Zero to Biocomp Biocompatibility 101 - Fundamentals for MedTech Professionals

Hello, and welcome everybody to 0 to bio comp bio compact compatibility. 1 0, 1 for med tech professionals. I'm very pleased to be joined today by Michelle Lott, Marina Dinico, and I'm going to ask them to introduce themselves. But before I do that just a couple of quick housekeeping announcements please use the chat vigorously during this event as well as the Q. And a. We're not promising that we get to all the questions during the call itself, but we'll follow up afterwards. This call is going to be recorded and the recording will be made available along with the slides. The presenter slides to everybody tomorrow in an email that will go out from zoom so there'll be links to that. We're gonna provide some other links as well in in the

while we're getting started. I would like you all to please. Take a moment to answer this quick 3 question, Poll. which will help us frame the remarks appropriately during the call. And yes. that you get the idea. And let's have Michelle introduce herself first.st Michelle.

Michelle | leanRAQA: Hi, I'm Michelle Lott, with lean Raqa lean Raqa helps people particularly startups and small to mid sized businesses. Navigate this challenging regulatory and quality environment. Michelle | leanRAQA: And we've helped over a hundred companies now bring their products to market and and keep them there.

That's wonderful. And Marina.

Hello, everyone. My name is Marina Dineka. I am biological evaluation consultant at Intrinsic medical group. So within intrinsic medical group we provide different services related to medical devices, such as biological evaluation, sterilization. cleaning as well as reusable devices. So very niche very specific. And I'm really happy to be there. So hopefully, we would have some fun.

Wonderful. Thank you.

Thank you.

I am going to share my desktop. I think so. okay. while I'm trying to bring up the agenda. Let's go ahead and start with the 1st question, I'm going to end the poll. Share the result. Are you seeing the results.

Yeah. wow.

So there you go. That's good information to have. And yes, so let's just go ahead and dive right in.

Michelle | leanRAQA: Sure. So Michelle | leanRAQA: we have a little bit of an action packed agenda here today. So we have got a lot of questions that were submitted in advance. Be sure to put your questions in, because I'm going to be as Marina Michelle | leanRAQA: is talking. I'm going to be kind of emceeing here and going back and forth between the chat and questions we've had submitted to to kind of get us started. Michelle | leanRAQA: But you know, for those of you who follow either one of us. She and I have been talking about biocompatibility, a lot on different platforms. I did a podcast recently with a wishy that Marina and I had discussed both beforehand and afterwards with the the results of the discussion. And then, shortly thereafter, Marina did a great presentation with the Medical device group.

Michelle | leanRAQA: and both of them just generated a lot of conversation. So here we are to kind of keep that conversation going with some of the most popular questions. Michelle | leanRAQA: So, Marina, you know, given that the title of this is from 0 to about biocompatible 0 to biocompatibility, biocompatibility 101, Michelle | leanRAQA: but with that said it looked like about 42% of people were a little bit more confident than maybe a 101. Let's start with like what is biocompatibility, and like? What are some of the nuances that the people who are at the the lower end of that 40 versus the higher end of the 40, like. What?

Michelle | leanRAQA: What are some nuances that both both groups need to know.

Yeah, I really like this question. And thank you very much. And I'm really glad to see, are the voting here like a little familiar or relatively familiar. So you know, biological evolution by compatibility, it's better to say it's the property of the system. So we can say, like some material or some component, is biocompatible? No, because we do not. We. We should know some specifics here. like, for instance, not only the materials that are used for this specific component. But what is intended use of our medical device and some other aspects here? So I prepared actually, really quickly the presentation. If you don't mind, I will share it because of.

Michelle | leanRAQA: Just quickly, I said, put put the questions in the chat. But if you could actually use the QA. Because that's a easier way to track it, for after the webinar, because Marina will be preparing like a question and answer for all the questions we got, that we may or may not have gotten to, so please use the the QA.

Yeah, please, I like questions. Just share them within the chat. Okay, I hope you can see my screen. Yeah, my presentation? So let's go. What's assessed within biocompatibility by a compatibility is applicable just to medical devices. And it's very important to understand and to use in our work. So 1st we need to talk to regulatory as well as clinical, to understand whether it's medical device, whether it's registered medical device. Then let's go into details. Not all the medical devices shall be assessed. We will talk about it a bit later, but within the standard we have to assess the medical devices that come into direct or indirect contact with the human body.

