Biocomp Beyond the Basics ISO 10993

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Okay. Hello, everyone. Welcome to our webinar biocom beyond the basics, Iso 1 0, 9, 9, 3 key revisions. You need to know. I'm Sean Smith, publisher of Medtech, leading voice. Welcome everyone before we get started. There's just a few housekeeping notes that I'd like to go over shortly. We're gonna kick off a poll. Please respond to the polls so that we understand who you are, where you're coming from. It will help us frame the discussions better. Second of all, there's going to be a survey at the end of the call. Your feedback is greatly appreciated. We love that you're all here, and we'd love to know what you thought of today's presentation. We encourage you to use the chat and the Q. And a features vigorously throughout this

webinar to submit your questions to the speakers. We may not be able to get to all of them during the call itself, but we will try to follow up with everyone. And now I should be able to. So this is the agenda for today, and we'll come back to that in a minute. Right now. I'd just like to take a moment to welcome our expert panel. I'm super excited to have Dr. Damian Mattek, and I'm going to slaughter this name, Dr. Lucas Semanski, and as speakers they both have extensive extensive experience, so this is awesome to have them here. And then Michelle Lott, founder and principal consultant for Leanra Qa. And she's gonna say a word about herself and obviously me pleased to be here as usual.

I'm gonna go ahead and try to launch the 1st poll. Question in a second as soon as I figure that out. And in the meantime, why don't Dr. Damian and Lucas tell us a little bit about themselves while I'm figuring out how to launch the poll question.

Yeah, Sean, okay, so I'll try to help you to fill the pulse and so on. Welcome everyone. It's very, very good to be here. I'm really happy about that, and thank you for the invitation. As Sean said, my name is Dan Mattak, and I'm responsible for the European Bioamerican Institute that we are specialized in biocompatibility testing of medical devices while we are in the industry for for many, many years at the beginning we were kind of Research and Development Company that was focused on research and development of music, new medical devices. And in a time we change our business core to to be focused on the testing itself. So what we are doing right now, we do comprehensive biocompatibility and chemistry, testing of medical devices. And I'm responsible for taking care of the business of European Biomedical Institute. I'm also associated with some organizations that are focusing on the biocompatibility itself. So

I will be more than happy to share my knowledge about what's going on right now. And what is the future of biocompatibility? What are going to be some changes in the Iso standard? So glad to be here. Thank you.

Thank you.

Łukasz Szymański: Okay. Hi, everyone. I think Damon said a lot about what we do. I am, on the other hand, more focused on scientific part of this testing, and R. And DI serve as chief scientific officer in both Abi and Nabi. I have been helping our clients for a long time now with designing and introducing to market different types of medical devices. Łukasz Szymański: I also serve as a expert for different bodies like Iocd, Ame. Łukasz Szymański: and more local ones in Europe. Łukasz Szymański: and I will be happy to share what we know about Isonorms and biocompatibility.

Wonderful! And Michelle. Yep.

So I'm the principal and founder of lean Reqa. We specialize in helping startups and small to mid-sized companies bring their products to market from early in concept development all the way to commercialization and then support them in their quality management, system, and design changes as they go. And we do a lot of pre-submissions and submissions 5, 10 ks. And novos and biocompatibility is inevitably a sticking point. No matter if it's FDA or EU, so I'm I'm really excited to get this kind of dual perspective here from these guys.

That's fantastic. Violetta, would you like to introduce yourself? Since you're here.

Hi, everyone! I'm Valeta Castellan, and I am business developer at North American Biomedical Institute. So I am the person that if you will have any inquiries about the quote or any questions regarding the biocompatibility testing after the webinar. Please contact me. My details will be, I think I believe they will be on the last slide. so feel free to reach out. Thank you.

So the poll results sharing them here. I believe you can see them. So a few people are beginners. The most vast majority are intermediate. So 70% device manufacturers, a number of consultants and a few notified bodies, and mostly regulatory and quality, some R&D and some consultant advisors very in clinical. So that's it. Let's go ahead and get started. Who wants to start.

I'll get started. So you know, most of you guys who know me and have been on my webinars and and seen my website, you know. 2 things is that I love my dogs. And then the second thing is that I have this, what I call the joke about. I love the the emojis that come up in zoom from time to time. But that gets me to the party we're talking about today is the biocompatibility. And you guys have seen the that I make this joke about. Being a regulatory grief counselor. And if there is anything that I see, bring out all of the stages of grief from anger, denial, bargaining, and not not even all the time. We don't make it to acceptance

is biocompatibility. So if it was given you heartburn before. Just wait till you hear all the exciting changes that Lucas and Damian are going to tell you about. So chunk me.

So should I advance the slide.

Yes. while you are doing that, you know, we usually have people put in the chat where they're from, and that that will kind of help us kind of guide the conversation because we are going to be having this kind of EU versus Us. Discussion. So put that put put in the chat where you guys are logging in from.

Are you seeing the Iso? 19, 9, 3. Dash, one slide. Yep.

Łukasz Szymański: Yeah. Łukasz Szymański: okay.

