0:01
By a PIM belt off as at Batavia Bioscience.
0:06
So PIM is a, is a, it's a bioprocess scientist at Batavia Bioscience.
0:11
I have over 15 years of experience, you know, on vaccines, bioprocess and you're going to you're going to talk, you know, he has also expertise, you know, on this, this specialty cell production assay, such as MRC 5 or 292 of Vero cells and, and, and also like, of course the the drive to deliver, you know, like GMP product, you know, so that's going to be really related also to to GMP product.
0:37
So, so I would, I would welcome you PIM, you know, for the, for the presentation that I'll let you discuss a little bit about.
0:46
Thank you.
0:51
Yes, thanks a lot for the kind introduction.
0:54
So and thanks also to the organisers giving me the opportunity to discuss some of our work here.
1:02
So I will discuss a bit about a rapid response and on, on the emerging diseases, all the threats out there.
1:10
I think a lot of it has already been passing the review over the last 1 1/2 days.
1:16
So, and, and there's many ways to present numbers, I think, and this speaks for itself.
1:22
And I think we've all been been discussing this, the, the vaccination of COVID has been a huge or maybe arguably success in, in Europe, but actually for the whole world, it has just proven that the inequality has just been been further apart than ever.
1:39
So, and, and there's still quite a lot of work to do.
1:44
And, and this picture was also coming by one of the earlier presentations, I think from the lady of IVI.
1:49
Yeah, it's, it's an excellent showcase of yeah, that things can can get better, things can get faster.
1:58
And especially of course for COVID, the mRNA has shown that it can go a lot faster.
2:03
And also for, for going through clinical phases, it, it can go much faster.
2:10
But at the same time, I also see now that we're all being held against this extremely tight timeline.
2:18
And for a lot of the emerging diseases, mRNA is not necessarily going to be the answer.
2:25
And, and maybe for short term or for first vaccination, but for the longer term also we might need to have other vaccines going around to boost the immune system further.
2:41
So what and, and that's where Batavia comes into play.
2:47
So we are in the field to accelerate and and basically help reaching the the gap between all of the candidates out there, all of the brilliant IDs.
2:59
There are lots of really nice publications out there in nature, science and so on, but that doesn't make AGMP product.
3:08
So that's all very nice.
3:11
And I think that basically the the gap between early discovery and and everyone also recognises you need to have proper late stage commercial manufacturing that's it's on the platform that's affordable giving let's say low cost vaccinations, et cetera, et cetera.
3:31
And then there's a gap in the middle.
3:33
And I've seen other presentations from from our company where they've presented that that's the failure of death.
3:40
But I would prefer this picture where we build a bridge together and overcome that stage.
3:48
But it is true that most, most of the candidates actually, they'll never really make it past the Phase 1-2 studies.
3:56
And, and so we are really in that, in that field.
4:00
And I think most of our customers over the last 10-15 years, they come from, from university, from, from government and they have a brilliant ID.
4:11
They, they've got a really nice candidate, they've got a really nice product, but then they come to us and then I say, oh, so how are you making currently?
4:20
What, what you're putting into your mouse studies?
4:23
And they start telling me that they are still in six well plates or in T170 fives to make really small volumes.
4:30
And then their outlook is to be on the market for the whole of Europe or the US and there's a huge, huge gap.
4:38
So, so we, we, we try to, to be in that gap and to help people along.
4:44
And, and that's what I have some examples about.
4:49
And I want to, we do more things than that.
4:51
But I want to focus a bit on the on the hip text platform, which is with, with the fixed pad technology, fixed pad bioreactors.
4:59
And I'll, I'll come back to that and explain a bit on, on, on how that works.
5:06
And basically what we, what we want to do is shortening time to clinic.
5:11
So I'll just go back and we know that that and also for the investors and everyone, you need to to show and fast progress to your face while in phase 2GO towards your phase three.
5:24
And then, you know, that's where the money gets interesting.
5:29
But at the same time, you cannot end up with a product that is just too costly.
5:35
And especially, I mean, I'm not talking maybe for, for the, for the cancer vaccines or the, let's say the current ATM PS, which, you know, have huge cost and, and we're still figuring out how to reduce it.
