Hi everyone, and welcome. My name is Saskia Kisa and I will serve as your moderator today. Thank you for joining us for today's webinar. What do you need to do to qualify as thing? Use assembly as your moderator. It is my role to ensure that we make the most of your time with us. I'm here today with Jessica Cher and Monica Cardona. Jessica is the improved program manager responsible for filters, singing use and chromatography resin portfolios within our company. Previously, she was responsible for extractables and leachables, global support for the Bio Reliance validation services and she has more than 15 years of extractables and leachables experience, including method validation, designing of custom testing and interpreting industry and regulatory guidance. Fasika has a Bachelor of Science in Biochemistry and a Master of Business Administration. Monica is a Senior Program Manager for Single Use and Integrated Systems. She has worked in Life sciences for over 20 years. She has had several global roles in technical, strategic and operational marketing and she holds a Bachelor's degree in Biology from Hofstra University and a Master's in Biology from Adelphi University. She has published and lectured internationally internationally on a wide range of filtration, validation and single use bioprocessing topics. Monica is on the Board of Directors and a founding member of Bioprocess System Alliance. She also is part of the Bioform Single Use Leadership Team. And at our company, Monica works cross functionally with quality, improve regulatory operations, R&D and commercial teams to create and implement product portfolio enhancement programs that differentiate product offering, improve customer satisfaction and Dr. portfolio growth. So before I turn things over to our presenter, I'd like to cover a few housekeeping items. At the bottom of your screen are multiple application widgets you can use. 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The webinar is being streamed through your computer, so there's no dial in number. And for the best audio quality, please make sure your computer, speakers or headset are turned on and the volume is up so you can hear the presenters. And 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. And lastly, attendees who wish to receive a webinar certification will need to fulfill the criteria of minimum 30 minutes during time and completing 2 part questions within the duration of this webinar. So that's it from my side, and it's my pleasure to turn things over to Monica and Jessica. So good morning, good evening, good afternoon. This is our agenda for today. We're going to do a short single use introduction, talk about quality by design, quality risk management, operator training and handling. Then my colleague Jessica is going to go through quality and regulatory documentation and very specifically as well on dossier content that we can provide to facilitate a lot of the these qualification challenges. To be honest, we can do an hour plus webinar on each one of these different topics. So today is really meant to be a broad overview. Now quality is embedded in everything we do within our organization from our people in our culture to our processes and our measurements. And we do understand that implementation of single use technology involves shared risks and shared responsibility amongst suppliers and end users. So it's really a partnership in how we qualify and implement these into your processes. When we look at the single use system life cycle chain of responsibility, as a supplier we are responsible for ensuring the integrity of your assembly from raw material qualification all the way through irradiation. By the same token, the end users are responsible for incoming receipt and inspection all the way through disposable to ensure that they are maintaining the integrity of the assembly itself. So like we said before, it's a partnership. As end users, you have the process and manufacturing knowledge. You know the end to end system design of your operation. You have your drug product knowledge and patient knowledge. You are the ones who are aware of your internal procedures and control and as well as the different risk tolerances based on your past experience. From our end, our knowledge lies in material and component knowledge designing and qualifying these assemblies. Definitely single use technology manufacturing and controls the best practices for handling, right, because one aspect of it is the qualification, but we also have you know best practices for handling and because we deal with a wide range of customers in a variety of products, right monoclonals, vaccines, plasma, we have experience across multiple processes. This is one of of my favorite quotes. It's a it's from a few years ago but it's from Robert Repetto from Pfizer and he really says that only a partnership with a single use suppliers can ensure that the quality is as good as or better than what is achieved with those traditional stainless steel systems. So these are some of the topics that how we consider when when we're looking at single use qualification. You know everything from how we control particulates, endotoxin and bio burden to extractables and leachables shelf life and you know integrity testing packaging and transport validation and and one of the things about our single use industry it's about let let's say 25 to 30 years old. And I think one of the challenges is adopting and adapting right standards that perhaps were not specifically designed for single use technology and using these to qualify our our assemblies. So that that is I think an industry challenge that is, is, is it's the paradigm is shifting it's changing right. We're we're starting to see some standards come through for single use assemblies like USP 665 for example and others that are being worked on in organizations such as in your