Hi everyone, and welcome. My name is Saska Kisa and I will serve as your moderator today. Thank you for joining us for today's webinar, Evaluating these P665 for Extractables Testing and Reducing Animal Testing for Biological Reactivity. As your moderator, it is my role to ensure that we make the most of your time with us. I am here today with Jessica Shea and Katarina Chrisley. Jessica Shea is the improved Program Manager responsible for filters, single use and chromatography arrest and portfolios within our company and previously she was responsible for extractables and leachables global support for the Fire Reliance validation services. She has more than 15 years of extractables and eachables experience, including method validation, designing of custom testing and interpreting, industry and regulatory guidance, and Jessica has a Bachelor of Science and Biochemistry and a Master of Business Administration. Caterina Kristlib is a Senior Marketing Operation Manager responsible for Senior Use Filtration and Chromatography, product Change, Communication and strategy at Damster, Germany. She has worked in Life sciences for over 16 years, having a broad experience in quality management systems including GMP, ISO 9001, 2015, risk analysis and continuous process improvements as well as quality. Control and API Excipient production Katarina has a diploma and chemistry from Ludwig Maximedians University Munich and at pH. D in Biochemistry with focus on protein characterization using attima technology from the Rhinochef, British Wilhelms University in the Bond. And 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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If you're watching this webinar on demand, you can still submit Paul responses and questions via the Q&A widget and 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 volumes 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 poor questions within the duration of this webinar. So that's it from my side. And it's my pleasure to turn things over to Jessica and Katerina. Thanks. Ask you. So stated I'm Jessica Shea, and I'll stop you through the first part of the presentation. So the first part will be around USB665 and we'll go through three different topics here. So an introduction to extractables. And what USB 665 is working through, then the level of risk and establishing the risk assessment and then finally obtaining USB665 data. So let's first start with the definition of extractables as well as leachables. Sometimes they're used interchangeably, but there are some different definitions. So extractables is really the worst case conditions related to components that are migrating from plastics into the process stream. For extractables this is done with model solvents under worst case conditions like higher temp sterilization cycle for example. Now moving to potentially leachables, you have this worst case, So what is the actual potential based off of your process conditions? So that is a smaller subset of those extractables to be able to to be able to do the potential leachables and then finally the actual leachables is done in real drug product and under real process conditions. So what is USP 665? So there are a number of other chapters related to extractables, but this is really the first chapter that is related to plastic components and systems used in the manufacturing process of pharmaceutical drug products. So the others are really related to maybe container closure or primary packaging, but this is really the first one that is related to the actual manufacturing equipment, for example, single use systems. That is important because I think in general this is considered to be a broader use for, for the, for everything, for the, for globally. So starting with it is effective in May of 2026. The actual final chapter was done in November of 2021. And the as you see the the different processes, the goal is really to establish the chemical suitability establishing the risk characterization. So starting with the initial risk assessment and then determining the different levels of risk after the risk assessment. So whether it is low, medium or high risk, it does go through the standard extractables protocol. So how to do the extraction and time points? And then in addition, there is also an information chapter, so USB 1665, which is its companion document that also provides additional information including an appendix, risk assessment as well. So what is in scope, so we already mentioned, right, it's related to the manufacturing systems. And it does cover all manufactured drug products as well as drug substances. So these are small molecule biologics or large molecule. It is both single use and multi use system. So for single use obviously primarily plastics but also multi use thinking about filters for example, so you have a plastic filter in a stainless steel housing, so those plastic components are also included in in the scope of. 665 and you can see a list of them at the bottom as well. I think the important part here is the processes are involving liquids or semi solids and not necessarily powders for example. So what is out of scope the actual active pharmaceutical ingredients, so those those materials like you you see pictures on the right hand side and those are essentially because those are the purified substances and actually going into the process stream. So, so different standards that for those. Also auxiliary items, so something that is used to transfer ingredients, Something with a relative short contact time