Satisfying ISO 18562 & FDA Biocompatibility Regulatory Requirements for Breathing Gas Pathway

hello my name is Audrey Turley and I am with Nelson Laboratories I have worked with Nelson Laboratories for over 20 years and working in biocompatibility for the last 15 years today we are going to learn about satisfying ISO 18 562 and USSD a biocompatibility requirements for breathing gas pathway devices I'd like to get started by a brief introduction to the standards I'm going to use for my presentation I'm going to use and discuss the 18 562 this is a vertical standard that goes along with up to 10 a nine three suite of testing so ISO 1009 three covers biocompatibility for medical devices it's a very broad application of biocompatibility considerations for all medical devices and eighteen 562 is what we would consider a vertical standard that helps us assess the additional risks that are inherent with gas pathway devices we will also discuss some information that is found in the US FDA guidance document on the use and interpretation of ISO 10 993 a biological safety evaluation really takes part in three phases so even though we're going to focus on 18 562 testing I want to talk about the big picture and how we're going to put everything together and a good approach to make sure that a submission to a government agency can be successful so we start with that with a biological evaluation plan this really serves as your initial risk assessment if you are familiar with ISO ten nine nine three standards already you know that part one discusses you know evaluating your medical device from a risk-based approach so when we look at a biological evaluation plan we're going to take into consideration everything we already know about our device including materials processes maybe previous devices where those same materials and processes are used and and then also if this device is brand new to market we're going to take all that into consideration and then determine where there are any gaps to mitigate risks to the patient so that can be that we need to still do testing maybe we need to just do some written risk assessments it could be a combination of all of these things we're going to write that out in this first document and this document can be used for two primary purposes the first is that this document can be submitted for a purely on discussion with F with whatever agency you are using to submit your device this can facilitate the plan and help them to know exactly how you're going to address the risks of the device the second purpose of this document is that it can help track internally why decisions were made down the road so that there's an understanding when changes to a device happened down the road you can understand what you did originally and what needs to be done to assess this change so that is the first step the second step is where we would do testing and risk assessments and again this could be a combination of both of these things and usually is and this is the longest phase of your biological safety evaluation program it takes the longest it's you know based on the testing that is performed and the type of risk assessments that need to be written this could take anywhere from three to six months completion typically then we go to the third phase which is a biological evaluation report this is called out in ISO 1009 3 as well where they are asking for a review of all the data and everything that has occurred in phase two and to come to an end conclusion whether the device is safe they specifically stay in the standard that this evaluation should be performed by professional experiences professional professionals with the appropriate experience and education to make that end conclusion so an important part of this full evaluation is to talk about risk ISO 18 562 you know the topic or the title of the guidance document is evaluation and testing within a risk management process this mimics the title for a ISO 1099 three part one as well so it's to run in you know good companionship between 10 9 9 3 and 18 5 62 and understanding that we still want to address risks appropriately and when we talk about risk here we're not talking about the risk of the intended function of the device we're talking about the risk of the materials and processes used to make the device risk has become such a large topic and such a focal point for biocompatibility that FDA has put in their guidance document which was published in 2016 a full section on risk management and the approach we should take when we are doing our biocompatibility evaluations within this section they've highlighted some components that should be considered in this evaluation and I have put them in bold on this slide specifically material components manufacturing processes the clinical use of the device these things shall be taken into consideration from a biocompatibility perspective and then they should be determined used to determine what met next needs to be evaluated and that can be done by testing or through written risk assessments I like to start out with a definition of risk that we get from ISO 14 971 which is you know a standard that talks about the application of risk management to medical devices so the definition in this document is the combination that risk is the combination of the probability of occurrence of harm and the severity of that harm so how likely is harm to happen and when it does happen how severe will it be is it just an allergic reaction or rash or are we talking field death or cancer or further issues down the road in the patient's life and you can see we have a mouse here who's out you know trying to decide what the risk is is he prepared enough has he mitigated as risk enough to get this cheese so just a visual to go along with this definition to keep in our mind as we go throughout this discussion today and all biocompatibility evaluations that we always want to do it from a risk-based approach I so 10 9 9 3 part 1 has a decision tree in it that helps you to decide where there are gaps in your medical device and the risks and what needs to be done to assess those gaps so we really start with what do we know about the device what materials we really focus on the materials and then we go to processing including sterilization and as we go through this decision tree it will guide us whether we need to do further testing or just risk assessments based on the information that we already have taking all the data that we have and applying it to this specific medical