ASTMASME. And then definitely we have organizations like the Bioprocess Systems Alliance. They have a great reference the quality test matrices that were recently released and and what it does is it gives you a reference guide of some of the tests that suppliers use to qualify different components. And then when you come to actually bringing these assemblies into your organization's, you know the bio forum organization has the single use user requirement kits and that that helps that that tool kit really helps in you know what types of information you should be asking your suppliers for. But again, these are all best practices, nothing is really set in stone and and that's probably one of the redundant themes that you will hear throughout this webinar, all right. So because you have a variety of suppliers, it's very important to understand what your respective suppliers do when it comes to manufacturing and control, right. Usually this is done you know, during your supplier audits, right, your qualification of the supplier itself, but really understanding you know their bag manufacturing, what type of equipment is used, whether you know whether it's automated, whether it's manual, what in process tests they have. This is all part of the due diligence right? Understanding what is being done at the assembly level, what types of release tests are being performed and also the understanding that the either leak release test or an integrity test as at the at the manufacturing facility that's releasing the assembly. There's various methods and and different sensitivity levels. At times you will notice that most of your suppliers will have different tiers of certification and those different tiers of certification usually correspond to the level of criticality of an application. I would like to say that you know those levels of certification are standard across the industry. They're not, but we can at least say each supplier has about 3 levels and understanding that you are using the right level of certification of product for your application, right? So what do I mean by that? For example, maybe if you're using something for a buffer a little bit further upstream, you may not need the same level of certification that you would need for example for your final fill assembly. That would be made based on your obviously internal risk assessment. So in our organization, we try to simplify things a little bit and we look at single use assembly qualification as a three pillar strategy that encompasses quality by design, quality risk management, followed by operator handling and training. And again each one of these bullet points under each of these pillars can probably have an hour webinar all on their own. So let's look at quality by design. So we want to make sure that the components are fit for use in the pharmaceutical process and that they're also fit for use within the manufacturing process. So understanding how your supplier qualifies components into their respective libraries is important within our organization. These are some of the the criteria. So for example, we want to ensure most obvious right, that all components are gamma stable, right, they're gamma compatible, that we've performed some sort of functional testing, poster radiation that there's packaging assessments, There's a slew of regulatory statements that we would request like animal origin free latex, free BPA from a biological reactivity perspective, you know ISO ten, 993-5, USP 8788 in order to ensure that these components are not adding to the endotoxin or particulate load. That is also part of the qualification, traditionally USP 661 and that usually entails 4 tests, right? It's usually NVR, residue on ignition, buffering capacity and heavy metals. And users really like this test because it's it's pass fail. It's not just data with the with 665 coming into the picture and 661 being sunsetted in 2025665 will take the place of this test. We want to ensure that these components can have a shelf life of greater than two years as that is what we're claiming for the assembly and we also have a bio burden monitoring program for these assemblies. So as I said before, there's different levels of certification and we want to make sure that the level of certification that you choose meets your needs. One of the highest levels and for example can include helium integrity testing for very critical applications and this has sensitivity down too two Micron. So let's go down the quality by design pillar. So we talk about initial component qualification and that was what we just reviewed in the past in the last pages. The next topic is junction validation or fastener qualification. And what this is really about is how does your supplier qualify all those hose barbs tubing connections, whether it's with an audacre or a cable tie. There's no, I don't want to say I have not seen a published industry best practice on junction validation. I think all suppliers perform a junction validation and it may be slightly different. So we want to make sure that you know, you request this information that you understand how your junctions in your assembly were were validated. Once we've qualified components, we've done junction validation, we do an engineering design assessment. So this is at the point now where you as an end user come in. Right now you're going to, along with either a single use specialist or otherwise design your assembly. And then this assembly within our organization goes through a design assessment to make sure it meets our design rules based on our experience. There's a design review, and then finally you get your assembly design, your drawing, and you sign off on that drawing. So now we come to something interactive and I'd like you to participate in our first part question. So what type of pharmaceutical application are you manufacturing with singer use? So you can