And why shall we assess it? Because of a general understanding? What safety, safety is freedom from unacceptable risks. And here we have to assess the potential for unacceptable adverse biological responses actually, from this contact. So hopefully, it's like, more or less clear. And here, just example, what's direct? What's indirect contact? Here you may see the medical device, and it has direct contact me, meaning physical contact with the patient. And here is the example of infusion set, and here I just marked the tube, and there is liquid that flows from the infusion back to from through this tube, so Tube doesn't have any physical contact with the patient but liquid.

From this tube has. So it means, according to the standard that the tube has indirect contact with the patient, and it means that the tube shall be assessed in our documents. And here yep.

Michelle | leanRAQA: There. One of the con. The questions I got you know, beforehand is like what happens about those products, because, especially like in some of the 6 0, 6 0. 1 series. They call out some biocompatibility requirements, and they say things like. Michelle | leanRAQA: You know, parts that are intended for direct or indirect contact with those biological tissues, etc, like you were talking about. But what about Michelle | leanRAQA: parts that that are are not or might be, not not indirect, but Michelle | leanRAQA: I've been trying to.

Like no contact, or like transient contact. Some such.

Michelle | leanRAQA: Kind of single.

Right like.

Michelle | leanRAQA: A a lead inside electrode that doesn't actually touch.

Yeah, actually, yeah.

Michelle | leanRAQA: That can sabotage your biocompatibility.

Actually, as I started this conversation. If we have categorized medical device, the device that is categorized as medical device. And it's registered medical device. Right? We need to perform biological evaluation. In any case, even if it doesn't have any contact with the patient, what does it mean? It means that we just need to prepare the document that states like, okay, we have medical device. It doesn't have any contact with the patient. we don't need to perform biological evaluation on it. But we need to document this information. So it's required. It's requirement to assess it in any way. So and here, actually very similar oops. I'm sorry. Very similar. Nope, wrong. Yeah. Here, example case study, because I took it from the questions that were asked

in advance. So here there is a question from a medical electronic equipment and standards. 60, 61, one, actually. And the question is that there is like a specific clause that asks about iso tenants, 3 series of standards. And there is another clause that states only about risk management. And the question that we got is whether we have to do biological evaluation for such kind of devices. So if I can just second, yeah, show you this closes how they look like from the standard. So here one more time is about mostly risk management

and applying risk management and parts that contact the patient as well as very specific about biocompatibility of a medical electrical equipment and systems. So 1st of all, we need to understand whether it's a registered medical device, whether it's a medical device itself. Then we need to understand whether we have, for instance, accessories, because there is a kind of Pandora box or tricky questions with accessories, because they can be able to be excluded from biological evolution at all, because they can be not part of medical device, and even do not Do not influence on medical device functionality, and when they are

excluded we we shall not do biological evaluation, for instance, for accessories. The example here you may see in a violet is a Karen bag for a pump, for instance. So it's.

Michelle | leanRAQA: Clarify, though you mean excluded in the evaluation. Do you mean like in the the actual testing, or in the analysis of the report about what you chose for testing and what you didn't, and why.

Are actually excluded, not only from the testing, but also excluded from biological evolution, because it's not a medical device. and going back to the definition of when? Not when. But yeah, when when we shall perform biological evaluation, we have. Here is a clause that it's for medical device, and when, together with regulatory as well as a clinical. This accessory is not part of medical device is not like registered medical device. It means that we should not do biological evaluation on it. It's Pandora box. It's like, you know, it depends because accessories. We can have very different accessories that can actually impact the functionality of the medical device. But it's it's the beauty of biological evolution to me to be honest, because we have to consider very carefully our device. We need to know our device.

and we need to copyright with other with other colleagues from other departments here.

Michelle | leanRAQA: Okay? And somebody asked about unclassified devices. Where does that fit.

Unclassified. Unclassified devices. Do you mean unclassified as per iso tenant? 3 medical device regulation, or Syria.

Michelle | leanRAQA: But we'll get some clarification on that, for for after the webinar.

Yeah, please, it would be really helpful. So yeah.

Michelle | leanRAQA: Very good.

