0:43
Thanks Vivek.
0:44
I appreciate it.
0:46
So for me, one of the things that I recently in terms of inhalation that has sort of come to the forefront is understanding of where we are really trying to go with inhalation in the future.
0:59
And one of the things that of course comes up time and time again is the idea of biologics.
1:05
And I know with a lot of the larger CMOs and CDMOs that they exist.
1:10
They have a lot of the necessary components in order to perform all of the different types of testing and all the different types of complex manufacturing.
1:18
But I did want to wonder as sort of as an industry and as a small manufacturer, what we can do to support biologics as a product.
1:29
And you know, part of the reason I did this was not just to do this in order to present this, but it's really to get this right in my head about kind of what we're talking about and where we're going to where we are going to go with this type of thing.
1:45
And largely I thought this was a bit conversational.
1:48
So if there is any point in time you guys want to ask questions, share insights at the end, I appreciate any kind of input from this perspective as well.
1:57
So why are the why is it important to talk about biologics from the perspective of inhalation?
2:03
Well, obviously biologics are becoming more and more important when it comes to new drugs and new products that are existing in the marketplace.
2:10
The percentage of drugs that are small molecule versus biologic is changing significantly with increasing amount number of biological products that are existing and are being approved versus the small molecules over time.
2:25
You know, there are some actually initiatives within the government that the Department of Health and Human Services has an initiative beyond the needle programme in order to try to increase the number of drug products that exist in this type of space.
2:39
From that perspective.
2:40
And it's not inhalation specifically, but it's really in that case about breaking the cold chain and also creating different ways to administer these type of drugs.
2:50
And so in a lot of these cases, inhalation does sort of fit in with that kind of strategy.
2:57
And of course, you know, if we talk about biologics from the perspective of other formats, most of the ones that were given are obviously injected were infused in some way, shape or form.
3:08
So, you know, the almost obvious route of administration beyond that would of course be the GI tract.
3:14
But of course there are issues with respect to that.
3:16
If we're talking about proteins, obviously those don't make it past the stomach from the perspective the acidification.
3:23
And then even when you're talking about the small intestines, there is a limit in terms of the size of the materials that can actually pass through the tight junctions in the small intestines.
3:34
And then finally, there are some other organisations like IPAQ Rs which are, have become interested in this type of topic as well.
3:40
So it seems like there is some reason to talk about this topic from that perspective.
3:46
And so in general, I wanted to sort of explore what we were actually be talking about here from that as well.
3:53
So when we talk about biologics, one of the things that I started to look at there is what are we talking about?
4:00
And there's just a huge list of different possible different routes.
4:04
We're talking about everything from DNA, mRNA, siRNAS, oligonucleotides, different kinds of proteins, including, you know, just receptor binding proteins.
4:17
And of course you also have the possibilities of looking at enzymes as well and from the protein spaces, oligo peptides, to name a few of these, but there's a large number of them.
4:26
Obviously most of them fall into the categories of DNA or nucleic acid type-based materials and then also nucleotide-based materials as well.
4:35
So we are looking at a number of different compounds from that perspective that are possible.
4:41
But I thought that I would focus on the sort of the nucleic acids and the proteins from that perspective and leave the more complex different possibilities in terms of monoclonal antibodies, which obviously I know are simply proteins.
4:53
And then CRISPR type of gene editing scenarios where we're talking about proteins and DNA's together.
4:58
So there are a number of different things that we could potentially explore here.
5:03
And I think that might be part of the problem when it comes to talking about these sort of biological systems, because when we talk about inhalation, we say inhalation and biologics, we're not really just talking about a single different single compound or a single different platform.
5:18
We're talking about a lot of different possibilities here.
5:21
And that's something that I think at least in my mind when I originally started looking at this, I didn't really understand that and something that really needed to really focus on from that perspective.
5:33
So, and of course, there's just the sort of the complex of how are we going to deliver them and we have our sort of standards in terms of OI and DP, right?
5:42
So nebulizers, soft mist inhalation with nebulizers.
5:46
Some people might disagree with that, but they are both liquid based systems from that perspective, nasal liquids, dry powder inhalation and pressurised metred dose inhalers and nasal systems and nasal powders.
5:57
And of course, there's a lot of things to consider when it comes to what kind of delivery technologies we're going to be looking at here from that perspective.
6:05
You know, with solid systems, you actually have to do conversion of the liquid into a dry powder before it can actually be used for inhalation.
6:14
Of course that there are different ways that you can convert these things into dry powder.
6:18
And we will talk about some of those ways later on.
6:21
I fundamentally am a dry powder person.
6:23
So that's of course where my focus is going to be mostly.
6:26
But it does bear to talk about the fact that sort of the easiest ways to get into some of these systems obviously is going to be something like a nebulizer.
