May 6, 2025 • 24 mins
Bringing novel cell and gene therapy products to market can be challenging for both nonclinical and CMC. David Pepperl, Diana Colleluori, and Robert Kutner return to talk with James C Taylor about it!
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(00:02):
Bringing novel cell and gene therapy products to market can be challenging both fornon-clinical and CMC.
Fortunately, I have a few colleagues who are up for the challenge and they happen to bethree people I've talked to before.
Let's meet them again and talk about it.
I'm James C.
Taylor and this is Insight at Biologics.
(00:22):
you uh
you
Thank you all for doing this with me.
It's wonderful to have you all back.
just for people who may not remember, we're going to go ahead and introduce ourselves.
And we'll start with.
Hi, thanks James.
My name is David Pepperl.
(00:42):
I'm a pharmacologist and toxicologist and principal consultant at Biologics Consulting.
been with the company 20 years and I've been supporting a broad spectrum of small moleculeand biologic products over the years.
So it's a pleasure to be here.
Hi, my name is Diana Colleluori.
I am a principal CMC consultant with Biologics Consulting.
(01:05):
I've been consulting for about three and a half years now, but I spent about 20 years inthe pharma and biotech industry, mostly as heads of quality control and quality assurance
for a variety of different companies, including cell and gene therapy companies.
And last but not least, Robert
(01:26):
Hi, thank you.
Robert Kutner, great to be here.
I am a senior CMC consultant here at Biologics Consulting.
I've been consulting for about three years and I come in with over 20 years of cell andgene therapy experience.
I was head of process and analytical development for industrial companies and haveexperience from discovery through validation in regards towards process manufacturing.
(01:51):
And again, great to be here.
Thank you, James.
You're very welcome.
I'm glad to have you guys all back now.
So our first question, what are some of the more critical challenges associated withevaluating novel cell gene therapy products in animal models
Yeah, thanks James.
That's, it's always been a challenge for us non-clinical developers with novel cell andgene therapy products, particularly because we're talking about with cell therapies, human
(02:19):
cellular products and naturally testing human products in animals poses a number ofchallenges.
Gene therapy products, perhaps a little bit less so provided the animals or the testsystem you're using, the rats, the mice, what it
whatever it may be, are amenable to or can be infected by the product.
(02:44):
But the challenge then is to expressing a human protein possibly or some other proteinthat may not work in that model.
So with both cell and gene therapy products and most of the work products I've seen overthe years have been AAV products, adeno-associated.
(03:06):
viral vectors, but certainly, you know, using animals, predominantly rodents, you know,there's always the issue of immunogenicity, which again, if it's a human cell or a vector
expressing a human protein, as well as the vector itself, which may be immunogenic in anyspecies, including humans, immunogenicity is always a concern, whether it's neutralizing
(03:30):
the cell or the vector clearing it
too quickly so that you lose the vector.
So in that case, it always poses a challenge.
There's certainly with animals, can use normal animals typically for toxicology safetytesting, but at the same time, you sponsors often need to test their product in an animal
(03:52):
model of disease, which they have to be pretty much designed or tailored to the diseasemodel.
In most cases, they are genetically deficient in whatever
protein or enzyme or they have the disease that hopefully mimics the clinical humanscenario as best as possible.
But that's not always a hundred percent feasible and regulators always want to see thatthe animal model properly mimics or will predict the safety of the product in the clinic.
(04:23):
And certainly while most studies are done in small animals, mainly mice, particularly forthe disease models where they can be more readily
engineered, genetically engineered or made transgenic to express a protein or be lacking aprotein.
Sometimes you need to use large animals, whether it's because of the site of delivery orthe mechanism of action.
(04:46):
Sometimes a sponsor may need to use a large animal like a non-human primate or even a pigor dog model.
Those aren't as common, but they are sometimes used.
And then showing that the model, whether it's rodent or non-rodent is representative andwill be predictive of the response that we want to see in the clinic.
(05:08):
So it's, you'll have to make that case to the regulators and show that your model isrelevant and representative.
So while CBER and the U.S.
regulators typically are fine with one animal model for safety, you often would need tolikely test multiple
models anyway.
And sometimes there's not even a good model and you may have to use a surrogate product,surrogate stem cells, surrogate vectors, surrogates, maybe not surrogate vectors, but
(05:37):
expressing the animal protein and checking and determining the safety of that product inthe animals if the human product isn't active.
and then you have to make the case that you're properly demonstrating the safety andefficacy function of
the human product by use of the surrogate animal product.