select all that, apply more molecules, map, ADC, mRNA, CGT or others. So we give you another few seconds, all right, Very interesting. And I think I would hand over to Monica again. OK, great. So now let's talk about our quality risk management pillar in in the qualification journey. And this includes environmental monitoring, control in process and release testing, sterilization, packaging, shelf life and to some extent point of use testing. So my colleague will be talking about extractables and shelf life at the end of the presentation. So I'll try to cover some of the other pillars here. So in terms of the room manufacturing controls, right, the monitoring program in our organization, we have kitting and gowning in an ISO Class 8 type of environment. Assemblies are made in an ISO 7 and there's continuous monitoring for particulates in the clean room. We ensure that there is appropriate gowning and that everything that's in the clean you know has been designed for cleanability and there are there is routine cleaning of of all surfaces. One of the questions I get is you know since particulates seem to be you know a a very hot topic within our industry, why are we manufacturing in an ISO Class 7 and and what I'd like to explain to some extent is that. A lot of the raw material components are manufactured in an ISO 8 or an ISO 7 and sometimes even in an unclassified environment. So just by bringing these components into an ISO Class 7 or ISO Class 5 doesn't necessarily clean them, right. And also there is increased OpEx cost that isn't necessarily going to improve particulate load of the assemblies especially if you know if we still have paper and people in these clean rooms going up in ISO classification isn't really the answer, right. It's more about continuous improvement of of the existing processes in these clean rooms. So now let's look at in process testing. So we have in process testing, we have a standard manufacturing release test and then there's some specialized release tests for those applications that are more critical. And then of course, we can do the due diligence based on your risk assessment. If you choose to do a point of use test, that is also an option as part of your qualification. So in terms of actual testing really it's it's really a a risk management approach. There's no regulations for integrity of single use assemblies. You know, we mostly rely on, you know USP Twelve O 7 for container closure and I think Annex One now has maybe some more poignant, you know ways of of of maybe helping us to understand what to do. But it's still at least for assemblies right. It it's still quite based on internal risk assessment where you're going to test, how you're going to test. There's several best practice guides or or things in the public domain that can help us, right. It's really working towards alignment of stakeholders whether that's you know regulators and and some of these organizations working with end users and suppliers to get to resolutions and things that we can all implement. So when we talk about integrity release testing, the sensitivity should be based on risk assessment. So for example, a regular pressure decay test may be of a sensitivity such that it's really calling out maybe improper bonding of the film or missing components or maybe some improper connections, right? But when you want to if you need like an integrity test, right? Which means it has a correlation not to a size of an RFS, but actual correlation to microbial ingress. Then our organization offers restraint plate testing and Helium Integrity test. Our strain plate testing is currently at about 20 microns. The Helium integrity test is at 2 microns. The only thing is these do have a design space and I don't want to call it limitations, right? I'd rather say design space. So at the point that you are maybe designing your assembly, it it's not it, it's probably the right time to start thinking what type of release test am I going to want a release test that's maybe a standard and related to a size of an orifice? Or does my application? Is it critical enough where I'm going to want an integrity test that's correlated to microbial ingress? Because this may also help guide your design. So again, in process test, it's pressure decay, right? We're detecting in improper bonding. The standard release test is. Now you have that bag right with all the other components of the assembly put together. And here again this standard pressure decay test is detecting more of these gross improper connections or missing components. And here we go down to 20 microns and at least in our organization we currently can provide these four assemblies with 50 liter 2D bags and that is the the same design space for our current helium integrity test offering sterilization validation. So basically you by purchasing A sterilized assembly from a supplier you're you're basically contracting out that that aspect of it. So understanding what your supplier does right, you know ensuring that there using and working towards the ISO 1137 standard. Most of us use VD Max, we establish A sterilization dolls and then we do release based on the symmetries and then there's quarterly dose audits. So most organizations are going to be doing quarterly bio burden followed by quarterly dose audits and sterility testing. So this is the continuous validation of that sterilization and you know, usually looking at certificates of quality even though there's no maybe industry standard certificate, most suppliers will state whether the product is sterile or whether they follow the ISO standard. And in addition to this, you should request from your individual suppliers A sterilization validation report that would substantiate how they set that minimum sterilizing dose. There's also a dose mapping study this for cobalt is done. You know this is revisited every time there is a change