Validation Challenges Facing Advanced Single-Use Technologies

In this episode of "Better Biopharma," host Tyler Menichiello is joined by BioPlan Associates’ director of research, Katrina Cordovado, as well as Joshua Nelson, Ph.D., a senior material qualification specialist at Takeda, and Paul Priebe, a consultant and single-use expert, to continue their conversation from the Bioprocess Online Live event, "Closing The Adoption Gap For Advanced Single-Use Materials."

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Transcript

SPEAKER_02 0:17

Hello and welcome back to Better Biopharma, the official podcast of Bioprocess Online. I'm your host, Tyler Minachello, and on this episode, we're going to be continuing our conversation from April's Bioprocess Online live event on closing the adoption gap for advanced single use technologies. Joining me are my three panelists from that event, Katrina Cordovado, the Director of Research at Bioplan Associates, Dr. Joshua Nelson, a senior material qualification specialist at Decata, and Paul Prieb, a consultant, single use expert, and member of the ASME, BPE, and the BPSA. Katrina, Josh, and Paul, thank you all so much for agreeing to come on the pod to continue our discussion. Thanks for having us. Thank you. Of course. Of course. I'm very, I'm very excited to continue doing this. And um, you know, most of the discussion when we were live a couple weeks ago was centered around defining advanced single use technologies and the impediments to their adoption. And we unfortunately didn't have enough time in that hour to really dive into the validation challenges facing single use. So I'm hoping that that's where we could start here and dig in. Um to our audience, if you're listening and you haven't already, go over to Bioprocess Online and listen to the full recording of our live event. Uh, there's also chapterized segments there that'll give you a good, a good level set for where we're going to pick up and continue today. Um, so we'll just jump right into it. Uh, Paul, we'll start with you here. I'm curious if you can, from your point of view, outline what you think the most consistent pain points are in validating new single-use technologies, and we'll we'll go around the the horn there.

SPEAKER_03 1:47

Well, I think um one of the tricks uh over the past 20 years, uh, which is made much easier today, is the whole extractables question question. Um, you know, it's here we are on May 5th, uh, 2026, recording this, and the uh USP 665 went uh became official on uh May 1st, so just a few days ago. And it's been uh I mean it's it's sort of a long journey that's more than 10 years to get to this point, but I think it's now pretty well accepted uh that this is the way to um to go with extractables. Um so while it's easier, it makes rationalizing what you should do and how you should report it and all of that. Um there's still a risk assessment which um sort of puts a little complexity to it, but at least really defending yourself if you're a supplier about what you did for extractables is is really a thing of the past. It doesn't make it um less expensive. Uh it's certainly a costly exercise for the suppliers. Um, and so they have to sort of choose the right moment in time in the maturation of their um uh their product offering, uh, whether they think they're gonna be iterating, you know, they would you shouldn't do all this um data generation with an early version of a product, right? You've got to uh sort of be in pursuit of GMP relevant applications before you spend that that uh that money. But you know, I think that that, you know, the shift has gone from defending how, why, when, and uh and with what solvents you did extractables to now deciding when the right time to do it is uh based on sort of you know the the maturity of of a product offering where it is in the product development lifecycle. So that's gotten easier.

SPEAKER_02 4:05

Good news. Thank you, Paul. Thank you, Josh. How about what do you think are the most uh consistent pain points in validating these technologies?

SPEAKER_05 4:14

I mean, it's extractables and leachables is both more straightforward and also the asks has become larger and larger and larger over time, and now also how these asks have been morphing over time. And of course, as I was saying during the live event, just data for everything in general, just getting all the information that we need up front and having a full picture of what the material we're going to implement is before you know it's too late to make a change if we actually have to, or if something isn't really compatible with our systems.

SPEAKER_01 4:50

Yeah. Yeah. Katrina, you agree?

SPEAKER_00 4:54

Yeah. I mean, there's a lot that goes into it, a lot of planning. And and I'm thinking of, you know, the end user side of things and how sometimes what they really want is that real world validation and and knowing that it's actually going to work in a real facility, but to get that, to get someone to try it out even, do an early beta test, like you need time to do that. And it's hard to find you know, facilities that even have the time to do that, and even to look at the data sometimes and go through all the data um for something new at any point of time, whether they're testing it out or buying it. Um, they need the time. And and I've we've seen a lot of new companies even the last few years, and a lot of growth maybe in the small players, and that that can be a challenge of you know, finding the time to test out all these things. And if you're just getting bombarded with all these requests to use this new thing and that new thing, and it's it's never an easy thing to sift through all of that and decide what you're even going to use. Uh, especially, you know, the big companies, everyone knows them, everyone wants to ask them to use their product. But I guess if you're small, I wouldn't necessarily recommend starting with like the the big pharma that may not have the time, or they may have everyone asking them um to be part of the process. Um, but you know, you need that that real data in whatever way you get it, whether you get it from a small tester or whatever other lab or academic or whatever you choose, like you need that data to even be considered sometimes.

SPEAKER_02 6:38

Thank you. Yeah, time is money, right? So any any burden that you put onto the the sponsor side. When I say sponsor, I mean the drug developer side to to that gap, it's gonna be a big ask. And in fact, when we polled our audience live, we had some responses there that kind of are reflecting what you guys are saying, where we we asked the people in attendance, where do you think adoption gets stuck? And we had pretty close. 30% said validation burden, um, you know, those comparability studies you guys are talking about. And then 33% uh said that insufficient vendor data or documentation is is a big part of that, that stalling of these technologies from advancing. And I'm curious, and we'll just kind of swing back the swing back over or go through all of you guys. Katrina, starting with you, where do you think vendors are dropping the ball in terms of providing these comprehensive data packages and you know, data on extractables or leachables? And um, I know Josh, this is like where you operate into the day-to-day. So we're I know we're all keen to hear from you. But Katrina, we'll start with you. Um, where do you think vendors are dropping the ball?