(05:59):
So there's quite a number of challenges using animal models.
And I think that you just have to understand your product and understand the model as bestyou can.
And that often happens in early stage discovery and translational research.
And I think that poses one of the largest challenges to us non-clinical developers today.
(06:20):
So in that light or in that vein, what are the most common CMC issues that CGD developersare facing today?
Thanks, James.
I will start by saying that the most common issue for cell and gene therapy developmentfrom a CMC perspective continues to be the potency assay.
(06:41):
It is probably the most difficult assay or assay strategy to navigate throughout productdevelopment from both a technical and a regulatory perspective.
And as most of us are aware, the FDA released the draft guidance for industry
for potency assurance for CGT products in December of 2023.
(07:03):
However, the drug development industry has continued to express some confusion with theinterpretation of this draft guidance.
And, you know, as we know, every product in development, CGT products, as well as others,require a potency assay, you know, basically to prove that a drug product should be
(07:27):
clinically potent and uh the guidance has, you know, so far been somewhat confusing todevelopers, probably the smaller to mid-size companies that are still unsure how to
navigate developing a potency assay strategy.
And I would say, you know, some of the lessons learned, some of the challenges that I've
(07:50):
witnessed for companies developing cell and gene therapies.
Lesson learned number one is to always have multiple potency assays in development asearly as possible.
And we have uh certainly witnessed specifically the FDA requiring a potency assay
even in phase one.
(08:11):
So for your IND submission, you do need some sort of potency assay, even if it is asurrogate assay for early development of your product.
But the idea is that you need to develop and implement potency assays incrementally.
And I say assays because it's often for cell and gene therapy products that you willprobably need a matrix approach to developing
(08:39):
a potency assay strategy to prove that your product is potent in either an in vitrosetting or in a cell-based bioassay setting, depending on the product.
You know, another lesson learned from a potency perspective is that potency assays, evenearly in development, should be designed with an eye towards commercial use.
(09:03):
And when I say that, it really implies that the
reagents, the kits, whatever materials that are used for the potency assay, includingreference standard, should be really thought out thoroughly as early in development as
possible.
And while that may not always be amenable in early development, another lesson learned isthat you store and control drug product or drug substance retains as early as you can
(09:35):
because if you
do have to change your potency assay or implement a new potency assay, you have productretains to go back to to retrospectively test.
My final point regarding potency would be ensure that you're engaging in open, frequent,and timely discussions
(09:57):
with the regulatory agency because they will oftentimes guide you in the right direction.
They may not tell you exactly what to do, but they will hold your hand and guide you downthe right path to ensure that the potency assay strategy that you have in place is
acceptable and amenable for current or even future clinical development.
(10:22):
So, with regard to potency, that
remains a hot topic and is probably the most common CMC challenge that I see for cell andgene therapy products.
The newer, I would say the newer challenge that we are starting to see now is regardingraw materials that are used in the manufacture of uh cell and gene therapy products.
(10:48):
And there was a
draft guidance released by the FDA in April of last year that was specifically targeted toconsiderations for the use of human and animal derived materials in the manufacture of CGT
products.
I would say hand in hand with that draft guidance is making sure that you're reviewing USP1043, which is the chapter on ancillary materials.
(11:23):
for cell, gene, and tissue engineered products because that chapter of USP providesadditional insights into the expectations surrounding other raw materials used during CGT
manufacturing and not just human and animal derived materials.
The issues and challenges that I see around raw materials is really ensuring that you'reusing the highest of materials that are available as
(11:51):
early in development as possible.
uh And, you know, we know with uh cell and gene therapy products today being such a uniquespin on manufacturing drug products is that there may not always be GMP-grade raw
materials available, particularly in early development with like rare additives.
(12:16):
um And so having
conversations again with the agency about the use of non-GMP grade raw materials isprobably warranted.
But I would definitely refer back to the draft FDA guidance as well as the USP chapter toreally go at your strategy by using as much risk mitigation as possible.
(12:43):
So I'll stop there
for now, but there are a lot of challenges and considerations surrounding the use of rawmaterials in cell and gene therapy manufacturing.
Okay, all right.
Well, are there any new tools or new technologies that developers might use to addressthese sorts of things?