would also be excluded from from the scope of 665. In addition, the non product contact materials are also excluded. So the goal of 665 is really around patient safety. So evaluating what compounds could potentially be in your drug product and so therefore non product contact materials are really out of scope of 665. So that's your non fluid contact, your sampling for example like Nova septum as well as hydrophobic filters. In addition, at the bottom you also have diaphragm gaskets and O rings. Constructive rubber based elastic materials are also out of scope of this specific chapter and now at least our first full question. No, we want to know, is your company already evaluating USP665 compliant data? So yes, USP 665 compliant data is required. Yes, USP 665 compliant data is preferred but not required. No, but plan to in the next 1-2 years or not. Currently interested in learning more so we give you another few seconds to participate in the poor questions. So thank you very much for your participation. And now I hand back to Jessica. Thanks asking definitely a lot of interest in the in 665 especially related to extractables. So now let's continue on with establishing the level of risk. So as I briefly mentioned, we already have essentially the initial risk assessment as well as establishing the risk. So based off of those two is really the first part here of evaluating all of the ENL evaluation is that initial assessment. So understanding what your level of risk is for those particular components and establishing whether you need data to then evaluate for patient safety. If you do need to evaluate data, then it's really collecting that data from different suppliers. To be able to to calculate and then interpret that data into your manufacturing process. So based off of the components identified the quantitation you then lead to calculating what could potentially be there in the patient dose and that's in the evaluation and mitigate phase. So if there is considered a risk of because of the worst case extractables, then a potential mitigation can be performed either by doing a leachable study or potentially a flush study or a change in the process. So just going a little deeper in that first initial assessment, as we mentioned already for some of the out of scope, it actually now just goes into a slightly different table. So going through the process, is the component isolated from the process stream. So if it is isolated means there's no product contact, so then the component is out of scope and no testing is required. Is the component in contact with a liquid or semi solid process stream? So as I mentioned if it is a powder for example that would be out of scope. So if it is a liquid then we know that it is in scope. Finally there is the possibility of having a comparator component. So has equivalents with a comparator component or system been established? So this is intended for for your companies who have similar processes. So maybe you have a set of skids to be able to manufacture a drug product and now you are changing the the drug product slightly, but the the actual system itself and all of the background work is essentially the same. So if it is considered equivalent or a comparator then the assessment is already complete. And then you don't need to do additional component testing as well. So after that, so if there's no comparator, then proceeding with the risk assessment. So with the risk assessment, we have three different levels that have to be determined within. So it is your responsibility to determine the risk level based off of risk assessment. USP 665 does not state that you have to use a specific risk assessment, but only that your risk assessment has a low, medium or high risk classification. So with the low risk is really basic testing to get an idea of the total amount of extractables. So. So looking at the MBR results and the UV absorbents with the 50% ethanol which is your C1 solution. Now moderate and high are really I would say more similar because it starts to get into the higher risk level and requiring organic extractables profiling. So this is actually determining the components in or the compounds and the quantity within that could potentially be in your product solution. So for moderate risk it is just one model solvent stream which is the 50% ethanol and then for high risk it is 3 model solvents adding in the high and the low pH. So as I mentioned, it doesn't specifically state which risk assessment to use, but there are two common ones that will go through here, the first being the one from Bioform or the Bioform Leachables risk assessment. As well as the USP Risk Assessment which is in the appendix of USP chapter 1665. So what are the differences between the two or what are similar between the two? Let's start there first. So in general they both look at the process streams and are looking at the chemical composition. I'll start on the left hand side of the process stream. This is actually equivalent to the process fluid interaction on the bio form Leachables risk assessment. Temperature and duration are also consistent between the two risk assessments as well. What is different on on the left hand side or with 1665, it does include the nature of components, materials of construction. So this is related to questions related to the additives that are in the plastics, but also more importantly if the component itself is sterilized. So whether that's gamma or X-ray sterilized. Or autoclave for example. Those would be actually classified as a higher risk. So