5:49
But there are lots of the, let's say, standard threats around or, or even for polio, measles, rubella, where cost prices can still be reduced.
5:58
So we always have the end product in mind and we do upfront, we do the cost calculations, we show that let's say the platform should be feasible to to, to have this eventual cost price.
6:14
I think someone named last yesterday, let's say a target cost price below $1.00 is what, what we should be aiming at.
6:23
And, and for a lot of.
6:26
So I don't have a slide on it, but I know for that we've done work for instance on rubella measles where we where we show that for the hip tax platform, we can be really below a dollar.
6:38
And I think there's publications around, come visit our marketing sales team, they'll probably have the, the, the, the publications ready for you.
6:48
So I also got this from my marketing and sales team, which is a way too busy slide for me.
6:54
So there's not much that, that, that I can, I can get.
6:58
But it, it shows all of the things that we do at Batavia, but not what I do because I'm only a cell culture scientist.
7:06
I produce cells, I produce virus and then it's off to the rest.
7:10
But what I, what I want to focus at is in this whole trajectory is that preparedness is the key.
7:18
So what I can do and what I do have influence about is to make sure that our that the platform works.
7:25
And I know that the word platform has been going around for quite a bit during this.
7:32
And I think a lot of people are seeing it as one approach with one cell line and one virus that can do let's say it all A1 pony trick.
7:43
But I would like to extend that scope a little bit with one platform as in one technology.
7:51
And, and I'll, I'll show you a bit of data in a bit that for the fixed bet technology, the diversity can be a bit bigger because lots of adherent cells will work quite well in the system.
8:06
And you can basically make cross, cross combinations of cell lines that work with other viruses better than others and so forth.
8:15
And, and that has some, some benefits in, in being ready for the next step and being ready to go faster towards these clinical phases.
8:26
So just a little bit of background on what the fixed bet technology actually means.
8:32
A lot of people are from different fields out here and I was just mentioning lots of early stage and especially in the let's say conventional vaccine field, lots of vaccines are made on adherent sales.
8:49
Lots of them are, are just better on adherent sales or give higher titers than on suspension.
8:55
Not saying old, but there is a huge variety out there and and most of our customers come to us with with products on adherent sales.
9:02
So you need something that they can, they can adhere to that they can, that they can, they can start on and and like I mentioned, a lot of them come with us in NT170 fives or something like that.
9:16
And of course that that can be that that process can be scaled up and scaled out.
9:21
So you can go into the cells tech type productions, even cell factory 40s, although they might have some issues in, in some of the gas transfers, but those are all things that you can, you can, you can study and then you can do something about.
9:36
But still there are limitations in in scaling that out.
9:40
So on, for instance, on on polio, you need about 50 of those really big self 40s that you cannot handle alone.
9:49
You need a robot and you still need a lot of handlings.
9:53
You need a, A grade A or B room classification, which is a nightmare if you're dealing with an aseptic process.
10:01
The cost of goods is on the high side.
10:04
The process development is, is easy because you scale out so that that's, that's the pro.
10:10
So you can go fast on that side, but you end up with something that's going to be bit difficult.
10:14
And the, the in process control.
10:17
Well, it's, it's hardly there.
10:18
I mean, you, you end up with, with your, with your harvest and, and it's basically a, a combination of 50 individual flasks.
10:25
So, and then of course the microcarriers have been around for a long time.
10:31
It's, it's a process that is, is working quite well.
10:37
You can go up in, in these bioreactors into, you know, I've worked at, at sulphate with what is it 1200 litres in the microcarriers all works very well.
10:50
But the cost of goods is more and more and, but the complexity of that process to get with all your carriers and all the transfers into that last, last stage is, is fairly high.
11:02
So, so that, that's, that's, that's a bit tricky.
11:06
And then you have to fix bets And they are now around Isalis, I think since 2016 seventeen, I've been working with them and later than now also with the Scalex from Geneva sales and you can go up to now to 200 and in the future to 600.
11:24
And it's basically as pretty much the same profile as how to deal with the carriers.
11:29
And but the process development complexity we see moving over a different cell lines with different viruses, there's a lot of similarities in, in how to handle these these processes.
11:43
So what, what is this fixed bat?
11:46
So I've been basically pulling it apart on the bottom.