Yeah.
(13:03):
I can field this one, James.
Thank you.
And I just quickly would like to add a little bit of color to what Diana was talking aboutin regards towards the challenges within CMC from a manufacturing perspective quickly.
One of the other aspects is the regulatory framework that's provided isn't really adaptedspecifically for cell and gene therapy products.
(13:25):
And what happens is in regards towards defining the
materials going into the process, what is considered the drug substance and what isconsidered the drug product and for the starting materials and how that gets communicated
to the agency in an effective manner.
And what happens also is within the cell products, there's a lot of complications includedwithin their production processes, such as extended culture times and use of vectors,
(13:53):
which in themselves are an active ingredient.
And each one of these require
basically the same levels of controls and being able to unpack that into the currentregulatory framework is a challenge.
And I think having a lot of experience with different product profiles and being able tocommunicate those nuances is important too.
And it segues into that advancements kind of coming into this space with regard towards,yeah,
(14:21):
with regard towards the tools that are coming on, because again, these will need to becommunicated to the agency in an effective manner.
And a lot of the advancements, particularly in the large language model systems with AIkind of coming onto the scene, there are some front runners within those technologies that
do have some legs.
Bringing up the potency aspect, Diana and I attended the Potency Summit this year and wereable to see some of these advancements coming in in regards towards imaging
(14:50):
analysis and those techniques certainly are able to elicit the differences often expectedbetween, let's say, a gene modified cell and one that has not been modified in a control
setting.
And so in turn, the ability to analyze all these phenotypic changes between the differentarms of the study kind of allows for a greater power of analysis because it's lot more
(15:18):
different--
difficult to have a high throughput in regards towards a manual evaluation of images,whereas being able to utilize, as one can imagine, the deep powers that can come in within
these large language models and such that can do these evaluations and provide correlativefeedback was very impressive.
(15:38):
And it's moving fast and also have experienced and seen.
the use of these AI systems in developing constructs in regards, and there's vendorscoming on the scene to help utilize these tools.
And it's fascinating to kind of see it take advancements into the field.
And having worked on technologies that are very novel and getting them through to thecommercial setting itself is important to kind of have individuals that have experience in
(16:04):
being able to establish what this would look like and how it could be utilized.
As Diana was noting,
you know, in preparation for the long-term commercial setting.
So as not to have to go back and reinvent aspects of your development and utilize theseretains and such uh for, yeah, to that end, I'd say that it's an exciting space to be in
(16:26):
at this time.
And we're going to be attending some of the conferences coming up on cell and gene therapyhere and look forward to seeing more of these advancements coming in too.
Awesome, and people should look forward to seeing you guys check the calendar and see ifany of our folks here will be at the conference you're going to.
But to get back to what we're talking about, what are some of the novel upcoming productclasses that may pose particular challenges to product developers?
(16:51):
Yeah, that's certainly a very, you know, it's a pertinent question, James.
And uh we've been seeing quite a, you know, a new variety of different types of cell andgene therapies, particularly gene therapies, but also uh more highly specialized modified
cellular products.
(17:12):
Certainly, and I don't want, I can't get into gruesome detail on every one, but, uh youknow, we're starting to see things like Regulatable
Gene therapy where you can administer a viral vector and then a small molecule, which willmaybe turn on or turn off the expression of the desired gene.
(17:32):
That would be more, instead of just having the gene crank out the protein constantly inthe target cell, if you need it to be modulated a little more or fine tuned, you can do
that.
If you have the right sort of genetic elements in your product and then you can add a.
small dose to patient with a small molecule and watch, you know, then turn on theexpression of of the protein.
(17:56):
So that, that's something that's kind of coming out now, certainly in the metabolic space,you know, we're certain to-- starting to see a lot of work and the implantable cellular
products for let's say type one diabetes where trying to implant, you know, islet cells.
the challenge is there with
(18:19):
trying to keep the implant functional and metabolically stable and happy.
It's interesting, in ensuring compatibility with a device or a scaffold, that's been anongoing challenge for a number of years in that field.
But as these products get more humanized and more specialized, obviously there tend to behuman cells or viral vectors expressing human proteins that
(18:48):
means if they're more human, they're going to be less amenable to testing in animals.
mean, they're still going to be immunogenic and that's always a concern.
And then, you know, there's gene editing.