you may have the question of of do you have additives. But overall the question would be, I would start with is, is it sterilized or not. On the bio form, you have at the top the distance along the process stream. So this is really starting to get into where in the process or the manufacturing process is this component and that really directly relates to the ability for it to actually be in the drug product itself. And then finally the dilution ratio. So this is adding the fact that some components are smaller and larger and that surface area to process liquid volume ratio is important. So if you have a small component with a large amount of extractables, even though it's a large amount that component, that surface area is so low in comparison to the the actual fluid volume. I think one other important note here is for 1665 that distance along the process stream is recognized as a mitigating factor. So you have a clearance step as well as clinical use mitigating factors that actually can lower your risk. So if you have a clearance step for example, it can go from a high risk to a medium risk as well as depending on the usage. So for example if it's used less than I think. Seven days or if it the dosage is less than 10 mils, then you can also reduce your mitigation factor just a little bit more on the clearance portion. You have essentially A monoclotal antibiotic manufacturing example here. What we're talking about specifically with clearance would be the ability to remove those extractables and it's demonstrated very well that the ultra filtration, dye filtration steps are really good at that. Clearance or mitigation factor. So the highest risk is really the final fill formulation, sterile filtration and final fill and then prior to UFDF is really that lower risk based off of the ability for clearance. So whether it's the distance along the process stream or the actual clearance in in USB1665. So now just a quick example here and I do have another webinar that does go through this a little bit more in depth if you are interested. But just taking a quick example here of a typical injectable application, we're talking specifically about a viral clearance step. So prior to the UFDF step, the drug product contains some organic ingredients including sugars and and API's and Poly survey Ed as a surfactant and then we have. A short contact time of eight hours and a filtration temperature of 25 degrees C So just based off of that, this is just showing you the leachables risk assessment on the left hand side and it does have ratings of four different options for each different consideration. So because this was prior to TFF and in a viral filtration you have it as a purification step, the exposure temperature is room. A room temper around 25 degrees shortterm duration, the medium salvation power because it does contain some some surfactants, and then finally the dilution ratio, which I did calculate here but based off of essentially the surface area and batch size. So based off of those ratings, multiplying by the weight, you're able to get a risk for, which is essentially summed up and based off of those conditions, you have a risk level of a medium for this virus filtration. Now moving to USP 1665, we have again four different questions here and then some clearance steps. So for the process stream and somewhat organic based off of the different additives because of the the multiple ingredients. So we have it as a medium risk. The material of construction is considered reactive or in that Level 3 category, primarily because of the sterilization. So it can be autoclave for example, and then finally with the temperature and duration you have essentially a level 2 and then a level one for the duration of less than 24 hours. So the scoring is based off of a table. Essentially if you have I think 2 threes within your risk score, it would be at a higher risk. And then for a three to two or below it tends to be a medium risk. But that is referenced again directly in 1665. So based off of A3221 score it is a risk level medium. And then with a mitigation factor, because this is prior to the UFDF step, you have a risk level of low. So it's important to note here is that the two risk profiles have resulted in different scores and that is fine. As long as you're consistent and you have a consistent approach within your risk assessment, there could be varying differences between the two. And now I lead to the last section of obtaining the USP665 data. So we've done our risk assessments. We know if for those that are medium and high risk that we need essentially extractable data with identification of the compounds and quantitation. So starting with our different products that we have with our company, we have many of them covered under the improved program and primarily the ones that you see on the bottom for single use filtration as well as chromatography resins. So these are covered under the improved program and have USB665 data available. So what does that testing include? So not only does it include the USP 665 results, but for any of our components, we also have incorporated the bio form requirements which really did come out first. So we actually started with Bio Forum and as USP 665 has been finalized or in multiple revisions, we have included both approaches in in our offerings for consumables. So that does include a total of five model solvents if applicable. So we have the 50% ethanol, which is the key one for USP 665, the high and low pH water for injection. And then what you see here is