So you know, we, we're going to touch on all of the parts of the 19, 3 series that that were impacted by the changes. We are going to focus, though, on part one for the general requirements. And then we're going to focus on the part 17 for the risk assessment and part 18 for chemical characterization, because those are going to have the biggest impacts on the device manufacturers where some of the others are going to be primarily impacting the labs so we can get started with the the general requirements and then be sure to put your your questions as we go and then we'll into the the Q. And a. I ideally, because that's easier for us to manage and then we'll try to answer, answer them as we go. But we'll start there with the

time at the end. So so guys tell us about this the changes to the general requirement section. That kind of is the umbrella over the whole 19, 9, 3 series and kind of sets the expectations, for you know the place to start, and then where to go from. There.

Okay. So maybe, Lucas, if you agree, I can start with that. Well, a new version of 1,901 is going to be changed a lot, let's say in my opinion, the 1st thing that is going to be changed is that the table? a 1 is going to be deleted, let's say probably there will be no table. a 1 inside the 19, 3 dash one standard the answer is, why? Because there's going to be, let's say, reclassification of medical devices externally communicating medical devices. Let's say I don't want to say that are going to be deleted from the from the table, but rather going to be renamed or reclassified. So we are going to have not only one table for the classification of medical devices. Instead of this, we are going to have a few tables.

probably 4. So this is, let's say, the main change that may have an impact on the on the biocompatibility itself. There are also some, in my opinion, minor changes like probably there is going to be less less less less force to the material mediated pyrogenicity. But we cannot forget about that. This is also very important. Still important endpoint to be evaluated for certain medical devices. There there is going to be more focus on the genotoxicity for the particular devices that are going to be classified, and, in my opinion, the most important thing that is going to be changed. There is that finally, biological evaluation report is going to be named

and described within 19, 3, 1, because currently, in the latest old version that is coming from 2018 is is a field only about biological evaluation plans or something that we have at the beginning.

Gave me sorry to interrupt you, but you know I I find that my clients don't even already understand the need for a a plan before they make their testing like all like, can you just speak quickly to a plan? What goes into it and why it's important to do it first, st and then talk about what needs to be in the report.

Yeah, of course. Thank you for that. Well, this is something that is mandatory for the European market. I mean, notified bodies are asking about that technical auditors are looking for that I was. I was participating in many audits with our customers that we are going to speak about the biocompatibilities. The 1st question of the auditor is, okay, guys, do you have biological evaluation plan? And if you have, please show me I need to check the number I need to check the the content and so on. So biological evaluation plan is kind of risk assessment of your medical device before we do any biocompatibility tests. So someone from someone with the experience, with the knowledge about the biocompatibility testing. And this, let's say, kind of external party of your company has to evaluate your medical device has to check it, and so on

and plan all the biocompatibility testing. So before any testing, you need to start with the biological evaluation plan. Within this plan we can check what kind of test can be waived on it? Or how can we handle the device? What methodologies should we choose, and so on. Because, for instance, for I don't know if you, if you I'm not sure if you know that. But, for instance, for the cytotoxicity testing. We have a lots of methods that can be used for the medical device testing and not every cytotoxicity method is applicable for every medical device. This is very important, and guys who who knows something about the biocompatibility, what should take care of it? So this is something that we start biological evaluation plan.

Okay. and just as we go we've had several interest of what is the anticipated release dates for these. So let's let's talk about that, you know.

Łukasz Szymański: And.

At the start of of these.

Łukasz Szymański: So the new 19, 9, 3, 1 was scheduled to be out this year, but obviously, as as always, with those regulatory bodies, it got a bit delayed. So right now it's scheduled, I would say. Second quarter of 2,025. Łukasz Szymański: Obviously the document needs to get all the votes from different countries, from different person meeting bodies, and after that it can be released. So that's the 1st thing. I also saw a couple of questions. Łukasz Szymański: if the Bp, and if the biological version report and Bra logical risk assessment are the same thing. Yes, they are for FDA. It's just named differently. But basically, basically, it's the same thing. It's a bit different when it comes to the construction of the document.

Łukasz Szymański: But At the end of the day it served the same purpose. So Diamond said the biology conversion report is the most important. And I think, yeah, it's it's very important from the Łukasz Szymański: from the point of view of someone that's filing the documents. But I would say that the groundbreaking change, that it's there, and that will like change all the scope of testing for for a lot of manufacturers Łukasz Szymański: is 1st of all, different calculation of cumulative contact. Łukasz Szymański: So basically, if you have a device that is, let's say, used an hour a day for 3 days.

Łukasz Szymański: It used to be, or for now it is that you just Łukasz Szymański: up those hours, and if you have less than 24, then usually you are fine to classify your Łukasz Szymański: device as a as a short term. Łukasz Szymański: as as a limited contact and contact device with the patient. Łukasz Szymański: But right now with the new version. Łukasz Szymański: if you have even 1 h or 30 min a day for 5 days, you have to classify it as a prolonged contact, which basically means that different set of tests for every class and every category of devices. And this will affect Łukasz Szymański: quite a few manufacturers. Obviously, if you are doing producing implants, there are long term contact. You don't have to worry about it. But all those short really devices that are used for 30 min, 40 min whatever, 2 HA day, they will have to be reclassified.