SPEAKER_00 7:46

Yeah, I mean, not to sound critical, but I think there are some vendors maybe that don't know everything that the facilities are expecting the them to give them at at the point of when they're developing something.

SPEAKER_02 7:59

They may not have to be time to be critical.

SPEAKER_00 8:02

Um they may not have done all the testing or or get it gotten their their um data yet on on certain things. And and maybe that is like as Paul was saying, you don't want to do all of that too soon and waste your resources on it, but it's it's striking that balance of being informed of the right phase-appropriate approach there.

SPEAKER_05 8:25

Thanks, Katrina. Absolutely. Uh we've also seen some of our suppliers or some of our materials that are introducing a next generation, so they call it, of a bag film or any single-use component. And when you start looking at the data, it doesn't truly offer an improved performance in some regards, or something that's been a pain point for me is the extractables profile is worse, or the quality of the data they're providing for the new generation film is worse quality than the original generation film. So it leaves us having to pay a higher price point for this new material itself, and then also have to spend money to generate additional data on top of it. I'd say another part that becomes really challenging here is sometimes some suppliers are really good about it, but other suppliers are just unresponsive at best. Uh, and for a massive pharmaceutical company of like where I work, we spend significant sums of money and we expect a certain level of customer service when you're paying through the nose to get what is supposed to be top-of-the-line best in class materials. But we do have some suppliers who sometimes it feels like they must be awake looking at their email 24-7 because they respond so quickly and they're so helpful. Uh I would say it's in the minority of suppliers that are reluctant to respond that cause the most problems for me.

SPEAKER_02 9:54

And I yeah, I don't want you to give away too much, but I'm just out of my own curiosity, when you it's obviously no secret that the these studies, the comparability studies, and um kind of completing that data package cost money, like you said. Do we is there like a rough dollar amount that will could kind of quantify or put into perspective just how much of a burden this is on the on the end user side?

SPEAKER_05 10:16

I mean, an extractable study, we've historically estimated it at about $30,000 to $40,000 per material. Uh so it's not inconsequential. It depends on who the testing lab is. Also, that's or if you're testing it in-house. Some uh companies do a lot of their own extractables testing in-house, and I'm very jealous of them. We do not have that capability within our organization anymore. Um so you're paying quite a bit of money, and then there's it's gotten a lot better now. But five years ago, if you think all the delays and lead times due to COVID, all of the restrictions that happened. So we were looking often at six to nine months before we could even get a sample into a lab to start testing. We could do some of the paperwork by generating a protocol up front, but you're looking at at least a six-month delay just to even begin your testing. So the timelines were just all over the place.

SPEAKER_02 11:12

Yeah. Yeah, that definitely throws a wrench in what's already a kind of tightrope of uh of timelines. It's a timeline game to begin with, right? Drug development, though, the entirety of it. Um, Josh, I'm gonna give you a chance now to say to vendors what you've always wanted to say. You're the you're on the you're like the equivalent on the sponsor side of you're qualifying the materials that these vendors are selling. If there's one message you could give to these vendors, what would it be? Now's your chance.

SPEAKER_05 11:39

Give us the data up front in a simple tabular format, no fussy formatting, no fussy anything, plain English or plain language or the geography you're selling the thing to. Um and be responsive and ready to answer questions. And we're not usually looking to find have an aha, we found a trick moment or found something wrong. We really just want to understand what's going on and we want to understand what we're using so that way we can best represent that information and present it to regulators and just move on with our lives and get our medications to the patients.

SPEAKER_02 12:18

Amen. Amen, brother. No more fuss. I'm sick of the fussing too, and I don't even deal with this kind of stuff.

SPEAKER_03 12:25

Paul, anything to add there on the you know, the kind of position that this is. I want to pick up uh on something Josh said and then and then reflect uh on some things Katrina shared. Um, so you know, one of the tricks, of course, with um despite the fact that extractables has been standardized uh through USP 665, the data are not directly comparable, even you know, from lab to lab, or even uh, you know, we these are screening studies, they're they lack authentic reference compounds. Um, so response factors are it's all semi-quantitative. So, you know, to Josh's point, if you're going to either do a change control or seek to convert business, whatever the the data package is supposed to support, I think it's relevant to talk about the data with an expert opinion. Um, oftentimes you've got folks who might look at these numbers and think that they can compare a five to a 10, and the 10 is greater than the five. And in fact, that's not supported, right? So it's important that uh an expert who understands response factors, the the closeness of the reference standard and all the analytical chemistry, black magic. I call it black magic because I'm a stupid engineer, I don't understand it. Um, you know, it it deserves somebody saying those two numbers are consistent with the levels being the same, even though one says 25 and one says five or whatever the numbers are, you know the you still need opinion on top of the semi-quant data, right? It it it is not directly comparable. So I it and I think that that's a frustration, you know, that maybe Josh was sharing is it's just kind of vomited onto a uh maybe not even a table where it's side by side, it's two different, differently formatted tables. So now it takes a little well, now we have AI to do a lot of this grunt work for us. But like in the you know, the old days, two years ago, before we had AI at our fingertips, somebody literally had to take two tables side by side and recreate a new table that had comparison side by side. But then the really the expert opinion that needs to say whether these numbers are comparable or not has to be right there. So that's my two cents on comparability guides. They really need that expert opinion piece. Um, but to Katrina's point, now I'll get over to the other side and say, you know, if I'm if I'm a supplier, yes, for sure this still remains a struggle. What's the appropriate, let's say, ticket? I call it sort of tickets to the dance data package, right? You don't get past the door to get in to discuss things unless you've you've prepared a minimum viable package of uh proving that you're relevant for the market space for the applications. That's let's say not the most complicated thing in the world, but some people don't know what the right package is. Um and certainly I help suppliers in that space in my consulting uh life. But I think the harder bit is the functional, and we talked about this during the during the um online uh the live event, you know, finding uh appropriate beta partners to generate relevant case study type data early on in a product lifestyle, uh lifestyle, life cycle. That's a weird slip. Um that I think that uh many many suppliers struggle with that. And so depending on again, that you talk about the cost of extractables, that could pale in comparison. Let's say you need to do hundreds of cell culture runs at a you know, even a bench top scale to generate relevant data for the function of your um technology that you're bringing to market, that's wildly more expensive than sending some bits of plastic out to a lab to to have them uh perform an extractable study on. So um access to those resources, whether it be in academia or with development partners who have PD labs, that uh, you know, that's part of their remit is to do technology evaluation. So finding those, um, you know, that's that's not easy. And and defining the problem statement and really generating relevant data is something that I think a lot of suppliers of novel technologies uh struggle with.