actually two different high phs or two different sorry basic solutions, one being the phosphate buffer PH10 as well as the .5 normal sodium hydroxide. And this is really related to USP thinking that the .5 normal sodium hydroxide used in the bioform can be to worst case for a typical process and it is actually in some cases not compatible. So we will perform the .5 normal if it makes. Makes sense for that particular material of construction. Finally with some of our other components, so for example chromatography resins which are not directly related to USB6S5 but just have product contact. We are doing high risk testing as well as any other third party or secondary supplier component for the data that we do have available. Other important note is we do have different time points, one to three depending for the bio form and USP 665 is always a subset of one of those components, so they do well together quite nicely. Just an example of those time points. So one day, seven days and 21 days. So again this is coming directly out of USB665. So that just shows you depending on the use the there is a predefined what is expected for that duration. And then in addition for for Bioform sometimes A7 day, 21 day or even a 70 day is added depending on the use. How do we get the data? The data is through our improve suite or and you can also go to improvesweet.com to be able to sign up and be able to look at the data available. We not only do USB665 data, but any technical, regulatory and supply information is also available actually free through our suite through the material qualification dossiers and quality management dossiers. And then through a sweet subscription, we have the ability to offer for operational excellence dossiers, which is really our USP 665 data. And then more newly launching is our Advanced Qualification Dossier, which is specific for single use assemblies and custom single use assemblies. And then in addition, those thirdparty component reports are actually included in the Advanced Qualification Dossier or the data associated with that as well. So how does that work for the Advanced Qualification Dossier? So it's essentially taking your assembly and developing a really it's first of its kind for to support the custom and configurable assemblies that you have. It includes the component qualification, the drill down of those particular components, as well as the extractables information for each of those components along with its surface area. It is available individually as well as through a Platinum subscription, and we're happy to say that we're able to provide updates for any changes to your assemblies that are are done through change control or offering ones if you do have a revision change as well. Just to give you a quick example of what it would look like for component information, and this is I think really key to your drill down when you're looking at USP 665 because it's really intended for the actual components themselves. So for example, you have the first one here which is essentially our pure Flex Mixer bag. But what's important to note that there are multiple components within that sub assembly. And So what we do is actually take that, drill it down and be able to. Provide the surface area, materials of construction, supplier information that are associated with all of the components within your assembly as well as the sub assemblies. So hopefully that provides you some some understanding of of the I think importance that you can do to be able to really streamline your approach of of your 665 and your component evaluation for your assemblies. And then finally, I'll end here with a summary. So as mentioned USP 665 will be effective in May of 2026. It is expected to to be enforceable once the chapters do reference it. And because this is really the first and only chapter, we do expect this to to continue with compliance and we know we already have questions associated with that. In addition, the important part is to establish a risk assessment process for yourself. So potentially taking the the two that I showed here today and adapting that to suit your needs. Any U SP665 data is really available through our improved program covering those medium and high risk components. And then finally specifically for custom assemblies, we have an offering of our Advanced Qualification Dossier. And with that, I'll hand it over to Katarina. Thank you, Jessica. Thank you very much. Yeah. So hello and welcome to our webinar. So I'm going to guide you through the transition out of the bio reactivity in depot task USB 88. So what are the upcoming regulatory changes in the USP regarding bio reactivity in single use plastic assemblies, devices and filters? So to understand this topic a little bit more, I would like to give you today some historical background of the USP biological reactivity testing and the future approach. Further, I would like to explain what the biological reactivity tests are about in comparison. And last but not least, how we transitioned to the in vitro methods and our approach of risk assessment. Yeah, and before I start with my presentation. I have a question for you. So keep in mind as it will be answered during our webinar. So do you actually know how many animals have to be used for the USB88 bioreactivity test? So now it's time for poll question. Yeah. So we come to our second poll question, does your company have animal testing reduction targets? Yes. No or I don't know. So we will give you another few seconds for your participation in this poor question. So