device so this is what guides and drives your biological evaluation plan the conversations that will be had within this written document as part of that conversation we want to talk about device categorization so the US FDA has defined in direct contact as those things like fluid gas pathway devices so a device that will have air or fluid passed through it and will come into contact with the body and then in eighteen fifty sixty two it states that under indirect tissue contact categorization according to ISO ten nine three there's an insufficient assessment of gas pathway devices so there's a gap in mitigating the appropriate risks so when we talk about writing our initial risk assessment we would want to include you know the 10 993 guidance documents because those are horizontal they're very broad they give us a place to stir but we want to include the appropriate vertical standards and so for gas pathway that would be 18 v 62 and most people who've done biocompatibility evaluations are familiar with this table this is from the FDA's guidance documents and I'm able to put that on a presentation because that is available for free online and but this also contains information from the ISO guidance documents as well what we're looking at here is that we're going to understand possible biological effects meaning risks to the patient based on contact type of the device and duration so when we look at this table this is half of the table the other half is on the following slide you can see that we start with device category surface device external communicating device and then where in the body those devices contact a patient and then of course the time duration limited prolonged and permanent the second half of this table is where we will focus our conversation on today breathing gas pathway devices fall within external communicating tissue contact and then appropriate time categories based on the use of the device you can see that we can range from just a few biological effects that we need to address in our viola biological evaluation plan or almost all of the endpoints possible listed here and we're going to talk about these but it's just important to understand how the regulatory agencies are categorizing these devices so that we can understand a starting point for our biological evaluation plan one thing that is important to remember or to take note is that just because there is either an X or an O in this table that does not mean that you go out you call the laboratory and you get this testing set up that means those are possible endpoints and justification for doing or not doing the endpoints needs to be written in your initial risk assessment okay so just to give us a summary for the ISO 18 562 standards it comes in four parts and the first part we talked about which is you know setting up your evaluation of your device by identifying the appropriate risks of the device and then parts two through four go through individual test considerations so part two we're going to assess particulates part 3 will be volatile organic compounds or VOCs and then part four is test for leachable in condense 8 we'll go through each one of these to understand how they apply to specific devices and the testing that's recommended within these standards so ISO 18 562 also has a flow chart to help you understand what should be expected in your biological assessment of these breathing gas pathway devices this is a bit vague as far as it's missing a few specifics but it does give you the big picture perspective to help you to know that you are going to start with your risk assessment which will help drive your evaluation plan so you need to identify your testing and then you go through and do phase 2 and as we outlined here and assess about compatibility and at the in the last box where it says determine acceptability that is where your BER would come into play your biological evaluation report which would state whether the testing and data supports the safe use of the device for the intended patient contact and patient population so I've simplified a figure that was in ISO 10.9 or excuse me ISO eighteen five sixty two part one that talks about how you decide which portion of eighteen 562 you need to follow for testing so I put a note here at the bottom that you can see Figure two in this standard for a detailed decision tree to help you be educated about the decisions you're making about the test selection but really we're going to separate these devices into two main categories dry air or humidified air pathways so dry air pathway on the left of the slide is going to require additional testing through particulates and air and VOCs in air so when we think about dry air pathway we're talking about a tube that does not touch the patient so the other considerations in 10 993 would not be appropriate these are the main concerns because we want to know what could transfer from that tube into the patient the particulates would be of great concern and then of course our volatile organic compounds one thing we have seen in the standard is that they did mention to do s VOCs which are semi volatile we haven't seen an agency be specifically concerned about that so our recommendation is to put in your BP to only do the VOCs and then see if they come back and ask for the additional testing only because in discussion with our chemists and some of our experts here we felt that this semi-volatile testing wasn't appropriate and wouldn't really assess the risk to the patient well and that documentation will also be written in the biological evaluation plan so then if you have humidified air that's on the right side of the slide there's some additional testing to be considered so you would still do particulates in air so when we think about the lungs anytime there could be direct contact into the lungs without our natural filters of our body to get rid of these particulates those are going to be concerned of concern as far as once they get in they're very difficult to get out of the lungs so particulates and air for this and again VOCs in air according to part three and then part four would say we would want to do condense eight testings so if there is water in the tube we would want to test some chemistry to see what's coming off in that water in the tube so we would recommend VOCs in water extract and then also a cytotoxicity sensitization and irritation testing so cytotoxicity and sensitization we are only recommending for devices who already have not had additional 10:09 