Yeah, talking about this example here, if we have medical device, we have to perform biological evaluation, even if it doesn't have any contact with the patient. We just need to document it. So we have the documents that okay, no contact with the patient and surely follow Iso 14, 9, 71 for risk management processes. Another case study that also was shared. And I really like it is, was it was about cable assembly. And actually this cable assembly, together with Connector, was shared with the laboratory. And what lab did? Actually they grinned it the entire assembly, and put it into solvent and predictably this test failed because of the process of bromide in the contact PIN. So

what's the challenge here, or or what was done wrong here that we have to be careful, and we need to consider each element, each component and identify what contact type it has with the user skin. For instance, here. These pins were designed in such ways that they have no any contact with the patient. So we just need to again document it within our biological evaluation, and prepare this sample for the lab properly, or describe this preparation properly. And here you may see, unfortunately, the manufacturer lost like 12,000 arrows, because they were forced to repeat this test just removing this connector spins. And yeah test passed and

all good here. So that's why biological evaluation shall contain the information on not only like medical device and full picture and intended use, but also we need to break into lines what components are here. What is the contact type with a patient for each component. Okay, if we can go next, here is a really cool example, and thank you very much for sharing this. So here we have measuring blood pressure device with a finger cuff. So here, this picture, I just took it from Aliexpress, is just for illustrative purpose how it can look like. So it's not about this particular specific device.

So what was the challenge here? The challenge was that the calf is connects to a wrist worn unit through a cable link to a central device. And this wrist unit is secured with Velcro band. And because it's only to fixate the wrist part in vicinity of the fingers. It might as well be worn over a sleeve. but all the documentation, like instruction for use all the marketing information, etc, etc. They had a picture that the wrist unit being worn directly on bare skin and notified body, noticed it. And they asked actually about biological evaluation of this part.

Unfortunately, tests that was performed to provide evidence that this wrist unit is biologically safe failed so because it was not considered. It was not intended even. But all the information, marketing, information, instruction for use, etc, had the this picture that this wrist unit can be used on bare skin. And here we have the contact with index skin. Right? So and here the numbers are really big. They're really huge, like 100,000 hero requires to revise all these materials like, together with translations, etc, etc. And what was done? Actually, it was like from business perspective. It was allocated 20,000 errors to be able to find new risk band materials. That

shell can be compliant with the requirements, and can be claimed as biologically safe, just because not to rewrite all the papers. And here you may see on the list all the documents as well as processes that required update when it was found. So that's really impressive. How how different teams shall be! Shall be shall talk to each other right, and understand how the device shall be used, actually.

Michelle | leanRAQA: So this is probably a good time to talk about Michelle | leanRAQA: changes and changes like both, like maybe in your your test plan or justifications that can be done. Maybe before a test takes place, or maybe after you got some, maybe unexpected results. And you realize that maybe you made some of these mistakes, you know. When? Wh, where are the the guidance or the boundaries around? Michelle | leanRAQA: how you can. The the justification process.

Yeah, absolutely. So. I just want to take a step back, if you don't mind and share with you. When a biocompatibility biological relation actually shall be performed. And here you may see number one is prototype phase, and you might think like it's something new. And you're absolutely right, because this assessing of biocompatibility on prototype phase was included in the current draft of Iso 10 and s. 3 1, and I do believe, on the very prototype phase, it's valuable and important information can be derived. Why? Because we don't need to perform a whole biological evaluation. We can do biological assessment if that makes sense just to

see whether we have any materials of concern, anything that can give us headache later, you know, and also some other points here like design, verification for sure, medical device change, emergent post market information. And here I'm talking not only about complaints, but to our device, to our specific device, but also some information for applicable, for instance, for predicate devices, or for devices from competitors, etc, as well as changes in bio comp. Related standards and regulations like, for instance, we had recently dash 17 updated significantly. So we need to consider whether we need to remediate all biological evaluation reports or they are still applicable. And here, just really, briefly,

to yeah, medical device changes. So they are a lot. Actually, they can relate to design or material or packaging changes, changes in intended use, changes in patient population. Just imagine you have a medical device for the adults and from business perspective. Yeah, the team decided to extend their target population, for instance, for pediatrics as well. So it means that we need to consider toxicological limits as well as do our assessment to include this new group, like pediatrics as well. Why? Because the weight is different for adults, according to the standard, we have like 70 kg for adults, for men sorry and 58 kg for women. But pediatrics we have like 13 kilo. So once 3 kilo. Yeah. So here we need to take this into consideration.

And there are some other changes like manufacturing and many, many others. And just a quick, actually, example. It's my favorite one. And I take it from from the FDA guidance. They just have it within this guidance that, for instance, there is medical device, and we are adding component internal components that has no contact with the patient. What does it mean for us? If, like follow the standard, we should not be formed by a comp right. But there is a trick here, because to be able to apply this component during manufacturing process, the heat is applied to join to another component. And this another component has contact with the body. And from this perspective we have to reevaluate our biocompatibility to do biological assessment.