thank you very much for your answers. And now I hand back to Katerina. Yeah. So thank you. Very interesting. Yeah. So the USB 88. Biological reactivity testing actually started off in the 60s, so where the first discussions actually started on plastic used for storage of medication and their potential risk to patients and involvement to the tech and and this lets actually to the to the actual test which is used now. Later the classes 126 were were introduced based on the application of the plastic material and duration of exposures. Later in the 90s, for all 30 years ago the USB added the biological reactivity in vitro test, the 87 to the compendia and actually the USB 1031 for materials used in drug containers, medical devices and implants was established. To give guidance with a decision tree to choose the right task for the bio biological reactivity. So it's really important to know that both tasks in vivo and in vitro are meant to be applied for medical devices like breast and hip implants or storage containers to minimize patient risk in direct contact with the plastic device. So how did the filtration industry and later single use industry adopted these tests? So the lack of industry standards for material qualification of plastics used in bioprocessing manufacturing lead the biopharmaceutical industry to adopt the most stringent medical device standard for biological reactivity testing for these polymers. The intention was to minimize risk for patients to a level As for a medical device. As it was considered to be very safe, but this industry practice had leads to unnecessary excessive animal testing. But recognizing of this had led to a reconsideration of these tests in EU SP87 and 88. And as the awareness of the importance of sustainability and ethical standards had increased the last years USP has proactively initiated the current revision of the USP87 and 88. To better meet the animal welfare 3 R's guiding principle of refine, replace and reduce the use of animals in product in product testing and scientific research. So the USB photo approach is explained here actually in this slide and I would really like to guide you through as it is a little bit crowded here. So for the USB88IN vivo testing they are looking to remove the implantation tests and safety tests especially for components that are not implantable classification of plastics. Is this cues is discussed too to be deleted since the since the plastic material? Into since the sorry for that. So since the classification of the plastic material used Angel six classes was was no longer served in a purpose. In practice only Class 6 is utilized by vendors and end users. So the Class 6 classification will be replaced by the term pharmaceutical grade polymeric material utilizing the same test procedure As for Class 6 for plastics. And alistomatic material for packaging and delivery systems. So let's move to the in vitro testing. So for the USB87, there will be some changes to dividing the test into two into the cytotoxicity test and the genotoxicity test adding, adding. The NRU test align it with the ISO 1099 3-5, actually the international standard for industrocytoxicity and actually the Agar diffusion test will be deleted. So for the genotoxicity test it is completely new and will be uptaken to the USB 87. So for the USP 1031, they are going to refuse the chapter to provide more guidance on the overall process, the utilization of chemical characterization, definition of pharmaceutical grades and bioreactivity failures. The respective compendia are now closed through comments and we're actually waiting for the final versions. So to sum it up. Are we required to perform USP88 Class 6 testing to qualify our plastic and pulmon material for the bioprocessing industry? No, we are not. There's no regulation that requires single use components or filtration material to be classified as U SP88. This test is a legacy test adopted from the filtration industry and the in vivo test is a testing method. More valuable based on observing and qualitative and not very appropriate for the kind of products we are producing and using in this industry. So now I will move to the two bioreactivity tasks in comparison to understand a little bit more what we are debating on and why a change to an in vitro task is more appropriate for the bioprocessing industry. So yeah, let's talk about differences. In vivo versus in vitro. So in vivo means within the living. These tests are performed in a whole living Organism like a person, animal or a plant, as you can see this nice little Bunny here per USP 88 class 6. So remember my question from the beginning? Here's the answer. There is a need of 40 mice and six rabbit per test. Versus the in vitro test now the ISO 1099 3-5 or the USB 87, so in metro means in glass it is a cell based test and actually more appropriate for the bioprocessing industry and how the filtration products and the single use devices are used. So let's dive deeper. So what do these tests entail? So as you can see on this slide, the USB 87 has three tests. It's for the first, the direct contact, the second AGO overlay, and the third memolution For the USB 88, same three tasks. It's for one, the systemic injection, the intercutaneous and actually the implantation. And on the left side you have the ISO references for EU for the USB counterparts, yeah, So what actually have do you have to do for the USB 88? So for the systemic injection in intercutaneous you would take the extraction solvents indicated in the table here and do the