Harsh Thakkar (00:01)
All right, welcome. Sorry, I'll start that again.

All right, welcome to another episode of Life Sciences 360. My guest today is Carlos Yuraszeck. And if you are in cell and gene therapy manufacturing, or you work at a CDMO, or maybe you're just interested about how cell and gene therapy manufacturing is different from setting up other types of manufacturing facilities, you definitely want to listen to this episode. Carlos is somebody who has tons of experience.

working in cell and gene therapy manufacturing, heading up some of these sites, bringing them, building sites from the ground up. He's worked at companies like Cellgene, Astellas. So I'm really excited for Carlos to be here with us today. And let's dive in and have a chat with Carlos. Welcome to the show.

Carlos (01:00)
Well, thank

you. Thank you, Harsh. Thank you for the invitation. I'm very excited to be here.

Harsh Thakkar (01:06)
Yeah, so I want to start off by asking you, you have an amazing journey. I think you worked at Cellgene for 16 years. That's how I first found you looking at your LinkedIn, because I worked briefly there for two years during the BMS acquisition time. But when was a point in your career where you decided that you wanted to sort of pick the Cell and Gene therapy lane? Do you remember that moment?

Carlos (01:13)
it is.

Yeah, I mean, I think it started a little bit earlier. I really fell in love with the pharmaceutical science and how it really interacts with operational excellence and compliance, right, to bring really life-saving products to patients. And cell and gene therapy or cell therapies was really just, when I first got in there, it was really just getting started. And it was this opportunity to bring like a new modality into the marketplace.

that could potentially be transformative. And I thought, yeah, this is a great opportunity. We don't know if it's gonna work, but it certainly had the potential. So I jumped in.

Harsh Thakkar (02:14)
Yeah, and you've worked at cell and gene therapy companies, you've scaled up sites, you've helped build up sites from the ground up. What's one critical factor that is unique to cell and gene therapy manufacturing facilities or operations or setting up a facility that most people might overlook if they haven't worked in cell and gene?

Carlos (02:37)
Yeah,

I mean, think it's, yeah, if you start to think about like the facilities themselves, right? In general, I think people think, okay, know, a cell and gene therapy facility, or let's just maybe talk about cell therapy facilities. They're much simpler in design, right? And lot less expensive to build. But the real challenge, I think, is really incorporating the needs of the living product, right? The cells themselves.

and incorporate at the same time the human factors that need to be, need to take into account people's sizes, their strengths, what they did for the weekend. I mean, you really need to account for basically everything that's human into the operation. And I think we need to keep in mind that the facility itself is really just the first step, right? The first you need to make the facility, but then

Harsh Thakkar (03:30)
Mm.

Carlos (03:32)
you really need to make it operational. And to make it operational, you need to take into account how these different aspects will come into play. And if you start these processes really in a complex manner, everything starts. So I think you really need to start simple and then layer in the complexities that you need, but only as you need them. And that is really a therapy or it's a strategy for success.

Harsh Thakkar (04:02)
Right, and even within cell therapy, maybe you can share your thoughts here because especially for our audience who are not from pharma or they don't know all these terms, but inside of cell therapy, there's also autologous, there's allergenic, there's different types, right? So yes, cell therapy versus traditional manufacturing has its challenges, but within cell therapy, when you talk about allergenic or autologous, maybe...

Carlos (04:12)
Mm.

Harsh Thakkar (04:29)
Can you share what those are just for our audience who are not familiar with those terms and maybe what are those challenges when you are inside those different models?

Carlos (04:38)
Yeah,

I mean, once we started into the autologous CAR-Ts, and I'll describe that. So the autologous versions is basically saying that we're cells specifically from one patient. We're taking them back to our facility, genetically modifying them, and then returning those same product back to the patient. So basically one lot per patient, which is very different than anything else that we as a...

Harsh Thakkar (04:51)
Mm.

Carlos (05:04)
biotech or pharmaceutical companies I've ever done before, right? Very personalized medicine. And I think the CAR-Ts are a really great example of the operational excellence concepts of looking to where is your largest amount of variability. And it turns out that the patients themselves, they actually represent the most variability that comes into a process and actually can account for a large amount of the variability that we see in the final product.

