What Chat GPT Doesn’tKnow About Sterilization

Hello, everyone, and welcome. Friday in Focus. I'm Sean Smith from MedTech Leading Voice. I want to welcome our guest speaker today, Manuel Grandy from, Germany, who is a sterilization expert, and he's going to be talking to us about sterilization, And what I had specifically asked him to talk about was to go beyond what ChatGPT is gonna tell us. Because, I think this is an important topic, a not well-understood topic. And one that deserves, broader attention in the med tech world. Before we get into that, and while people are still joining the call, I just wanted to, bring up the upcoming events, and you see that I have way too many tabs open.

And we go to… sorry. Canva… And… What's coming up? So… next… Friday, we have… This is wrong. in silico is not next Friday, it's YMDR technical files keep breaking down. The operational bottlenecks slowing down reviews, creating rework, and draining RAQA teams. These are the guys from CertHub. I met them, at RAPS in Lisbon. Super interesting company. The CEO is former Tufsood auditor, and, has…

built a pretty cool product with his, partner, so that's nice. And then the actual in-silico one, is also former Two-Sude, our… or no, current Tuosud clinical reviewer, Sirash Sirash, and, super interesting guy, lots of opinions, lots of ideas about in-silico evidence testing. And I think that's going to be an outstanding event. Final plug for next week is, yeah, I'm gonna be in Boston Tuesday through Friday, be reporting live from this thing, and I'm also gonna be interviewing a lot of the speakers. And, taking pictures and videos and basically, earning my keeps. So the, but there is still time to register. Lastly, last I checked, we had more than 4,250 votes and nominations on the…

Linkedin thing, now would be a great time to go to mlvx.ai slash MLV100 and cast your votes. I'd love to get to 5,000 votes before end of day tomorrow. That's when voting closes, and it's… it's neck and neck in the top 10. There's people with a lot of votes. Some of them are on the call, I can see. And, congratulations, Stephanie. But, you know, you can always write in Manuel Grandy, you know, as a nominee. So please, go to that. I'll put the link in the chat, in a minute. Anyway, lots of exciting stuff happening. Coming up, a new, packaging webinar is coming up mid-June.

And then… then, in July, Lean is gonna do a Culture of Quality webinar, that I think will be really good. I'm gonna stop sharing, I'm gonna let… Manuel introduce himself, and I want to start with my favorite softball question. Manuel, when you were a small child in Germany, did you dream of one day becoming a sterilization expert in the med tech industry?

Absolutely not. So it… as most of the sterilization experts, it was a coincidence. There was a job here in the town I chose to live. And I took that job, and that was 2009. And in the interview, I found out I'm gonna be sterilization experts. And since 2009, I'm in this topic.

Great. And… how has it evolved over… since 2009? Have you… have you seen many changes? What's going on?

So, it was very relatively conservative and, yeah, boring in a way, but it changed a lot, let's say, the last 5 years, and this is something I'm going to present today.

Cool. Well, let's get started, shall we?

Yes, sure. And let me share my screen.

Now, I would like to remind the panelists, and anybody who would like to become a panelist, to just raise your hand, get promoted to panelists, you know, that we do want some interaction on this, so, you know, it's not just straight lecture, but feel free to, chime in, and or raise your hand, or put questions in the Q&A, or the chat, wherever you want to, and Yeah, looking forward to it.

I want to get this started, but it's covered with this.

I understand.

Hang on a second time. So, let's see… Do you see my screen?

Not at the moment.

In the future.

Zoom doesn't like to have your presentation in full on Zoom.

Fair enough.

There it is.

Do you see my coaser as well? My mouse moving? Okay, great. Then we have everything we need. Alright, so what ChatGTP doesn't know about sterilization? ChatGTP doesn't know much about sterilization. It seems like there is not much training material, so it failed, big time, with many questions. And what I'm going to, present today is about, the pressure we have on EO sterilization, so this is where everything is starting. Maybe 5 years ago, this became more and more. And then, as we respond to this pressure, some controversial validation approach, I want to present to you, which is used. And, of course, and also alternatives to ethylene oxide.

So, first of all, acknowledging the risks with EO. So, there is definitely, risks for staff and patient, okay? It's, cancer organic, it's an IR IARC Group 1 cancer organic, which means that there is no doubt about it, that it's cancer organic, by exposure, by inhalation, and with direct body contact. So it means that in the facility and surrounding areas, there is potential risk if it, gets into contact. And, the direct body contact is then for the patient. There is rest of EO on the medical device, and it's also risk that you must address, okay? Then, of course, it's also toxic and mutagenic.