6:39
And there have been a lot of talks, a lot of work where they have actually taken nebulized products and converted them and simply put them into a nebulizer system to see if they could actually be turn them into an inhaled product.
6:52
When we talk about nasal liquid formulations, some of the comments that have been made really about that are about the amount of delivery that is actually possible with a nasal delivery system.
7:02
Now, a lot of the proteins we're delivering, we're not delivering micrograms of protein like we're delivering with a lot of the a lot of the inhalation compounds they're working with.
7:12
We're actually talking about delivering milligrammes of material and in those cases concentrating the proteins in such a way that you actually are able to deliver that material without getting the kind of stability issues that come from aggregation and such are relatively difficult with pressurised metred dose inhalers.
7:34
You of course also have the issue of basically the quantity of material that we're working with.
7:40
As was mentioned earlier, when we're talking about delivering milligrams of material, when your largest metering valve for an inhaled pressurised metred dose inhalers usually around 600 microliters, it's hard to deliver enough material in order to actually get this material.
7:56
And in those kinds of cases.
7:57
And then dry powder nasal systems, there are a couple of examples of dry powder nasal systems exist right now.
8:03
There's obviously, I think ICO Novo has one and then of course Aptar has one as well, but those are relatively rare as well.
8:12
So there are things to deal with when it comes to that as well.
8:16
And then you're dealing with stability, reformulation, native state of protein.
8:20
If you actually were to put something like this in an MDI, you have to be concerned the fact that you're really in a liquid system with a completely different state of different native state and also something that largely acts like a surfactant in those kinds of cases.
8:36
And then of course, the idea of sterility.
8:38
And of course, you know, dry powder inhalation systems, pressurised metred dose inhalation systems and dry powder nasal systems don't have to be sterile, but SMIs and nebulizers have a tendency to need sterilisation.
8:53
Of course, if you don't use any kind of preservatives with those systems.
8:59
So, and then we're all kind of aware of the normal performance characteristics you expect in small molecule OINDP.
9:08
And whether we're talking about assay or simple things like unit dose uniformity, typically, of course, aerosol particle size distribution is important to all these systems.
9:16
And we'd expect that would probably stay the same for any type of delivery for a biological product as well.
9:24
Deliver dose uniformity.
9:25
And then when you're dealing with liquid systems, you may be dealing with drop droplet size, dose weight and then for MDIs and for nasal sprays, you are obviously dealing with spray pattern and plume geometry as well.
9:37
And we'd expect when you go to a biological system, you wouldn't you really, we really wouldn't be changing from that perspective, but what would be changing?
9:46
So you know, in those kind of cases, you are also dealing with sort of the additional performance characteristics you'd be dealing with either an oligonucleotide or a protein.
9:55
And this isn't necessarily a complete list, but just some of the thoughts and processes that go along with performance characteristics.
10:02
So you have aggregation that of course is something that happens when you have when you expose and denature proteins.
10:12
Assay is of course, that's the same as assay with any other system, but the measurement of the assay can become complex potency and then oxidation.
10:22
And I will talk a little bit more about potency actually.
10:27
Sorry, this is the old version of my talk.
10:30
I had actually another additional thing here, potency as defined by 21CFR 600.3.
10:40
I think S talks about potency from that perspective as being essentially A characteristic that's very much unlike when we talk about small molecules.
10:50
In those kind of cases, really the fact that the molecule exists alone is really to deal with the potency in these kind of cases because the molecule itself can be disrupted or destroyed, then the effect of the biological characteristic can actually be affected by that.
11:09
And so there is a difference between when we're talking about potency in these kinds of cases and whether it has to do with the an enzyme acting to cause a specific reaction to occur or a binding to occur, or a piece of mRNA actually synthesising a protein within a cell.
11:32
These things of course, are different from that perspective.
11:36
And the requirement to actually look at the potency is not simple either.
11:42
When you think about it from the perspective of when these things can occur.
11:46
If you have a nebulization system as well, the creation of surface area during the nebulization process can actually create situations where essentially the denaturation actually of the protein could actually occur.
12:05
So it might be where are you actually testing the potency of the system might actually be very important in these kind of cases.
12:17
The other thing that we would say here is I mentioned this very small list of materials here.
12:22
You know, we're just talking about aggregation, assay potency, oxidation again, assay potency and fragmentation in terms of this.
12:31
But when we look at the number of oh, I think I did that, let's try again.
12:53
And anyway, you know, the analytical needs could be quite significant now.
12:59
And I think from Intertech, there were actually some conversations, I saw some talks some time ago that actually talked about the possible different kinds of techniques that might be needed in order to characterise a protein from that perspective.
13:12
Everything from, you know, dynamic light scattering to LC-MS and then different various forms of capillary electrophoresis as well.
13:22
And of course that again doesn't again address the idea of potency.