out in the cobalt pencils at at the commercial sterilizer you can request the certificate of a radiation from your supplier. And this is good because this actually lists what technology was used, right? Right. Whether it was X-ray, E beam or gamma irradiation and it tells you the exact dose that that particular assembly received. These documents are very important to have because it is possible, for example, if you are audited by regulators for them to say, OK, company XY and Z. You purchased this assembly and it's received sterile. Where is your due diligence, you know, Do you know what your supplier does? Where, where is this information? And so again asking for quarterly dose audits, ensuring that you're getting certificates of irradiation at with with the certificate of quality, the periodic dose mapping studies, all of this is good information to have readily available at the plant. So now we have something again for you. Do you require certificates of irradiation with each assembly? Yes, yes for some applications or no. So we give you another few seconds to answer the question if you want. All. Right. Thank you very much. That looks very interesting and I hand back. Thank you. All right, so now we've gotten our assembly through sterilization and now we want to ensure that this assembly arrives at your facility in the same state that it left our facility. So what does that entail? Most suppliers, you know, they do some bracketing. They defined a a worst case representative assembly or or nowadays it it would be multiple representative assemblies and so then that would undergo some ista testing. Traditionally it was 2A. Now we're doing more of that, the 3A3B type of testing. So one of the things that is recommended for example for end users to ask your suppliers for support or supporting document or a report with the packaging and transport validation in addition to having that report, the other thing that's very important to have is to please Mr. Supplier. Can you give me a letter that says how my assembly A is represented in the assembly that is that was tested in the report provided because that could be another question that may be raised during an audit. And again, it's all this due diligence. So, so these we manufacture these representative assemblies they're manufactured package vacuum you know undergoes the regular process and some of the testing that has been done in the past is like a static compression test, vibration tests impact these drop tests, all these ISTA we call them like the ISTA two or three type tests in order to meet those requirements they actually perform tests to ASTM standards. And and this and this is the one area where I would say it's probably more standardized than the other areas of single use qualification. After the testing is complete, what is generally done is for example the assembly would be sent for a bubble emission test and this is to make sure that that that seal the packaging is still integral right? Because we know if the packaging is not integral then that means you're the sterility of what's inside has been compromised and we definitely don't want that. And then there may be depending on the type of representative assembly, there may be some functional tests that are that are done post the ISTA testing for you know for filters it could be integrity testing for the assemblies, it could be that standard pressure decay. In some cases we may also perform maybe some of the lot release testing post the the ISTA tests point of use testing. In my experience, there's usually 2 camps for this, right? There's those customers that say, you know what, Monica, I'm purchasing from my Tier 1 supplier. I have the packaging validation, the transport validation that proves that that assembly got to my facility in one piece. I don't want to do additional manipulation of that and perhaps, you know, damage my assembly with the additional handling or heavens forbid you know, compromise the sterility. So I I I'm not going to do point of use testing and and that's fine. And then there's others that say, you know what, I'm going to do my due diligence and even though I have all this information from my supplier based on my risk assessment, for certain applications I am going to perform a pre use test. Again, this is totally based on on your risk assessment, but it's something that you know whether you're doing it or not. It it you should have this documented right? How? How did you come to the conclusion of whether you wanted to do the test or not do the test? And the last part is operator handling and training, right? We want to make sure for example your incoming receipt and inspection procedures sort of match our release procedures so that we are on the same page with regards to visual acceptance. And you know your suppliers are the experts in their specific products. So most suppliers have programs where they are happy to come in and train your operators on how to use their their products and there's also a bio forum best practices tool kit that is pretty industry standard and can be very useful for operator training. So really, it's all about making sure that we're securing the integrity of that assembly all the way through before you use it, right? And everything from the types of shelvings that you're using to you know how you're stacking these boxes in your warehouse, you know what type of carts you're using, you know how you're installing it in the hardware. All of this is is critical. I'll just pop in here because I don't see Monica talking, but I'm just a an. Important to make sure on mute, I'm sorry I was on mute. I said this, it's a true partnership, right? Your, your suppliers are happy to provide pictures to provide you know aids anything that can ensure that you adopt and adapt the these best practices recommendations and that they're reflected in your respective. SO PS most