We've got CRISPR and all the talent and all these other gene editing modalities that arecoming out and are being extensively used, but they have their own challenges and, you
(19:11):
know, certainly off target editing of where you don't want to.
change somebody's genome, but you know, getting the gene inserted in the right location inthe patient, ensuring that it's expressing or repressing whatever the case may be,
ensuring that it does not somehow turn on an oncogene or turn off a tumor repressor, whichmight lead to cancer or tumor formation.
(19:35):
So there's, there's quite a lot of work going on in those, you know, in those areas andeven--
uh I mean, you've seen in vivo gene editing.
haven't seen a lot of that directly in our immediate experience, but when the news and theliterature, there's certainly that that's another option.
I think that that's going to be the wave of the future.
And there's other kinds of things out there in left field, which don't get a lot ofattention like phage therapy, which is essentially gene therapy, which really only target
(20:05):
bacteria, which we harbor in our
microbiomes predominantly in our GI tracts and other parts of the body and to delivergenes to those target bacteria.
They're very selective, phager everywhere.
They outnumber us and every organism on the planet, I think by probably thousand fold, butthey are an incredibly useful tools to deliver novel genetic material and they're very,
(20:32):
tend to be very safe.
So the challenge for
non-clinical developers is there really isn't much you can do in terms of non-clinicalsafety, but you still have to prove to the regulators that they're safe.
Because they don't tend to target human cells, they target bacteria.
And animals tend to have different flora, gut, GI, bacteria than we do.
(20:54):
Every species, every person within humans and then across species have a very differentbacterial flora.
And so it makes it challenge to study
safety of those products, but they tend to be pretty safe.
that's been something that think phage therapy is still on the horizon, but it's up andcoming, I think.
(21:14):
So there's quite a lot of interesting developments right now.
And again, as Robert alluded to, we're hoping to see some of those other novel approachesat some of these upcoming conferences.
We've been talking a lot about challenges, but there is one other challenge going on.
The changing regulatory environment is the FDA.
(21:35):
How does that impact development of cell and gene therapy products?
And I'll start here, but I think we can all chime in on this one.
That certainly with the recent change in administration, there's certainly been changes uhat all levels.
A number of staff have been let go, new leadership, solid leadership in terms of at CBER,particularly Dr.
(22:03):
Marks who resigned his position at CBER.
He'd been there a long time and helped shepherd a number of products through, and he wasquite the champion for cell and gene therapy for some of these small, rare diseases.
And so it remains to be seen who will replace him in that role and what their position onsome of these issues will be.
(22:24):
And as well, if they do let staff go, reviewers go, it could impact timelines.
It could impact investment in cell and gene therapy
products.
People may be more hesitant to invest in these products.
So I see it could have a down, you know, a downward effect on cell and gene therapy.
(22:44):
But again, as we discussed, there's so much going on.
I don't think you get like a juggernaut.
I don't think you can necessarily slow it down too much.
Anybody
want to talk to this?
I can quickly speak towards it in regards towards, but there are changes again, cell andgene therapy, as I alluded to earlier, has a lot of changes just inherent to it as a
(23:04):
profile advancing in its therapeutic opportunities.
But yes, I think the expectation for there to be some turnover within the regulatorybodies uh
potential that is likely to emerge.
And I just think, following the codes of regulation and USP guidance and such, making sureeverything's in a suitable, compliant state is foremost, generally, the expectation,
(23:30):
regardless of the turnover.
And so having all the pieces in place is of paramount importance, basically.
And I think that's one thing that can be expected is that there may be a newer viewer andthings that might not have been picked up before might
be brought up in a response.
And so having a good gap analysis and or evaluation of your product profile is somethingwe have available as one of our services and can be able to potentially see some of the
(23:55):
things that we've seen the agency kind of over our years discuss, want further discussionon.
And so just in regards towards the impact to cell and gene therapy, it's difficult tocalculate, but having everything in place, I think is important overall.
Well, and if anybody would like more information on this or to get in touch with Diana orDavid or Robert, you can write to us here at insight at biologics consulting dot com.
(24:24):
That's insight at biologics consulting, all one word dot com.
Thank you guys for coming on and doing this.
It was great to talk to all of you again.
And the executive producer of Insight at Biologics is Ana Muresan.
This episode was produced and edited by James C.
Taylor.
Technical supervisor is Jeff Wease.
The Insight at Biologics theme is by Tom Rory Parsons.
