0:00
Thank you Mr. Chairman for the kind invitation and thank you for having me today to speak.
0:06
But this rather long title just reflects the fact that I'm going to show you today four different applications that we did together with our customers or our customers did with our equipment for some different injectable formulations using both our crystallisation and encapsulation platforms, which I can also then introduce to you.
0:27
So Secoya is a spin off company from the Université Libre de Bruxelles.
0:31
So it's a Belgian spin off company.
0:33
We started in 2020 with lots of experience before that with different people in the field of process engineering, developing these new kind of technologies based on flow chemistry and all sorts of physical chemical changes using flow conditions always with the in the heart of the system to be scalable to the complete production scale inside of GMP plants.
0:59
So we have 4 different pillars, technologies of which crystallisation, emulsification and pervaporation are all patent pending and granted technologies that we own ourselves and that we distribute exclusively or do a servicing on.
1:14
And then we also have the process intensification pillar, which is much more based on a consultancy basis, let's say, where we also construct machines, but then those are completely custom made for our customers.
1:27
So Secoya’s crystallisation technology is based on a continuous flow system, meaning that you would have your heated product and in some complete soluble conditions and you will cool it down using our millifluidic reactors in a very fast and controlled way to the temperature that you would reach spontaneous nucleation conditions.
1:47
In case you would need it to play around with the particle size to go to even smaller sizes.
1:52
You can also add with different ways of mechanisms of mixing using anti-solvents which can also be cooled and so you can have a combination of anti-solvent crystallisation combined with cooling crystallisation.
2:03
As I said, we always at the core of the systems the scalability in mind.
2:10
So we have developed these different instruments that can help you to do kind of complete process development from scratch using the laboratory machine which is also on display booth #2 here where you can do with really reduce the amount of quantity to do complete, let's say parametrization of all the important parameters that are important for your specific process.
2:32
Once you have developed that, you can just easily translate that exact same recipe to the pilot scale where you will do kilogramme runs already with using the same combination of mixings and reactors.
2:45
Whenever you have validated that complete setup, then you can go to for a multiplication of the same, again the same reactors to multiply it to be according to the complete production scale that you will need to be.
2:58
We have done a lot of testing on that, but that's not the exact topic of today.
3:01
So if you want to have a discussion of the upscaling part, we can always have a good discussion later on.
3:10
So the benefits of this technology is that we have a very tight control of all the different parameters that are important.
3:15
So of course, concentrations, those are things that you can generate easily manipulate, but we have a very tight control of temperature, the way that you mix and also on the shear rate that you apply inside of this tubing, which plays a dominant role in the total nucleation rate that you can achieve.
3:31
And by doing so, there's a small example there of the nucleation rates.
3:36
In fact, the resulting particle size of in this case aspirin when subjected to different nucleation temperatures and you see the stepwise drop in average particle size, which is in there in blue to very tiny particles like 3 micrometre average particle size.
3:52
While you retain always a very narrow particle size distribution because of the product is always injected in a continuous way inside of these reactors, the reactor is always completely renewed.
4:03
And so all the product is completely treated in homogeneous way.
4:06
And therefore you always have a very reduced particle sizes and particle size distributions.
4:13
So there on the right, you have some, let's say, the total application range that you already have achieved for doing precipitations and crystallizations using this machine.
4:21
So we have already done nanometric precipitations, oral dosage from crystallizations, whatever you want.
4:31
So now let's go a little bit into the work that has been done.
4:35
So colleagues of the next speaker of today have done this work using our equipment.
4:40
So they did this work completely independent from us, were able to distribute this as a set of total guideline of how they treated the product.
4:48
So in this case it's itraconazole as a product.
4:52
They wanted to have a PSD with a D90 below 10 micrometre, meaning that nearly all material had to be crystalline and below the 10 micrometre mark.
5:01
And then they wanted to see if that they can using our machine achieve the same kind of long active stability for the system because they want the product to remain in suspension for over 120 days.