So risks, again, handling it in the facility, but also for the patient, there is some toxic risks with EO, So, with ECH, And it's also explosive, so there must also be addressed. It's also definitely an important risk. So now the question is, are these risks manageable long-term, okay? So, I believe, yes, I believe they are appropriately and can be appropriately addressed. It is definitely cancer-organic, but that's not the reason to 100% ban it, okay? So, just one example, similar to vinyl chloride used for PVC production. It's still there, it will be still there, but it's managed, okay?

And we managed it by, explosive, by several technological, Mitigations? We, addressed this by several, limits and so on, we must, keep. So, from our view, this is manageable, okay? So now the public and regulatory attention. So in the US, there were, Big, site closures. I believe it was in 2000, 2021. A big site closed. And, this had huge, issues with medical device manufacturers. So, quarterly financial warnings from very big companies, and so on.

So they really… this really caused a lot of trouble. The site closures was because of, yeah, surrounding areas, discussions about high cancer rates, and so on. I'm not expert for the US situation, okay? But, but this is what happened, and this is what caused a lot of attention. Then there are, quite a few litigations also in the US, so companies that paid, several, or hundred thousand… hundred million of, dollars. And there is ongoing EPA rulemaking. It means that EPA made some stricter rules in 2024, and now these rules are still discussed, okay, and are made here in the attachment. You will find,

source, where, congressmen just, it's just a comment, two or three weeks ago, congressman commented on this, on the EPA. That wanted to, make the rules a little bit less challenging. They insisted to keep them on the level from 2024. So it's still discussed, and there are still, let's say, risks, not clear where it's going to go… where it's going to go. This, rule… the rules. So, in Europe, we have no comparable closure grants, and we have established UN national controls. So I'm asking this a lot, okay? I talk with many people from Europe mainly, both from the US, but mainly in Europe.

And, there is, not much pressure from the authorities to, for example, reduce, EO emissions or, increase worker safety and so on. But definitely, you, the topics, EO residuals, worker safety, emissions, and permitting, it remains sensitive. And I can give you a few examples also in Europe. For example, currently two of my clients from Europe, they are in the same country, and they are both extending their, EO sterilization capacities. They built a new chamber. even though it's in the same country and pretty much the same case, one, it's, it's, it's different,

authorities who are checking them. So, for one, it's relatively smooth. I mean, they still do have to keep the rules and so on, but it's relatively smooth, and the other one has to do, like, tons of paper and has already a year of delay because of the permits. So also, permitting is, it's getting more difficult, because EO, Cancer Organic, and so on, it still, it still is… could be a red flag, okay? So there are also, risks, definitely, in Europe. Or, I'll give you another example, I heard from… I worked for a middle manufacturer who was not allowed to, to sterilize a new device with EO. It was for neonates, and this authority pretty much forced them to search for another option, okay?

So… The regulatory risks remain. And then the supply chain dependency. So, a company's entire product portfolio may depend on EOS sterilization. As I said before, that site closes, and a very big company has less sales. I also know companies that are sterilizing everything, for example, in-house, through one sterilizer… EO sterilization site. So if they have no issues, for example, by regulatory pressure. Changing the sterilization site can take months. So, in this case, sterilization can become very business critical, and I know quite a few such cases. This is when you as a consultant, often, are getting into it.

Hey, Manuel, I wanted to ask you, this is very clear what you're presenting, but I wonder if there has been any discussion in terms of… risk-benefit ratio from a supply chain perspective, patient access to these medical devices, because again, if somebody said, no more EO sterilization. We will create a crisis that would actually put patients at higher risk.

List.

Than if we had a controlled, program.

Silicon.

based approach. So, has there been any discussion from a risk-based perspective?

Yes, a lot. So this is discussed definitely a lot, in the US mainly, in Europe not. But, there is, so there are several discussions about exactly this point, and, many people then advocating for EO and saying, We would have big risks, if we would put it down.

So, I'd just like to see a show of hands, like, how many people in the audience are well familiar with sterilization versus… or, you know, put in, like, you know, your level of familiarity on a scale of 1 to 10. 10 being, I'm a sterilization expert, and 1 being, Sean. You can… That's interesting. Oh, we got a zero. We gotta sub, Sean. Okay.

So, how many sterilization experts? I don't see yet, can you tell me?

I don't think I've seen a 10. I… I… I'm gonna average it at… at 6 or 7.

Alright, that's great. Very good. All right, so EO is indisplaceable in the medium term, and it's very clear. There are 20 billion devices, produced, sterilized with EO per year alone in the US. So 20,000 million, okay? And more than 50% of the single-use medical devices worldwide are currently, still, sterilized with ETO. And here's this first, Rutelin Weber, 2023. Also saying ETO is irreplaceable for years, and also discussing, Daniel, what you just said, risk, the benefit, risk-benefit issues, and so on.