Yeah, just to understand whether there is any effect from this applying heat from this manufacturing process to cool our device. So that's very interesting. And if talking about If talking about changes it also, it's very important. And it's actually common mistake when people are trying to assess something alone. So if even we have a look in the eyes of what's in 9 71, there would be a close about cross functional team, because we need to sit down altogether and understand? What is the impact? What exactly are is the change about? And yeah, who else shall be involved? There.

Michelle | leanRAQA: So, Marina, we've got a good one, and that was on my list from before, but but came up in the the question and answer again, and Michelle | leanRAQA: And I'm going to rephrase it a bit, because everybody in industry got a little excited about the FDA guidance that came out with the whole Appendix of Material.

Oh, yeah.

Michelle | leanRAQA: Didn't inquire about, you know, testing or whatnot. Michelle | leanRAQA: Can you speak a little bit about those exemptions? And when they apply and can be used in justifications when you're first.st

Yeah.

Michelle | leanRAQA: Testing.

Absolutely when talking about this this exemption from FDA guidance. That's really cool thing. Why? Because, we can just use this information and refer to this document. But there are surely bad we need to take. We need to remember that this attachment is applicable to the components or materials that have contact with intact skin, only. So not compromised, not like implant, but just intact skin. And there is like very specific list of materials within this within this attachment right? But we still need to do a biological evaluation from, for instance, literature review right? Just to add

the information, because the materials, especially polymers, can vary from one supplier to another supplier. But surely we can just refer additionally, not just, but additionally referred to FDA guidance saying, like, okay. we have this material. It's like, used for intact skin. It's used for devices that would be sold only in their states, because we are talking about the FDA right here. This material is used for this type of device, also to show that okay, it's applicable. It's kind of clinically established, and because it's included into their FDA guidance, so it can be considered as biologically safe. But also we need to take into consideration some other materials and possible manufacturing residuals, and so on. So

for us. So we need to see whole picture we need to assess whether there are any additional risks there, for instance, from manufacturing standpoint, if we have cleaning. So, for instance, residuals from cleaning, if we have, I don't know some sterilization by Acelan oxides, and maybe we have residuals of Acelan oxide or ech, you know such kind of things shall be considered as well. But again, we can use it like back and forth like all the time. And surely just puts in. Okay, this is from this attachment of FDA guidance. Yeah.

Michelle | leanRAQA: And so it's. It's fair to say that, you know. Don't get too excited because something is in that list of of chemicals or materials, because you still have to do a lot of work in just the justification and research and applicability to your product, you know, etc, and that that process. And then something else that you brought up hit home with me. Michelle | leanRAQA: is that okay? Yeah. If you're gonna only go into the Us with your product. Yeah, maybe that approach will work. But what about differences? For by by country that you have to consider.

Yeah, I I love this question. Thank you very much. Because in most cases, say, companies are trying to have. And that's okay from financial from business perspective, right to have one biological evaluation for different countries. And that's absolutely okay. But here we have to consider the differences like you just mentioned. Right? We could have this exception for the States because of the FDA and the guidance. But EU Europe here, and medical Device regulation and iso tenants. Redesh Fund doesn't have such list. And okay, polypropylene is pretty inert, it can it? I? I saw some articles that call it like biocompatible, but I hate, you know, when it happens, because we have to consider by a medical device in its final finished form. So it means that we still have to consider manufacturing residuals. What's done with our polypropylan and some other things. So from

So here I would say, if we consider, like both the States, for instance, and Europe. We need to do comprehensive analysis in any case, I mean from literature. Review, for instance, assessing a manufacturing flow, understanding what is our device collecting complaints. If it's a clinically established medical device but for Europe. for instance, we can't use this justifications that it is within FDA guidance, so we need to do all this evaluation and document. It surely.

Michelle | leanRAQA: I think that that's also a good thing to to at least touch on on Michelle | leanRAQA: briefly, is that you know there's a big push in Europe to go to non animal testing.

Yeah.

Michelle | leanRAQA: And the F, and everybody's like, when is the FDA gonna adopt non animal testing 1st off. Speak a little bit to. I I don't think it's that exciting, because I don't think it's going to be any cheaper or quicker. And then B. The FDA is not nearly as excited about the rest of the world about this, so speak a little bit to that.

Yeah.

Michelle | leanRAQA: I'm fine.