SPEAKER_02 17:39

Yeah, thank you guys. That's great responses all around there. Um Paul, you you raised a good point. I just kind of been it's it's setting in the kind of diversity of backgrounds we have. Like you said, you're an engineer, Josh. Your backgrounds in chemistry, right? And Katrina, how would you describe your background?

SPEAKER_00 17:54

Statistics if you're director of research, or is it biochemistry or uh I guess more of the commercialization for for biotech, bioprocessing side, um, like market research and and more on the business side, technical and business kind of combination.

SPEAKER_02 18:16

Nice. And I'm an editor, so how how well rounded of us. What a what a balanced podcast. Um, so thank you guys again. And I I know you uh Josh, you had a great message to vendors out there, but I want to go around the horn and have you guys share your message to sponsors and end users that, you know, ultimately, yes, it would be great if vendors would just provide all the necessary data, extractables, leachables, data up front in these data packages. But until we get to a point where that's homogenous and happening across the space, what would your advice be to end users in the meantime? Oh, we'll start with you.

SPEAKER_05 19:02

No, no, go ahead. If you've never heard of a type of testing before, don't try and ask 100,000 questions of a supplier of material about that area. Find somebody in your organization or somebody you can bounce the idea of to be informed before you start asking all of these questions.

unknown 19:33

Yeah.

SPEAKER_03 19:34

I you know, I I wasn't thinking of that, Josh, but uh, you know, in case I mean my background is, you know, on supply side. So of course I was at Sertorius for almost 18 years. So, you know, one of the big suppliers. Um and I wasn't thinking of this story, Josh, but for sure, a lot of times some something, some topic, and I'll talk about back in um, let's see, what's my favorite one? Let's say um animal-derived uh ADCF, right? Back in uh, I think it was 2012-ish, something like that. All of a sudden we're getting a lot of questions about um animal-derived uh materials in our products. Um it seems like it must go back further than 2012. Maybe it was 07. Uh uh anyway, it was a long time ago. But by the time the question was transferred from the end user to the supplier, it was being asked through a non-technical uh person. And to some extent, I think they kind of played the telephone game before the question was transmitted over. Same thing with um, I don't know if you remember white tank rings, right? So there was there was some uh um oleamide or ruchamide used as a slip agent in some um dry powder packaging, and it bloomed to the surface, and it happened repeatedly, was used for buffer prep or media prep tank. Uh, and there was a white tank ring, and there was a big investigation, and somebody figured out that the fatty acids that uh were used for slip agents for this plastic bags used to package um these dry powders, eventually got into the dry powder, got into the tank, floated to the surface, and you got a white tank ring, and everybody freaked out. And then it came from above on the end user side. Thou shalt not have a ruchamide or uh oleomide in the packaging materials. And then it wasn't just packaging materials for dry powder, media, salts, buffers, etc. It was packaging for anything they bought. And it wasn't, you know, then the question comes across. So it goes from purchasing to uh, you know, the order management folks on the supplier side, then it bubbles up maybe through quality, eventually ends up in my case on my desk, where I started asking, well, what the heck is this really about? Why are they asking this question? Peel the onion, peel the onion. A year later, we find out why that question came about in the first place. And then we do a risk assessment and say, well, the risk of a plastic bag containing this slip agent going through the single-use system to the inside of the single-use system and contaminating the fluid path and coming out. Of course, they just wanted to know we don't have olemide or rigmide in our as a slip, or no, we don't have any slip agents, I think, in our packaging. Well, you need slip agents because otherwise you get saran wrapped. But um in any event, that's so sorry to talk so long about that. But Josh, that's a perfect example of what you're saying is the person asking the question had no idea what they were asking for. And then the person receiving the question had no idea how to answer it. And so a lot of inefficiency baked into the relationship, right?

SPEAKER_05 23:38

Yep. I often offer to my colleagues, I'll join whatever meeting with whatever testing lab you need. I will write the email, I will do the first contact, uh, and then let them take over the relationship once I've established kind of what are the boundaries of this uh to try and minimize some of those issues.

SPEAKER_03 23:58

And hopefully the person who hosted that meeting, they incrementally gain uh some subject matter expertise. So the next time you don't have to go to that meeting, right? Um so yeah, exactly.

SPEAKER_02 24:14

Great. Uh could before we keep going, Katrina, did you have any advice to end users, sponsors, manufacturers using these advanced single-use technologies?

SPEAKER_00 24:24

Yeah, I mean, I'm just thinking in general, like looking at our industry, not to generalize too much, but I think we always hear about the hesitation to try anything new in our industry in general, um, and the kind of like fear that something's gonna go wrong if you use something new that is different than what's been being used for the last decades. Um so so in general, I feel that it it would be maybe helpful if if sponsors were a little bit more open to just seeing what's out there and I mean within the the time and resources that they have to play around with things. But um that hesitation sometimes maybe can be stopping them from using something that could actually be saving them money or something like that.