of your suppliers and also in the bio forum training guide you'll also find film observations, right. So and these are the proper terms with pictures. What this helps is to ensure that we are all speaking the same language and describing what we see in the same way. So that that's a great start right to to make sure we're aligned and how we're describing defects when we do see them and and to also determine which of these observations are cosmetic versus those that may be of more impact. I'm going to hand over to Jessica. So this is the journey that we just went on. Again, this is a partnership. Your suppliers are here to help you, to assist you. And again, not every assembly used requires the same level of certification, the same level of testing. So it's really all based on risk assessment. Thanks Monica. And just to a different way to to view that is really around the component qualification validation of the product to the manufacturing and assembly and quality assurance. So the next chapter here is really now that you've seen all of the data that we have done as a supplier, also what you need as as a manufacturer to be able to qualify your systems and and how we can support that. So working through the the documentation piece through the improve program is really here to support your qualification, your risk assessment and ultimately to save you time. In general, we have the Canadian access to the information and it covers a wide portfolio that our company has. I do split this into to two different groups. So, so we've talked a lot about single use today, but it's also including our chemicals portfolio. So, so covering those APIs as well as any of the excipients and all the way down to just the buffer applications. Those chemicals are covered under the improved program along with our single use components, filters, connectors, film, so a wide range of products to make sure that you have all the information you need to qualify them. This is a ton of information. The dossiers, as I'll show in the next slide, is really a culmination of all of the behind the scenes work that we've done to ensure that you have the information. So using the resources internally, those are coming from our testing areas, our quality areas and being able to use those validated content and putting them into a dossier format for your review and an ultimate use. Here's the dossier structure that we have. So talking about all about the product. So in choosing your your different components for so for example a film or connector, making sure that all of those requirements for that particular material is satisfied, all of that information will be covered under the Material Qualification Dossier. US as a supplier and where the the materials are being manufactured is covered under the Quality management dossier. This also includes and I'll show you a little bit later around shelf life and and in addition the radiation and validations that were also discussed by Monica. And then finally, moving more into the patient safety aspect is the operational excellence dossier. In general, the three dossier approach works great for our standalone products. We do also have new offerings that I'll discuss a little bit around the assembly as a whole. So what is the information you need to qualify your custom assembly and that will be covered under the Advanced Qualification Dossier. In addition, we know that components, whether there are components or or components from our suppliers, you may need that information as well and we do cover that under our component extractable reports as well. So let's take a deep dive now into the actual dossier content. So as I mentioned with the material Qualification Dossier, this is all about the product itself. So what are the test specifications, the release criteria, the regulatory information for those particular components. So starting with the general information, So it's all about that product. At the end of that, you'll have the specifications, which starts going into what tests were performed. This leads into those, those specific summaries. So how did we qualify component material toxicity, for example, what is the acceptance or the data for TOC if we're talking about filters and then regulatory statements. So what are the materials that are used to manufacture these components? Is there any animal origin? Is there BPA for example? All of those statements are included in the regulatory section as well. Now going into the quality management dossier. So as we we've heard here radiation is, is really important making sure that you understand about how us as a supplier validate that we do have that that criteria and how our radiation program is running. That's all in that section. In the quality management dossier, there's also examples of the certificate of a radiation. This is batch specific. So as you get your your actual materials in and by batch you're able then to obtain the actual certificate of a radiation and then also in addition the packaging test and results. So this is going through all of those different validation studies that we've done to qualify the packaging in the also in the the QMD of the quality management dossier is around shelf life testing. And what's important here is that there's no specific standards that are that are required by suppliers to report this information. But we do have that information in our quality management dossier and is here for your review and to to satisfy your requirements that your internal requirements on that. Now I'll actually move it into a little bit more around extractables. So Monica mentioned a little bit around USP 661 being sunsetted and the emergence of USP 665. This was finalized in November of 2021 and we know that it will be effective coming in May of 2026. But it has been probably over the last decade that we've seen the emergence of Epog initially or bio