Absolutely. There is a big tendency within medical device regulation, and even with their draft of current draft of Iso tenant and Swedish ones that right now is under vote if I'm not mistaken. So to minimize animal testing and switch to 3 are like, replace, reuse, replace, reuse. I'm like all the time forget since the 3rd one. 3, 3 h, principle or concept, right? So within our Mtr. If we are applying here in Europe. So Mtr. The regulatory bodies would not accept animal testing. And unfortunately and there are some exceptions like, for instance, for sensitization.

also for implantation. But there is like more and more shift to non animal testing. And also one more concept that I can talk a bit here is about using real world evidence and information. So here we are talking about streamlining and structuring the data that is already available for some medical devices, because we can find critical medical devices or equivalent or similar medical devices. So how they perform what are clinical studies? What is the data about it? And using this data liver agency's data. We can also make conclusions about biological safety. Because, look. when I was talking to Dr. Hopkins, he, he actually made some time ago, quite a long ago he made a very nice post about

about how how can we use this test? This animal test, if their reliability is around like 60%. If I'm not mistaken, you know. So what about other 40%? So what to do here? Right? Because some tests can be unappropriate. Because so big difference between what we have within the test lab and clinical conditions when actual patient is using this test. So that's why real world. Data and evidence are like, very popular. Right now, if I can use this word. And I do believe that this data can be leveraged leveraged for our medical device. But when we are talking about the FDA, the case is a bit different, because I know. I know that there are some discussions around it. And people some people are

are trying to go within non animal testing more and using also real world evidence. But some people are not so eager to jump to in vitro or in silica in silicar testing. Actually, yeah, so, and when we are talking about the FDA, they tend to use animal testing preferable to in vitro testing just because of this approach. But again, I faced these different cases there, and it depends on the personality, I would say, but mainstream, yes, to use animal testing so here

it's very important that we can share the information that we can educate each other that we can actually yeah, leverage the information we have. when we are applying, for instance, for both like the FDA and here in Europe. So I know that Europe can accept animal testing because we can say, like, Okay, FDA is asking for it. Or, for instance, it was done for the FDA, like 1st entry to the market, and then leveraged here for Europe. So it depends. Again. Unfortunately, the answer is not like.

Michelle | leanRAQA: I could say it was already. It was already done, you know.

Exactly, exactly.

Michelle | leanRAQA: Exactly.

Exactly. It was already done, for instance, for the FDA and market is, it's sold on the American market. And then people want to. Yeah, bring it to European markets. And like.

Michelle | leanRAQA: Might be one more justification for a Us. Market entry over an EU right now.

Yes, yes, yes, yes.

Michelle | leanRAQA: So here's another, good one, and something that you and I have talked extensively about, and that almost the whole podcast. I did with Wushi was about this. But Michelle | leanRAQA: how does one go about selecting a test lab? And Michelle | leanRAQA: what is what's going on politically right now, with all the biocompatibility test labs. How do you know what a good one versus what Michelle | leanRAQA: you know? One on the naughty list is right now.

Oh, yeah, it's it's very hot topic. Actually, right now in Iraq, quite a lot of questions like this. How to pick the right lab and what to do with it. Right? So maybe I I do believe that it's not a secret that right now it's kind of ban from the FDA to perform tests in Chinese and Indians labs. So but I have heard the information that the test can be performed in Chinese or Indian markets after FDA. They inspect after FDA inspection. Actually, so, FDA is going to inspect such labs. And surely this information would be available on their website. And when it's available on the website, like, okay, it's safe to use here. Yeah. So then I.

Michelle | leanRAQA: By by on the FDA website. Are you referring to the.

Oscar.

Michelle | leanRAQA: Accred 8. 8. Yeah. Oscar accred date.

So now support.

Michelle | leanRAQA: For conformity assessment. Is that right?

It's another. It's another point. But the 1st point is that every day is going to audit them. It's just a just recent usage.

Michelle | leanRAQA: Process. Yeah.

Yes, yes, yes, yes, yes. So regarding ask, it's actually second point to be 100% sure what to do right now, before. Like all this audits before, like some other information is available. is just to go to the FDA's website to ask a pro to ask a program actually and and have a look like, you know, type in biocompatibility and see what labs are available for the testing regarding biological safety here. So and from this standpoint again, safe to safe, to test. And yes.

Michelle | leanRAQA: Point out to people that that may not understand the Asco program just because a lab is on the list for Asco. You've got to look for 2 things. Michelle | leanRAQA: first, st that it's certified for its sampling methodology as a whole, because that's like Step One. Because if you can't, you know properly sample, then they won't qualify you for any of the tests. Michelle | leanRAQA: And that's also a basic quality system. But then the the next level of that is, not only do you have to have this kind of general quality system and sampling technique? You also have to have test specific

Michelle | leanRAQA: inspections. So you've got to look for. Not only is the lab got on the Asca list, but they're on the list for the test that you're hiring them for. Michelle | leanRAQA: So.