Okay. So, why there is no like-for-like replacement? So, it's a combination of things. So, first of all, there's a very high penetration into packaging, lumens, and difficult-to-sterize location, and very dense pallet slots, okay? It works very well, it penetrates very well, and better than other modalities. Then there is a high material compatibility for a very wide range of materials. So there are not many materials that have an issue with EO sterilization, opposed to All, all other, or pretty much all other, modalities, where you have, for certain materials, certain, issues. And then, there are many sites for contract sterilization available. It's… when I work with customers and they think about alternatives with a new device, I mean, this is often an important argument, saying, well, there is a contract sterilization facility, but it's,

on the other side of the globe, okay? Basically, so, this is a big, advantage for EEO. And it's difficult to build that up, you can imagine, okay? And then there are also many capacities for building your sterilization plants, so if we say now we want to sterilize this 20 billion devices very soon with other modalities, well, there must be also companies building that capacity, and this is simply not existed and also discussed in this paper here. So what I believe is, that, And I could see this differently in a few years, but what I believe now is that EO will likely stay for decades, especially for sensitive, difficult to sterilize, low-cost products.

So, for example, sets, very complex, sets, that are relatively low cost, with very different materials inside. There's procedure, packs, for example. That are sterilized in big pellets, and very dense, and a hundred different materials, or hundreds. this will be the last devices that will be, not EO sterilized, and it's hard to imagine how they would be EO sterilized. It would be a big project to get all these materials changed, and so on, or… To, find a modality that works.

May I just jump in?

Yeah.

With regards to alternative methodologies, I actually had, a few years ago, an opportunity to do a clinical evaluation about the alternative, possibilities, like using oso and hydrogen peroxide. And I fully recognize that EO is a low-cost method of sterilization, but at the same time, it does have toxicity, it, products that are EO sterilized need to be in a warehouse for a certain amount of time, so the EO can expire. And what a lot of people don't realize is that the medical device regulation EU made, actually, these products more dangerous, because the label on the package became even bigger, which prevented a lot of the EU from expiring. Now, you say in the future, that

you know… EO will be… still around for decades, but I think… There is a push to find alternatives. Why are you not presenting ozone or the other ones, or…

I am definitely… I'm very excited about these alternatives, and I think we should work on this, but I tell you from experience and what I see on the market and so on, that I see this trend, and for me, it's super interesting, business-wise also, okay? Nevertheless…

financials… is the financials blocking the implementation? I mean, there's a one firm, one of the big firms is Steris, right? Which I'm sure you're aware of. Is the financial, you know, the cost, the cost of the alternatives blocking the alternatives?

Being…

used.

I mean, the thing is that, So I started a big project, where I contacted several manufacturers and presenting them, possibilities for the alternatives. And most of them just had other priorities, and I totally understood this, because in Europe at least, okay, I can tell you for sure, it works pretty well with the austerization. I don't see that this is going to be changed in 10, 15, 20 years Maybe 20 years, because it works well, it's cheap, we have limits that are acceptable, that are, challenged a lot. And there is a very low list, risk for, harm to the patient, to the workers, and so on.

So, and these risks you have in… often in the industry. I did an apprenticeship, with 17 as chemical lab technician, and I dealt, I, I, we created, we cooked some new, Some new, substances. that were never tested on humans, some very complex substances, so there was also a risk that they were cancer-organic, or toxic, and so on, definitely. So there are… but we addressed this by, procedures, and so on. And it's… I think it's similar with EO, so you can address this, and the companies, so back to your question, the companies just say, I don't see the reason for me to change. Change. Where are the benefits? I have many other projects. It's interesting.

We want to do it, but then, on a higher level, it's often then decided, hmm, let's do this, let's do this again, let's discuss this again in a few years.

Yeah, Manuel, I just wanted to also comment that when you talk about compatibility between material and the sterilant, this is important, because in some cases, if we had to comply. with a different sterilant. We may have to also change our… the material,

Yes.

that we use, so… and that brings now another set of challenges to the industry.

Absolutely.

cost of development, so I just wanted to erase that.

That's a very important point, yes. But we will come to that also later, I have a few slides for the alternatives, but thanks for the good discussions. So, what do, what manufacturers do and experience right now? with regards to that pressure, what are the reactions? Okay? So one is, lower EO concentration cycles. let's say lower than 400 milligrams per liter is usually something you will see. This, I think, came from an EPA, an earlier model, or an earlier requirement, saying that you must go under 400 milligrams, if I remember correct. So this is now picked up from,

sterilization service providers who are in the US, but also worldwide, they reduce their cycles accordingly. And also, big, mainly US companies, who are saying, well, we want to have cycles lower 400 milligrams per liter. It can reduce workers' exposure and emissions, definitely, so I also saw some data on this, and this can have positive effects, but often it's, there is no technical need to reduce it. So what I want to say is that if you have a cycle especially in Europe, with 600 milligrams, 650, you will be usually fine, and it's still used, and there is often no pressure to reduce this. Nevertheless, this is an important trend.