three testing so if you've already run cytotoxicity sensitization and irritation on this specific component or this specific material that testing does not need to be repeated under-18 562 we can simply write and justify that it has already been completed again that would be contained in the BEP one thing you may be asking is well if we're doing VOCs in air why do we need to do VOCs in water can't we just do one or the other that's a question we're actually asking ourselves so according to the standards this is the testing that would be requested however we don't know or feel that both are necessary so if you feel like you would like to have a conversation with the agency or submitting to a great thing to start with in your biological evaluation plan is to just say that you will do the VOCs and water provide a scientific justification for that if you have a humidified air pathway device and then see if they accept that or if they still feel like you will need to do it in error so this is where this document this biological evaluation plan really facilitates a great initial conversation and we can educate each other as far as the agency can the agencies can see the perspective from a manufacturing and a testing side and then we can also see and understand what the agency is staying on their side you the FDA has recently published their acceptance of 18 5 62 so what they've accepted in full is parts 2 & 3 so the testing specifics for particulates in air and the testing part of em specifics for volatile organic compounds in air the documents that they've accepted in part are the part 1 and part 4 portions of 18 562 so there is a concern that in 18 552 part 1 when they discuss all of the testing options they don't talk about testing for irritation of this leachate typically and also testing for irritation of devices that actually contact the patient so the FDA does not agree with that because that does not comply with how the ISO 1009 3 standards are written as well and so the FDA would like to see irritation testing when it's appropriate and or to justify why it doesn't need to be done because you already have information about irritation testing and then for part 4 where it talks about testing in the condensate there's a lot of language about this 1 mil of condensate per day dose to a patient however there's no support literature that was identified for that specific 1 milliliter per day dose so the SCA doesn't support addressing it that way and so as I talked about part 4 testing later on in this presentation I'll give specifics about the testing that we have worked out with the FDA and let you know they're mine thought on what they'd like to see and then and then in part 4 again it goes on to talk about testing this leachate and it does not talk about testing for irritation so we would want to just make sure we're staying you know incorporating all the testing outlined in 10 9 9 3 part 1 and that 18 5 62 is supplemental testing and then I've listed here where you can find that information published by the FDA so this is just an outline of what we typically include in our biological evaluation plans we start with a nice discussion about you know material characterization identifying what your materials are and giving the OP the opportunity to stay and present the information we already have on these materials and then a nice device description and categorization which helps put everybody on the same page because some device categorizations can be a little tricky so it's nice to have this upfront so that the testing outline below following this device description matches you know how we're interpreting they use a device of the device we also will outline special test sample preparations this is a nice benefit to clients to get this addressed upfront and gives the lab opportunity to work together for all the different laboratories that may be involved in testing these products so we can discuss you know what's going to be included or excluded we can troubleshoot extraction issues that we may find compatibility with solvents and then we have this written in this nice document and this again is where it's valuable as an internal document so that there's understanding of how decisions were made and how the product is to be tested so that that stays consistent through the life of the product and then we'll talk about testing and risk assessments where we'll outline the specific tests but not only you know if we need to do particulate testing we don't just say do particulates according to the standard we actually will specify the method the standard that's going to be followed and give specific details so that when you submit your tests we've already made all of those submit your device for testing we've made all the decisions up front and now it's time to just get the work done so that is phase one of your biological safety evaluation moving on to phase two testing and risk assessments so I'll just go over some of the testing not in a lot of detail but just enough to help you understand what we're looking for and to identify some of the standards that are followed for the testing and again this is a review of the categories or the tests that are considered in each part of the 18 562 standards so one thing we want to talk about at front is really the test sample selection so on the Left we see we have some raw material which is just a polypropylene pellets placed inside an extract media so this would be inside staylene in a tube and it's ready to be extracted for testing and then on the Left we have a finished device who's gone through which has gone through all the processing and sterilization and now this nested box is going to save a patient's life and before we do that we want to get it into testing so when we say we want to capture all the information we can on the raw material there might be some testing that you've had done on that raw material but we want to make sure that we are incorporating our assessments to include the processes and sterilization of the device that is important and there is so much variance there between manufacturers that that's really where the difference lies and the Act the greatest risk because that's what we haven't assessed for every single device because it's different for every manufacturer and 1099 three part one says that the testing shall be performed on a sterile final product for a representative sample of the final product but it must include all of the processes before assessing for biocompatibility so