Yeah.

Michelle | leanRAQA: It's not just a part, Blanche.

Yeah, that's very valid point. And thank you for bringing it up. Because when you are looking for the lab in this, ask a program on FDA website. It's actually very clear, like, okay, they can perform site at Texas. Just example, you know, such kind of thing. So it's very important to have a look into it. Yeah, very valid point. Thank you. I also know that there would be a discussion around. Ask a program and dash 17 extractables and leachables in October, November. I don't remember, so it's it's open and free. So feel free to read like register, because I'm I'm just waiting this popcorn to be honest.

Michelle | leanRAQA: Is that? For with the FDA like one of their town halls, or open.

Yes, but but not like Town Hall, where? Where they just present, but rather open discussion, actually.

Michelle | leanRAQA: Okay.

So here we would. Yeah. yeah. And maybe maybe I will provide the link to their website where you can register, because here on this call, we would be able to talk from like industry. Representatives, actually. And like, yeah, really, important interesting topic. Yeah, I will provide the link. And I do believe Sean can help us with distribution of this link to everyone. Yeah. So

Michelle | leanRAQA: So here's the other one that that I I see a couple of questions that are kind of related to this this topic. Michelle | leanRAQA: and that's con understanding contact, duration. And I'm going to go beyond just the standard, you know, 24 h or less, 30 days or less or more to like. Let's start thinking about continuous use. So Michelle | leanRAQA: talk about a little bit about those 2 topics, and Michelle | leanRAQA: and how you have to think about them together.

You mean, like contact duration, like, okay, all the time. Right. And second, sorry I.

Michelle | leanRAQA: Like, if you say something that you need to replace it daily. And so like, are you gonna do a 24 h less or.

Thank you.

Michelle | leanRAQA: To like, put on the nasal cannula every day.

Yeah, yeah, yeah, I see, I see what you're talking about. So actually, it's very common mistake that sometimes accumulative effect is not considered. and not only within the classification of octagorisation of our medical device and full assessment in biological evaluation, but also duration of use during testing, because it's important, for instance, for toxicological actually risk assessment to understand how long our medical device can be can be used. Oh, I could see some heart, some, you know some obstacles. Thank you. So and here we need to work in collaboration with clinical affairs as well as regulatory affairs

to understand their okay, whether it's like, really can be used. I don't know. Like like, altogether, I don't know for years, right? Or their usage of this particular medical device can be can be limited to some. I don't know to some standpoint so, and surely. when we have this cumulative effect. For medical device like life long. If that makes sense right? So we need to go into very throughout biological evolution. And, for instance, for instance, for for our type of medical device. This, for instance, chronic toxicity. Let's consider right? So it's not required for our type of medical device. But when we consider cumulative effect.

and consider like, okay, this is life like lifelong duration of use. So we need to do not only like literature, review and assessing all the things that we are doing for each biological evolution right? But we also need to have a look in the toxicological risk assessment and bring this contact duration here, as well to be able to calculate the right limits.

Michelle | leanRAQA: yeah.

Hopefully, yeah. hopefully, that helps.

Michelle | leanRAQA: So we talked about some of the case studies. What are some of the other common mistakes that you might have seen either in Michelle | leanRAQA: sample submission, test selection. Michelle | leanRAQA: the wrong type of test like or is there anything else that you feel like? Yeah, you need to leave us with some with with some wisdom on here to.

Oh, there are quite a lot of common mistakes, maybe the most common. I would say. It's our absence of biological evaluation plan when we you are going to the lab, because lab, surely they can help. They can test whatever you like, bring to them. But they're their core the core idea of biological evaluation is to understand medical device to utilize the data we have for our medical device. I mean, in, for instance, from clinical from post market. If we have available post market information from a literature review, from available databases with toxicological profiles whatsoever. So what's biological evaluation plan about is just to structure the information, to understand what's covered, what biological effect covered, what's not covered and help to understand biological hazards, because we just can't go and test

everything we just need to understand. Okay, when we test what we are checking. So you know, here, that's why biological in ideal world biological evaluation plan shall be signed off before you go to the lab. Because what biological evaluation plan comes.