11:50
It's, it's, it's one bat.
11:51
It's, it's a super compact process.
11:56
Inside that bat is a roll up of fibres and then if you zoom in into those fibres, it's a rearrangement.
12:03
It's it's a, it's a sort of net where all the cells will start to adhere and then they can, they can grow in that, in that very yeah, concentrated environment.
12:15
So what you would need for Wellness to of course, start the start the the cell suspension or or the virus in a batch mode, you need to load everything into those into those carriers.
12:29
So once they are settled, you can actually start a recirculation process because the volume alone is is is going to be too concentrated to to halt all the all the nutrients and and get the process running for the complete time.
12:45
But you can play with all these different variants.
12:47
So during during the process.
12:49
So standard process will look probably something like first the loading than a growth phase in recirculation or something in profusion.
13:00
Then go back into batch mode for either an infection or there are also applications for for transfections around now, which which I'm not discussing here today.
13:11
And then go back into either recirculation modes or something like a profusion for an unstable product or even a profusion fallout with an inline concentration before something is continued into the DSP train.
13:27
So I, I'm, I'm just going to go over to, to case studies on, on, on what we did and then process that we've had in hand already for quite some time.
13:36
Just to also to show that although it's a very nice system, but it's never an easy Rd.
13:45
So there are always some, some issues to overcome when you're in process development.
13:51
But just a quick Lance, I think most of us will probably recognise what the Yafi is doing with the fees fee virus, but they are already in the pipeline and we're supporting them with the clinical production of of some of these.
14:08
So in the Yafi process, the the fees fee is basically adapted to different antigens by adapting the the G protein and they are together with them.
14:20
We're already working on loss MARF Sudan, which is Ebola and SARS COV 2.
14:27
So all of them basically have the same, the fairest stays intact.
14:32
It's just the G protein that's expressed on the on the outer surface that has changed for all of these products.
14:41
So I'm just going to go over some of little bit of history on how we went over this with with the Yafi.
14:49
So we did early development with them to show sort of proof concept and we went into the into the Isalis Nano with the first candidate and we followed up with some work with the Scalyx Hydro, which are both on the one litre sort of harvest scale size.
15:06
And we got let's say pretty good titers.
15:09
Everyone was happy with the proof of concept.
15:13
And so it showed that the fixed bed could be used here quite well.
15:19
We did see some, let's say some variation, although it was, you know, we, we didn't take much notice between the first candidate and the and the second also because we were switching still from from system system to system here.
15:34
And then we scaled out or scaled up because the, the Scalix comes in different sizes.
15:40
So we first went with the the one litre size, which is the, the hydro, just the official name.
15:47
Then there's the carbo which can go up to a sort of 50 litre harvest size and it has a 30 square metre size bed.
15:56
So we we followed up that candidate 2 into the into the next, into the next size of the process.
16:04
Also already scaling up towards what we needed for phase two, phase 1-2 clinical trial material production and that's where we were reaching really same title.
16:15
So everything hunky Dory, but then we we translated that and we went into the the third candidate also in the in the carbo and also on the on the scale for for the G to be ready on the GMP productions.
16:34
And then we started to notice some of these titers dropping.
16:37
So even though it's a relatively minor adaptation of the G protein, we are following this up because most likely there's something happening with this replication process just by the, but it changed the environment of the of the, of the local environment of this G protein on the on the surface of the virus.
16:57
So that's where, where you see that you should never lean back and just you can, you can never just rely on, on the platform like that.
17:07
There's always things happening which you hope would not would not happen, but still, because we are on the really good range in terms of dieters and in terms of process readiness.
17:21
And, and, and the point is also here to make that for and also to be ready for, for next, next threats.
17:30
And then for next phase is, is that once we were going through the train and and we were ready with the second candidate and going into these we were making already clinical products for, for the for the candidate 2.
17:44
It shaved off a lot of time to have candidate 3 go into the production for clinical face.
17:53
So that's really saved us I think something like four to five months if I compare the trajectory of candidate 2 to the one of candidate 3.
18:02
And I still believe that there's a lot to gain.
18:06
I have included tip of the day, one of our learnings.
18:10
Of course we knew, but it's so easy to be in research and development and, and have one of the materials that is not fully GP compliant.