we'll talk first about particulates and this is an 18-5 62 part two this is required for dry air pathway devices and I should have had him in here also for humidified air we're always concerned about particulates when we have direct access to the lungs so there's three different test options laid out in the standard you can do a single particulate filter and inertial particulate separators or you can use a particulate counter or particle counter in our conversations with SCA they've requested a NIOSH manual of analytical methods o 500 and this is just a particulate and test procedure that's already been established and they would like us to do it with a two micron filter so when we look into – – of 18 560 – it talks about size of particles and limits so what we recommend doing is that so and these limits were set according to the US EPA 40 CFR part 50 so there's a lot of crossover between EPA and FDA in these guidance documents because the chemistry testing that's usually based on EPA and we're translating that over to these FDA applications so we start with a 2.5 micron filter or micron size particle so what typically we recommend is that clients start with this testing and just use the 2 micron filter and then if they fall below or you know substantially below a write out this limit of 12 micrograms per meter cube of particles that no further assessment is needed we don't have to worry about these larger size particles because we've already captured them with this first test however if the first test you fall outside that 12 microgram per meter cube then we would want to do further testing to separate out the size of particles so we can see how many of those are small particles and how many of those are larger and of course the larger particles aren't as great of a concern because they don't penetrate as far so smaller particles are more toxic because they can even be absorbed into the bloodstream part three 418 562 is our that discusses the test for emissions of volatile organic compounds so these again are required for dry air pathway devices and this is what we've seen from the FDA is that they requested tio – 15 which is an EPA canister method analyzed by GCMs so what we do is we will hook up these canisters to to your device pass air through them and then capture the VOCs in the canister and then submit that canister for testing by the analytical laboratory so these exposure limits are set based on you know typical breathing rates that have already been established and and so we have these this criteria here one thing that's that's important to notice and remember is that the results of this testing need to be analyzed by toxic a toxicologist the reason for that is the chemistry data you get is just a known amount of compounds and for this it would just identify you know maybe so much alcohol or isopropyl alcohol but we need to translate that back to the patient dose and determine if the amount of alcohol coming off the device is safe for the patient exposure and so this TT see here it listed is a threshold of toxicological concern and this is listed in the standard and this sets just basic limits you know if it's below the TTC you don't need to assess it further where there's not a great risk to the patient however if it's above the TTC then further assessment needs to be done either way the chemistry results need to be looked at by a toxicologist who will appropriately assess the risk of the patient and give you that conclusion whether there's a risk to the patient or whether the device can be considered safe based on this data and the fourth testing the fourth part is testing for leachable Xin condemn state so this is required for all humidified air gas pathway devices so the test method is listed in 18 562 are all based on this one mill convinced 8 dose to the patient that is you know a huge issue in the industry and a lot of disagreement about that and about how it came about so how we're handling it is to run a full extractable eligibles panel according to iso 10 & 9 3 – 18 and so this is where we do it with a water based extract just on the internal portion of the pathway so this is another thing that you would want to write in your initial BEP and submit to an agency or justify in this initial BEP so you can have the scientific rationale for the testing that was performed because it's difficult to correlate and create a 1 mil condensate to simulate that in laboratory testing and then that one milliliter isn't enough fluid to run the appropriate tests that have been asked for in an 18-5 62 so there's just some discord with what's recommended and what can actually be performed in the laboratory and so what we've done is recommend these full this full panel ml and that has been accepted so just a little conversation about how extractable eligible works so we do this according to iso 1009 3-part 12 again we're going to flip back and forth between these two different standards we do it at 50 degrees for 72 hours this is considered an exaggerated extraction conditions and we only use water because we're only expecting it to be a polar solution that would go through here so just a water that's going to be exposed in that tube so no nonpolar extraction is needed then we cast a wide net and search for a variety of compounds so we see here we have our volatile organic compounds which are easily evaporated because they are so small and then we go up in size on the organic side down to our non volatile organics which are very heavy and typically analyzed through liquid chromatography so how we do the gas chromatography and liquor chromatography just to give you an idea is that we have the extracts go through a machine that will separate the compounds based on size and that's what we're seeing here is that they've differentiated here by size the compounds found in this extract solution and then we put it through a mass spectrometer and we can see that it's actually breaking it out to the individual atoms and bonds and then we can put together that this mass spec is for benzoic acid so this is the type of chemistry data that you would see from these results displayed in the table here on the left-hand side and so if you looked and saw this data we still don't know what this means to a patient and that's where we move on to the toxicological risk assessment so I wanted to go into what's included in a toxicological risk assessment and our assessments are done according to 1093 part 17 where we talk about tolerable exposures from compounds to