0:00
A little bit of a trend, right?
0:01
So let's say this part of Europe has a lot of blue, this part of Europe has a lot of pink.
0:07
So if we sum up this, we can say basically we have a division where in Northern Europe there a lot of biotech and pharma and in Southern Europe its mainly academia and hospitals.
0:21
Why are academia and hospitals so strong?
0:24
Why do we have so many blue dots?
0:27
They are close to the patients.
0:29
The patients are there, you can interact with them directly, you have a direct connection to them, specialised technical knowledge, the talents are there before ever go to pharma, they start their career there and innovation starts here.
0:47
We have a lot of clinical samples available and due to being close to the patients and importantly a lot you can directly treat a patient and try to cure a disease of this one patient.
1:04
So the scale is sometimes 1:00 to 1:00.
1:10
How does the development of the ATMP in such a such a situation start?
1:18
So let's start from the research lab.
1:23
The research lab could be basic R&D, could be clinical research, whatever.
1:29
Everything starts with a problem statement.
1:32
So there is an illness, there is a situation, there is a problem statement.
1:37
I studied the literature, I knew exactly what I want to tackle down and start making hypothesis how to treat that.
1:46
I develop a method, and I use a risk-based approach.
1:50
The reason why I do this is that I have devices and reagents in the research lab which are released for R&D.
2:00
So I need a risk-based approach to check whether I can use that to produce therapies that I can infuse in humans.
2:10
So we have lab protocols.
2:12
What is a lab protocol?
2:14
A lot of manual steps, a lot of open handling, a lot of spiking, a lot of steps.
2:19
Simply sometimes because I have the possibility to test, because I need to find a way to do something.
2:28
And those protocols are quite different to manufacturing protocols where I need to be fast and direct and I have the CPP I need to keep in.
2:39
I have the flexibility to change the protocol if something is not working, modify the parameters and if I'm lucky I have a clean room, maybe I have an isolator.
2:49
Most of the time I have biosafety cabinets.
3:07
Small volume, tailor made applications, So we need something which is successful and we need to transfer this picture into GMP.
3:16
It's a huge step.
3:17
It's a big step.
3:20
How do we do this?
3:22
Normally if you rush this street that I showed you now into clinic, you will work into silos.
3:31
So you get an R&D process.
3:34
You will think this through a very quick MCT work into something which is clinical or supposed to be clinical.
3:46
The result is that you get the process 1 to one into a B environment with lots of bio safety cabinets, lots of open handling, lots of people dressed up like astronauts with 35° outside who need to handle blood of a human being who maybe has just one shot.
4:05
This is not the way it should be.
4:08
This is the way it is sometimes now.
4:10
This is not the way it should be in the future.
4:12
So we need to work with the GMP state of mind.
4:15
GMP state of mind means we need to start with the end in mind.
4:20
Where do we want to go when we develop our lab protocols and when we develop our strategy?
4:25
We need to think with the end in mind.
4:28
And here you get 6 questions.
4:31
This is a paper I published with my colleagues at CRB.
4:35
You need to go through these six questions to be able to get a good, fast and efficient tech transfer.
4:47
Let's start going through that.
4:49
So are my protocols GMP ready?
4:52
That's what I mentioned before.
4:53
You start in the lab with a lot of discrete process steps, maybe a lot of devices not even communicating to each other, but you have something which is somehow closed.
5:03
Maybe you have in any case something that is working for your protocol.
5:07
So if we stop thinking in dots and we start thinking in a circle, into a manufacturing platform, we get devices working, but within an automation system that gives us a full trail, that gives us a full control of our system.
5:28
Maybe it's also even able to do predictive analysis telling you that we should pay attention: this and this could happen if we have enough experience and if we produce enough.
5:41
Am I ready for commercial manufacturing when I'm doing this therapy?
5:44
Is this therapy an autologous one?
5:46
Do I need to scale out or do I need to scale up?
5:49
What would the experimental setup look like if instead of just treating one patient, I treat 100,000 of them?
5:59
Equipment selection.
6:01
Let's be honest, sometimes it's just complicated to find a device which is working.
6:05
So we're happy when we found one and we just move it to clinic.
6:08
It's probably not the best choice, but when we think about the equipment selection, we need to calculate not only the consequences it has on our process.
6:19
Of course, we need something we can work with, but we need to think about the building.
6:25
Where is this therapy being produced in a GMP situation?
6:30
Can I do I have the technical capabilities and to fit the device?
6:36
Do I have a strategic facility planning in mind that I know what's going to happen in the future?
6:42
Is this choice sustainable or not?
6:46
And then of course the device, it has to be available.
6:49
It has to be fit for purpose and flexible and it has to be cleaned.