Łukasz Szymański: Also the new thing that that was talked about and was some sometimes asked by notified bodies. Łukasz Szymański: is the life cycle of the device? Łukasz Szymański: So the main idea is Łukasz Szymański: so main. The main idea about it is that if the biocompatibility is still valid for devices Łukasz Szymański: at the end of their life cycle Łukasz Szymański: because it might happen that device. Let's say that this was manufactured, and Łukasz Szymański: and it fully fies all or the requirements, and is biocompatible but biocompatible. But what's what happens after 2 or 3 years in storage.

Łukasz Szymański: So how it's going to be handled? It's something that everyone is wondering. We already had some cases like this when notified bodies asked about it. So we have our own way in kind of of dealing with it. Łukasz Szymański: basically showing the equivalence during the lifetime of the device. Just to avoid doing biocompatibility full biocompatibility Łukasz Szymański: in 2 time points or 3 time points, because that's what might get costly. And I don't think. Łukasz Szymański: to be honest, it will bring a lot of Łukasz Szymański: useful information. Basically, it's just doing the test for doing the test. So we kind of have a way for it. And this is very specific to the device. So so there are some couple of things that that have to be

Łukasz Szymański: decided. We're doing the test based on the device that is tested. But if you need any help, then definitely, we can go into more into it. Łukasz Szymański: lighter. Łukasz Szymański: So.

Just one.

One other point I'd like to bring up. Here is the lifecycle approach being incorporated. Which is more than just, you know, thinking about your product upfront, or maybe even thinking about it just when you make a design change. Can you speak a little to what the expectations are going to be in the lifecycle.

Łukasz Szymański: So like, like I said so. So it didn't. It's basically to show that the the biocompatibility goes throughout the lifecycle. Right? So so it's it's not just a a momentarily thing. Łukasz Szymański: And then that that's where Bp comes in. Actually, for every device that that's why we plan what to do to take into the account, because, knowing the materials, knowing the device and how it, how it should work, we can plan. If if we should check it, check it after a year, or maybe 2 years.

Concept sounds similar to the clinical evaluation plan. you know, in Europe, for the Mdr. Is you know, you have to make that make it upfront. It's really important that you know. It's approved. First, st that and it has a very specific criteria. So the concept seems similar to me in.

Łukasz Szymański: Exactly. That's that's what it's done. And actually it saves money a lot of times for the client, because sometimes you do the study which Łukasz Szymański: it's not appropriate for this device you might sometimes you do the study and you get the results that the client is not happy with, and sometimes it's not the fault of the device, but like just choosing inappropriate test for it. You have a bunch of different tests for the same endpoints. Łukasz Szymański: Let's let's say, even like basic cytos toxicity. You have Łukasz Szymański: 5 or 6 different methods to perform it. So if you know upfront what you are dealing with, then you can plan it accordingly.

Has the or do you? And has have they? Or do you anticipate that? There will be any Mdcg. Guidance documents on the what's expected for the bep, and then the ber.

Łukasz Szymański: So so what's expected of the Bpn. Br. Is already in the 19, 9, 3, dash one. Łukasz Szymański: So so the main points are there what should be evaluated. Łukasz Szymański: I can just say that we are getting ready to to for the new norm. So we are doing our, let's say, new set of documents as to be prepared, and for now it already has, like 75 pages, just to get through that everything that is required. So so it's very, very long and complicated document. But what should be in there, of course, is already described. Łukasz Szymański: The only problem that is not, in my opinion, comprehensively described is the life cycle. So basically, it's there in the new norm.

Łukasz Szymański: But they are not. Łukasz Szymański: Yeah. I didn't miss it.

And misuse of the device.

Łukasz Szymański: But but it's not specified like to what extent it will be evaluated by FDA or Ndr. So I think with that we will see in time what is happening, what's changing and what is required of us. And I also think that there will be our law in there to discuss with notified bodies Łukasz Szymański: and FDA that Łukasz Szymański: that sometimes we don't agree with their approach. So so part of our work with B and Br. For this, for this matter is to to justify our results or our approach to testing, so we can not only show the the results, but also convince the the auditor that our approach is the one that should be taken.

Yeah, Lucas, you probably agree with me that we have lots of medical device on the market that are, for instance, cytotoxic, cytotoxic, and if they wouldn't be cytotoxic, probably they will not work. So, for instance, surgical glues that polymerize in situ. So this is this. From from my point of view, the Ber requirement is the most important part, and I'm really happy about that, because in the past I checked with some customers they thought that the bug. But the biocompatible device is only when their device pass. Pass all the all the tests. No, it's not. You can have the device that is cytotoxic, for instance. So this is something very important, because, let's say, the the people, the group of the people with the experience and the knowledge, after all, at the end over the all the reports are looking at them, and just evaluate the device.

The reports, if it's good or not. So this is, in my opinion, the the most important, rather than doing everything to have a pass for all, for all of the tests, because this is something that is.

You'd be.

Not going to be work anymore.