So when we started looking at manufacturing, right, we need to start looking, okay, where is this variability come from? And then go there to try to figure out how to reduce it. So at least in the CAR-Ts, we're now understanding everything about that patient and their journeys to the time that we actually collect those cells makes a difference into the outcome. Now the outcomes are...

you know, multifactorial and they're crazy complex, right? But we're starting to really understand that everything about that journey could make a difference. And their status, the different therapies that they've been on, the therapies that they might be on at the time that we collect the cells, all can make a difference to the outcome. So now we're starting to adjust our processes so that we continue this, you know, personalized medicine.

and really adjust the front end of the process to understand when to collect the cells, when we need to stop the current therapies, what kind of bridging therapies should be on, all those things will have an impact to the final product. In the allogeneic space, so now allogeneic meaning that you can take a cell product and make it in a way that actually can be given to anybody, or at least that's the hope.

Harsh Thakkar (06:44)
Right.

Mmm.

Carlos (06:57)
There's no approved products yet for the allogeneic versions, but that is something that will be really important for us to continue to fulfill this promise and make products that are more consistent, of better quality, and more accessible to patients because we can make a bunch more widely available. There's lots of strategies that are being tried. I think that in general, you can kind of break them down into three different versions.

The first one is really from healthy donors, right? So just taking healthy cells and then we use them therapeutically. The other is to take the cells, genetically modify them, and then return those to a patient. And the third, I think, is from stem cells, right? The more popular one is going to be the IPSC derived or the induced pluripotent stem cell versions where we take a stem cell, we differentiate it to the cell of interest, and then

we can either impart new capabilities to that cell and then return those, or we can just generate the cell that we want and then introduce that as a therapeutic. So once we get to that allogeneic version, I think that's where we'll see this more consistent product.

Harsh Thakkar (08:09)
Okay.

Okay. And have you seen like, I'm not aware of this, but I want to ask you because you're, you're spending a ton of time in this space, but our, biotech or, or, know, biotech companies mostly having a pipeline in one space like autologous, or have you seen companies that are trying to, you know, run trials on both different types and then figure out which one is their most promising candidate?

Carlos (08:25)
Hmm.

Yeah, no, think that, you know, so depends, this depends on the disease, right? So I think that because of the success that we've had with CAR T, by the way, right? So those CAR T products for the audience, these have been really transformative to a whole range of patients that have had no other options and they really have been, you know, amazingly successful. So because of that, we have a really good benchmark for those products.

Harsh Thakkar (08:52)
Hmm.

Carlos (09:14)
So when we talk about a new technology or a new way of imparting different capabilities to these cells, they're trying to compare them back to what's been working. Those are very long and very expensive trials, but sometimes you have to kind go down that path to make sure your strategy is going to work. But I think that in the long term, really having both doesn't seem to work. You know, I think that you need to...

concentrate on one or the other because your decision making, especially, you know, we're talking today about facilities, makes a big difference in the way you design your facilities.

Harsh Thakkar (09:44)
Hmm.

right and talking about decision-making you you you almost went into the other area that was on my brain and Which is I'm assuming you've been on tons of project teams You know designing a cell or gene therapy facility and you've emphasized on some of your you know At least when I talked to you in one of our previous calls that making the right strategic decisions early on

Carlos (10:02)
Mm.

Harsh Thakkar (10:22)
Knowing what you want that facility what you how efficient you want that to be? What's the output? So is there can you share an example of maybe in your rules? In like the facility design and automation stage was there a decision that you made and that turned out to be you know few years or a few months down the line a favorable outcome and Can you share something like that?

Carlos (10:44)
Sure. Yeah, yeah,

sure. mean, think that, first of all, I think it makes a big difference what you're designing for, right? So I think that if you think about the facilities and the pace of innovation that is occurring right now, if you're an early phase development, the facility really should focus on one of the primary aspects of that facility should be flexibility.

Harsh Thakkar (10:54)
Hmm.

Carlos (11:10)
you need to be able to maybe bring in different products. You may need to reconfigure the facility. You may need to do construction in the facility while you're actually producing. So flexibility in early phases is a huge importance. When you think about late phase manufacturing for these things, the process is more stable. You're done sort tinkering and the consistency and efficiency become much more important.