(24:45):
I'm James C.
Taylor.
Thank you for joining us.
And please come back for more Insight at Biologics.
you
Bringing novel cell and gene therapy products to market can be challenging both fornon-clinical and CMC.
Fortunately, I have a few colleagues who are up for the challenge and they happen to bethree people I've talked to before.
Let's meet them again and talk about it.
I'm James C.
Taylor and this is Insight at Biologics.
(00:22):
you uh
you
Thank you all for doing this with me.
It's wonderful to have you all back.
just for people who may not remember, we're going to go ahead and introduce ourselves.
And we'll start with.
Hi, thanks James.
My name is David Pepperl.
(00:42):
I'm a pharmacologist and toxicologist and principal consultant at Biologics Consulting.
been with the company 20 years and I've been supporting a broad spectrum of small moleculeand biologic products over the years.
So it's a pleasure to be here.
Hi, my name is Diana Colleluori.
I am a principal CMC consultant with Biologics Consulting.
(01:05):
I've been consulting for about three and a half years now, but I spent about 20 years inthe pharma and biotech industry, mostly as heads of quality control and quality assurance
for a variety of different companies, including cell and gene therapy companies.
And last but not least, Robert
(01:26):
Hi, thank you.
Robert Kutner, great to be here.
I am a senior CMC consultant here at Biologics Consulting.
I've been consulting for about three years and I come in with over 20 years of cell andgene therapy experience.
I was head of process and analytical development for industrial companies and haveexperience from discovery through validation in regards towards process manufacturing.
(01:51):
And again, great to be here.
Thank you, James.
You're very welcome.
I'm glad to have you guys all back now.
So our first question, what are some of the more critical challenges associated withevaluating novel cell gene therapy products in animal models
Yeah, thanks James.
That's, it's always been a challenge for us non-clinical developers with novel cell andgene therapy products, particularly because we're talking about with cell therapies, human
(02:19):
cellular products and naturally testing human products in animals poses a number ofchallenges.
Gene therapy products, perhaps a little bit less so provided the animals or the testsystem you're using, the rats, the mice, what it
whatever it may be, are amenable to or can be infected by the product.
(02:44):
But the challenge then is to expressing a human protein possibly or some other proteinthat may not work in that model.
So with both cell and gene therapy products and most of the work products I've seen overthe years have been AAV products, adeno-associated.
(03:06):
viral vectors, but certainly, you know, using animals, predominantly rodents, you know,there's always the issue of immunogenicity, which again, if it's a human cell or a vector
expressing a human protein, as well as the vector itself, which may be immunogenic in anyspecies, including humans, immunogenicity is always a concern, whether it's neutralizing
(03:30):
the cell or the vector clearing it
too quickly so that you lose the vector.
So in that case, it always poses a challenge.
There's certainly with animals, can use normal animals typically for toxicology safetytesting, but at the same time, you sponsors often need to test their product in an animal
(03:52):
model of disease, which they have to be pretty much designed or tailored to the diseasemodel.
In most cases, they are genetically deficient in whatever
protein or enzyme or they have the disease that hopefully mimics the clinical humanscenario as best as possible.
But that's not always a hundred percent feasible and regulators always want to see thatthe animal model properly mimics or will predict the safety of the product in the clinic.
(04:23):
And certainly while most studies are done in small animals, mainly mice, particularly forthe disease models where they can be more readily
engineered, genetically engineered or made transgenic to express a protein or be lacking aprotein.
Sometimes you need to use large animals, whether it's because of the site of delivery orthe mechanism of action.
(04:46):
Sometimes a sponsor may need to use a large animal like a non-human primate or even a pigor dog model.
Those aren't as common, but they are sometimes used.
And then showing that the model, whether it's rodent or non-rodent is representative andwill be predictive of the response that we want to see in the clinic.
(05:08):
So it's, you'll have to make that case to the regulators and show that your model isrelevant and representative.
So while CBER and the U.S.
regulators typically are fine with one animal model for safety, you often would need tolikely test multiple
models anyway.
And sometimes there's not even a good model and you may have to use a surrogate product,surrogate stem cells, surrogate vectors, surrogates, maybe not surrogate vectors, but
(05:37):
expressing the animal protein and checking and determining the safety of that product inthe animals if the human product isn't active.
and then you have to make the case that you're properly demonstrating the safety andefficacy function of
the human product by use of the surrogate animal product.