extraction as shown and after that you would apply the extracts to the mouse or to the rabbit. So for the implantation test a strip of small sample is implanted under the skin of the rabbit or the mouse. So depending on the use of the medical device or the container you would do the one or the other test. But as these tests were adopted to the filtration and single use industry, we did it all just for risk mitigation purposes. Yes, so but how do you score actually these tests? So this table is showing you how the tests are being scored. So for a systemic injection test, basically all animals have to survive and in addition you are looking at the shape and the good health condition. Of the animals you look at the weights and then you would judge if the test was OK. So look for the intercutaneous and implantation test. You would look at the color of the skin if it is swollen, where you have implanted actually your material you would look for edema and capsule with it. Has to be mentioned here of course too that actually this test rarely fails. So for the in vitro test, there are also three tests to be chosen out of. So there's the direct contact tests in performed typically to evaluate medical devices, material or packaging sample pieces with flat surface in contact. In contrast, the elution test assess the BIOS tytoxity of liquid extracts from sample pieces. The extract conditions are the same as we have seen for the USP88. And the other diffusion test is bad for evaluating elastomer closures due to the utilization of agros layers for cytotoxicity testing. And as you can see in the table for the scoring, you are actually measuring either the zone or you're counting the defects or the death cells. So to sum it up, the cytotoxicity testing used to be 87 or the counterpart ISO 1099 3-5. Is a proven alternative to animal testing, so in vitro testing is more appropriate for assessing the risk of polymers using In the bioprocessing manufacturing, testing is actually done in mammalian cell lines, not in animals. Its results and its results are more objective and quantitative than animal testing, which involves A subjective rating of animal response to the plastic, as we have seen. So, OK, so we have heard so far the historical background of the use of the USB 88, the test procedures and their readout. And now I would like to focus on the transition. So they already mentioned in vitro test, which is more applicable from the results to the to our industry and how to make this change happen so. Overcoming the challenge. As you've heard, the in vitro test is already available for more than 30 years. Still, it seems to be a big challenge to change to change it to the more applicable test. Actually, it's been a journey to the top of the mountain, but now the time is right to change. As the USB and the FDA and the Mai have been focusing on reducing animal testing and improving animal welfare, if no regulatory burdens exist, it is considered inhuman to use animals for tests. So this was actually presented by our company at the Bioprocess Systemic Systems Alliance where all 66 member companies agreed to replace animal testing with in vitro test methods. And the outcome was sent in a letter to the use key principal scientifically as your Desmond Hunt. Further, the topic was picked up at the bioethic conferences and comments were made on the existing monographs through the Bio forum governance team stating that these tests are not required for characterization of filtration and signal views. So we have sponsored actually a Webina with Desmond Hunt from the USB where he endorsed a proposal of stating that for single use and filtration chemical characterization takes presidency over biological reactivity and that the new released USB665 is what we should do for material characterization, while earlier versions of the USB665 included biological reactivity testing. The final version does not include any references to bio reactivity and rather concentrates on chemical characterization. So coming from the USB animal testing to know bio reactivity testing, it's a little bit scary I think right and I think not the right step for the industry. So changing to a more appropriate in vitro test, we can give our customers a data set to work on and to do their risk assessments. So now, yeah, it's time to change, reduce, refine, replace and we have actually started to reduce, refine and replace animal testing in our company. So our chair Board and CEO Belangericho, they did it very well. Our company will lead the way in developing innovative alternatives to supersede all animal use across our life science, healthcare and electronic business. And we are not alone actually. So there is a Mercedes declaration on the worldwide implementation of high standards for animal housed and used internally and externally by the industry for scientific purposes. And actually there it was signs in September last year by us Novartis, no one, Ordis and Sanofi. And you see we are not alone going this path. So one term aspiration is really to replace all animal utilization with better and non animal alternatives. And actually as you can see here on the slides, we do have additional art, we do have responsibility. So that we have the responsibility and highest ethical and animal welfare standards to all animals in our reach and I think it's worth going this path. So moving forward, our company has started a change control procedure where we have performed risk assessments with this change and looking deeper into the following aspects and to plan