13:26
And then when you look at nucleic acids and RNAs, there's everything from characterization of the RNAs themselves to if you're dealing with the lipid nanoparticles, there are of course different types of potential characterizations that may have to deal with any kind of nanoparticles you're working with as well.
13:45
So the number of techniques that are needed for doing this type of characterization is also relatively large.
13:53
And you know, from the perspective of a small molecule, much larger than we would expect in terms of the number of characterizations that we would normally see.
14:05
In general, most of the characterization techniques we work with reverse phase HPLC, at least from the perspective of most things that are not microbial based or you know, assessment of water content or things of that nature.
14:21
While in here we have to be a lot more we have to expect that there are going to be a lot more techniques and maybe a lot more orthogonal techniques will be necessary to characterise the same type of compounds.
14:34
The other part that of course comes in here is when are we going to have to use these techniques?
14:39
Is it simply going to be done as part of the test scenarios or are we going to have to include some of the aerosol performance characteristics and then also do some of the testing afterwards in order to show that the material is maintained after it has gone through the delivery process as well?
15:04
And I did want to talk a little bit about the different types of delivery techniques as well.
15:08
And this is by no means a complete list, but I did quite a lot of reading in terms of trying to understand what are the possible, some possible ways of delivering these sort of nucleic acids.
15:21
Obviously, lipid nanoparticles are important and those have actually been well.
15:25
Well, some of them from the vaccine perspective have not been done with inhalation.
15:29
At least the COVID-19 virus has actually been delivered as a lipid nanoparticle.
15:34
I believe the Pfizer vaccine actually contains lipid nanoparticles.
15:38
Well, it contains nanoparticles, maybe not lipid nanoparticles.
15:40
From that perspective, naked RNA has been used as well as lipid nanoparticles and then RNA lipoplexes.
15:50
And then there's been some discussion about including synthetic surfactants that mimic surfactants within the lung from that perspective, as well as the addition of leucine and different kinds of and different kinds of surfactant based systems such as DSPC, dotap and then DOP as well have been used as well as PLGA and nanoparticles.
16:17
So a lot of different possibilities in terms of how to do it.
16:20
So a lot of different possible platforms or a lot of different possible techniques have been tried this type of system and then protein delivery.
16:37
So we have, you know, obviously there have been some stabilisation with buffers and salts and sugars with proteins.
16:44
Nanoparticles have been used in some cases.
16:46
Note for sort of traditionalist and inhalation that lactose and other types of reducing sugars may not be possible with these kinds of systems because of the possibility of a shift base reaction causing degradation of amine group into a hemiaminal group.
17:04
That may of course be an issue.
17:07
In addition, you can of course use mannitol sugars and then pegylation has been used to improve muco adhesive or muco penetrated properties of these systems as well.
17:20
And then I did want to talk a little bit also about sort of processing methods for creating dry powder systems.
17:25
You know, we obviously have spray drying, spray freeze drying, super critical precipitation to name and thin film freezing and print to name a few.
17:35
And I just wanted to briefly touch on some of these techniques from that perspective as well.
17:40
So obviously spray drying has been used for a lot of different technologies.
17:45
A lot of small molecules have been done by spray drying and there have been some studies on spray drying large molecules as well.
17:53
Obviously you have good control of particle size distribution, which is incredibly important and large volume production is possible with spray drying.
18:01
Large temperatures, large interfacial surface areas and then large shear forces may also have deleterious effects on some of these systems as well.
18:10
As we know that interfacial surface areas has a possibility of potentially causing denaturation of different kinds of proteins in these cases.
18:19
And so these may not be ideal in all cases.
18:23
I also did want to mention the possibility of electrostatic spray drying company called fluid air recently is putting in place a spray drying system called an essentially an electrostatic spray dryer where they basically charge the surface of the droplets as they come out of the spray drying nozzle.
18:38
Which is interesting in that what it's supposed to do is basically drive the hydrophobic materials in the droplet to the centre of the surface and allow for, we'll say, more gentle drying by draining the water essentially to the outside.
18:52
So you get what's called essentially latent heat effects, more so essentially the vaporisation of the material at a constant temperature versus the heating of the material.
19:02
This may or may not be may useful for inhalation.
19:05
We've done a few studies at with that type of spray drying system and the results were sort of, you know, we'll just say they were up and down in terms of whether the performance was good or not.
19:19
And what I mean by that essentially is we couldn't tell, you know, your spray drying prop droplets with very small surface areas to begin with.
19:27
So the question there is whether or not you know, with that large amount of surface area or large surface area to volume ratio, whether or not you're getting any additional effect from by trying to drive the hydrophobic compounds into the centre of the droplet.
19:42
But it remains to be seen.
19:44
It's possible that could actually be of effect.
19:47
And I think that there is actually one installed at microsphere over in Europe.