5:13
And they wanted to see if they can play around with the quantity of surfactant that is used for this application.
5:21
And so and here you have all these particle size distributions that they have measured.
5:25
So there on the left you see the mixing ratio in between the solution, which is always kept at one, an anti-solvent.
5:33
So we have a variation of one in three, to one in eight.
5:36
And the top part is our co-flow mixer that they have applied.
5:39
And at the bottom part is the T cross mixer that we that they have used for this system.
5:46
And you'll see that when you have let's say a slight excess in anti-solvent, you already have quite a good particle size distribution.
5:54
So I guess that the D50 there, so the top one, the D50 is about 8 to 9 micrometre.
5:59
The D90 is a bit too high in that case.
6:01
But just by stepwise increasing the amount of anti-solvent that is added to the system, they easily can go below that mark without any problem.
6:11
Then what they also did is a very nice study on different amount and different let's say surfactants that they have used in the system.
6:19
And you see that using exact the same mixing condition in the same parameter.
6:24
Just by changing the surfactant itself, you have this influence on the particle size of the system with visibly the vitamin E surfactant having the properties let's say for this application.
6:40
So in the end, so there's a very nice publication that they have put out as well.
6:45
You saw that they can really easily achieve the same and identical particle size distribution as they want.
6:52
They were able to already increase also the solid content and doing the tests.
6:56
But was most staggering is in fact that they have now a 53/1 weight-based API over surfactant instead of the two weights of API per one weight of surfactant.
7:07
So nearly 35 times less surfactant can be needed if you use our machine.
7:13
And that's only because the surfactant is already premixed inside of the anti-solvent system.
7:19
And when both systems arrive together and you have the precipitation of your particles, the surfactant is already present at that point in time and can then globe directly the surfactant.
7:29
And so you arrest growth of the system, but also the efficiency of the surfactant is much more increased if you use this approach.
7:37
And even with using this 53/1 weight ratio, they have the same stability for this long active injectable.
7:43
So it's an excellent result that Johnson and Johnson has achieved using our machine.
7:51
Another example is Naproxen.
7:53
So Eurofins is a Belgian CRO CDMO company and usually for Naproxen they needed a product that is less slightly below the one micrometre mark.
8:04
So they truly wanted to have a product that is in the order of 500 to 600 nanometre in size.
8:10
And they usually perform wet milling to do so.
8:12
Now wet milling is just you have a flask, you have a lot of hard beads, they put Naproxen inside and they just let that roll for 24 hours, 48 hours, whatever you want.
8:23
And so like we wanted to do a bottom up generation of so these standard sized particles.
8:27
So in one single step.
8:28
So you come with your solution with naproxen, you use in isopropyl alcohol, you use water as an anti-solvent and in this case we added the surfactant in both the anti-solvent and in the collection phase to do so.
8:44
Now we saw that in the case of naproxen there was a very fast de-mixing occurring when you use T cross mixers.
8:51
So they're on the left and the right.
8:55
You see two times the T cross mixers we have on the one the solution coming in and the other one that the anti-solvent.
9:04
And when you see that you have the same flow rates, like 20 and 20 millilitre per minute, you have an ideal mixing in the centre and then all of that product is evacuated at the other end.
9:14
If you have an increased anti-solvent flow rate already there, some discrepancies occur in where the product is going to be mixed.
9:22
And therefore we saw some clogging of this system and therefore we changed the setup a little bit in this case to a side entry of the system.
9:32
So in this case, your anti-solvent flow is coming from the side, and your solution is added in the middle and you will have the mixing at the interface between both systems, especially if you go to higher and higher flow rates of the anti-solvent as opposed to the solution.
9:47
However, we did not observe any clogging anymore because the solution flow is always pushed into this mixer.
9:54
And so we didn't have that issue.
9:58
And what we saw this directly at the same time using both especially the side mixers at different sizes of those mixers because you can have them in different mixing size that you have with the one in three and one in four mixing ratio, you easily achieve this kind of nanometric project, in the case of naproxen.