out internal strategies and actions. So we were actually doing. Risk associated with customer acceptance of this change. We did look at the product claims impact on additional testing and completed on subcomponents our company's finished goods and also have to change of course internal procedures and further and I think this is very interesting also to you as the audience. We have done a regulatory assessment to estimate, estimate the patient risk on the elimination of the USP 88 plastics testing by utilizing our PN model, looking into the intent of use and material chemical assessment. And actually our conclusion is that the change from animal bioreactivity testing by USP 88 Classics to an in vitro testing method as detailed in the ISO 109935. All the USB design confirms that the risk to patients safety is neglectable. So our rationale is based actually on the following aspects. First, looking deeper into the regulations, as you have heard here, the USB 88 Class 6 and the ISO 1099 3-5 standards are for pharmaceutical, drug product, primary packaging, delivery systems and medical devices respectively and have never applied. To polymeric materials used for pharmaceutical and biopharmaceutical manufacturing. Second, the extent of chemical information characterization and testing that occurs mitigates the risk of toxic chemicals. And 3rd certain aspects of manufacturing process, controls and intended use further mitigate the risk. And finally, bioreactivity testing. Compatibility compart We compared the studies actually of selected materials and confirm equivalent results using both in vivo and in mutual methods. So this is an estimate was and has concluded that the risk of the change is neglectable and the new materials will be evaluate evaluated by the new. Or not very new by the ISO 109935 in vitro bio reactivity testing method and aligned with the USP and FDA initiative referenced here. Our company will remove animal testing and use only the in vitro methods for both filter and single use material plastic for qualification. So the current USP 88 plastics claims are still valid and exists. Until actually product change occurs. So now it's time for book question. So we come to our last one. Are you implementing the ISO One 0993-5 and or use P87 in your company? Yes, no or I need more information. So another few seconds for you to answer the poor question. And now we're coming to your answers. And yeah, I hand over again to Katerina. Thank you very much. Yeah. So what's new in a nutshell for our company? So start from this year for new products and development. Any qualification of raw materials or any products undergoing raw material changes will no longer have USP 88 Class 6 testing completed to demonstrate bio reactivity compliance. We have started to inform our customers end of last year and now and are now implementing the change to certificates of quality where we are going to state. The bio reactivity claim on on on the Certificates of Quality will reflect either the ISO 1099 3-5, all the USB87, or the USB88 Class 6 testing until all affected products have undergone a change. All USB 88 Class 6 claims are still valid until raw material change occurs and 3rd the Millipor Improved products. And the associated bioactivity data will be included in the revised material qualification disease, yes. And I'm at the end of my presentation. So thank you very much for listening. It was a pleasure to present this topic today to you. Thank you, Jessica and Katarina for this great presentation. And 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 Q&A, which is also this also applied to our demand viewers and we will try to get through all of them, but if we run out of time, 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 viewing. Yeah. Now back to Jessica and Katarina who was that answering questions that have come in. Perfect. Thanks asking. So I'll take the the first question that has come in. Will USP665 replace Vpug testing or use in conjunction with How will that be determined? So in general from because USB 665 is now essentially the, let's say under the regulatory umbrella, I think we'll see a lot of movement there to say USP 665 is a requirement. EPOG or Bio Forum testing was more as a guidance raise an industry guidance and was never actually a requirement. So in general though I'll talk about in summary what what our company is doing. So so essentially for all of our filtration and single use products, we are planning on doing both. The nice part is, is because USB 665 is essentially A subset of bio forum then we actually will be covering both sets of standards and also to be able to differentiate the products. As we move forward, I think for for some of the ones that are not necessarily in critical applications or maybe secondary supplier type components. So you may see more of the 665 because they're usually of a lower risk or in potentially a lower surface area. So that we may see that movement going away from B pug not necessary for essentially those other components. That answers that question. Maybe. Kasi, do you want to answer a question? Yeah, thank you very much. So let me go through the chat. So, yeah, so there's a question for me. So you state that USP 88 was adopted first by the filtration business is to USP 88 in vivo tasks required for filters. Yeah. And my answer is no. There's actually no requirement for the for the filters to be tested in in vivo methods. As I have stated before, so all the tests, EU SP88 as well as EU SP87 was meant for to be used for medical