19:52
If for those who are interested in it, thin film freezing, of course, kind of interesting in the fact that it's a low temperature system.
20:02
So in these kind of cases, you're dripping a liquid feed onto a stainless steel drum that's at cryogenic temperature, so like less than -120 C, sometimes as low as minus 170 C. You're stripping those off little discs of powder off or this disc of material off and then lyophilize and they create a powder.
20:24
And you do create really interesting powders from that perspective.
20:27
They have very low densities, hard to define particle size distribution, but tend to actually act in the inhalable range.
20:38
The disadvantage of course is there aren't really any marketed products from that.
20:41
So we don't really know how the FDA is going to really handle it from that perspective.
20:46
And the scales for these processes tend to be very small.
20:48
Still, it is a lyophilization process.
20:51
And what that means then, of course, is that you're limited by the cycle in terms of the lyophilization as well, which could be potentially problematic from that perspective.
21:01
And finally print technology, which is Liquidia’s technology, their technology, of course, is interesting in the fact that you can design.
21:11
And so for those who don't know Liquidia’s technology, essentially what you are doing here is you're creating a template and impressing the material onto the template.
21:20
From that perspective, essentially that template, there is the green piece there.
21:24
And there's different ways to which that can be then harvested.
21:27
But essentially the particles are created on a film.
21:30
They're created through a process of essentially nano lithography.
21:36
And they can be of different sizes that if you look at the one product that is actually coming in market, the Eutripia product, that product actually almost has like a Y shape, which is pretty interesting from that perspective.
21:50
And they've shown the ability to make that into inhalable particles in certain ranges.
21:54
A lot of variation to that product as well.
21:57
Right now it's, it remains to be seen how that product what other technologies will be used with print.
22:04
But there is some indications that it can be used for proteins and nanoparticles and potentially for other types of techniques from there.
22:13
And finally, I did want to talk a little about nanoparticle formation.
22:17
Lipid nanoparticles, of course, can be formed by a number of different techniques.
22:21
Some of them are batch techniques, some of them are more continuous techniques.
22:25
As a pharmaceutical process guy, I'm more interested in the continuous techniques from that perspective, because those of course, will be the ones that are going to be more easily industrializable as well.
22:36
And those techniques obviously will be coupled with any of the other techniques that we talked about.
22:41
And of course there's nano-milling.
22:42
And then flash precipitation was actually used.
22:45
And flash precipitation was actually used as part of the creation of the vaccine for the Pfizer project too.
22:51
So it's an interesting technique and that comes out of Princeton from Professor Prudhomme's group and has some potential application for these types of things in the future.
23:02
And then of course electro spraying.
23:06
Finally, just some thoughts about regulatory guidances too.
23:12
You know, looking through the regulatory guidance and drug device combination product delivery, of course, it really focuses more on Part 2 10 and Part 2 11, how that interacts with Part 820 for those who know through part 4.
23:27
And that of course leaves a lot to be desired when it comes to how to deal with these biologic products.
23:35
There is a mention of 21 CFR part 600 through 680 in the combination guidance.
23:44
But it really just kind of says you need to do whatever what would be expected for the those type of biological products and doesn't really give any guidance in terms of how that might be different than how you would treat a small molecule product in the first place.
23:58
Couple things of course mentioned the problem with potency there in terms of how we would evaluate potency for these types of products and how that would have to be done either through an in vivo test or an in vitro test.
24:09
And then sterility of course there is a mention of sterility and generally through all biological products, it does mention that there would be dispensation given for these kinds of products for potentially from the from Sieber for not using them in non biological or non sterile applications.
24:33
You know, if you think about the products that exist in the market that are biologics for an inhalation perspective, we're really talking about not very many.
24:39
We're talking about inhaled insulin, we're talking about inhaled dornase alpha, which is of course for CF DNAs from that perspective.
24:49
And both of those have passed through the NDA route from that perspective.
24:53
And of course, the dornase Alpha is already going to be a sterilised product because it is actually delivered as a nebulizer, thoughI haven't heard whether or not we have any sort of sterilisation issues when it comes to the inhaled insulin.
25:08
I suspect that they didn't worry about that, right.
25:13
So, and then of course, the last thing is whether or not we would be doing this through an NDA or a BLA or from CDER or from CBER.
25:21
So you know, and then just key takeaways, obviously we have to be much more specific about the definition of what we're talking about when we're looking at biologics and inhalation. instrumentation is by ab initio is going to be difficult to put in place.
25:38
So a strategy needs to be developed in order to actually handle how we're going to deal with these types of products.
25:45
And then finally, it looks like most of the manufacturing techniques that are needed to start with these inhalation products may actually already exist at least in some shape or form, though that some, though some reformulation may be necessary.
26:00
All right.
26:00
So thanks and I'll take any questions.