SPEAKER_02 25:16

Yeah. Yeah, no, that's a good point. I do think to play devil's advocate, I'd say that they have good reason to be yeah, apprehensive to try these new things with how how highly regulated the industry is. But again, I think it circles back to vendors. If you're out there listening, we're talking to you, get the data packages together so people will will use it. I mean, we had almost 70%, 68.4% of our our audience the other day said that they would be somewhat confident uh that the data packages provided by vendors would be comprehensive and um would not require a supplementation. So the people will trust you if you put the if you put the packages together and again lower that risk threshold, like you're like you're saying, Katrina. That's great, guys. Well, I want to move ahead into kind of how we could move the industry overall or how you in a perfect world, how you'd like to see it uh progressing towards more or less risk-averse in in the way of adopting these technologies and kind of moving that needle forward. So I'm curious to go around the horn and hear what role you think industry standards can play in accelerating adoption, um, and specifically what the role of, as we call them, the alphabet organizations, the BPSAs, ISPEs, ASMEs, bioforums of the world are doing to drive harmonization and interchangeability, what their role is there. Um, Katrina, we'll start with you since you're on my screen and then we'll just swing back the other way.

SPEAKER_00 26:46

I mean, what's coming to mind for me at least is that there's an opportunity maybe for these standards to help clear up a little bit of that hesitation. Like if you can say that we've already been approved and have passed certain requirements and standards, there may be a little bit less fear and a little bit less of a need to recheck everything from an end user. Um like we already have certain grades, materials, and you know, like that are used typically, and and that's not really a big question when you use those things. Um, so if if that was very much across the board, that could maybe simplify things even more.

SPEAKER_05 27:26

Thank you, Katrina. Josh. Yeah, I mean, part of what these organizations can do is also provide education for regulators, education for um sponsors, so that way you understand the technical aspects of what is being done and what you need to do. So you people can do things with more confidence and hopefully understand the information presented in front of them correctly. Thank you.

SPEAKER_03 27:57

Well, I mean uh you know, one of the things about the alphabet soup is there's there's a hierarchy um, you know, within it. Um, and certainly your regulations are on top, that's law, and then compendia below that, and then uh consensus, uh, voluntary consensus standards below that. And then you've got sort of the we always call them stimulus bodies, um, that's like BPSA, bioforum, um, potentially ISPE in there. And that's where they sort of can write, let's say, best practice guides or or things of that nature. Um, my uh personally, I've recently come to appreciate that even the lowest level of that hierarchy can bring value. Um, you know, the these can these best practices or consensus um, you know, this is how we do things type documents, white papers, etc. Um, at least the drug sponsors, the you know, the people who are seeking regulatory approval, um, can say that they're not the only ones doing it this way, right? There's there's strength in numbers that these I'm just trying to think of, you know, whether it be dealing with, let's say, particulates or, you know, a validation strategy or whatever, whatever the case may be, um, there's safety in numbers to some extent. Um it's certainly not as powerful as a voluntary consensus standard compendia or you know, law above all. Um uh, but yeah, there's there's still value to those uh those publications coming out of um BPSA I SPE bioform. Uh they do bring a lot of value still, just because it's nobody feels alone in the in their wilderness. The the the the lone flag bearer running up the hill getting the spear in the chest, you know. So to make it very graphic.

SPEAKER_02 30:12

Yeah. Everybody, and it might be the thumbnail for this podcast. Somebody run up the hill getting spear.

SPEAKER_05 30:19

That's what it feels like sometimes to be uh just a to add on to what Paul was saying very briefly. Uh a lot of these lower level organizations, as you call them, the members of them are also people that are providing the comments to USP and those compendia, and also the ones that are writing the provisions and updating them. So those voices can trickle up and come together in that way.

SPEAKER_03 30:46

Yeah, Josh, thanks for reminding me of that. It I think it's a well, this there's multiple versions of what you're talking about. One is most of the um energy going into standards writing bodies, whether it be the ASTM E55 uh subcommittee for uh biopharmaceutical manufacturing, um, the ASME BPE, uh ISO um working groups that are appropriate around uh biopharmaceutical manufacturing. A lot of the same people participate at the lowest level organizations. These are the where there's sort of the ideation for, hey, we need a standard here. Um that's they then take that energy into a standards writing process, go through the process, it um with the appropriate structure, it can become a standard, internationally recognized standard. So that's that's one thing. Um in addition, um, the alphabet soup organizations at the bottom are uh typically commenters on during public comment period, whether it be uh an ICH uh guidance, so the Scientific Advisory Council of BPSA, we submitted IC uh comments to ICHQ3E. Um we submitted comments to the USP and uh wrote a position statement supporting the BPE's stance on the evolution of the bio uh biological reactivity standards. So there's it's all sort of trying to create this critical mass where everywhere you look, things are all pointing in the right direction and pulling on the rope in the in the right direction, you know, together.

SPEAKER_02 32:33

That's awesome. Thank you, guys. Thank you. Um, and taking a bit of a step back here, I meant to ask this during our our event, but of course we we ran out of time. Um, if we could kind of trace back, I'm sure there's always been more of more or less a push for standardization, but specifically, I want to know how how you guys see COVID-19, the pandemic as the impact on supply chains. How do you think that accelerated this conversation around material interchangeability and the long-term benefits of innovation in single-use technologies?

SPEAKER_03 33:07

Got to start with Josh on that one. He probably uh spent a fair amount of his uh sleeping and and uh waking hours on this.

SPEAKER_05 33:17

Well, it's an interesting time frame because I joined Takeda September of 2020. So I joined remotely uh from quarantines, basically. So that was an interesting experience, but it was extremely challenging. So being such a large organization spanning the globe, uh, but also at many locations across the US, there was a bit of an endeavor to also prioritize which drug products would get the resources and have strategic procurement to actually get the materials they need to continue to manufacture and get product out the door uh so patients could continue to get their care. Um and then there were rescheduling of manufacturing batches. So it was a lot of effort on the logistics side to avoid having to qualify alternates when possible. Um but yeah, that supply chain nightmare was not fun. Um quite challenging. And a lot of it also the huge delays and timelines. Um, so I don't know if it really helped to speed up adoption of interchangeability or anything, but it did slow down um a lot of other work because it's just there was no availability of resource to do some of the things.