But what happens? If I reduce the EO concentration in the cycle, so if I put inside 400 milligrams per liter instead of, say, 600, 700, then my cycle leads more time It needs more time to kill the bacteria or the microorganisms to a certain level. And, but, But you don't want this. You have a certain capacity, and of course, you still want to have your, for example, 8-hour cycles, okay? So this reduced efficiency is addressed by, often, or mainly addressed by a change in the validation approach. So now very high level. Cycle calculation approach, rather than half-cycle approach, I will just briefly discuss this later, but this here.

use of product as of sterility as a reason not to inoculate the product. This is the ugly one. This is, unfortunately, by some, companies, done. proposed? And, and this will put you in trouble, and there I'm going to, present quite a while and explain you what is the consequences and what is the reason why this is not a good idea, okay? Then there are the alternative modalities, and I'm also going to have a few slides on that. And, the current efforts appear to be largely driven by U.S.-based medical device manufacturers. Why? Because there is this higher pressure. However, the alternative modalities may offer significant benefits beyond the US as well, particularly for in-house sterilization. So this is, what I'm really excited about. I see some, potential benefits there for companies.

Then what you also see now a lot, and this is in the US, but also, in Europe, you see technology upgrades, okay? Step by step in Europe, and the US now much faster. So, filter and abatement systems, so, Quite expensive catalyzers, or also filters in the desorption holes. some dry bed filters that do recirculation and reduce the EO concentration in the dissorption holes. than automated handling during the absorption. So, after the EO sterilization, when the pellet is packed with a lot of EO, you should take some measure, or you can, expose the operators even less if you have an automated handling. And I think this is

a brilliant, brilliant, technology that it goes directly into a tunnel, and then, into a… I saw it in an automated warehouse, and the operator does not touch the pallet in routine production for 3 or 4 days. Then sealed cap forklifts into the desorption hole. And then extended desorption time, so it's very interesting. So instead of, you know, after 3 days, you would often be under the limits for the patient. For example, 4mg Etlanoxet per device is the limit, and you will drop under this limit after 3 days. After your sterilization, and then you could release it to the market. But still, there is EO on the pallets, and so on, and of course also in the product.

So some companies say, well, I want to have it 7 days in your desorption, in your control desorption, and this helps a lot, then downstream also in the warehouses, or 14 days, okay? Extended desorption times. And then also EO monitoring, okay? Just monitoring more on the fence line, or at the chimney, or in the dissorption, how much EO do I actually have? This is also increased. So all this, makes sense and, gives you more safety, definitely, but of course, these are all major coast drivers, okay? EO sterilization gets more expensive. And then, just quickly, backup sterilization, or a second source. So, pros, it strengthens your supply chain.

And also, it can help you in negotiations if you have a second supplier. But cons is more validations than suppliers, so you have another validation in the second side that you must do and revalidate. You have another supplier that you must manage. And what is interesting, what I find interesting, is that if you have high volumes, like, let's say, for example, 10,000 pallets per year, or 20,000, at supplier A, and the same at supplier B, well, it will be difficult for supplier B to, in case there is an issue with supplier A, to just ramp up to 40,000 pallets per year. So you usually… your high volumes are usually not 100% covered, also if you have a backup stabilization.

Alright. So, no. I'm going to present you, let's say, the usual validation approach that is accepted. And this is now a lot of, diagrams and so on. I hope I don't put you to sleep, but, But if you… if you, Watch this, if you, follow this, you know, then you will understand the most important part about sterilization. So let's say, you have such a… this is a tubing set, and on top there will be always a Tyvek or a paper, usually a Tyvek here, okay? So there is this… it's a sterile barrier. But now the sterile barrier is removed, we just have this tray here and this tubing set.