10:13
Of course precipitation kinetics differ from molecule to molecule.
10:20
So this was just a kind of being lucky that within 38 tests as you see there, we already achieved this kind of result, but that's a typical turnover in testing that we have when we are trying to do a new project like today.
10:36
Now if we switch to the encapsulation emulsification technology, so that's a bit of a different set up.
10:43
So there we really targeted the construction of singular beads.
10:49
So where you have a water in oil emulsion or the oil in water emulsion, then those beats can then be solidified, or we also can generate these microcapsules.
10:58
So where you have a core phase at the inner part, a shell phase protecting the interface for the environment, which can be anything.
11:06
But we'll have some examples later on of which we can and also change the thickness of both the shell and core phases.
11:14
And so we have a wide range of possible particle sizes that we can achieve.
11:19
And so, of the work that we have been doing up to now, if you look at singular beads, we can have PLGA solidified beads with lysozyme and trapped inside of these beads.
11:30
We have done alginate hydrogen beads as also to together with some API mixed inside.
11:36
And if you then look at the double emulsion systems, we have done PLGA, chitosan, polymethacrylate, we also encapsulate living bacteria inside of the systems which keep which tend to remain alive up to the point that we can also do very high efficiently lipid nanoparticle encapsulations.
11:53
How do we do that?
11:54
Well, we have generated this device which is also on display at our booth which is the RayDrop.
12:00
And in fact it is a true microfluidic device.
12:03
But it was really born out of frustration with every other microfluidic chip that existed in the market to do either hydrophilic or hydrophobic beads.
12:13
Because usually in microfluidics people work with treated surfaces which will wear and tear down.
12:20
And so all of these things usually get you a production of about 5 to 10 minutes and then your chip is going to die.
12:27
This we want to absolutely avoid because we are a company that's interested in doing productions of things.
12:32
And so the RayDrop is a system that uses a fully non confined production of your beads.
12:39
So the moment and you see there the nozzle, which is an actual measurement that you see there on top, the once the product comes out of the nozzle, it will be pinched off by the continuous phase flowing inside of the tubing and you will extract directly the bead inside of the collection capillary to the right.
12:57
But at no point in time that bead will touch the walls and therefore we don't need to have any surface treatments.
13:04
So in fact, the system there is complete.
13:07
A nozzle can be in resin or glass, and your extraction capillary is also fully in glass.
13:13
And you see that the way that we do that for single beads, you see the stacking there of the sample on the right.
13:18
It's the uniformity of the beads that you generate is just practically unmatched.
13:24
So it's you have a polydispersity which is extremely low thanks to the fact that you always will generate these new beads. And inside of one generator for a single emotion setup, it produces about 4000 to 5000 beads per second.
13:40
So it can have a high throughput.
13:42
On the other hand, if you have a double emulsion system, so there you have two entry points, so a shell phase and a core phase.
13:49
And you see there again, the nozzle, a true image of the nozzle, a working nozzle.
13:53
In fact, we have your inner part, the red part, the core phase coming from the inside, the shell phase is coming around it.
14:01
And again you have your continuous phase which will pinch off both of them so that you can extract always the same particle.
14:08
And again, you see there the nice, the red dots, those are the centre parts englobed in fact around that with its shell phase.
14:18
That's an example of chitosan, for example. This RayDrop is embedded inside of our laboratory screening device.
14:27
So again, as for the crystallisation, also here we have a lab scale screening device which is the InstaDrop and it has everything that you need from solvent containers up to the embedded RayDrop together with a microscope, taking pictures or videos at all times.
14:44
We have an injection loop to even reduce the quantity of product that you will use.
14:48
Everything is present on the system and it's a plug and play system.
14:52
So you just plug it in.
14:53
It's a standalone system that runs on its own. And you can also put this thing just the temperature at 40° up to 40° if you like.
15:05
And again so the InstaDrop is not but the starting point.