SPEAKER_02 34:40

Yeah, thank you, Josh. Anyone else want to speak to their experiences during that uh unspeakable time?

SPEAKER_03 34:48

Well, I mean, from from my side, um, you know, at the end of the day, it proved anything is possible with regard to demonstrating comparability. You just have to be motivated enough. Um and you know, the certain impenetrable barriers to adoption were penetrated because top management said you're gonna run the process, figure out a way to do it. Well, you know, in different times, the top management says you don't get resources to adopt the new material because we're we're in cash cow status on this drug product and and it we're not investing in it, you know. So um, but you know, it's possible and for sure there's been some continued momentum in the standards writing um organizations to uh talk about interchangeability. Um you know it's a it's a tough topic because GMPs are written so um conceptually that each drug manufacturer's approach toward qualifying a material and validating it defies a standard approach toward interchanging them. You've got it, it's if you use a risk-based approach, you're gonna end up with a different strategy from process to process to process. So I think um I'm a big proponent of um sort of minimum viable data packages. And so uh at least everyone should if if two suppliers are offering comparable products, uh or uh let's say two films, just to keep a very easy example. Well, the data package should include all of these things, be reported according in these units and this you know way and you know, if and it's from and this is sort of pre-AI, but you take two validation guides from two suppliers, they both are offering their best information. It would take a week of a decent, you know, decently motivated and trained engineer to take those two and create something that compares them side by side, find the exceptions, focus on the exceptions, and then get to the point where I say yes, they're the same and can be comparable. But I think I said this during the online thing, and the at the end 211.65 says beyond the official um specifications. Well, years of um years of stability data is hard to accelerate. Yeah, and Josh, I'm I'm looking right at you when I you know how did you live without years of data to say they're the same, right? If you did go through a comparability and interchangeability assessment, just cry.

SPEAKER_05 38:08

When in doubt, cry it out. That's my motto. I mean, I mean the sad reality is at a certain point, you can't release until you have all the information you need to verify that everything's appropriate. So you can continue to manufacture. And there's some things where you could consider it a business risk if you manufacture it. Uh and let's say you can't qualify it. And depending on what it is, the chances of failure are low. Uh, other times you're taking an unnecessary patient safety risk um while you're sitting on it. And then it that of course also has a double-down business risk. So if you manufacture something that you can't sell because it's unsafe for patients, and you don't know until way too late it's a huge problem. Um, I'm usually unlike unwilling, yeah. I shouldn't say usually, I'm always unwilling to take risks where it comes to patient safety. There are some things where I say, you know, this is technically a business risk, but I don't think it's gonna fail. So we can move forward and we can generate information in parallel with production, um, and it should be fine. And so far, so good. Um, I haven't caused any business failures and I don't plan to.

SPEAKER_03 39:23

So yeah, but with with good technical due diligence, right? You follow down, you make sure your CMC is adequate to to assess if there is a difference between two different materials. Um, but but I mean at the end, yeah, if there's a patient risk, then then it's a no-fly zone.

SPEAKER_02 39:45

And if you're listening to this and you're in a leadership position, um, and you you work with material qualifications or supply chains experts that were were working during during the pandemic, I'd say stop by, give them a hug, take them off for a drink, lunch, care package, do something, right, Josh?

SPEAKER_03 40:02

I'd take a raise. A raise would be great as well. Hey, Tyler, I'd like to pivot and and see what Katrina's take is it and take is on this. I mean, uh, bioplan does a lot of benchmarking of people's attitudes uh toward new and different and everything else. It now we're you know, I guess the is the the 26th version is um in production now, right? So you've got survey responses.

SPEAKER_00 40:34

I'm sorry, only 23, not 26th version.

SPEAKER_03 40:40

2023.

SPEAKER_00 40:42

No, the 23rd version. Oh, 23rd version, yes, yes.

SPEAKER_03 40:47

Yes, so so you've we've had enough time since COVID. Like uh do the data, I I don't know which questions I would lean on specifically, having listened to Eric present uh every year at the BPSA event. Uh I'm always fascinated by what by uh plans hearing from the survey respondents. I I'm sorry to put you on the spot. Do you have any tidbits along this subject matter questions that you might pull out about people's either retained attitudes post-COVID or rebounded or anything with regard to interchangeability, new technologies, supply chain stuff? Good question, Paul.

SPEAKER_00 41:32

Sorry, it's uh I know it could go anywhere, and you need to I have something prepared in mind, but I don't know if it's exactly what you're thinking of. And while you were talking, I was really thinking of you know how we did see a little bit of a blip of that single-use use after COVID, and then it kind of plateaued out, and and now we see maybe almost 90% of all facilities are using single use, maybe in at least some capacity in their processes, somewhere in their facility. Um, and so it's almost like we feel it feels like it's reached almost like everything is full, everyone who's using it is gonna use it, and and like maybe it's not gonna go up much more, um, but it's gonna still be used because the value has been seen. Um but there is, you know, still that hesitation maybe around the supply chain. Like even in 2023 and and still a little bit now, um, but up until 2023, we were seeing like 85% of the vendors saying that they had to still keep fielding questions from users about supply chain and and concerns that they had, whether or not that's founded or not. Um the vendors feel that they're making a lot spending a lot of time having to field those questions and reassure people that supply chain may no longer be an issue now, like it was five years ago.

SPEAKER_03 43:01

Um until the next pandemic.

SPEAKER_00 43:03

Yeah.

SPEAKER_05 43:04

Whether or not it is a among other things that could be happening globally.