Now you say, okay, I want to have… I want to label this sterile, I want to have this sterile, what do I have to do? So what we use is these BIs, biological indicators. They have a bacillus atrophios, it's called the microorganism, around a million of them on one strip, okay? So you know the exact type, you know the number of microorganisms. And these you use for the validation. It's a BI-based method, not a bioburden-based method, like other sterilization modalities, okay? Absolutely not. It's based on BI. So where to put these PIs? you would put them at parts where you want to show that EO, or

Also, steam and lethal conditions are reached, because this is your indicator that is showing you, I killed a million spores. So if you put it somewhere, it will be, of course, easier for EO to kill a hero spore on the surface of this tray, opposed to, here in this lipse. So this is a very usual place where to put a BI. Then also here, you want to investigate, this is a volume inside of this tubing. Here, you would also like to know, well, how much, how much lethal conditions, how much kill do I have? And then… The third PI you would maybe put here, okay? This is the so-called longest gas pathway. You close here, you can do this, and then you make sure that the O goes through this, duck, duck, duck, through the whole set.

to this point here. So this is a height challenge, you could also remove it and place the BI here in the middle with a T or something, but this is also something that is done a lot if you can afford it to challenge the process a bit, okay? So now, now we come to this diagram here. And, let me explain it to you quickly. So, we have here on the x-axis the EO contacting time. It meets just half hour of EO contact, one hour of EO contact, one and a half, two hours. This is the EEO contact. And this year is the… or this year. is the number of microorganisms, or surviving microorganisms. For example, you start at T0, if you have no EO contact, you have, from the BIs, this 1 million here, okay? This is your starting point.

And then the EO will reduce the population of your BI, And that's why… and here we have the probability of surviving microorganisms. So, after some time. You will have, one microorganism, and then 10 to the minus 1, 10 to the minus 2, so a probability of 1 to 100, until you go down to 10 to the minus 6, which is the probability you usually want to have, for your, sterilization process, your SAL, okay? So, If we would have, you know, several data points, if we would measure after half hour, after one hour, after, and so on, it would more or, like. look like this, okay? The curve. It's, a log linear reduction, because you have it at a certain location.

You have, constant, conditions with regards to EO and temperature and so on. And you have, this bacillus atrophiosis, so just one type of microorganism, and not several types that would die off differently. And then this leads to this log linear, reduction, more or less, okay? And now, the bioburden behaves different. The bioburden is the microorganisms you have every day in your production. And here you have, first of all, it's not in a certain position, it's distributed in the whole set. And second, you have different kind of, microorganisms on it. So it will die the easy-to-kill microorganisms, and at the easy-to-kill positions, it will die off very fast, and then you will have such kind of chorophoca- a tail, it's called.

This is how bioburden inactivation behaves. So you could also do some tests and measure it, and we assume now, for this set, this kind of bioburden inactivation. So now what you would do first in this usual validation approach is a so-called sublethal cycle, okay? So you still have some… you would… this is, like, let's say one and a half hour, for example, or 15 minutes better. So you would do this sublethal cycle, and you would measure how much survivors do I have on this PI, on this PI, on this PI, And you would see that I had the highest number of survivors on this BI in the syringe. And this is now your worst-case BI inactivation. So, the EO is the most difficult part for the EO to reach, or maybe, in other words, to create lethal conditions, is this BI, and this you want to know. This is now your, your worst-case BI inactivation, your rate.

And this, when we come to that, how are you going to use this? Now, the bioburden, you would, in the sublethal cycle, you would also do tests of sterility of this product, and you would see it's sterile or it's not sterile. So in this example here, it would be definitely most likely sterile. There is a certain probability of growth, but let's say this is then sterile. And what is also interesting, this rate here that is important, and I will discuss in more detail in a minute, this rate here for the bioburden will now be not much worse than parallel to this worst case BIN activation. Why? Because in the worst case, there are some highly resistant microorganisms, like the bacillus atrophius, at this position, okay? All other positions, will be less resistant, so you will have more or less a parallel curve, alright?

And this is important, I'm gonna tell you later. So, now I'm doing a half cycle with the set here, but only this inoculated with this PI here. You could also use an internal PCD, this is possible, but you have to show that it has this rate here, alright? So you do a half cycle, you show total kill of this BI here, and then you showed 6 borelock reductions, yes? Then you do… then you, for your full cycle. Also for your routine cycle, you double the time here. So let's say this is 2 hours, you would double it, and it would be… you would have a 4 hours EO contacting time in routine. In 4 hours, you are able to, reduce the,

You need to reduce to zero, and then also this probability. So, to extrapolate it to 10 to the minus 6. By the way, there is also a cycle calculation approach, I mentioned it before, that will lead to less EO contacting time, but I'm not going into that now. In detail. So, if I do this here, what I just explained, then I will have a BI better than 10 to the minus 6. If I follow this curve now, and this was the actual worst-case BI inactivation, I must add a bit in my half cycle to see total kill, but if I follow this curve now. After this time here, I'm at the SAL of 10 to the minus 8 or something, okay?