Harsh Thakkar (11:39)
Hmm.

Carlos (11:39)
If you're

gonna take a facility that is late-phase and you're gonna make it a commercial facility, there is yet other aspects that you need to take into account, including things like how inspection-friendly it is, for instance. Sometimes we overlook the fact that regulators, especially the more innovative your product, the more attention you're probably gonna get, the more likely that you can have inspections. And although the inspections are...

they are of course to make sure that you're on the control and you have the right GMPs and everything. They're also there to learn, right? So they want to spend time to see how these things occur. And you need to make a facility that is inspection friendly for those things, right? Expecting that they're going to be needed. And they're a very important customer that you need to account for. So again, the design changes or design aspects to your facility will change depending on first, you know, early phases, mid phases or late phases and commercial.

Harsh Thakkar (12:16)
Hmm.

Carlos (12:37)
will have different aspects to it.

Harsh Thakkar (12:41)
Yeah, and another thing I've noticed, just working with clients in our company at Cultivate, we work with lot of cell and gene therapy cancer research companies and our primary bread and butter type of project is anything related to quality management, compliance, data and technology management. So even there I've seen, we had some clients, like big companies that have acquired smaller startups, but they're doing cell and gene.

And then we have like these 11 to 50 person companies that really have nothing and they're just starting from scratch, right? So I've seen that difference. What have you seen, like you talked about facility design and the architecture and all of that. But once you pass that phase and now you're bringing in quality systems, manufacturing, lab systems, equipment, that's where kind of my team comes in, because we help companies with that.

Carlos (13:35)
I see.

Harsh Thakkar (13:37)
In that area of systems, what have you seen or what can you share for cell and gene therapy companies who are early stage versus those that are close to commercializing? Is there something they should watch out for?

Carlos (13:47)
Yeah.

Yeah, I mean, I

think that what you're describing really is about phase appropriate quality systems. that sort of? Yeah, I love this topic, right? It's something that I've been really involved in for a very long time. And when we talk about phase appropriateness of quality systems, I first like to start really with describing the challenge, right? The challenge doesn't change really too much where it is, but it's always a balance, right? Between

Harsh Thakkar (13:57)
Yes.

Carlos (14:19)
quality, cost, and time. Those are the three things that you always are challenged with. And with new innovative therapies, you need to think about that these patients that you're making these products for, they are waiting for this product and many of them are out of options and running out of time. So I feel like there's this urgency to get these products to the clinic as fast as possible. The second aspect I think of

of these policy systems is the FDA themselves. So they've revised the Code of Federal Regulations to exclude phase one products from complying to 210 to 11. And many of us sort of are aware of this. So you say, well, why would the FDA do that? Why would they make this change? The regulations have been there since the 1970s, and they've been successfully

adjusting their regulatory scrutiny depending on the phase without changing the GMPs, right? So why make the change? And you can find the answer to that in the official preamble to the GMPs themselves, where the FDA specifically says that they want to promote and streamline the process development process. And by excluding the phase one products, what they're signaling to us is more flexibility about how you design your quality systems, okay?

Harsh Thakkar (15:24)
Hmm.

Carlos (15:45)
All right, so with these two things in mind, the urgency from these patients that are waiting and the agency saying, yes, you can have some more flexibility in the early phases. Then you start to think about, how should my quality systems change? And I can give you some examples that I think maybe illustrate what these things look like. So my favorite one to start with is really change control. And change control in early phases really should be something that enables change.

Harsh Thakkar (16:09)
Hmm.

Carlos (16:14)
If you think about change controls, often thought about as an obstacle or something that controls change, which is part of the name. But in early phases, it should enable change. It should go fast. It should be able to allow the changes to occur quickly. Compare that to your later phases where the change control system should make it very difficult to make a change, right? Because there should be a stable by then. We should not be tinkering in late phases or commercial.

Harsh Thakkar (16:30)
Mm-hmm.

Right.

Carlos (16:42)
So therefore the hurdle to make a change needs to be much, much higher. And that then dictates really the type of people that are involved in change control, the way that they make their decisions, the way they document and implement the changes, all change depending on where in this continuum you're in. Let give you another example. So for instance, another one like batch records, for instance.