Michelle | leanRAQA: Service announcement. People, all of your protocols and plans should be signed off on before you do the testing, regardless of Michelle | leanRAQA: biological evaluation or or otherwise.

Yeah, it's it's very. It's very valid point. And thank you for for highlighting it. And Bp also contains normally test strategy. Like, okay. we have, we identified gaps. Okay, so how we are going to provide evidence, or what shall we do? And one of the input here, like, what shall we do. It's actually to do the test right. But here it's not too easy, like, say, Okay, Cyter, we had done, you know, like 5 samples. That's it. Now, there are different types of site, like what exact exact site we are going to use because of the of our device. Like, whether we have just the contact with intact skin or the implant. So

we need to consider this and put all these details within. Our biological relation. Plan also is a common, quite common mistake is with extractables and bleachables like wrong solvents, for instance, are chosen or wrong temperatures are chosen, or, for instance, we have adhesives, and oh, my gosh! We have adhesives, and this adhesives can can, absorb some water or some other liquids, so it shall be considered as well. And all these details. Normally, yeah, please.

Michelle | leanRAQA: Share with the good people like, how much time and money average extractables and leachables cost.

A lot, I mean, I mean, with it's actually If it's not the most expensive. I would say this is the most expensive.

Michelle | leanRAQA: It's easily, because usually in it, like a 6 figure song. And it's like it's 8 to 10, sometimes 12 months.

Yeah. And why so long? Because usually our, the labs need to identify the their basics. I mean, they are checking how it works, whether it works. In some cases it doesn't work. So they are trying to understand or find other solvent, or maybe mixture, you know. And all these things are taking time also. Here there is a trick. If you're talking about extractables and leachables, so leachables are more similar to clinical use, like, actually, what can Leech, from from our medical device to our body and extractables is about everything. It's kind of net that we are trying to get everything. And this analysis, like, 1st of all, extraction, it takes time in different solvents. And then we need to do the

we need to do proper analysis to be able to identify what we actually found within our medical device. And here there is also a trick to a question how to choose the lab, because for for the customers I usually recommend to reach out to the lab that have experience working with similar devices. Why? Because they can have good libraries to be able to identify these chemicals that are pretty important to toxicological risk assessment to extractables and leachables. Chemical characterization, I mean here. So.

Michelle | leanRAQA: Important back to link back to our discussion about how to select a lab. Michelle | leanRAQA: That's an important question is to ask them specifically about your device type Michelle | leanRAQA: and their experience. Again. Michelle | leanRAQA: test by test with your device.

Yeah, yeah, that's that's really because, I would even, yeah, recommend to ask all possible questions, not only about certifications or checking them, but also asking for showing their protocol templates, you know, and absolutely asking about their the devices, whether they have experience working it. It's important. One more thing is that maybe I would like to. Highlight are final thing. Here is about It's about expertise requirement as per iso tenant and 3, 1, that here we can have our education. Here we can have our experience at work, but also taking part in different conferences, summits networking with people, and

not doing biological evolution alone, but rather with talented team. Yeah, to. So to be able to do proper evaluation. So unfortunately, it's also quite a common mistake just to do everything alone. But yeah, we we just need to talk. We need to share the information. And we need to think loudly and discuss the things with other professionals. I do believe that this soft skill of communication is our must to be able to find the information share the information. And yeah, make some conclusions. Actually, here.

Michelle | leanRAQA: what about are there any trends that we haven't talked about that either from things that you've seen in active review being challenged by either the FDA or the notified bodies, or or what do you? And what do you see Michelle | leanRAQA: coming for the future?

Oh, just a short case. Actually, because I really, really like it, are the company submitted a technical files here in Europe and net safari body. It's actually about surgical instrument and net safari body said like, okay, you have stainless steel. Please provide justification about cobalt and their beauty here is that surgical? According to the technical specifications. There is no any cobalt in this stainless steel, you know. but cobalt is residual, and it goes directly together with Iran, no matter what. So you would, you will find cobalt if you have iron, any iron material like stainless steel, for instance, you know, and what they actually asked and what I did, I provided justification about this very small amount of cobalt

within biological evolution. So so be careful here. And here I'm talking actually about carcinogenic, mutogenic toxic to reproduction as well as endocrine disruptors all the things that are mentioned within medical device regulation. And it's actually main difference from what we have within the FDA, because FDA doesn't have such lists. Yeah.

