing that you know there's some challenges viral filtration, column packing. So there's still areas where the industry does not, may not feel comfortable because they don't have, they're not playing with the latest technology, they are not comfortable on leaving clothes. But for the most part, everything is going towards great D and CNC and because they just do a proper closure analysis when they have to do now. Another very cool thing I'm saying a lot lately by lately, I mean the past two years is developers getting into our industry, people that they don't have much experience within biotech, but they want to be able to attract as much public as possible. And in doing so, they are doing very flexible facilities where they are able to isolate or ballroom the space. And they have the HVC built to go as as as conservative as grade B or low way to C or D depending on the comfort zone of the clientele as well as depending on the tech transfer of their process if it allows or not for a closure. So, but yeah, overall, yes. Sarah, we are definitely moving to great D and CMC space industry and people by the way are loving it because as you as you saw on the on the on the first slide of presentation is now the people are able to go in much less counting, it's much, much more comfortable for them. Yeah, that's great. That's a great sign. OK. I think that was our last question, right, Sarah and Alejandro? Yep. OK, well, we have two minutes, so I'm gonna squeeze one in cuz I'm seeing the last one just came in. So what do we see as technology gaps right now in the industry for proper closure? Sure, I can take that one. So there's definitely some some technology gaps still today that prevent foreclosure especially in the downstream process. So that's where we think about traditional column packing, chromatography, columns and filtration technologies. These still require in most cases some open manipulations, you know which warrant the need for post insulation flushing or sanitization to functionally close the system. So the goal would be if we can get those processes fully closed then we can eliminate the need to sanitize and sterilize those. And this is something that Millipore is actively working on taking our industry leading filtration products and fully closing them. So they are really plug and play and you're able to eliminate the need for pre flushing and pre sanitization. And then I would say one other area that will become more of a critical need as we move towards more intensified and continuous processing is the ability to quote UN quote hot swap to basically do in process change outs of filters, sample bags, surge bags in process without impacting the system closure, right. So this is going to require technology that allows for connecting, disconnecting and reconnecting without reaching the integrity of the system itself. And there are some technologies on the market today that can do that, you know, tube welding and ceiling, the LINK Cdr manifolding, but they all have drawbacks and limitations. So this is really a big technology gap that we have that will become more and more critical over the next 5 or 10 years. And so hope to see some good, good progress in that area from a technology development standpoint as well. So thank you. And with that, I think we're out of time. Sorry, sorry, sorry. Yeah. I was thinking when you said the hot swaps, it's becoming very important with continued manufacturing that you are for long periods of time manufacturing there and you need to change out. So, yeah. Thank you, Sarah. All right, Veronica, do you wanna close this out? Yeah. Thank you, guys. Yeah, so thank you everyone for all the questions. And if we didn't get to your question, please feel free to e-mail our presenters directly to register for our future webinars or to access our archived webinar library library, you can use our website. I would like to thank Sarah and Alejandro again for today's presentation. And thank you to the audience for joining us. Have a good day everybody. Bye. Thank you, guys. Thank you. Bye everyone. _1732521760514

 


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