Early phase batch records should really be much more flexible. They should probably have less detail in them. Allow for more judgment of the operators in making decisions about how the products are made. It should allow for commenting and observations, and that should be the important part of them without generating some kind of automatic deviation. In later phases, your batch record should be really detailed.

Harsh Thakkar (17:14)
Mm-hmm.

Carlos (17:37)
or detailed enough to make sure you're consistently making the same product and tinkering or deviating is not allowed. And those things, then you really need very thorough investigations if they occur. So you have these contrasts. Maybe one more, just to give you one more. For training, for instance, in early phase products, training should really be focused on the science, the technology.

so that they can have the preparation to make those judgment calls when the batch record may be incorrectly written. They should be confident that they should maybe make a deviation from the current written record. In later phases, what you really need to reward is consistency, right? The consistent execution of that batch record without deviation. So again, the training, the emphasis, all that kind of stuff changes depending on the phase. Make sense?

Harsh Thakkar (18:05)
Hmm.

Right, yeah, and I love the example that you gave of change control because I've seen that working with companies where, as you rightly said, early on, you should be able to have that flexibility to make quick changes because you're still trying to get your process locked down or figure out what you're trying to achieve. But then as you go later, you start having things like a change control review board. You have additional stakeholders.

So all of those are, to me, not, people might think that as hurdles, like, why is it so hard? But you're rightly, as you rightly said, the reason for that is because you don't want too much variability that late in the game, because then you're gonna have to explain that to the regulators as to why you changed things. So that was a great example.

Carlos (19:23)
Sure. Yeah, I know.

I think that when you start digging into this, if you make the change control in an early phase, for instance, very data driven, well, you have very little data. It's by definition, you're early in that development. So you need to account or you need to count on people's judgment much more than you are in actual physical data. But if you make the changes later in the phases of development, you could

really depart from the process that generated the clinical data that was the basis for the approval. So there, you better have a lot more data about your process and be able to judge whether or not a process change will have a major impact and change your product. So I think you really need to design them very differently depending on the phase.

Harsh Thakkar (20:04)
Mm.

Yep, I actually need to step away because I need to I'm having like really sore throat So give me like 10 seconds and I'll be right back

Carlos (20:30)
Okay.

Harsh Thakkar (21:23)
I'm back.

I'm gonna skip the next one around automation, if you're okay with that and go straight into compliance, leadership, stuff like that.

Yeah, so those are some really good examples and I love when guests like you who've spent so much time in a particular space are coming here and sharing these practical examples that other people who are in cell and gene can relate to, right? So I totally love that. I wanna go into compliance and your role as a leader in the cell and gene therapy space. you've been in lot of...

You I'm sure you've been in a lot of projects. You've interacted with a lot of regulatory authorities while you were either building a cell therapy facility or scaling it up. And one of the, one of the questions that I see often come up in, that, in those kinds of projects is how do we balance the need for, meeting the regulatory requirements, but then also innovating at the same time. So what if you are in a meeting and

That's the debate. How have you handled it and what's your take on

Carlos (22:48)
Yeah, I mean, that's such a great question and about just how do you adjust, right? How do you adjust the rigor that you need to take in complying or driving towards some endpoint? And I think the answer really, which is difficult, right? But it is really having the patient's interest in the end, right? What's their most important thing to that patient?

Harsh Thakkar (22:56)
Mm.

Carlos (23:17)
And that really comes from an understanding of their disease, right? Their own journey and really what are the necessities that they have. And I think, you know, for professionals within, especially compliance and quality assurance that might be a little bit separated from the patients themselves, it's a difficult situation to be in. But you really need to step into that process because that's the only way to really do

proper risk mitigation and risk assessment, whether or not the risk is appropriate. So I'll give you an example. So the calculus is very different for a patient who is relapsed and refractory and basically out of options. And you have a new technology that could potentially help them. The more urgent that need, well, the more flexibility and more risk that we should be allowed to take. Because...

Harsh Thakkar (24:03)
Hmm.