Michelle | leanRAQA: Which kind of sums up like, I think several of these questions that I have seen come through about. I'm just gonna rattle off a couple of them, and then make a point about it, like our biocompatibility studies strictly supposed to be performed for finished products or material studies fine to show in a 510 k. Michelle | leanRAQA: If my supplier does not mention the grade of raw material, what should I do to demonstrate? So on and so forth. We've got several kind of a little bit more specific questions about that.

Well.

Michelle | leanRAQA: I think the answer to all of those, and kind of Michelle | leanRAQA: a a point of a lot of the questions we've talked about is that it comes back to that biological evaluation plan, and that it is comprehensive that it's done in advance. And if you have any hope of being able to justify Michelle | leanRAQA: doing or not doing or doing. A smaller set subset of testing is going to be from a very thorough, well researched and well documented biological evaluation plan.

Yeah, absolutely. And I would say that in some cases because usually biological relation plan again, contains the information about sample, how the sample was chosen. Why, this exact sample, you know, with justification, like whether it's worst case or whatsoever. So in some cases they, this can be justified. But, as you said, everything shall be documented within biological relation plan. not only like, okay. We picked this one because something is not provided or something not done. But no, it shall be a scientifically valid justification. Why we can use, and why we don't see any additional risks

while using this exact sample to to to testing, but really very shortly, if you don't mind about future. So here I could see several streams. Actually, one of the stream is using AI for biological relations that can help to streamline the information. But I don't think it would replace us, because we need to see, like full picture the dependencies, etc, etc. Rather like, help us there. Yeah, yeah.

Michelle | leanRAQA: Might streamline, but not replace.

Yeah, yeah, streamline helping to accumulate the information. Because, I like the approach when we can reuse some specific information about materials that are used for different medical devices, but used for us for our medical device, for instance. Right? What else can I name here? So surely going into in vitro testing mostly, and are reusing already existing data, for instance, from clinical evaluations. And here I'm talking about real world evidence that is pretty popular right now. and I hope that are in future. When we have this dash, one published hopefully this year, incentives this year. Right? We would be able to identify some concerns in the very beginning, like on prototype phase. So it would help us to save a lot of

money and time, because we would know hopefully some concern since the very beginning. And we would be able to do something with this like to implement some control measures. Yeah.

Michelle | leanRAQA: Well, we're almost out of time here. There are Michelle | leanRAQA: So I think this is relevant. Luke just asked who who was an earlier early contributor to our questions here do consulting firms exist that can specifically advise on biocompatibility plans throughout the design phases Michelle | leanRAQA: like on what is and not stupid to design. Michelle | leanRAQA: I think the answer to that is is, yes, Luke, both both Img and lean Raqa can help you sort out this. This stupidity. Michelle | leanRAQA: Okay.

Yeah, I I just wanted to add really quickly here that on the design phases like, if you're talking about prototype, for instance, not design verification. We can use biological assessment, not like plan very deep with the testing, but rather assessing, together with cross functional team. Yeah, on the very beginning. But yeah. both lean Raqqa as well as Img, can definitely help.

Michelle | leanRAQA: I would like to.

A moment to thank both of the speakers for joining us today. This has been very, very informative. Thank you very much. I would like to remind everybody to take the survey which is gonna pop up on your screen when you leave the call your feedback is very important to us. I've put a number of links in the chat. I recommend that you make use of those links if you'd like to connect with either Marina or Michelle on Linkedin. Please do so. And if you have any questions, please email me, Shawn at virtu B, 2 b.com which, again is in the thing. If you haven't requested your certificate of participation.

or attendance. Please put your name as you would like it to appear along with, your email address in the chat, and that will be sent to you in the next couple of days. We have to do those manually. So please be patient. again. There are 2 upcoming webinars, our 1st Spanish language webinar, which is Latin health tech Latin is going to be really exciting about getting your 5, 10 k, and then clinical data requirements EU versus us both. Really exciting. Coming up this month. Please check those out and remember, subscribe to Med tech leading voice, com, and get all of the latest from experts

like Michelle and Marina. Thank you both very much. Any closing words or thoughts.

Michelle | leanRAQA: BEP.

Yeah, just remember this.

Michelle | leanRAQA: Yup. Michelle | leanRAQA: if there's anything you take, it's due. A biological evaluation plan Michelle | leanRAQA: to Luke's Point early and often.

And if you have some additional questions that you like were too shy to put into the chat, please feel free to reach out to any of us. we would be more than happy to address the question and to help, but surely, like on high level, because because of the nda.

Wonderful. Thank you very, very much, both of you. I hope everybody has a great day and a great weekend.

Thank you. Likewise enjoy a day. Bye-bye. take care.