(05:59):
So there's quite a number of challenges using animal models.
And I think that you just have to understand your product and understand the model as bestyou can.
And that often happens in early stage discovery and translational research.
And I think that poses one of the largest challenges to us non-clinical developers today.
(06:20):
So in that light or in that vein, what are the most common CMC issues that CGD developersare facing today?
Thanks, James.
I will start by saying that the most common issue for cell and gene therapy developmentfrom a CMC perspective continues to be the potency assay.
(06:41):
It is probably the most difficult assay or assay strategy to navigate throughout productdevelopment from both a technical and a regulatory perspective.
And as most of us are aware, the FDA released the draft guidance for industry
for potency assurance for CGT products in December of 2023.
(07:03):
However, the drug development industry has continued to express some confusion with theinterpretation of this draft guidance.
And, you know, as we know, every product in development, CGT products, as well as others,require a potency assay, you know, basically to prove that a drug product should be
(07:27):
clinically potent and uh the guidance has, you know, so far been somewhat confusing todevelopers, probably the smaller to mid-size companies that are still unsure how to
navigate developing a potency assay strategy.
And I would say, you know, some of the lessons learned, some of the challenges that I've
(07:50):
witnessed for companies developing cell and gene therapies.
Lesson learned number one is to always have multiple potency assays in development asearly as possible.
And we have uh certainly witnessed specifically the FDA requiring a potency assay
even in phase one.
(08:11):
So for your IND submission, you do need some sort of potency assay, even if it is asurrogate assay for early development of your product.
But the idea is that you need to develop and implement potency assays incrementally.
And I say assays because it's often for cell and gene therapy products that you willprobably need a matrix approach to developing
(08:39):
a potency assay strategy to prove that your product is potent in either an in vitrosetting or in a cell-based bioassay setting, depending on the product.
You know, another lesson learned from a potency perspective is that potency assays, evenearly in development, should be designed with an eye towards commercial use.
(09:03):
And when I say that, it really implies that the
reagents, the kits, whatever materials that are used for the potency assay, includingreference standard, should be really thought out thoroughly as early in development as
possible.
And while that may not always be amenable in early development, another lesson learned isthat you store and control drug product or drug substance retains as early as you can
(09:35):
because if you
do have to change your potency assay or implement a new potency assay, you have productretains to go back to to retrospectively test.
My final point regarding potency would be ensure that you're engaging in open, frequent,and timely discussions
(09:57):
with the regulatory agency because they will oftentimes guide you in the right direction.
They may not tell you exactly what to do, but they will hold your hand and guide you downthe right path to ensure that the potency assay strategy that you have in place is
acceptable and amenable for current or even future clinical development.
(10:22):
So, with regard to potency, that
remains a hot topic and is probably the most common CMC challenge that I see for cell andgene therapy products.
The newer, I would say the newer challenge that we are starting to see now is regardingraw materials that are used in the manufacture of uh cell and gene therapy products.
(10:48):
And there was a
draft guidance released by the FDA in April of last year that was specifically targeted toconsiderations for the use of human and animal derived materials in the manufacture of CGT
products.
I would say hand in hand with that draft guidance is making sure that you're reviewing USP1043, which is the chapter on ancillary materials.
(11:23):
for cell, gene, and tissue engineered products because that chapter of USP providesadditional insights into the expectations surrounding other raw materials used during CGT
manufacturing and not just human and animal derived materials.
The issues and challenges that I see around raw materials is really ensuring that you'reusing the highest of materials that are available as
(11:51):
early in development as possible.
uh And, you know, we know with uh cell and gene therapy products today being such a uniquespin on manufacturing drug products is that there may not always be GMP-grade raw
materials available, particularly in early development with like rare additives.
(12:16):
um And so having
conversations again with the agency about the use of non-GMP grade raw materials isprobably warranted.
But I would definitely refer back to the draft FDA guidance as well as the USP chapter toreally go at your strategy by using as much risk mitigation as possible.
(12:43):
So I'll stop there
for now, but there are a lot of challenges and considerations surrounding the use of rawmaterials in cell and gene therapy manufacturing.
Okay, all right.
Well, are there any new tools or new technologies that developers might use to addressthese sorts of things?
Yeah.
(13:03):
I can field this one, James.
Thank you.