18:20
And then when you once, once you start to translate that and, and be in your late stage development, you start using all of your GP materials, you also start to realise they might have an impact either on your yield or, or on the, on the process ability of this.
18:36
So really try to stick with that as early as you can.
18:41
And then there's a second case study, which was on COVID, but also a bit on the traditional, let's say on the traditional virus, actually on yellow fever.
18:50
I think also I heard earlier that actually the yellow fever vaccine itself is already one of could already show some of benefit towards COVID.
19:01
So actually this was the the product here, what came from work done at at 11 University, which is a really good combination on on the eye to insert the COVID spike protein into the yellow fever virus.
19:17
So there's a really nice nature article for this.
19:21
And then they came to us and really again on a on AT flash process.
19:25
So as you can imagine, we were a bit, bit late in the game at the end of the day to, to reach the market and, and still have basically COVID cases around to go into the clinic.
19:39
But the work we did with them is really nice because they what we could do quite fast because we were already doing BHK 21 is for ourselves as a showcase in the, in the fixed bed.
19:54
We already knew basically some of this ground, some of the work on the on the bottom.
20:00
That we could grow cells on, on fairly high densities.
20:04
We could also play with those densities to be on different, different endpoints at the time of infection.
20:11
And, and we basically did a lot of some work to show that actually the distribution of that in inside the complete path is, is is fairly good.
20:21
And then we we used their process in AT Flask.
20:24
We did some, some, some, some studies and also then entered this into the fixed bet and basically did different conditions on different densities at the affection showing that we could actually increase their original process already with quite some with quite some higher yields.
20:45
That was good.
20:47
Unfortunately, up till now, it only stayed as a proof of concept, although we did already do, let's say we did do the showcase to them that we could fairly easy make millions of doses with with the process like this.
21:04
So that's just two of the showcases that I could share today.
21:09
And I just just to summarise of the of the fixed bed process development and, and how we currently go go about it at at Batavia Biosciences.
21:19
So yeah, we can sustain fairly high cell densities, especially considering these are adherent cultures.
21:28
We use pretty early on in R&D as much as we can already all the all the GMP materials and equipment, everything is ready for GMP.
21:37
So to say.
21:39
We didn't really touch up on the aseptic process, but it's, it really has a lot of benefits if you have one process for aseptic validation.
21:47
And, and even we are already now in the next phase where we can show that we can probably do a septic process for a wide variety of cells of viruses because the basic operations stay pretty much the same.
22:02
So that that saves a lot in the, in the manufacturability and having the manufacturing site also available for really making batches instead of only doing a septic validations all the time.
22:16
So it's, it's a pretty robust scalable platform.
22:20
And yeah, I think we can also lower the cost of goods.
22:23
Now there's been, I haven't been able to include the slide for today, but please come and visit us later if you want to know more about that.
22:32
And yeah, so I just want to finish that.
22:35
There is lots of work ongoing with the Batavia.
22:38
We've partnered with CJ, there's expansion of our research facility in in Leiden.
22:46
We are expanding in Woburn.
22:48
We are also put making this new manufacturing site also located in Leiden, which is coming up.
22:56
So there's a really interesting journey going around and that's what I have to share today.
23:05
So thanks for the attention.
23:15
Thank you for that.
23:16
Does anyone have any questions they'd like to ask about what Harvey is doing?
23:23
I would have one.
23:24
So very interesting talk and nice technology.
23:28
Do you have any insights on principles where an adherence cell culture might be more suitable compared to a liquid cell or liquid cell culture suspension?
23:40
Philtre suspension.
23:42
Yeah, I I was kind of expecting that question.
23:45
So what I've seen is that let's say some viruses do super well in suspension things like most viruses have a capsid.
23:55
I would say, you know, I don't know polio.
23:59
They can go fairly well on, on suspension cultures.
24:03
And, and by all means, maybe stay with suspension cultures because it's, it's easier to handle.
24:11
But then a lot of the, let's say more envelope viruses, they, they tend to like to have an, an adherent site and A, and a shedding site.
24:22
So then then once you start to put these in a suspension cell line or something, you adapt or you try to adapt, most most likely your titers will drop a lot.
24:35
So that's that's, that's what I see mostly happening now.