SPEAKER_02 43:09

Um supply chain PTSD, if you will. Can't fault anybody for that. Sorry, Katrina. Did you have more?

SPEAKER_00 43:18

Yeah, no, and and like you said, it's almost like something that maybe it's never really going to fully go away as a concern in people's mind. And and rightly so. I mean, you don't want to run into an issue, you want to be prepared for every eventuality and not lose your you know, clinical or or uh patient material because of all of a sudden running out of something and not being able to get more. Um so so it is obviously a fair question. Um, not that it shouldn't be shouldn't be addressed, but uh there could be perhaps maybe more worry than there needs to be at this point in time.

SPEAKER_03 43:58

Well, I'm gonna I'm gonna Um I'm taking over, Tyler. We're gonna do a uh bioplan survey N equals one. Josh, that's the solo responded. Um, were there permanent changes to the uh onboarding techniques within your business? Meaning, were you qualifying more than one source of something on a new uh system by by um you know top-down directive that this is now the way of doing business that we're going to sort of protect ourselves in the in the post-COVID supply? I want to say yes.

SPEAKER_05 44:41

I want to say yes, but I can't really say yes. Um it also really depends on what the material is. Some materials it's just so trivial to find alternate suppliers and alternate supply chains like sodium chloride, just trivial. Um, but other things where we would potentially classify it not by SOP by but by like what I feel in my heart as a more critical material. Well, you don't really have many alternates for it. But there are other things where we have directives for ways in which we do not want to be sourcing materials as an organization, um, just because of potentially geopolitical issues or just risks to material quality where there's low quality of that what we'd be receiving and ended up rejecting lots and just waste a lot of time and energy um in doing things like that. Uh so yes, but also oftentimes once something gets implemented, the cost you know of bringing another material on board is usually kind of a lot in the scheme of things. Uh sometimes something seems so trivial, but it's actually a lot of effort to and a lot of time to bring that on board. And we're constantly being asked to do more with less. Uh they're never saying, oh, we want you to build up a secondary supply chain for this drug product. Here's another FTE to do it. They'll say, We have restrained your resources and now we still want you to do everything, but now we really have to prioritize and focus our energy. And so something that would be nice to have, like an alternate supply chain for something, kind of falls by the wayside because we're still getting constant notifications of change from our suppliers. We're doing tech transfers, bringing in our pipeline products, uh, and focusing on other things to also, you know, secure the future of the organization. This is definitely going to go a little bit off topic, but many of the major pharmaceutical company players are facing patent cliffs where their blockbuster drugs are coming off patent in the next five or so years. And you need to be prepared to continue to maintain your revenue streams through the challenges from all of the generics that'll be coming online. So thinking there's just so many different things that are coming into play that sometimes these topics fall by the wayside, or we struggle to find the resource to actually address them. I'm actually we're starting up a team within our organization trying to tackle some of our supply chain questions. Where can we find opportunities to potentially improve cost, improve material quality, improve uh vendor relationships? Um we're seeing what we can accomplish with that. Again, we're resource constrained, uh, and we have a lot to do still.

SPEAKER_02 47:36

Um, and Josh, I had a question specifically for you here as it relates to materials and qualification. If you wouldn't mind explaining for me and our audience uh the transition away from USP 88 and the impact of evolving biocompatibility standards on material adoption. I meant to ask you this during the event and we just didn't have time.

SPEAKER_05 47:58

Yeah, um I'm not sure it's really that big of an issue, in my opinion. There's still vendors that are no longer, it's not really a requirement anymore, uh, but vendors are still providing certifications with it because you know the materials have met USP 88. So they're just gonna keep leaving it on their technical documents. Uh, there is kind of some question sometimes about like, oh, what are we supposed to do in place? But if we're being overly honest, you can do a quick Google search of like, what do I do instead of USP 88? And a pretty good response has come out. So replacing with you know extractable and mutual testing, there's ISO standards. Uh so just seeing what are the other options that are out there.

SPEAKER_03 48:39

Josh, I'm gonna ask a follow-on question because that's what I do, Tyler, you know. Um good cohesion. Um just did you go through? I don't know what you the Takeda's standard sort of baseline requirement set is for um process contact materials, but did it reference 88 class six in the past? And did you go through a global change control to remove it from specification?

SPEAKER_05 49:08

It has, to my knowledge, it hasn't been part of our specification that hasn't been part of our procedures. However, when we're really thinking about this from the extractables, bleachables perspective, you go through the risk-based approach, low, medium, high risk, however you end up there. And then our minimum requirement for things that are low risk is that it's a well-characterized material otherwise. And something like USP 88, USP class six would be demonstration of a certain level of quality of that material, and it would satisfy some of that requirement. Things that have medium or higher risk, we would then go through the gambit as you know, extractables, leachables testing, depending on how appropriate whatever, and what the material happened to be and full on assessment. And we have honestly a very mature extractables, leachables program at Takeda. So it hasn't really been an issue for us. There's been many a times um where I've seen in some of these alphabet super organizations where people are concerned about, oh, this has changed. They're asking us for this. I'm like, oh, we've been doing that. We've been doing it anyway. So it's not an ask for us. We're we've been a bit of out of the curve, and now we're probably at curve for a lot of things, just because that's where the organ the world has moved to. So not a problem for us.

SPEAKER_03 50:31

It's good to hear. Um, because I'm I sort of see this endless loop of somebody doesn't design it out of their spec, ask for it, supplier supplies it, and and it just sort of a self-perpetuating cycle because the suppliers don't want to have long conversations about this either. And if somebody asks for it, they're just gonna give it. Um, and just you know, between the BPSA and the ASMA BPE, there uh certainly some writings around this topic. 88 is uh not supported, and that's you know, uh it it the history is in case people don't know, it's you know, this is non-value-added animal testing, right? Um so the the baseline that's expected and this is supported in both the BPE and and BPSA um has written a position statement on this baseline is uh 10998 ISO 10993-5, or the equivalent USP 87 um in vitro cytotoxicity assay, right? So 87's revised now that 88's going away with um, or I shouldn't say 88's going away, class six is going away. Um, there's two new chapters in 87, but the baseline is just the cytotoxicity um assay. So um, you know, that plus extractables data really gets you there, right? There's no reason to sacrifice a bunch of laboratory animals if you're doing extractables anyway, which can lead to an actual, you know, value-added tox assessment. Um, you know, so um, yeah, that's that's the way to go there.