Carlos (24:13)
they don't have anything else, right? So they can't wait for us to make it perfect before we can bring it to them. They're much more willing to take a little bit more risk. That's very different than a patient which is newly diagnosed, for instance, and they're considering their first line therapy where there's lots of options and there you need to actually have a product that is far more consistent because, or less

variable and of higher quality because now you're in a realm of different options that this patient has and the urgency is not the same. So those are the differences. And the CAR-Ts actually give you a really good example of what is happening right now. The CAR-Ts now, the autologous versions are moving up in the lines of therapy. They were four plus and then three, and now they're in second line.

Harsh Thakkar (25:02)
Mm-hmm.

Carlos (25:14)
You know, I think you can make a really good argument that the CAR-Ts, as you move them up into the earlier lines, you'll actually get a better product, safer product actually, because the patients themselves have seen fewer lines of therapies that affect the cells. They are healthier in general, right? Because they haven't been through a decade worth of chemotherapies and other things. So their own immune systems are better.

So all these things will tell you, this is probably a good idea, is to move these products into earlier lines. But because they have more options, and now potentially they may not be the largest amount of variability into the process like I described before, right? It might be something else. It might be your raw materials, right? Where the variability comes from will change. Well, then that changes the responsibility of the CNC team.

Harsh Thakkar (25:58)
Hmm.

Carlos (26:10)
to have more consistent product and better assays, right? To make sure that anything that we actually do can actually be detected through our testing. So just because they're moving up into the different lines changes the responsibility of the manufacturer, right?

Harsh Thakkar (26:30)
All right. Yeah, it's really evident. I think we've been here for 30 minutes. I'm not sure exactly how long, but it's really evident that you love this space so much and you have so many different takes and examples. It's obvious because you work in so many different companies. One of the challenges with cell and gene therapy is...

Carlos (26:41)
Thank

Harsh Thakkar (26:55)
lot of the times I'm talking to recruiters or hiring managers where we do some consulting work and they're trying to build their team. And it's really, really hard to find somebody with the exact experience. mean, there's only a handful of companies that have approved products. there's those people. I'm sure you are one of those sought after candidates that companies reach out to. What is so exciting to you? What is so exciting about cell therapy?

Carlos (27:24)
Yeah, I mean, I think that first, they've been really transformative. I think that all the progress of the pharmaceutical and biotech industry have been fantastic, right? But for this refractory relapse patient population for CAR-Ts, it's just been so good. And so maybe not completely unexpected, but certainly people maybe didn't think it was gonna be this good.

Harsh Thakkar (27:29)
Yeah.

Mm-hmm.

Carlos (27:53)
And just for reference for your audience, in these patients that have really nothing left, the response rates are in the 70, 80%, complete response. And long-term survival now, where patients may only live three to six months or so, now with CAR-Ts, they're probably going to live for decades. And so it really is transformative. So where do we go from here?

Harsh Thakkar (28:06)
Hmm.

right.

Carlos (28:20)
And I think the allogeneic version that we mentioned before is probably the most obvious, is to take that same potential for being curative in a lot of cases and bringing that to a much wider audience. And really the allogeneic space, I think will give us more control. Because right now, like I mentioned before, the patient and their history makes such a huge difference to the quality of our products. Once we get to the allogeneic version,

you know, there's going to be this donor derived, right? And those will have variability as well because the donors vary. But eventually we will get to the stem cell version where we can establish a cell bank, right? And we can establish the criteria for that cell bank. We will have much more controlled mechanisms to get to the cell of interest. We will be able to impart more consistent the abilities of that cell to respond to their environment.

Harsh Thakkar (29:06)
Hmm.

Carlos (29:20)
All those things will be much more within our control and then will help us produce better products. So that is definitely where I think the most exciting part of it is. And we're on a journey. We're just getting really started in making sure we can get these products to a large group of people.

Harsh Thakkar (29:41)
Yeah, that's definitely one of the exciting, and you can really see in even the people and the companies, their culture, their way of operating. Every cell and gene therapy company I've worked with, I've really seen that deeper purpose that they know they're working on something unique, something that's going to change the landscape of how these therapeutics are going through clinical trials and commercializing.

and then at the end meeting an unmet need or as you mentioned, the example of having going from months to decades. So like that's what we're working for, right? So that's definitely hearing that makes you refocus and whatever role you're in in that company, it gives you that deeper sense of purpose.