And I just quickly would like to add a little bit of color to what Diana was talking aboutin regards towards the challenges within CMC from a manufacturing perspective quickly.
One of the other aspects is the regulatory framework that's provided isn't really adaptedspecifically for cell and gene therapy products.
(13:25):
And what happens is in regards towards defining the
materials going into the process, what is considered the drug substance and what isconsidered the drug product and for the starting materials and how that gets communicated
to the agency in an effective manner.
And what happens also is within the cell products, there's a lot of complications includedwithin their production processes, such as extended culture times and use of vectors,
(13:53):
which in themselves are an active ingredient.
And each one of these require
basically the same levels of controls and being able to unpack that into the currentregulatory framework is a challenge.
And I think having a lot of experience with different product profiles and being able tocommunicate those nuances is important too.
And it segues into that advancements kind of coming into this space with regard towards,yeah,
(14:21):
with regard towards the tools that are coming on, because again, these will need to becommunicated to the agency in an effective manner.
And a lot of the advancements, particularly in the large language model systems with AIkind of coming onto the scene, there are some front runners within those technologies that
do have some legs.
Bringing up the potency aspect, Diana and I attended the Potency Summit this year and wereable to see some of these advancements coming in in regards towards imaging
(14:50):
analysis and those techniques certainly are able to elicit the differences often expectedbetween, let's say, a gene modified cell and one that has not been modified in a control
setting.
And so in turn, the ability to analyze all these phenotypic changes between the differentarms of the study kind of allows for a greater power of analysis because it's lot more
(15:18):
different--
difficult to have a high throughput in regards towards a manual evaluation of images,whereas being able to utilize, as one can imagine, the deep powers that can come in within
these large language models and such that can do these evaluations and provide correlativefeedback was very impressive.
(15:38):
And it's moving fast and also have experienced and seen.
the use of these AI systems in developing constructs in regards, and there's vendorscoming on the scene to help utilize these tools.
And it's fascinating to kind of see it take advancements into the field.
And having worked on technologies that are very novel and getting them through to thecommercial setting itself is important to kind of have individuals that have experience in
(16:04):
being able to establish what this would look like and how it could be utilized.
As Diana was noting,
you know, in preparation for the long-term commercial setting.
So as not to have to go back and reinvent aspects of your development and utilize theseretains and such uh for, yeah, to that end, I'd say that it's an exciting space to be in
(16:26):
at this time.
And we're going to be attending some of the conferences coming up on cell and gene therapyhere and look forward to seeing more of these advancements coming in too.
Awesome, and people should look forward to seeing you guys check the calendar and see ifany of our folks here will be at the conference you're going to.
But to get back to what we're talking about, what are some of the novel upcoming productclasses that may pose particular challenges to product developers?
(16:51):
Yeah, that's certainly a very, you know, it's a pertinent question, James.
And uh we've been seeing quite a, you know, a new variety of different types of cell andgene therapies, particularly gene therapies, but also uh more highly specialized modified
cellular products.
(17:12):
Certainly, and I don't want, I can't get into gruesome detail on every one, but, uh youknow, we're starting to see things like Regulatable
Gene therapy where you can administer a viral vector and then a small molecule, which willmaybe turn on or turn off the expression of the desired gene.
(17:32):
That would be more, instead of just having the gene crank out the protein constantly inthe target cell, if you need it to be modulated a little more or fine tuned, you can do
that.
If you have the right sort of genetic elements in your product and then you can add a.
small dose to patient with a small molecule and watch, you know, then turn on theexpression of of the protein.
(17:56):
So that, that's something that's kind of coming out now, certainly in the metabolic space,you know, we're certain to-- starting to see a lot of work and the implantable cellular
products for let's say type one diabetes where trying to implant, you know, islet cells.
the challenge is there with
(18:19):
trying to keep the implant functional and metabolically stable and happy.
It's interesting, in ensuring compatibility with a device or a scaffold, that's been anongoing challenge for a number of years in that field.
But as these products get more humanized and more specialized, obviously there tend to behuman cells or viral vectors expressing human proteins that
(18:48):
means if they're more human, they're going to be less amenable to testing in animals.
mean, they're still going to be immunogenic and that's always a concern.
And then, you know, there's gene editing.