Łukasz Szymański: But I think that to summarize like that, the biggest biggest changes are the life cycle, different cumulative use, and the documentation requirements for for filing.

okay, so let's move on, what is the the main issue changing with the hemocompatibility, standard part 4.

Well, a chemo compatibility standard is going to have an amendment don't know when it's going to be published, and so on. But as we check the draft of of the documents. In my opinion, don't know if you agree with me, but in my opinion this is something that is going to be mostly to the to the labs is not going to be very important for for the customers, for the medical device, manufacturers, and so on. But Labs are going to change some. Let's say.

Łukasz Szymański: You know, it might be important for the manufacturers to know that the lab knows what they are doing like.

Yeah, okay.

That was the point I was just about to make is that you need to know enough to ask this question, or you're gonna get compatibility rejected by one of the agencies.

Łukasz Szymański: So so FDA somehow lost compatibility. I don't know why, really, but they are always having question to that. To that part, even for devices that are not that Łukasz Szymański: high risk, but from my experience and our clients. Łukasz Szymański: We have a lot of questions from them about this part. Łukasz Szymański: And there are small differences like between us and Łukasz Szymański: European Union. Łukasz Szymański: like, for example, FDA prefers C, 5 B over C, 3, A for complement. And that's something that is very important for a laboratory to know and for the manufacturer, because if you do the study using 33 a. And that I mean, you order the study with chemo compatibility

Łukasz Szymański: for the complement, and then the laboratory does the study for you, and you get results, and everything is fine. But then, after a month or 2. FDA says that. Yeah, but you used the wrong reagent, which is a minor change. Really, I mean from the Łukasz Szymański: from from the scientific point of view that probably is not much difference. But there are 2 or 3 publications showing that sc. Łukasz Szymański: 5 B is like more Łukasz Szymański: specific for medical devices and potential complements. And that's why they prefer it. And that's just not only cost you money, but it costs you time. So

Łukasz Szymański: asking those questions and seeing like if they're about to know what they are doing is very important and new. A new amendment really is just a bunch of those Łukasz Szymański: few technical details. I'm not going to to list them right now, but Łukasz Szymański: but it's always good even not to. If ask specific questions about, let's say, all those techniques. Sometimes it's good to ask the laboratory if they know that there are difference between FDA and Mdr. For example, when we do testing for our clients, we do. Bp, the 1st thing we do is like, we ask, what market are you looking for?

Łukasz Szymański: And based on that? We can, we can design testing? If you are looking for both markets, that's fine, too. We can design tests that will be working for both of them. So so so yeah, that's that's something to to look for.

Okay, let's move on to the next one, because that is a big hitter here, and that's chemical characterization. And it is very closely related to oh, gosh! I'm blind! Yes. yes, thank you. So we're probably gonna flow in and out of these 2. But let's let's start with, when is this gonna be published? Is this a lab versus a manufacturer and and then go. Yeah, there's.

Łukasz Szymański: Was was published recently. And so it's not going to change that fast. We recently got an amendment for it regarding factors for a T. Łukasz Szymański: But what is going on right now is like one has to know that the Iso 19, 3, 18 is very broad. I mean, it's it just says that you have to do Łukasz Szymański: chemical characterization, and you have to provide data that your device is safe and so on. So it doesn't really go into the details, how it should be done. Łukasz Szymański: and the biggest difference, because of the lack of the standards. Really, the biggest difference between European Union and us is in this study because FDA just prepared their guidance for it, saying that you have to do everything in triplicate instead of just one sample. So basically, it's way, way more expensive because there's a lot of work involved.

Understand that.

I just want to bring up again here. Risk assessments are comprehensive. you know, this isn't just a casual justification. It's it all ties back into that bep. You know it has to be a very detailed, and you know my customers ask me all the time. Well, can't we just justify this. And I'm like, well, it's not a justification anymore. It's a full out risk assessment and the level of detail and the comprehensiveness have got to be just very thoughtful and well planned out throughout the whole test series.

Yeah.

Throughout, like, we've been talking about the product life cycle. So.

Michelle. It depends, as as Lukash mentioned, depends on first, st the device type, second, the market that we are going to access because we need to keep in mind that Mdr. Especially, Gspr. 10.4 is dedicated to invasive medical devices, or those devices that are going to deliver drugs. tissues, body fluids to the patient, and so on. So we are. We are not talking about this Gspr requirement in terms of the devices that have an intact scene contact. And this is something that we are discussing every time with Lucas. Because we have, let's say, a little bit different opinion about that. But yeah, exactly. I totally agree with you that it's going to be.

fully describe in a bep how to do chemical characterization for this particular device for this particular market.

yeah.