So, but I'm not in the BI-killing business, I'm in the sterilization business, I'm interested what is going on with my bioburden activation. And my… for my product… the product SAL, let's say, is much better. I said here, BI SAL and product SAL. The product SAL is much better than 10 to the minus 6. So if you follow this line here, it's somewhere here, I don't know, 10 to the minus… 12 or so, but you don't really know it, okay, because this was just an assumption. What you know is that this is parallel to this. And, and you have some safety margin. So you can tell for sure you are much better than 10 to the minus 6 for your product bioburden. And this is where many say, wait a second, I,

I don't want a cycle with so much overkill. I want a cycle that was just 10 to the minus 6, And there are possibilities, I already said the cycle calculation approach, or you say, I don't have a million bucks on it, I have 10 to the 3, you could even reduce it more. So there are possibilities. But always, you must take care of this rate here. This is your indicator that is showing you, at your difficulty sterilize locations, your die-off, okay? So… This is the accepted approach. It's overkill, it's the accepted approach, and if you come up now with another approach that is more efficient, that don't have so much overkill, then you must really explain this statistically. This here is easy to explain, easy to defend.

And now there is, this, EO validation. relying on test of sterility TOS, and it's really very much, with this lower concentration EO cycles, combined. Because you want to address this loss of efficiency. And, yeah, high risk of rejections, I wrote here. So what, what is done? The product is not inoculated. I'm going to show you some pictures, later. The product is not inoculated. In this approach, instead, a separate internal PCD is used. or the BI is placed outside of the product. And then, the comparison of the internal PCD versus the product bioburden is intended to be performed using a sublethal cycle, which I showed you before, after which sterility is demonstrated from the products, while growth is demonstrated from the internal PCD. Okay?

So you say, now my internal PCD is okay, it's more resistant than this, product bioburden. Because here I have growth, here I have no growth. And this is the, let's say, easy logic behind, but… There is a big problem with this, and this… I'm going to, show you in a minute. So, there is no deactivation rate quantified at the difficult-to-sterilize locations of the device, which I showed you before. So how is this now done? You have, again, same device, And now you use some kind of BI, whatever it is, some kind of PCD, and it can be very easy to sterilize, okay? Or you place your BI here instead of the syringe.

This is also possible. So now we have these situations. The BI is now relatively easy to inactivate. And this was more or less the situation before, so we can have much shorter times also, or reduce the EO concentration. And this is, again, the bi-burden, inactivation. So now we run this sublethal cycle, and as you can see, this criteria I said before, growth in the internal PCD and sterile products from the test of ceridity, it's easily achievable, so it's very likely that it will be achieved. But the question is, what is it going to tell me about my SAL, of the product? So, you would now run the half cycle with this BI here, or with this PCD here, double it, this is now your, more or less, it's now a bit simplified, but this is your full cycle time, or your root cycle time.

And the SL of 10 to the minus 6 is definitely reached for this BI, okay? You showed this, and there's… this is okay. But, the bioburden, if you look at the bioburden, it's simply… the curve here is, flatter, so it takes more time, and after a while, it crosses, so you have an SAL of 10 to the minus 4 here for your bioburden, okay? Theoretically. So this test doesn't tell you much, and it can be worse also. So if you have this kind of situation, the SL will be, like, 10 to the minus 2. And this is the main issue with this approach. I want to share with you.

Now… This approach, so using product tests of sereity to relate to the internal PCD, remains controversial in standardization committees, so we have lots of discussions there and are asking for a rational, which we don't get so far. And, and this is really important, I often see it rejected during submissions, and I totally understand notified bodies or authorities rejecting this. And these rejections, from my view, are unlikely to change with the IZO1135 update. I was asked, two weeks ago, well, yeah, I use this approach. With the update, is it going to be fixed? I heard it's going to be fixed.

And no, it's not going to be fixed, so there are still… it is proposed in a certain way in this ISO update, and you can also download it, by the way. But due to ambiguities, and I want you to have a look on Chapter 8.5, which is telling you about this activation… inactivation rate, I told you. But also B23, which is telling you about complex devices, or devices where gas is difficult to reach. And especially in the after this update, I want you to have a look on these chapters, and then, again, reflect, this validation approach, this, with a test of sterility. Well, and then there is lack of statistical soundrational for this validation approach, and there is a paper I also attached.

So we're still waiting for a rational, it's simply not existent, you will not find it anywhere, how, at the end of the day, this should add up. And now I give you this audit killer phrase, what spore lock reduction or sterility assurance level did this validation actually demonstrate at the most difficult to sterilize location of the device I'm holding? You're not able to tell, at the most difficult historic location, what's your SAL, or your sporlock reduction, sorry, because you did not measure it with this method. So now, quickly, if your recent validations relied on this approach, the potential downstream cost, if challenged, are…

You must repeat the validation, you do a new… and if it fails, and this is very likely, if it fails with… if you put the BI to the worst-case location, then you must develop a new cycle, do again a validation. And then, maybe you did your packaging and product testing with the initial… with this initial, process. So maybe you have to do this again, because now you have a process with more EO concentration, or longer dwell times, and so on, EO dwell times. So you have definitely high submission delays and very high costs. And, you know, this is my main concern here, that this happens. Also, for the auditors, it's not a pleasant situation.