SPEAKER_01 52:29

Right on.

SPEAKER_02 52:30

Thank you guys. Um I had uh really quick before we before we wrap up, I wanted to ask you some some audience questions we didn't have the opportunity to get to during our hour, our live hour. There's really two that I think are worth asking on the show. Um, and the first one, I'll just lob up whoever wants to answer it. It's about how can regulatory affairs involvement during development help address the going back to our vendor data gaps and validation expectations uh before these become submission blockers. And I was asked by Ivtisem. Ivtasem, I hope I'm pronouncing your name right. Um, but Josh, maybe we'll hear from you. How do you how do you think, at least maybe at Takeda, how how involved our regulatory affairs appears?

SPEAKER_05 53:17

Yeah, um, as far as on the development side, I don't know uh exactly what that relationship looks like. So I'm in the commercial space. However, I do know when we want to change things in the commercial space, and that's an elective change, not necessarily something that's kind of being forced upon us. You know, if if something is discontinued as a supply, we have no choice. We have to change it. You kind of have to accept that there's a change. Uh, but if we're doing something more elective, really getting regulatory on board for the strategy and making sure they're prepared to support that change up front definitely facilitates the whole process for us. But it's more of um an internal streamlining of the process instead of getting up to the regulatory stage and them saying, no, this is we're not gonna accept this, this can't go out the door. And it doesn't really have as much of an impact for us on getting data from the vendors. It's uh more so a willingness from regulatory in that way or an understanding. But it's it's just really a communication thing and making sure pe your stakeholders are kept in the loop up front and you have a unified path forward before you spend all the money on trying to accomplish something.

SPEAKER_01 54:35

Thanks, Josh. Oh, Katrina, any any two cents to add there?

SPEAKER_03 54:44

Um I don't have direct experience here, but I I infer uh and and maybe Josh, you can weigh in. You know, the the reality is that um well, particularly early stage clinical, you know, you have a high attrition rate. So does regulatory have the time and energy to consult on a bunch of molecules that may never make it to the point where their input's actually relevant. Um and so they're resource constrained, and so they're like, Yeah, call me in five years when this is something I need to worry about. And so it's you know, there's a certain pragmatism that that conflicts with the ideal state of everybody being, you know, holistically involved, all stakeholders at every step of the way. Um, you sort of keep the small, agile team, minimum bunch of uh, I don't know. I I again I haven't lived that life, but I see Josh smiling. I mean, it's probably uh uh not that far from the truth. You you they just don't have the time and and resources to participate before their input's really needed.

unknown 56:05

Yeah.

SPEAKER_05 56:05

Yeah, absolutely on that front. I do want to refine one of the points I made. It's not that regulatory is unwilling to change things with us or submit the change we're making, but more often they are the ones directly interacting with the agencies. And it's very helpful to make sure we're getting kind of like the pulse of the regulators, making sure what we're doing is satisfying that. And they're the ones who will often be seeing that. Um so if we don't get their input earlier on, we might be missing the mark a little bit in whatever we're trying to accomplish.

SPEAKER_02 56:43

Makes sense. Thank you. Um, and one last audience question here. Um, I'll throw this up to any of you, but is there a database to test data for USP class six and extractables and leachables for commonly used plastics? These I seem these seem to just be Josh questions, and I apologize for that, but uh I think they office hours with Josh. Yeah.

SPEAKER_05 57:08

Um the short answer is no. Um the long answer is kind of. Um so it depend it's challenging to share this type of data. Vendors are often or suppliers who are performing this time testing on their own materials will share it with their end user, sometimes for a fee, sometimes free of charge. Uh, but they're not necessarily willing to dump it into just a generic database. Um, and then I've been part, I am part of an industry working group where they're asking the member organization to donate their extractables data. However, at Takeda, we have a very mature extractables program. We have contracted out tons and tons and tons of testing, and we have the ability to access much of the vendor data that we want. So we didn't really get any value back if we were going to donate some of our data in. But then part of the purpose of sharing the data would ultimately be to make generic material profiles. So, as a simple example, platinum-cured silicone tubing. Presumably, they're all going to have, regardless of for the manufacturers, a relatively similar extractables profile. Because at the end of the day, it's some kind of siloxane that we have going on. But so you have this general profile, generic profile. But now is a regulator going to accept that you performed your evaluation on some generic data set? Is it actually representative of your process? And with the push for constantly add having more authentic data on your actual use case materials? What value are you really getting out of that common database? But part of that common database that I am referencing, part of the value is that they're also trying to combine all of the mass spectra for the extractables profiles for these different materials. So then you can also start seeing oh, this specific compound is coming out of this type of material. So we can start using it as a research tool to do some better data matching, data evaluation for people performing new extractables testing on other materials so they can help get better matches locked away.

SPEAKER_02 59:22

Got it. Thank you for explaining that, Josh. And I think office hours with Josh should be a show of itself, honestly. I think I think that could do numbers on bioprocess online. We'll we'll hit you up.