Łukasz Szymański: FDA is going crazy about chemistry. They are just they, for now they like usually when they do chemical studies. And it's not semi quantitative study. So it's semi quantitative study. So basically sometimes you are not sure what you found. Łukasz Szymański: And usually for Mdr, it's fine. You just have to show that you don't have a card of concert chemicals. You, of course, go into toxic risk assessment and you do it. But, FDA, lately they want to have all the compounds identified, which is something that's sometimes hard to do. At the same time, you might have 100 compounds. So it's a lot of work that you have to be prepared to

Łukasz Szymański: to do and plan it Łukasz Szymański: in a good way because of another difference between FDA and Mdr. For FDA Łukasz Szymański: as nonpolar medium. They want only want to use hexane Łukasz Szymański: and nothing else for them is nonpolar, which scientifically it's not true. There are a couple different nonpolar media. But their idea is that it has to behave same, even if it's not compatible with your device. And then it arises into the problem because you use Łukasz Szymański: hexane for polymers, and you get degradation, which by the Normans or the common sense, doesn't shouldn't happen, because there is no point of degrading the device. But that's something that has to be planned in Bp, and then it has to be discussed.

Łukasz Szymański: involved of psychological risk assessment. If you are doing one. Łukasz Szymański: And if you're going kind of using a shortcut, not doing toxicological risk assessment, because sometimes there is no known there is no, I mean, there's no point in doing so. But then, what you have to do in biological investment report, you at least have to touch the subject of toxicological risk. Łukasz Szymański: So Łukasz Szymański: so that's something that has to be Łukasz Szymański: done in a in a, in a, in a way that makes sense, because otherwise Łukasz Szymański: you end up with costs running very high, because chemical characterization can get very costly and very quickly. This is quite a complicated study, but fortunately, what happened at the time so like, I said, there is no new norm, 1,903, 18 coming. But there is something that is called Iso 2, 5, 3, 6, 4,

Łukasz Szymański: which which doesn't have previous version, because it's something that is completely new. Łukasz Szymański: And this will be a norm describing how those studies should be performed. Łukasz Szymański: And it's also something that FDA is doing on their own, and they released something called chemical analysis for biocompatibility, assessment, guidance. It's at the draft stage. Luckily for us, for all of us they are pretty Łukasz Szymański: similar, not maybe not in every way. Hope I am. I'm hoping that the Iso and FDA can come to some agreement before they publish their final version. So so it's it's similar. But hopefully it will get regulated soon.

I'm just gonna.

Very important for for the lab, because there will be more content how to how to do the testing, and so on, rather than, let's say, do the test.

Yeah, it'll, it'll kind of help. Standardize the process and the interpretation and and should put it, you know from lab to lab at some consistency. It sounds like for that standard. So that that's brand new. The iso, you said 2 0 3, 6, 4.

Łukasz Szymański: 5, 3, 6, 4, but.

5, 3, 6, 4.

Łukasz Szymański: Yeah.

Yeah, this one.

Łukasz Szymański: Draft version. So it it will still take time to Łukasz Szymański: to implement worldwide. For now I would go for the draft version of chemical analysis for biocompatibility. Assessment by FDA. It's not as detailed as this iso 2, 5, 3, 6, 4, but it's already there. So for sure, FDA will be looking for what's in the draft. Łukasz Szymański: And actually, that's good. Because for those studies this is very subjective. I mean in the way that Łukasz Szymański: if you do it in the wrong way. You can always say there is nothing risky about the medical device, because if you use one standard or not, upper PA, standard, you can always say, yeah, that there were no results, and you have to know what you are doing with chemical characterization.

Yeah, it's definitely.

Or.

Expertise. Yeah.

At the end or at the end. You have 300 compounds to be analyzed for toxicological risk assessment that those compounds are not going to be present on your device itself, because, as Lucas mentioned at the beginning, we had to use the hexing that that degradates the material. So there is no point to do this kind of analysis. So yeah, but it's tricky.

Łukasz Szymański: As a manufacturer. You want someone who knows what they are doing in both ways. So if you don't get any results that was funny that we got from the client. The client came to us because he did it with someone that the chemical test and he got an answer from FDA saying, we don't believe in your results like there's stuff in there. Nothing in Gcms. Nothing else. Cms. Łukasz Szymański: The results were that no compounds are present on the on the device. Now it can be extractable. And FDA said that there is no way. So the manufacturer you want someone who knows what they are doing that they can find those things, but also the laboratory that doesn't over interpret. So also, you don't want a laboratory who will find you 10,000 compounds that aren't actually there.

Łukasz Szymański: So so.

So how does this dovetail into the next hot topic here? The taxiological risk assessment.

Łukasz Szymański: So I would say. Łukasz Szymański: this is, as an old rule goes garbage in garbage out. Right? So if you have garbage results from characterization. You'll have garbage results for toxicological risk assessments. Łukasz Szymański: and for that to have good toxicological risk assessment, you need good quality data and why the toxicological risk assessment is that critical? It's for Mdr. For example, you have this this role that Damon mentioned, that Łukasz Szymański: for invasive medical devices you cannot have cohort of concern compounds. If you do over 1 0 1%, you have to do everything in your power to change your manufacturing process to get rid of those compounds. If you cannot, because they should be there because of the whatever the device is doing, then you have to label it to be honest, like, if you label it as cohort of concern devices that are cancerous. No one is going to buy it.