Well, and then also there is the sterility, of course, the risk for the patient, okay? Good, so we have 50 minutes left, and I wanted to tell you about alternatives. Are there questions so far with regards to that? Or do we want to ask them later in the Q&A?

Yeah, Manuel, I think that was an interesting question. I think the topic, included a discussion on chat GPT. And somebody was asking, how do I make that link? Is that something you're gonna bring up, Relatively soon, or is this something that maybe it's apropos to be brought right now? Just, just a question.

He did mention at the beginning that ChatGPT doesn't tell you very much about sterilization. I think the person may not have heard that. Yeah, I think that, I'm certainly seeing a level of detail here that I, didn't get from my own look at ChatGPT. around this topic, I don't know about anybody else.

And I think you're absolutely right, Sean and Manuel. I mean, when you think about ChatGPT, ChatGPT, like any other AI forum, it's highly dependent on the input it gets from.

Yes.

you know, the technical papers that are developed, the guidance documents, and this topic that Manuel is talking about is evolving, so ChatGPT has no ability to rationalize anything that is extremely relevant on specific aspects of this topic, and this is why the human element is still the leading force behind which way these concepts are going to go. Yeah. So as soon as we start feeding into ChantGPT, you're going to see more ChatGPT reaction, which is going to be based on human input, and that's still not necessarily there, I guess, yeah.

And where else are you going to have a sterilization expert come on and speak to you for free, and educate you on the importance and understanding and the level of detail that Manuel is giving us today? You know, I don't know of any other forum that is presenting this free to the public.

Manuel, the last time I remember reading the standard, there was no differentiation between, Small children and adults. in fact, humans were all in one bucket. Has anything changed there? Because really, the E… yeah, okay, good.

It's a bit of a different topic now, but it's… I'm going to answer it. So, there is an update of the standards, it's the ISO 10993-7, and it's a very good update, it's a very good standard, and it's absolutely addressing this topic.

Thank you.

Oh, right.

comp… that's a BioComp standard that you're talking about.

the Bible? It is, but it's for EO residuals.

Okay, so the… the EEO, standard, I mean, standards for… associated with sterilization do not address the topic, so it would be really the bio count, because, of course, that would be…

They are, they are. So, all standards are referring to this Biocomp standard, and sterilization experts use this standard, even though it's in the Biocomp family, let's say.

10993-7 is directly tied to EO.

Yes. Alright, we have 10 minutes left, so I would like to… Tell you about this, Modalities. So, sterilization modalities, this is from AMETR17. And, so right now, we have here ethylene oxide, and what is interesting, it works by alkylation, okay? So, it's a very specific chemical reaction, which works very good with proteins or DNA. But, does not react much with, with all other, with almost most of the other materials. And this is why it works, so well and so specific, to kill, DNA, or to kill bacteria and microorganisms, but not to damage your product.

Then we have, which is also an important modality, ionizing, so radiation, gamma, e-beam, X-ray. It's very interesting, and I think for some medical device manufacturers, it's the right thing to go. I saw a very interesting presentation about E-Beam two weeks ago. But it's ionizing, and you will also, you might have some material effects, so you must test it. And then very interesting candidates are then nitrogen dioxide, hydrogen peroxide, which we heard before, and chlorine dioxide. And they are all oxidizing chemicals, so they might… there might be some effects with, with your plastics, but also with your metals, and so on, okay?

So now, for me in particular, interesting for in-house sterilization, but there are also some advantages if you do this with the contract sterilization manufacturers. But in-house, I'm going to show you what I think is interesting for many, many suppliers, medical device manufacturers also in Europe. Is, so you, in your facility, you build the device. You do this terrible packaging. And then you sterilize it, this is from Steris here, for example, but basically the same with these modalities. You sterilize it on a tray, without cardboard. You pack it in a cardboard afterwards. Works a little bit less than EO, it doesn't penetrate so well through cardboard.

So you pack it afterwards, and then you ship it. So you are super lean, okay? So it has a lot of advantages with regards to lead time. If you have an expensive product with inventory and so on, this can be a brilliant solution. You have a low footprint, so you don't need so much space with EO. You have, almost no dissorption times. I know suppliers that wait 2 months for the product, so that could be a good reason to change. You have low risk for permits for extension or new sterilization sites. I told you before with EO, this can be a problem. Here, it's less of a problem. And, yeah, it reduces all these risks we discussed before with EO.