form group extractables program along with USP 665 just a little bit on extractables and leechable some sometimes you hear the term used interchangeably but extractables is really the materials that are being migrated or removed from the plastic in worst case conditions. So this is done with worst case solvents as well as the worst case irradiation or sterilization along with temperature and duration. What we do see here and this is a broad range, right, So you can get a number of different extractables from these different conditions, but what is actually related to your actual process. So taking that broad range of data and understanding what is the potential leechables or sometimes referred to as process specific extractables. So a lot of times we hear potential leachables. It doesn't necessarily mean a leachable study was performed, but what have you evaluated based off of the broad range of the actual potential of it getting into your drug product. And then leachables is the actual real drug product under realistic conditions from a testing perspective. So us as a supplier from a general data set, we would always be performing extractables and then based off of your risk assessment is evaluation of the Leech bulls a little bit more. So I've already mentioned that the USP 665 you see the, the, the title here around plastic components used in the manufacturing of drug product. So this is really the first chapter that is associated with single use manufacturing. There are a number of others around container closure for example, but this is really the first chapter that we've seen globally that is really related to that in process systems. So the goal of it here is making sure that the materials are appropriate for its intended use, understanding that not everything will be in scope. So there's the an initial determination of that initial risk assessment and then classifying the product contact components. So it's important, right, not all components for the product contact that goes to the patient has a a level of risk associated with that, so a low, medium or high risk and the protocol demonstrates that extraction protocol in comparison to the risk. If you have not checked out USB 16161665 is the companion document associated with that and that also helps with the risk assessment and some additional information around the analytical methods as well. So we've talked about what are extractables. We know that 665 has that initial risk assessment of classifying below medium and high risk. So this is just a nice way to show kind of the process that would need to be done. So you have your initial assessment of what are the components used in the manufacturing process. You have to determine your own assessment, your risk assessment. There are the bio form Leachable's risk assessment which is a really good one along with the risk assessment in 1665 S essentially establishing your risk assessment and performing that for each of those. Those components, the ones that are more in the medium and high risk are requiring organic extractables testing. And so really the next step is to collect that data and then interpret it, how do we interpret it. So potentially scaling it to the particular device that you're using and then understanding the manufacturing process and interpreting it to how it's used in your manufacturing process. So down essentially to the patient dose level. The risk mitigation here really starts with if there is a level of concern. So you've established the dose and you've compared it to the patient safety or using a patient safety evaluation, so determining the permissible daily exposure limit for those particular chemicals for example. If there is a concern, there is that evaluation step and potentially a risk mitigation. So if there's no risk, then and you can for the most part stop at the extractables. But if there is a level of concern then performing a leechables test or other risk mitigation may be required to be able to to demonstrate patient safety. So I've talked about USP 665, I've mentioned Bioform and the what's interesting is 665 does discuss the actual solvents and Bioform also does as well too. So Bioform did initially start. This is as you see on the left hand side is an updated test requirements established in April is the last April of 2020 and you do see some slight differences here in USP and Bio Forum. So for our company and for for our approach, we are typically performing a test strategy that covers both and in general this does include the the 50% ethanol which is is equivalent for both an acid stream and again the equivalency is is assumed for the phosphoric acid and the KCL PH3 established by USP. But the basic solution is either a .5 normal sodium hydroxide for biophorum but it's not considered equivalent for for USP 665 S with the phosphate buffer PH10 and then to round out the 5th solvent is water for injection. So you do see some slight nuances, but our goal is to be able to test all of them and to have that available. I think one thing to note is the phosphate buffer PH10 was added later. So you'll see I think throughout suppliers data some with and without that phosphate buffer PH10 for some of our other components like component extractable reports and for chromatography resins. We've also adopted the USP 6665 for that testing strategy. And I think that leads us to our last poll question. Yes, what materials do you evaluate for extractables? So select all that, apply a final filters, BS derived connectors and back foams, C tubing, all single use components and filters. And yeah the last one, not sure. So looking forward for your submissions seconds. All right. Thank you very much. I think that looks interesting and I will hand over to Jessica. So I think as the poll question kind of alludes to is, I would say prior to 665 is you may have done testing on just the large surface