6:53
How many devices for cell and gene therapy have a lot of holes, USB access and corners you cannot clean.
7:05
Vendor relations are important, you need a vendor you trust.
7:07
You need someone who comes to you immediately when your device is not working, when you have a problem, you cannot rely on an assistance.
7:14
I come when I have time.
7:18
Sterility is a combination of different things.
7:22
It's not just a closed process.
7:26
Your closed process takes place under the umbrella of a manufacturing platform.
7:34
It is embedded into a facility with an all logistics and the contamination control strategy works together with all those points to get your sterility.
7:45
So don't just look at the process, think of the whole thing together.
7:50
It's the facility, the logistics and the people.
7:57
Now think about if you have an autologous therapy, how many data you produce per patient, how many steps you have, how many data you can produce per patient.
8:06
Now think about treating, I don't know, 100,000 patients a year is a huge amount of data and the only aim cannot just be to store them just for the sake of having them because the regulators are happy.
8:20
You need to store this data, you need to use those data, you need to interpret those data, you need to make them available.
8:25
So there is a lot of potential into automation, and this is something that we do not think at all when we are in the lab environment.
8:33
That's at least not the first thought that we have in the morning where we reach the lab.
8:38
I come from a lab so I can see if we have the right team in place. When it comes to doing tech transfer is it's a combination of people working together.
8:51
You need to have you need to have a facility, a location, you need to have strategic facility planning working together with the building and process engineers planning the facility together with you.
9:08
You have a process which needs to go around MSAT and you need people coordinating these processes.
9:20
You need procurement, you need to know what you want to test.
9:23
How extensive is the testing you're going to do?
9:26
Do you rely on a full blown out testing in house or you go to partner for the lab?
9:33
What does it mean when it comes to data and QA?
9:37
How much quality assurance do I have to do to keep this in the to develop this in the proper way?
9:45
So you see, it's not just like I have found six devices which work together, I can move to clinic.
9:53
It's much more than that.
9:56
So for this part, how to do the tech transfer, how we do it at Skan, I would like to hand over to Kaji.
10:07
So I will explain how to tech transfer to an isolator because now we're talking about the tech transfer in general.
10:16
It's a really long journey starting from decision, coming to the planning, preparation, execution and evaluation.
10:27
And those milestones usually takes 24 months to launching the product.
10:35
And this is this, 24 months is the shortest, fastest, the time we have to think about and then to fulfil this tech transfer, to make the end-to-end platform.
10:48
What we need is facility capability.
10:51
Of course the facility has to have capability from clinical to GMP production. The team has to be trained as GMP experts and the solution which includes the other equipment has to be state-of-the-art and at the lowest risk of the contamination mainly microbial contamination.
11:12
And this is really important part to have the GMP commercial production.
11:16
Why? When we look at the other major recall of the traditional injections in the world, most of the recall is coming from the non-sterile risk of the product.
11:29
That's the reason why that the other company has to recall all their product and why non-sterile risk is happening in the market.
11:38
It's because of your equipment selection and your operation. As long as you have aseptic open handling operator, that's going to be the major risk of the other microbial contamination.
11:53
And when we look at the current situation of the ATMP market, it's clear that most of the other biosafety cabinet operation is aseptic open handling.
12:04
So operator has to access to their product which is the sterile core by manual.
12:14
So all the other procedures are already at high risk of the microbiome contamination, which is the one of the biggest challenges in ATMP field. How can we commercialise the other production?
12:27
And of course the remaining options are QMS and automation.
12:34
And then when we talk about the other tech transfer, our SKAN way, we have another six different points, which is the GMP, the protocol that is ready and ready for the commercial manufacturing.
12:48
How do I guarantee the 3D?
12:50
Again, this is all about the equipment you're going to select and the operation you will execute.
12:56
And then do I have automation in place and do I have the right team in place?
13:02
And together with this type of questions, we also have to think about the how we can suck create process development coming from R&D going to the GMP and then coming back to the original requirement of the product quality.
13:17
So it's the chain of the other whole structure that we use to execute the tech transfer. And how we do this?
13:28
We usually use the user story map.
13:37
This is the other the procedure for the IT industry.
13:41
But mainly what we are doing a user story mapping here is we have the whole Excel sheet of the information about your process including which material goes into the process, which material goes out of the process?
14:01
The timings of when you will take the samples, when you have to put the other your product into the incubator, and when you have to place the product in the centrifuge.
14:11
Each process step is described in here.
14:15
And then you can divide by batch size, process component inside or outside the isolator, materials, volume, process step and flow, material flow and aseptic transfer.
14:27
All the information you need to implement your process to the GMP commercial production is in this user's story map.
14:34
So this is the Bible to execute the tech transfer.
14:41
And then as I said, the microbiome contamination is the highest risk of the other three.