So, so I think using this, especially in-house, is interesting, like, with steam sterilization, you would usually do this in-house, because it's steam, it's not EO, which is cancer organic, and so on, and all these substances are definitely much less dangerous than EO, so you could think about to do this in-house. There is also E-Beam is another option I did not go into, just for in-house also. Good to know. just quickly, how would you do now this? How would you start working on these alternative sterilization modalities? So, first of all, what is your opportunities, the evaluation of opportunities?

So I named it before, less inventory could be a good reason, less EO residuals, less EO desorption time, so 2 months waiting for the product, and so on. These are all chances, or opportunities, benefits, And this is the first thing you do. And if you see here, if you have, basically, a business case here, then you would move forward and do this feasibility study. So, as we already… you would do this, In providers who are, producing, or manufacturing these plants, you can do some feasibility tests, you would, create a process that will most likely be able to be validated, so robust enough for your product, lethal enough. And then you would, with this process, you would then do testing of your materials and so on, and then you can see if it works for which

Part of your product, maybe, and… How does it work? Is it feasible for you? You would then do this regulatory approval, and this can take some time, so we have a lot of movement here, and moving forward here, but this can take time, and this would be the next step, and you don't have to buy equipment for this. You could also do this in a certified contract sterilization facility. Start with the approval, maybe with one product, get it through. And then maybe, so stay with this external sterilization provider, and maybe in parallel do this transfer to an in-house sterilization. So this is where you then start with a bigger investment, and you would, implement, buy such equipment, implement it in-house.

But this is when you know it works, it's feasible, it pays off. And I will get regulatory approval. Alright, so just quickly, main working groups, Amy TIRs are working on this, Kilmer is working on this. international scientific exchanges working on this, which is, basically, Medtronic, and Johnson & Johnson started this. You see this bunch of people, this was 2024, and when I saw this picture here, I thought, well, all these people would not come from the States and so on, and from Asia to Munich to talk about this, if it wouldn't be, interesting and important. So I joined also in 2025, We are much more people, but we don't have such beautiful picture.

So, key takeaways? Please be very, very, very critical of EO validations approaches that only rely on product sterility testing, that rely on productivity testing, instead of inoculating the medical device with the BI. And then, EO serialization will likely remain essential, but alternatives should be evaluated.

Thank you for the presentation.

Okay.

I don't know if anybody wants to chime in with any questions. We have a couple minutes left. I would encourage you, to connect with Manuel on LinkedIn, and if you are in need of a sterilization expert, I'm sure he would be happy to, advise you. And, Anybody learn anything new today? I, I, I, I know I did, personally. It was, A world that, I've… I just have… really have never… thought about in any, in any, in any detail, so I appreciate this.

Thank you.

Oh… Amazing.

Nice job, Manuel.

Thank you very much.

That was a lot of detailed information that you actually put in front of us that made sense, so… great job.

Thank you. Yeah, if you have questions, just reach me out, I'm very happy to answer them.

Manuel, I have one question. And it's a… with a current client, they have a new single-use device, and it's so, to me, as an engineer, backward, their solution. I'm trying to figure out what they're thinking, and they don't explain it well. Their packaging is way oversized, so anything from storage to… I'm thinking of… 10993-7 residuals. Is there any reason… they said it's to protect the product. So, to me, their product packaging is perhaps… 3 times larger than it needs to be, which… I would think every stakeholder in the company would be saying, why are we doing this? But it's made it through all of that. Is there any reason, from a sterilization perspective, that you would have a larger-than-normal package?

If everything else is done well.

I mean, it costs, it's mainly costs, and, you must explain well why you do this. So you need data, why, smaller packaging, let's say double instead of triple size, does not work for you. You need data for this. Otherwise, I don't believe that there is a reason, sterilization-wise, to do this.

Okay. Yeah, it just was so off the wall to me, I didn't even know what to say.

I've never seen that.

Yes, thank you.

So, that reminds me, mid-June, Clarimed and Canyon Labs is going to be doing, packaging. webinar. I hope you all tune in for that. Look for details on upcoming issues or emails going out. But yeah. Well, thank you, everyone, for your time and attention today. Remember to vote early and vote often for your favorite MedTech Leading Voices, you have, you know, like, 30 hours left to get your votes in, and you know, there might be a big upset in the last… in the final stretch, you know? Manuel might rocket to the top of the nominations list if you all write his name in, you know? Thought.

That'd be nice.

Please don't nominate me. I get enough airtime, I don't need any more. The, But, thank you to those who did. And, yeah, we look forward to seeing you next week, with a CertHub. Thanks!

Thank you all. Take care. Have a good day.