area components. So whether that's the filter, the film and potentially the tubing. In some cases you may have done the connectors as well. But with coming up with 665, it's really the question around evaluating all components and this can be quite cumbersome. So depending on your assembly, you may have multiple components, some may be product contact, some may not be. And being able to get really that deep dive into your assembly and not just providing the extractables data, but also all of that other information for your custom assembly. And so our goal through this Advanced Qualification Dossier is really to combine all of that information into one place for your specific assembly assembly. So this does include the bill of materials and and the drill down which I'll show in a couple slides, as well as the regulatory statements, original manufacturer information, shelf life statements and also your approved drawing. So which version of your approved drawing that this covers? Just quickly going through the the specific sections, very similar. You'll see a combination of a lot of stuff already in the Material Qualification Dossier. So you have your general information, but that component information really is a is a new section here also includes your product contact. So whether it is product contact or not, the surface area supplier information and which extractable reports are covered under which components, which is also included further in the sections as well. So here's just an example of that drill down of the bill of materials and and when you're evaluating an assembly, it's important to understand that some of your line items for example may actually be sub assemblies. So this is an example here on the left hand side. That first line is a bag Pureflex mixer and that actually leads into on the right hand side in our components a drill down of that mixer into its each individual components. So going from that sub assembly to the raw material and then providing information for each of those materials. So as a product contact, what's the material of construction, how does it then relate to that extractables and patient safety at the end. So really the ultimate goal here is to hope to be able to provide that information easily and to help streamline your approval process for your assembly. So in conclusion here really the ultimate goal here is that as we start through your process, the supplier selection. So if you're coming to us initially, what is important for you and really is to start with that quality management dossier to understand how we as a supplier work, what are our validations to make sure that we irradiate it correctly, that we have the validation of the packaging and and it gets to you as intended then leading to the material and component selection. So if you're choosing which filter is most appropriate or which film is most appropriate, you can consult those individual dossiers if there's a a particular question. But ultimately, once you've approved that drawing, to be able to have the Advanced Qualification Dossier that has all of the information that you would need to qualify it and from a patient safety perspective. And with that, I'll hand it back over to Saskia. And thank you very much for your time. Thank you. Yeah, thank you, Monica and Jessica for this great presentation. Now it's time to answer a few questions that have come in from our audience. But before we do, I would like to remind you that it is not too late to send us your questions now using the QA widget. This also applies to on demand viewers. We will try to get through all of them, but if we if we run out of time and we will 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 is available for Fuel. Yeah. So now back to Monica and Jessica, who will start answering questions that have come in. Monica, did you want to start with a question or do you want me to go first? You go ahead, I. OK. So I will go ahead with a question and actually I'll summarize this question. So it was, it was a discussing essentially this customer was talking about having various products that were very similar to each other. So the active ingredient is negligible. So it's really around the buffer application and they're wondering how to perform essentially the E&L studies and specifically if leechables was required. So as I mentioned from a potential leechables perspective you may be able to do evaluation on essentially the USP 665 model solvents if you did want to go into because of risk eligible set but not wanting to use that actual radioactive ingredient for example on many cases we could also do a simulated reachable so. So potentially having a A bracketed worst case buffer application to be able to satisfy all of your of your different formulations if they're they're similar to each other so maybe slightly worse case but you can take a general representative representative of that and I have another question here. So qualification of single use systems is included in e-mail studies that is largely provided for your main products. But how do we get global approach including other components that are non, non our company's components. So essentially for for us and and we recognize that this is difficult in some cases because we don't manufacture every single component that is in our assemblies. And so we have and through our component extractable reports have been able to provide many of the components that that we do not manufacture. There is some of the manufacturers though that do have extractables data also available and I think we do recognize this as well along in our AQD. So if that is available, then obviously getting that direct from the suppliers can also be useful as well too. Monica, do you want to take one? Sure, I'll take some the best approach for qualification of X-ray irradiated materials. There's a lot of information in the public