Łukasz Szymański: So that's the 1st thing. So you you need to go for for that Łukasz Szymański: Also, from manufacturer point of view, good toxicological assessment that recently changed, how it's performed, which is a good thing, because it's now Łukasz Szymański: better described, and it's not calculated as a 1 point thing, it's like, it depends on the, on the duration contact of the device with the patient, which is, which is better for the analysis, but it allows to skip some tests. You can avoid different endpoints, like based on the chemical characterization and toxicological assessment. If there is no

Łukasz Szymański: compounds that show you any Łukasz Szymański: systemic toxicity risk, then there is no need to do. Let's say, chronic toxicity, which is a long and expensive study. Łukasz Szymański: The same goes for Cancellation City.

That that's something that I want to ask about. And and I think it really goes into this. You know theme of the importance of the risk assessment. and that is time and money. What it? Because extractables and leachables, the chemical characterization, like all of those tests, are already lengthy and expensive. And so what is going to be the impact of these changes? To how much time, and possibly how much money is going to be involved here, and then does that make? Then I think that will help manufacturers understand the importance of investing in that biological evaluation plan, and all of these points of analysis and risk assessments and rationales based off of the risk, assessment.

Okay, I just wanted to say that I think, Michelle, it depends on the device that we have in hands, because when you have the device that, let's say, based on the categorization that Lukash mentioned. Let's say subacute toxicity is, let's say, recommended to be evaluated. So we have, let's say, less positive feedback rather than we have the device that chronic toxicity is needed because the chronic toxicity takes more time. And let's say you can. We can have the device that needs, for instance, carcinogenicity that can be avoid based on the chemical authorization and toxicological risk assessment. So we can have good benefit or extremely good benefit, and depends on what the device we have in hands.

I suppose.

Łukasz Szymański: Yeah. And I just want to correlate it with the changes, with 19, 9, 3, dash one, if you're Łukasz Szymański: if if you're Łukasz Szymański: if you already have Łukasz Szymański: and Łukasz Szymański: chemical characterization that is performed according to the regulations, and Łukasz Szymański: and it's a good quality study, and then due to the changes in dash one, your classification of duration of cardiac changes because it might like, if it's a repeated contact, for, let's say, 5 or 10 days for an hour. Now you're going to be prolonged. You have to do more studies. Łukasz Szymański: or if it's even a long term contact, because you're using it every day for

Łukasz Szymański: 1 min or 2 min, maybe not 1 min. But let's say 10 min every day for 50 days. You're going to the long term contact, which means that you have plenty of studies to perform, and if you already have chemical characterization, you can use it, and you can leverage it to your benefit to show that you don't really need to do systemic systemic Łukasz Szymański: toxicity study because it can be answered Łukasz Szymański: with good toxicological risk assessment. So I think that actually, the 19, 9, 3, 17, and 19, 3, 18 are really are even becoming more important than they were due to the changes in.

And I just wanted to mention one thing very important. Be of. Be aware of the company that you are cooperate with, because I saw toxicological risk assessment that was that was made based on Ld 50 doses of the compounds, which is something kind of, let's say, clear, stupid. or and I so, and the toxicological risk assessment that one of the toxicologists tried to avoid sensitization testing based on the chemical characterization. So this is.

And that's that's 1 of the I'll call it the Big 3, like you've got to have a really good rationale like outside of my device is naturally cytotoxic. because of, say, like hydro gels, or whatever there's always fail. But you, you've got to have those big 3, you know, are kind of like the baseline and can also help predict. You know what other tests you need, based off of the outcomes of those. So I had a couple of questions, asking for clarification, like about the establishing limits. Where? Where you know. What? What are you talking about? The like? The points of departure, Ttc or Tsl. And then then also, maybe, if this seems related, how to establish that analytical evaluation threshold.

Yeah, before we go to that, I think, Lucas, you can answer these questions. I just wanted to highlight one very important thing the latest Iso 19, 3, 17 is currently harmonized with the Mdr. So this is very important, and we need to use it. But as but as far as I know, FDA gave us 2 or 3 years for, let's say, working on the previous version, Lucas, you can. You can confirm that.

Łukasz Szymański: Actually, I was working on the on on writing New 19, 3, 17, with Amy. So the idea was that if you already have toxicological risk assessment. There's no need to to redo it, because, like, I mean, it's already done. So, it's just interpretation of data. But if you want to. If you have new results, of course do it in the according to the new one. Łukasz Szymański: FDA put a deadline on it. It's like, I think, the end of next year, or end of 2026, some some something like.

Something like that.