patients and medical devices so the first thing we do for a chuck's quadrakill risk assessment is to determine the chemistry results in milligram per device so that was done on the previous slide and now the toxicologist is going to research the tox data available for each compound so the toxicologist will look for these noelle or low L values so no adverse effects level or Lois adverse effects level this data is published based on research that was already done so this is where we eliminate some needs need to do additional work we're using what's already available in the databases for us to research and then once that those levels are found we move on to do calculations according to ten nine and three part 17 which we're calculating a tolerable intake a tolerable exposure and then in the end a margin of safety that is a ratio of what came off the device and what's acceptable or considered safe and hopefully we want to be very well above a one be considered safe I'll walk through some of these calculations just on a very high level so that you can understand what's included here so the first calculation that is done once the Noel has been researched and established that that's the value we're going to use and is most appropriate for the medical device that we're assessing we take that Noel and then we use correction factors so UF one two and three and those are defined below where we talked about inter individual variation among humans you know we're not all the same so we want to have a default and a default correction factor here which is typically 10 and then for the u.s. – this is the differences between animals and humans the default is 10 here but the toxicologists will adjust this value based on the subject animal that was used to establish this Noel value because some of those factors are you know they stay at 10 but sometimes they can be reduced depending if it's a large animal when we're comparing it from animals to humans and then the third utilization factor is quality and relevance of the experimental data so we'll look at replications what how great was the sample size how long was the study run does it appropriately correlate to the device and sometimes we'll have to adjust here for route of exposure and which is done for inhalations can be done quite frequently for inhalation when we consider a systemic exposure versus a breathing pathway exposure and then we've correlate that and we calculate it out to microgram per meters cubed per day to get a breathing dose then we move on to do our tolerable exposure which takes into account our TI which is our daily dose and then we take into account this inhalation rate and then we add another safety factor which is actually a combination of two additional safety factors which is the number of medical devices that can have the same compound in it that may be used at the patient at the same time or how often we may be exposed to the compound through other sources maybe our food maybe it's naturally found in the air those sorts of considerations and then we get our dollar able exposure dose per day then we run our margin of safety oh I wanted to stay on this our exposure it takes into account the patient population that's the inhalation rate here where we take into can't account the breathing rate for Pediatrics neonates and adults and so we use published breathing rates that have already been established and we use those in the calculation here so we really take into account that patient population and if it's exposed to multiple patient populations like maybe it can be used for pediatrics and adults and then we'll run the calculation for both populations and then we get to the last calculation which is margin of safety and this is where everything hangs on this conclusion of whether we get a margin of safety that's above a 1 so we take our tolerable exposure that we've determined based on published data and these calculations above and then we divide it by what was detected in the device so this is where the chemistry results come into effect and then we come up with our ratio this is your dream conclusion for toxicological risk assessment where we identify that we've used chemical characterization data published literature and we've derived our margins of safety and then we can assess if all the margins of safety are above a 1 that the risk and to the patient is low for all compounds identified additional considerations to think about when you do this testing there may be possible follow up on analytical testing to demonstrate safety of the device if when we run the general chemistry this full extractable in leachable we cast the wide net and sometimes we find that there's a compound that would be of concern but it was below the detection limit so we would want to do some targeted chemistry analysis with a lower limit of detection so that we can determine if it's really there this compound is really present and at what concentration and then run some toxicological calculations as we discussed to determine our margin of safety and then for components that touch the skin of the patient so say you know you have a pathway a breathing gas pathway but you also have a component of your device that actually touches the skin you would need to do testing according to iso 1009 three part one where this would typically include cytotoxicity irritation and sensitization testing again to be laid out in your BEP as you discuss your full device so I wanted to talk quickly about those three tests cytotoxicity and sensitization and irritation so for cytotoxicity we take an extract so if you think back to the slide on sample preparation and it had the test tube with the pellets in it that is how we extract a device for for these tests and then we take some of that extract and we would place it in a plate that has these cells growing and this is a happy these are happy cells we can see that they're attached and that they've got this orange colorant in it which is we put a dye in and if they take it up that means that they're living they're taking nutrients from their environment so this is what a negative response would look like and as the analyst looks at the cells under the microscope this is what they're looking for this is a positive so this would mean that you had a severe cytotoxicity response you can see it's such a severe difference from the first if we saw just a zero or four you know it'd be no question that you can tell this this is a problem we don't see that they're attached we don't see good