14:47
And then when we compare two solutions out there, which is the biosafety cabinet in grade B and the other solution is isolator in grade C, what are the differences between them?
15:02
The biosafety cabinet, as I said, it's open process.
15:05
So operator can access directly your product process itself, which is convenient, which could be precise, but it also has the highest risk of the microbiome contamination.
15:17
And instead the isolator is the one which is perfectly closed system.
15:23
So all the process will be inside the isolator chamber and operator can only access your process by using the glove and glass.
15:34
So this is the major difference between the biosafety cabinet and the isolator.
15:39
And then when we look at the legal information in the other authority, they strictly try to avoid the material transfer in between grade A and B because B is the place that the operator is standing.
15:56
A is a product process core.
15:59
So if you have many material transfers in between grade A and grade B, it's simply increasing the risk of the microbiome contamination.
16:12
And when we look at the other biosafety cabinet, you have the open handling in here.
16:19
But if you like to place it into the centrifuge, you have to take it out and then place it into the centrifuge.
16:25
And after centrifugation process, you have to take it out from the centrifuge and bring it back to the other grade A.
16:32
So this is the already the material transfer in between grade A and B which you cannot avoid as long as you use the bio safety cabinet in grade B instead the isolator, you can integrate the centrifuge in the incubator with the isolator.
16:49
So all the process from the beginning to till the end will be done in aseptic.
16:55
So that's the major difference.
16:58
And also we have to think about the other the manual operation.
17:03
So manual operation in lab scale doesn't think about anything about the GMP.
17:08
But in GMP we have to think about so many precise movements and what we can do and what we are not allowed to do.
17:15
We have to go through each step of your process mainly by using this virtual reality stuff.
17:24
And then you can find out which process has the risk of the other infringement of the GMP requirement and then you can fix it before you start working with your own process with the GMP equipment.
17:40
So why we're doing the technology transfer, we can also offer to start up the other user story map and then doing the technology transfer from biosafety cabinet to the isolator.
18:02
We will start production with the isolator, then throughout the technology transfer down to the production, which is the training for the operator.
18:16
So this is how we can achieve the other technology transfer for the other SKAN isolator from the biosafety cabinet.
18:25
So isolator should look like it's not the same isolator from the off the shelf because the isolator has to be unique because your process is unique.
18:36
And that is the reason why the isolator that you will use in the GMP production has to be either customizable or the modular type, which means the isolator itself will fit to your process.
18:51
And this is some examples, this is the other mesenchymal stem cells open handling upstream downstream isolators and this is again the mesenchymal stem cells.
19:03
And this is the other just stem cell open handling part by using the modular type of the isolator.
19:09
And this is the CAR-T process.
19:11
And for the CAR T process, there are some aseptic open handling in between the closed system.
19:18
And if you don't have the isolator, you have to place everything into the grade B instead.
19:22
With the isolator, you can place everything into grade C and this is a tissue engineering and this is the finish with the other closed bio.
19:31
We have the booths over there.
19:33
So from aseptic technology and this is the last slide, why use the isolator?
19:41
So I will skip this one and then come to this point.
19:44
Isolator has really big benefits compared to the biosafety cabinet.
19:47
One is the energy cost.
19:50
You can save the energy cost up to 50% with the isolator.
19:54
And environmental monitoring cost you can save up to 80% and the initial building cost you can save up to 35%.
20:05
Regarding total life cost, with the isolator you can save up to 50% and when we go into the details about the quality with the other clean room and biosafety cabinet, you can only guarantee the 10 to -3 through the assurance level.
20:19
With the isolator, you can reach the 10 to -6 which means 1000 times better.
20:27
And the bio safety cabinet is a high-risk open handling from the cross contamination point of view and microbiome contamination point of view.
20:34
But with isolator, it's low risk because it's cross handling.
20:37
And then when we look at the other gowning, when you go into the Grade B, as Michela has already mentioned it's the astronaut spacesuit, which is around nine different gowning you have to wear to go into the Grade B room.
20:59
Instead with a grade C, you only have four gowning and that's it.
21:13
So the comfortable, the way you can work in grade C and the manual time and the quality, the management by the biosafety cabinet with the standalone equipment.
21:27
But with the isolator integrated equipment, you can have the automatic quick and perfect data integrity, the scatter data management.
21:36
So these are the differences between the biosafety cabinet and the isolator.
21:42
So the solution has to be regulation and high level of the risk of the open process.
21:49
Isolator technology is a natural next step to increase the process and quality control.
21:53
Isolator technology is attractive to investors since it is most effective solution to minimise cost of bringing your product to the market.
22:04
At SKAN, we can offer a solution for all the stages of the ATMP manufacturing process.