Łukasz Szymański: But yeah, I would recommend doing it, using new standard. And, as I already said, it's better that the new standard is way better, because it's more comprehensive. As you mentioned Michelle, it has point of departure, not strict like studies. The values so point of departure is, is Łukasz Szymański: it's a good thing, because you can use different values. Of course, Ld, 50, when you know that 50% or whatever you have is dying, it's not a good point of departure. But due to this definition, you can use like I said, use different values you can use, let's say, surrogate based on the surrogate standards. You can also

Łukasz Szymański: use read across methods. So basically, you look for a compound that is very similar to something that you are evaluating. But it doesn't have Łukasz Szymański: good point of departure. So there are many more things that allows toxicologists to do their job and and he also said, You do not look only at one time point. So before it was assumed that let's say, for device that is, contacting a patient for 30 years. Łukasz Szymański: you would have to calculate and assume that everything that is released by the device is released on one day. Łukasz Szymański: and based on that, you'd you usually would have very, very high

Łukasz Szymański: margin of safety values which ended up. Łukasz Szymański: which ends up Łukasz Szymański: in the recommendation of doing an additional biocompatibility test, now based on the on the time of the duration of contact with the patient. You you divide it between a day, a month, a year, and so on, so based on that you can. Łukasz Szymański: I don't want to use the term, increase your chances of passing this evaluation. But in essence, it's just that. So it's more scientifically accurate to to do it in this way, and basically it gives a benefit to the manufacturer and their devices Łukasz Szymański: when it comes to a T.

Łukasz Szymański: This is just pretty technical, but you take into account. The number of devices that you have to use per day per patient. Obviously, you have to take into account the number of devices that you use for for extraction, for the tests, the size and of the device and the volume. I mean, basically the volume of the extra hand. Łukasz Szymański: And and then you go to Tcc. So the Tcc. Is a value that is derived on long term. Łukasz Szymański: Long-term systemic studies Łukasz Szymański: that were done over the last, we would say, 40, 50 years, and based on that, you have different values

Łukasz Szymański: per day that you assume for depending on how long the device is contacting the the patient. So you start with 120 micrograms per day for short term contact devices, and for the the long term you have 5, I think, 5 or 10. I don't remember sorry Łukasz Szymański: micrograms per day.

I suppose? Then.

Łukasz Szymański: I think that. Yeah. So so based on that. And during you use all those calculations to have. The idea, what is the analytical evaluation threshold. And of course you have the uncertainty factor, which is always a big discussion between Łukasz Szymański: the hemis involved in the studies, because the old one on the I mean the old one, the current 1093 dot 18 without the amendment that was released like a year or 2 ago Łukasz Szymański: said that we can assume the uncertainty factor of 2. Łukasz Szymański: And basically it's not a bad idea. But FDA said that there's no way every laboratory has to calculate their own.

Łukasz Szymański: So for and oh! And of course, FDA said that we should use instead of 2 we should use, and if someone doesn't calculate. So it should use 4 for Gcms and 10 for scms. So the 10 Łukasz Szymański: is a huge uncertainty factor. Because when you look at it, you assume that Łukasz Szymański: 90% of your Łukasz Szymański: results are not correct. Łukasz Szymański: or they are like under Łukasz Szymański: under, calculated by 1010 times. So this is, this is a lot. But nevertheless, like the amendment came in. FDA is fine with it. So you have to do the validation. I mean. Every lab has to do a validation of their methods and based on that, they have to

Łukasz Szymański: kind of calculate what they are using. It's more work for the laboratories. But it's there to be honest. There is a talk between like laboratories and regulators to maybe do some kind of round robin study to to see what are the values globally? And just Łukasz Szymański: do they just use them? Łukasz Szymański: Around. For as a standard. Łukasz Szymański: and based on that, you know, like how low you have to go. So if you have a very big device that is, contacting a patient for a long time, and you use a lot of it per patient. Sometimes the 80 is very, very low Łukasz Szymański: which might give you a problem because it might end up being lower than

Łukasz Szymański: laboratory, and the possibility of the equipment to detect the compounds which is called limit of detection and limit of quantification. So if you have those values that are not correct. Łukasz Szymański: then that's something that Łukasz Szymański: will be questioned by every authority, either FDA and or European Union Łukasz Szymański: bodies. So so yeah, that's also something that should be planned ahead and should be laboratory that knows what they are doing.

Let's let's move on. Now, we're kind of getting ready to wrap up here. So what are going to be the practical implications for manufacturers and these 3 big areas that we've we've seen kind of consistently.

Michelle. Sorry for interrupting you, but I think we skip the skin irritation slide. I don't know if we have still time, but it's good to say something about that.

Okay.

Good. So just just to just to briefly currently the latest 1093 dash 23 is is harmonized with the Mdr. The latest version, and what we have in EU in EU right now is that in vitro alternative test is, let's say. semi accepted by the most of the notified bodies. and and the outdoors, because right now, in a in the European Union, we have a force to, let's say, stop animal testing, or, let's say, hold some of them, and so on. But the problem is that. in my opinion, the round robin study and the internal validation that was done for those reconstituted human epidermis was done was done too fast, in my opinion, because what what is the problem here is that.

Łukasz Szymański: Strong origins.

Yeah, exactly so, for the validation, only strong irritants were analyzed. So we check the correlation. This in vitro irritation method only on strong irritants. And last time, I suppose, this year, on assault annual meeting, there was a presentation about the correlation of dermal irritation on the rabbit and intracutaneous reactivity on a rabbit with in vitro alternative method, where mild and moderate irritants were used. And suddenly the correlation was 33% only. So this is the problem here. And I suppose this is the reason why FDA currently does not accept this in vitro alternative testing method. What we do generally we do if we have the medical device with intact skin contact only, and irritation testing is necessary. We do in vitro irritation for the European Union. But those devices that have, let's say, contact with the internal tissue.