cell walls I'm not a lot of orange uptake some of these are surviving but not very many so this would be a severe cytotoxic response cytotoxicity is scored from zero to four and it's a path if you're a two or below and it's a fail if you're three or above these are published in the standard for cytotoxicity testing and so it's great to have cytotoxicity testing on your raw materials as well because you wouldn't want to start with a material that's already coming in at a two and then be manufactured because typically manufacturing is additive and so there's a good chance you would push over into a moderate or severe reactivity if you're starting it mild already so it's a good screening test for your raw materials but also lets us know if there's some toxic or toxic leachable coming off of the device after manufacturing irritation testing this is an injection or an extract based test as well and so we would take some of that extract from the test tube and injected just under the skin of a rabbit and then we will look at the skin 24 48 and 72 hours after injection and then we score it on a scale of zero to four again for redness and swelling erythema and edema then we tally up all of the scores and divide them to get our average and compare it to our negative control so again here we want to be one or less to be considered non-irritant some devices are categorized as slight irritants but again we would want to look at that result in your biological evaluation report your summary report and determine if that is an appropriate risk to take based on exposure of the device to the patient so if you score above a one on your irritation test it's not necessarily the end of everything and going back to the drawing board so there can be some conversations had about how relevant the results are to the patient and we talked about the risk to benefit of the use of the device sensitization testing I like to use this image because I think it demonstrates that this is a more complex response we're looking for this is a longer term test and for sensitization responses you have to have an initial exposure and then you have to wait for a couple of weeks and then have another exposure to the same material to elicit a true sensitization response this is really what differentiates between irritation and sensitization and we have three different pest methods available and we typically do the guinea pig maximization that's the most common test method local lymph node assay is another one sorry I flipped back and forth too quickly so that's another as sensitization assay that's available and I've laid out here the differences between the two tests other than the local lymph node assay is run on mice and the guinea pig is run or the maximization is run on guinea pigs there is some time saving here with the local lymph node assay so it's only six weeks where the guinea pig is eight weeks and the quality of the data can be a little bit nicer for the local lymph node assay because it's not subjective it's not based on what the analyst is seeing as far as redness or swelling it's based on it you know a number we're actually looking for a compound within the lope as the lymph nodes however local lymph node assayed is not recommended for metals or known irritants because there's such a severe response to be animals for the known irritants that they can't elicit or determine a sensitization response so if you're doing a submission for a seee mark ll na is accepted but if you're submitting to the FDA they would expect to see a guinea pig maximization so if you are submitting to both markets we recommend doing the guinea pig maximization test because it is excessive as well for CV mark so that's a summary of all of the testing for phase two and so I wanted to just go over briefly what should be incorporated into a biological valuation report and I've addressed that as we've gone through the presentation so you can see where some of these conversations can be had when problems arise because we'd love everything that goes smoothly but it doesn't always happen but we can also have a you know an intelligent logical conversation about it in these documents so for a biological evaluation report I just put in our table of contents you could see some of the conversations that we would have and we give a background of the device why we're doing all of this testing is it new did you change it you're moving to a new market it also gives you an opportunity to say hey it's already been on this market for this long you know we have no adverse events reported so again another place to have that conversation where it's relevant to the safety of the device we go through device description and categorization again and then we go into the assessment where we talk about the material characterization so we can talk about some this additional chemistry testing that was done we go into the biocompatibility testing and then we can talk about particulates you know if we did that for the vias for the 18 552 and go into the chemistry testing results and run through the toxicological risk assessment and then I like to leave this section in here for a material change not that everyone's going to have one but it's so common from when you get this device and your engineers say we're done this is it we love it and you submit it for testing and you spend a lot of time and money on this testing and then they come back and say we're going to use this material because our supplier backed out or something like that so we can assess that change right in your biological evaluation report where you're not starting from scratch and everything is contained in one document this goes over very well for the agencies so they can see everything up front when we see clients who submit just their test reports and there's no initial conversation no final conversation to address the test results in what was found there's a lot more questions and a lot longer time to get their product through to market this really saves a lot of time and the conclusion for a biological evaluation report is hopefully that it meets the requirements of ISO 1099 three part one and can be considered safe and no additional testing is needed so that concludes our conversation for today I'd like to invite you if you have a breathing gas pathway device please feel free to contact us to help get your testing set up and we'd be happy to go through some of those details thank you and have a great day

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