15:10
We also are working on the ScaleDrop, which is in the multiplication of the amount of reactors inside one block that we can then put in parallel to increase the productivity of the system.
15:22
So now for some examples.
15:24
So for the single emotion systems, we have done a lot of work on the precipitation of antibodies.
15:31
So where in this case again we want to have a very uniform particle formation with very fast precipitation and try to generate spherical particles in the best possible way.
15:42
So that our customer was able to study the impact of the size in a discrete way because they wanted to have 15, 20, 25, 30, 45 micrometre size to see what the impact was of the size on the activity of the antibody.
16:00
And so again, as you already saw, so in this case we have our droplet phase is deionised water together with the protein.
16:09
No surfactant was used in this case.
16:11
So also benefit for the system, it's not always possible. Continuous phase was n-Butyl acetate in this case; we used an injection nozzle of 30 micrometre and then a small out that capillary of 150.
16:25
And so this is a slowed down production of the beads.
16:30
So this is about I think 100 milliseconds in total, that video.
16:35
Now if we even use an extraction capillary, which is a bit smaller, then we can still reduce further the size of the droplets.
16:41
And then after drying, we obtained particles in this case for this example here of about 13 to 15 micrometres.
16:49
If you look at the particle size distribution, so there's a small antenna on the left and the right.
16:53
But if you look at the polydispersity index, that is just incredibly low.
16:57
And so they're for the customer in this case, an unmatched uniformity of the product because usually they have a span value of about 3 to 4, where in this case we have around 0.2 for this particular example.
17:13
The next example is a double emulsion system.
17:15
So in this case, we have worked a lot for people to do some ocular implants, but also injections in brain tissue that we're working on and as well with knee joint injections, but also fillers for the cosmetic industries as well.
17:34
So for these cases, we either have, or you can either have a water soluble API.
17:39
So then we will use, normally we will still use a PLGA.
17:42
So from the Resomer family from Evonik as a shell phase or when you have an oil soluble API, then you can change the shell phase, for example, to chitosan too much both systems so that they can still be nicely encapsulated inside.
17:58
There are many different ways of having the solidifications strategies that you can do.
18:04
We have done acidity changes for precipitation.
18:09
You also have UV cross linkable to have a solidified resin around that.
18:15
So in fact, it's the versatility of the system is also laying in the fact that we can use many different types of chemistries to perform what you want.
18:23
And what we saw is that typically your shell is for a long time still porous enough to also extract solvent from the inner part so that you can have a drying of both systems at the same time, both the core and the shell phase.
18:38
So in this example we had an API inside the system.
18:45
We had PLGA dissolved in either ethyl acetate, which works the best in this case or isopropyl acetate.
18:53
Usually the solvent that you select is to do something with the solubility inside of the continuous phase to see what the extraction rates would be from the shell phase to the eventual continuous phase inside of the collection vessel.
19:07
And we had there, so PBS on the inside.
19:11
So the API dissolved in PBS buffer and then the continuous phase was a PBS buffer as well.
19:16
So we collect the complete system.
19:20
Yeah.
19:20
And then we did solvent extraction.
19:24
You nicely see that in this case the core face stays intact.
19:28
And you do have here upon drying and precipitation a little bit of a change in the shell itself which is not completely homogeneous.
19:37
But in the end we easily solve that problem.
19:41
So in this case this was a fluorescein tagged peptide that we did for the customer.
19:46
And so we had 100% encapsulation with complete spherical system that we have generated to build unmatched uniformity of the size of the particle.
19:57
And so with that just our key points.
19:59
So Secoya Technologies is really a company that's focusing on particle engineering, whether it be via crystallisation or via encapsulation emulsification devices.
20:09
But we want to produce quality of product, not only the quantity but the quality of the product knowing that.
20:15
With using that kind of a project we have because of the easy way to scale up these things, you can do your early development screening to the production scale using the same production technique.
20:26
And with that, I would like to thank you for your kind attention.