devices. It was actually adopted by the filtration and later on by the single use industry to minimize the risk actually for patients because. People thought if it's good enough for medical devices, it's also good enough for filtration and single use plastics used for the bio Pharmaceutical industry. So yeah, thanks. I'll take another one here. So please explain more on the approach of selecting A comparator from MOC perspective as not all manufacturers use the same additives or source resin and how to defend better. So thank you for that question. So when I guess I'll start with the comparator, right. So at the beginning of the presentation, I talked about the comparator which is more related to to as a customer and evaluating that particular component. That's already in a manufacturing process and now you're trying to do a new similar manufacturing process and trying to use that comparator perspective now when we're talking about the comparator from. Material construction perspective, it is different, right. So, so when we're performing or evaluating for example our component library, it is done on the resin source, right. So and as stated in the question, right, each resin has a different type of additive and those additives are very particular, right. They they help with the stability, they help with light or heat for example and so when we're testing. Those are some of the key extractables that are coming out. So, so we'll do it by a resin based approach. OK. So I take the next one if I may. So thank you very much. So my next question for the USB Ada transition is when will when will you change to the ISO 1099 3-5 in vitro testing? Yeah. So that's a good question. Thank you for that. Yeah, so for new materials in qualification for our library, we will conduct from this year on the ice two 1099 3-5 or the respective USP 87 in vitro test. So actually it will be then also indicated in a change. As a change notification to all customers that we have actually qualified a new material, tested it and inserted that also in the claims of specification of this products, the next way of here USP 1665. Has in scope API's formulated upstream processes with non biological or non biologic drug products, liquid semi solvents made in bulk be included and so. So the answer to that is yes there is definitely all of essentially the plastics used in the manufacturing process whether it is upstream or downstream are included in the risk assessment portion. I think what's important to point out, especially if you have a clearance or mitigation stuff, maybe not necessarily for for non biologics, but depending on where you are within the process you may not, you may potentially have a lower risk based off of that. But but both drug substance especially because it has potentially a long term storage at maybe if it's at room temperature I would say would be included in that risk assessment and and would want to calculate that for patient safety. We do have one here Kotti potentially free when will USP 88 be updated USP 88 be required testing and I'm guessing it's probably USP 87. So let me talk a little bit about our our change control process. Yes, so going forward will be required testing. Yeah. So it's, it's it's all that qualification of of our new raw materials when we will conduct actually the USP 87 and I'm not sure if the answer will actually hit what is questioned here. But there's another question about ISO 1099 3-5 or the USP87 interchargeable here, and I can tell here actually that both tasks are almost the same. The only difference between the the ISO 1099 3-5 and the USP87 is that in the one it's a typical testing and then the one triplical testing, so it's it's almost the same, right? Next question I have, if extractable study done by component supplier and certified, will it, would it be required again for a fresh study for the component to be used? So maybe I'll just summarize the question. So, so if an extractable study was already done by a supplier, would you have to to repeat the testing? And I think that is, you know, one of the main reasons why we have now USB 665 coming out so that we have a consistent testing approach with standards of conditions, so that repeat testing. Would not necessarily need to be done again. So I think when you're evaluating the studies, is it done under the USP 665, If for some reason it has a slight change in the conditions, do they justify those conditions and and does the actual testing make sense? If that is the case, then you don't need to repeat an extractable study. Maybe I'll go a little further with the question is if you do have. Done your patient safety evaluation and potentially there's demonstrated a risk because it is a worst case extractables. Maybe the the 50% ethanol resulted in a number of compounds at high concentration. Then it would be recommended to do either an aleachable study or potentially a simulated. A buffer study or something similar to your drug product, if you can't do drug product on to demonstrate patient safety. So extractables first evaluation, then leachables or some sort of mitigation study from that side. I think maybe that's all we have time for today, Saskia. So much everyone for joining this webinar. Thanks to Jessica. Thanks to Karti was a super interesting presentation. As mentioned you will receive a follow up e-mail and the webinar will be streamed on demand. So Please wait for for the e-mail to come in and look forward to our next webinars. _1732520225183

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