We rather go for the intracutaneous reactivity. And, to be honest, this is my personal opinion. I don't know why that the voices are going to stop these tests on a rabbit. I will tell you why, because people may think that animal testing is something that is very hard to accept, and so on. But from the practical point of view, I just wanted to explain. How does it go when we have? Let's say, dermal irritation on the rabbit. We need to take 3 rabbits. We soak the goals, and we attach the goals to the to the skin of the rabbit. Those rabbits are kept, let's say, for 4 h, 24 h. Something like that depends on the device. What we have to be tested, and later on, after the test

those rabbits are going to be adopted. They are going to the families to have new homes and so on. For instance, European Biomedical Institute is working with Lab Rescue Foundation when we cooperate together, and those rabbits are then transferred for free for new homes. So, to be honest, I don't feel the point to stop this kind of this kind of test, I would rather to be more focused on more, let's say, sophisticated animal tests, like toxicities, and so on, rather than trying to do as much as possible to stop animal testing on the hand of in vitro irritation. As we know right now, the in vitro irritation is not going to be good correlation with the mild and moderate irritants. I think I totally

agree with the with the FDA voice that I heard that needs. They need more. They need more tests to to do, the, to to see what's going on. What is the reason, and maybe how to the methodology should be changed to have better correlation of the results.

Yeah, that's a great point. So quickly. Let's wrap up on the overarching impacts to industry here on the next slide. Sean, if you could advance the slides, please. Okay. so what are what are the big implications and takeaways that people should leave here today with.

My, I I can start find a good cooperator that shows you different strategies. Not only one option, not only one opinion, but different ways. How to, let's say, fill the biocompatibility field. This is my, let's say, idea.

Yep. So what are the emerging trends? And what do you foresee coming? You know. Besides, just these updates like, what are what? What is the future, or what is next? Is there any kind of alignment between FDA and EU coming? What are they going to come together? Are they going to continue to have different.

Łukasz Szymański: To be honest for what I see like over the years when we do this Łukasz Szymański: there's even more scrutiny, and it will be even more strict testing of biocompatibility, both Regulators FDA and Ndr. And, to be honest all around the world, they are looking more and more on the safety of the patients, and they are Łukasz Szymański: designing or thinking about new tests. I think that at some point, will it? It will have to stop, because, like you cannot obviously change test for everything, and or or sometimes it doesn't. Łukasz Szymański: there's no point but looking to say at the new dash one, the periodicity is no longer in the spotlight.

Łukasz Szymański: And why? Because, like 99% of tests done around the world showed that devices are not pyrogenic. So now they want us to focus or center on certain devices which are, let's say, novel devices or have novel components. And that makes sense. So what I think will happen that we will have Łukasz Szymański: new requirements, but at the same time we will be getting rid of something that we know that is always correct, because there's no point of in checking that. Łukasz Szymański: And and more data we have. And every year we do have more data. And this way the chemical characterization will become even more important.

Yep. okay. Well, we had a lot of comments that we will address in a follow up with a FAQ. Some of them were, were kind of very specific. We'll we'll try to like make it, you know, broader to the make, perhaps the whole audience for those. and you will get the slides. You'll get a link to this. And I believe our good friends here from European Biomedical Institute and North American Biomedical Institute are going to put together just a quick reference guide, because, of course, we talked about way more things than would fit on a slide. So thank you, guys.

Łukasz Szymański: I see one question that I have to answer Łukasz Szymański: that if the Cros ever advised not to do the testing, and that's something that has always come up. And basically what we do is like, we help every every client to do the testing. And obviously for us more testing. It's more money. But I don't think it's a good idea. So that's why we always start with Vp. If the clients is wants to, because most of the time we are able to skip something or omit something, or advice not to do it, but Łukasz Szymański: to from the other side. I'm I'm never going to say that we will skip all the tests.

Łukasz Szymański: I know that there are Cros, or some that do do that, that do it. Basically, you pay the money, and they just come up with some justification that it's not scientific, correct. Łukasz Szymański: And they say that, yeah, you should be fine, and usually you end up with us a year thereafter you get rejected but notified body. But Łukasz Szymański: yeah, I I think that there are some. There are some zeros that will Łukasz Szymański: will try to help you not only to get your money, and that's something you should look for.

Yep. Generally the problem is only when the problem is so at the end. Finally.

Pardon me.

Łukasz Szymański: Sorry for interrupting, but I I had to go with this one, because that's something that we always hear.

Okay, well, I'd like to thank everybody for joining the call today, especially the people that dialed in. If you'd like a certificate of attendance. We can provide that. Please please give us a day or 2 to email them to you. We have to make them by hand. So patience is appreciated. I'd like to thank our speakers, Dr. Damian. Dr. Lucas. Thank you so much. And, Michelle, thank you so much for moderating Violetta. Thank you for joining us and please complete the surveys. Provide your feedback. Let us know if you'd like to be contacted in the surveys. And yeah, everybody have a great day, thanks so much.

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