We've got CRISPR and all the talent and all these other gene editing modalities that arecoming out and are being extensively used, but they have their own challenges and, you
(19:11):
know, certainly off target editing of where you don't want to.
change somebody's genome, but you know, getting the gene inserted in the right location inthe patient, ensuring that it's expressing or repressing whatever the case may be,
ensuring that it does not somehow turn on an oncogene or turn off a tumor repressor, whichmight lead to cancer or tumor formation.
(19:35):
So there's, there's quite a lot of work going on in those, you know, in those areas andeven--
uh I mean, you've seen in vivo gene editing.
haven't seen a lot of that directly in our immediate experience, but when the news and theliterature, there's certainly that that's another option.
I think that that's going to be the wave of the future.
And there's other kinds of things out there in left field, which don't get a lot ofattention like phage therapy, which is essentially gene therapy, which really only target
(20:05):
bacteria, which we harbor in our
microbiomes predominantly in our GI tracts and other parts of the body and to delivergenes to those target bacteria.
They're very selective, phager everywhere.
They outnumber us and every organism on the planet, I think by probably thousand fold, butthey are an incredibly useful tools to deliver novel genetic material and they're very,
(20:32):
tend to be very safe.
So the challenge for
non-clinical developers is there really isn't much you can do in terms of non-clinicalsafety, but you still have to prove to the regulators that they're safe.
Because they don't tend to target human cells, they target bacteria.
And animals tend to have different flora, gut, GI, bacteria than we do.
(20:54):
Every species, every person within humans and then across species have a very differentbacterial flora.
And so it makes it challenge to study
safety of those products, but they tend to be pretty safe.
that's been something that think phage therapy is still on the horizon, but it's up andcoming, I think.
(21:14):
So there's quite a lot of interesting developments right now.
And again, as Robert alluded to, we're hoping to see some of those other novel approachesat some of these upcoming conferences.
We've been talking a lot about challenges, but there is one other challenge going on.
The changing regulatory environment is the FDA.
(21:35):
How does that impact development of cell and gene therapy products?
And I'll start here, but I think we can all chime in on this one.
That certainly with the recent change in administration, there's certainly been changes uhat all levels.
A number of staff have been let go, new leadership, solid leadership in terms of at CBER,particularly Dr.
(22:03):
Marks who resigned his position at CBER.
He'd been there a long time and helped shepherd a number of products through, and he wasquite the champion for cell and gene therapy for some of these small, rare diseases.
And so it remains to be seen who will replace him in that role and what their position onsome of these issues will be.
(22:24):
And as well, if they do let staff go, reviewers go, it could impact timelines.
It could impact investment in cell and gene therapy
products.
People may be more hesitant to invest in these products.
So I see it could have a down, you know, a downward effect on cell and gene therapy.
(22:44):
But again, as we discussed, there's so much going on.
I don't think you get like a juggernaut.
I don't think you can necessarily slow it down too much.
Anybody
want to talk to this?
I can quickly speak towards it in regards towards, but there are changes again, cell andgene therapy, as I alluded to earlier, has a lot of changes just inherent to it as a
(23:04):
profile advancing in its therapeutic opportunities.
But yes, I think the expectation for there to be some turnover within the regulatorybodies uh
potential that is likely to emerge.
And I just think, following the codes of regulation and USP guidance and such, making sureeverything's in a suitable, compliant state is foremost, generally, the expectation,
(23:30):
regardless of the turnover.
And so having all the pieces in place is of paramount importance, basically.
And I think that's one thing that can be expected is that there may be a newer viewer andthings that might not have been picked up before might
be brought up in a response.
And so having a good gap analysis and or evaluation of your product profile is somethingwe have available as one of our services and can be able to potentially see some of the
(23:55):
things that we've seen the agency kind of over our years discuss, want further discussionon.
And so just in regards towards the impact to cell and gene therapy, it's difficult tocalculate, but having everything in place, I think is important overall.
Well, and if anybody would like more information on this or to get in touch with Diana orDavid or Robert, you can write to us here at insight at biologics consulting dot com.
(24:24):
That's insight at biologics consulting, all one word dot com.
Thank you guys for coming on and doing this.
It was great to talk to all of you again.
And the executive producer of Insight at Biologics is Ana Muresan.
This episode was produced and edited by James C.
Taylor.
Technical supervisor is Jeff Wease.
The Insight at Biologics theme is by Tom Rory Parsons.
(24:45):
I'm James C.
Taylor.
Thank you for joining us.
And please come back for more Insight at Biologics.
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