Carlos (30:30)
Yeah, no,

absolutely. think you can pretty much generalize that for everybody that's working within this field. They are touched by those patients and their experience. at Celgene, we had so much of that where because we were picking up Myeloma of patients who were refracted and relapsed, again, life expectancy was about three months or so for those patients. Once you...

Harsh Thakkar (30:38)
Yeah.

Mm.

Carlos (30:58)
get them through the therapy, which is not inconsequential. I mean, it's tough. But once they make it through that and they see the success in their own health and they feel better and they're able to get back to doing the things they want, they come find you. And it's funny, we've had so many patients that come to the sites and they want to meet the people who made this product for them and that kind of stuff. And it's really transformative for us ourselves that are working in this space.

And if you're thinking about getting into the space as part of your audience, I highly recommend it, but it's hard and it takes a lot of studying and making sure you understand not just your own space, you for me, it's manufacturing compliance, but also understand how does clinical work, how does drug safety work, you know, and it's really the combination of all these things that makes it really work.

Harsh Thakkar (31:48)
Right.

Yep. As you were talking about that, I was reflecting on my days at Juno and then getting acquired by Celgene, because we used to also get lots of patient stories and patient visits at Juno in Seattle where they would explain how they're going through one of the trials or how they're taking these. It's like you're in that room and you basically are

Like I said, you come out of that room and you have this renewed sense of energy and everyone sees their impact in real life.

Carlos (32:30)
Yeah,

and it's rare within our industry to be that close to the patients. you know, so yeah, definitely.

Harsh Thakkar (32:36)
Yeah.

What's, yeah, in your career in cell therapy or just in life sciences and pharma, when you look at today what you have accomplished, what's one important lesson that you've learned in your career that you maybe wish that you had known earlier?

Carlos (32:58)
Well, I I started in an automation, right? So I wish I would have started directly into the space. But no, I think that in general, you need to not be afraid. I think a lot of the concerns, especially as we move into these new modalities and even transitioning from autologous into the allogeneic space, I see a lot of this as just this concern, this...

Harsh Thakkar (33:02)
Yeah.

Hmm.

Carlos (33:26)
I want to call it fear, but it certainly is this sort of like, I guess it's fear from the unknown, But is it really in the best interest of those patients? And I think that that's a lesson. Whatever it is that we're doing, the first question should be, is it good for them? And if the answer is yes, then tackle it, or at least try to tackle it, because everything else really will come later, right? The success of the company, the success of the products.

All those things will come later as long as you pay attention to what's really good for those patients first. So that's, I think, the basis. Yeah, I mean, I don't know. You want to dig into more of that, but.

Harsh Thakkar (34:04)
Yeah.

Yeah,

that's really great to hear. And for our audience, you're listening here at this point, and if you enjoyed this conversation on the cell therapy topic and with all the experience and insights from Carlos, please, please go ahead and subscribe onto the YouTube channel or follow us on your favorite podcast platform so we can bring you more guests like Carlos.

and go really deep into these very niche topics within the life sciences industry. So back to you, Carlos. Thank you so much for your time. I know you're extremely busy and I appreciate everything you've shared on the show. I've learned a lot from you that I'm gonna apply and review this recording and apply to some of the projects that we're doing with cell and gene therapy clients.

One, what's your last, before we drop off, how can people connect with you? How can they learn more about you? Or if they just wanna pick your brain, what's the best way to get to you?

Carlos (35:16)
Yeah, probably.

So I think LinkedIn is probably the best. Go ahead and search my name. Send me a link request. And I'm happy to discuss things even without an agenda. If you just want to discuss anything, go ahead and reach out. I'm happy to engage.

Harsh Thakkar (35:35)
Yeah, that's what I love about you because I reached out to you completely out of the blue and I'm like, hey, I want to talk to you and our prep session went to be like an hour. And I was like, we should talk about this maybe on the podcast, not today. So thank you for being that open, you know, to just, you know, talking to people because that's how we're all just in the same space. And these kinds of conversations, you know, help everybody in the industry. So thank you for being flexible and open there.

Carlos (35:58)
Mm-hmm.

Well, thank you for

the invite. mean, it's been a pleasure.

Harsh Thakkar (36:08)
Yeah, that's it here and we will see you in the next one. Thank you.