SPEAKER_03 59:35

You know, I try. Amen. Sorry, Paul, go ahead. I was just gonna say, you know, Josh, I'm sure you've read enough extractables reports um that you know, the quality of the work performed by the contract labs and sort of the way it's reported and and um is a wide variety out there. And and just throwing it all into a clearinghouse. I mean, I think there's definitely a lot of folks are in a protective mode, right? The suppliers don't want to willy-nilly spray it all over because they think that they've got some magic sauce and they don't want to give that away, right? Um, or they think that there will be competitive positioning against them by their by their competitors uh based on extractables data. So there's a lot of fear there is a big investment. Um uh and on the end user side, you're like, I spent the money on created value for my business here. Am I enabling a generic competitor to come in and implement that material in their product at a lower cost? You know, why what's in it for me? So I think there's a lot of what's in it for me, um, protectionism around this idea um that'll persist for a long time. Um certainly around the extractable stuff. Uh, with regard to the biological reactivity, it's a much lower cost. And every and it should be not a material but a finished article too, right? Because manufacturing matters. Uh uh and certainly especially and post-treatment as well, right? So if you're going to supply something steamed or gamma radiated or sterilized by ethylene oxide, that's what you need to test because the polymers change, right?

SPEAKER_05 1:01:39

Oh, absolutely. Absolutely. And then also the other part that you kind of lose is any control over the data quality when you're pulling it out of some, you know, cloud data source. Uh, and it depends on what is readily available for that data source. Are you getting the source data packages, the protocols, all of that fun stuff where you could do the deep dive if you have the expertise or desire to do so? Or are you going to get your run-of-the-mill AI slop evaluation of this data set and have people drawing wildly incorrect conclusions? So as much as I believe in accessible data and everything, uh, you do want informed, educated individuals doing the evaluation of the data that's in front of them to make the appropriate assessments to draw the correct conclusions, or again, ultimately, what is the safety of our patients out of this?

SPEAKER_01 1:02:38

For sure.

SPEAKER_02 1:02:40

For sure. Thank you guys. Um and you know, wrapping up here, I just have two more questions. Um one of which being, we look into the future, the next couple of years, three to five years from now, what do you hope to see change as it relates to single-use standardization, adoption, validation? I, for one, after this sequence of conversations, I hope uh vendors start putting together more comprehensive data packages. And I didn't even realize how big of a problem that was before we started talking about this. So I'm curious to hear from all of you what you hope to see change in the next three to five years.

SPEAKER_00 1:03:19

I guess uh I'll start us off. I'm just thinking of what I think I shared during the live event about the demand for better single use and improved single use innovation from Cell and Gene, especially as a sector. Like I think we are getting there and and um cell and gene in general is is progressing fast. Um, but uh if single use can can keep up with the needs of of that industry, which is really, I think maybe I'm biased. Um, but uh I think it's a a modality that is really has a high potential for a lot of patients.

SPEAKER_01 1:03:56

I agree, Katrina. Thank you. Josh, Paul?

SPEAKER_03 1:04:05

Well, uh um you know, I'm encouraged by uh USP 665. It's a significant milestone in and when I talk about standardization, I talk about standardizing, let's say, test and evaluation methodologies. We're not ready really for standardization of technology itself, uh, because that can hamper innovation if not done right. And I think um that we can create interchangeability if that's really the goal of standardization by qualifying the materials according to standard methods. USP665, they just sent out a call for experts for the next revision. I mean, before May 1st, uh, I think it was a week or two before May 1st when it was going live, they're already saying, hey, come join the party uh to uh rewrite this thing. Um, but there's you know, it's not just extractables. I think particulates remain um a bugaboo. Um there's no easy answers there. How much is okay, how much is not okay, how to assess, how do you even test methods are in development within ACM, but not complete uh yet. Uh so articulates integrity. Um uh I think sterilization is pretty solid. Um compatibility is pretty solid. So uh, you know, particulates and integrity, I would say, are areas that uh could use some standardization to facilitate adoption. Great.

SPEAKER_02 1:05:56

Thank you. And last but not least, I will ask you guys the hallmark question of this show. I ask every guest, and that is in your opinion, big, small, broad niche, how do you think we can better biopharma?

SPEAKER_03 1:06:09

You know what I I think that the the best way, you know, if if both sides of the supplier and end user community can look at the other side with a greater degree of respect we can create a a better bunch of relationships that bring value. It's when it's you know there's it's it's the transactional or bully approach um either direction, right? It can go both ways, right? The big supplier is like I'm the big supplier you shall buy for me. And then but I'm a top 10 biopharma I'm gonna tell you what to do.

SPEAKER_05 1:06:54

Both are businesses with their own needs uh one serving patients uh both serving stockholders uh you know they need to figure out how to get along and and to have a a a good a more value added relationship that's sort of behind the stuff I mean that's very Pollyanish of me that's a good answer Paul thank you Josh curious to hear your thoughts and Katrina I mean I I do feel that I often talk to suppliers and the other side of things because I'm not afraid to just pick up the phone and just start calling people and I think we kind of need to bring that back bring the human element back to this you think about this industry as much as it's run by capitalism at the end of the day it's all about the patients and bringing care and life saving medications to patients and Corb is the people so we need to behave like people and treat each other with dignity and sometimes it's just nice to I have a basement office here.

SPEAKER_00 1:07:55

I don't see the light a day very much it's nice to hear a voice other than the one inside my head yeah amen amen Josh Katrina how do you think we get better bioparamo I mean I really am on the perspective that we have the potential to use biomanufacturing innovation to really enable global health and and access for everyone to to medications that they need. And um I think the technologies exist they're out there and and if we find the best ways to use that and improve yields and and bring down costs that can really enable us to you know dose more patients or or make it things affordable for LMICs and and um I I know that's the the desire of a lot of people in the industry and I I don't think it's an impossible aim at all by any means that's great.

SPEAKER_02 1:08:47

Thank you all uh for your for your great answers to that question Paul Josh Katrina thank you so much for joining me on this episode of Better Biopharma the official podcast of Bioprocesson if you'd like to watch the full live event that these three were featured on some time ago head on over to Bioprocess Online. The link is in the description and stay tuned for new episodes of Better Biopharma every other week I'm Tyler Manichello and I'll see you next time.