domain for that. I would say the best approach is I would start off by looking at the BPSA papers that were written and this was basically with end users and suppliers and it looked at what a minimal viable qualification package would look like. Other tools that are available are the Bio Forum X-ray Risk assessment also has a decision trade that can also help with that qualification. For most components in your assembly, your supplier has performed testing. So I would really start off with your suppliers data to feed your risk assessment and then determine what that gap is. Another question here is on the relationship between USP 878861661 and 665. S 665, as it has been released in November does not include Biocompatibility component, so neither 87 nor 88 is listed. For the original 661, there wasn't any, at least for the four physiochemical tests that are performed. They didn't include 87 or 88661.1 and 661.2 do have a recommendation, but it it starts off with test 87 and then depending on those results you can move on to 88. Differences between 87 and 88, right? 87 is mostly in vitro testing, right? You can have cytotoxicity etcetera 88, even though it has six classes. Traditionally people went for the worst case test, which was class six. That includes sacrificing about 40 mice and 10 rabbits and it's really only meant for implantable medical devices. I can tell you that 87 and 88 are currently under revision by USP and that there is discussions about adding more in vitro testing options 287 and perhaps you know removing the classic current classifications from 88 to be replaced like for the worst case testing with a a pharmaceutical grade classification. But in the end, right, if we really look at this from the perspective of chemical characterization of our single use components, biological reactivity, you know, can be fulfilled with either one of these because in reality neither were meant for single use assemblies to begin with. Go ahead. Do you want to take one, Jess? Yep, Yep. I actually have two that I'll do 2 quick ones here. So is there any nitrosamine risk for single use products? And so in general, we do have a nitrosamine risk statement that's also included. Sorry, I didn't put it on the the full list there. And in general there's there's not really too much risk associated with nitrosamines related to to the single use manual manufacturing and and we have that information available. This is I think more of a we do see this quite a bit from a chemicals perspective with nitrosamines as well as the nitrosamine precursors of nitrite some. So I think maybe more to come on on that information around the chemical side. And then I also have a question here if I can still find it here. There's a number of questions. So we we promise we will we will get back to you on on all of them for that. I guess I I missed that question. So give me one second, Monica. If you have another one, I can can find the other one I. Was I have a question here on single use assemblies that have been qualified and specifically with respects to integrity, is there an option to have additional integrity test qualifications for an older product? I would say yes right? It's really about contacting your your, your supplier, reviewing your drawing rate, your existing drawing, and seeing that you know in its current design space what additional testing can be provided. You know does that assembly fake fit into AB, helium, integrity testing or restraint plate testing. But it it's it's possible to it's worth a review to see if if it does fit into the the criteria right of of the other more sensitive tests, and also if it is a critical application where you've deemed to be a risk assessment that you need additional higher sensitivity testing. It may require you know, redesign of the assembly unfortunately, but yes it it can't be done. Another question I have here is on shelf life, which is a topic that is deer and close to my heart. So again shelf life. There is no industry standard on on shelf life. So for example most suppliers will provide either a two or three-year shelf life. How? What data the respective suppliers provide to support that shelf life is different supplier to supplier. So that's the first thing I want to say. The second thing is yes, everybody is asking for extended shelf lives. The issue becomes do we think in my experience most suppliers are not testing for shelf life, We don't test to failure, right. So when we say here's a two year shelf life or here's a three-year shelf life, it means we have either accelerated or real time data for whatever data set based on our internal risk assessment we deemed necessary to provide to support that shelf life. But if we don't have data beyond that, then it's really about using that existing data to feed your risk assessment to help you extend the life of the existing shelf life. So it's it's not so straightforward, but the answer is yes, definitely get lots of requests for that. Perfect. And I think I'll end with this last one here. And I and I know we have more, so maybe Saskia can mention that, but does extractables and leachables need to be explored or evaluated for single use glass or metal items? And so the answer for that is, is at this point no. The extractables and leachables is primarily for polymeric materials. You can also have you know, I think different let's say non glass or metal items that may be included, but at this point there's no no chapter for that specifically. All right. Thank you very much for all the questions you handed in. If we did not get to your question, yeah, please feel free to e-mail our presenter directly. And I would like to thank Monica and Jessica again for today's presentation. And thank you also to our audience for joining us. And yeah, have a great day. _1732520568455

       

   

       

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