1:25
Thank you very much, John.
1:26
I will maybe try to speak from here so everyone can hear.
1:32
Yeah, I know it's 12:15 is the third day of conference is on a Friday.
1:37
So I will try to be entertaining and mainly brief for my talk.
1:43
I don't want to keep you here while your stomach is screaming food.
1:47
So as John said today I'm going to speak about a strategic CMC framework for successful drug development with a particular focus on peptides.
1:57
But of course these can be applied to other drug modalities, in particular oligos in our case.
2:06
So let's start with the agenda.
2:09
We are going to start with an introduction of the peptide landscape.
2:13
We will be looking both at approved peptides on the market, but also looking at what the future holds for us with the peptides in development.
2:23
And then we will look as I said at Bachem CMC framework, CMC concept and we will look at how this is applied to a case study where we work with clients.
2:36
So with a client project and finally, of course some conclusions and the take home messages.
2:45
So since the approval of the first peptide therapeutic agent, we are in 1923 with insulin over 100 years ago, the drug discovery has expanded between the chemical space between small molecules and large biologics.
3:01
And so peptides have emerged as a new modality and we’ve seen the approval of many peptides over the years.
3:09
In 2024, we reached the milestone of 120 peptides approved on the market and this is outlined.
3:17
I'm really proud of this work because it's part of my PhD work.
3:20
I worked on a database of approved peptide therapeutics called PepTherDia, where we collected information around, you know, all the structural analysis, but also indication and interesting information that is still freely available online.
3:38
You can check it out.
3:39
But importantly, we reached the milestone of 120 peptides approved on the market in 2024.
3:46
Can really say this is not a niche market anymore.
3:48
It's actually more of a mainstream market now, in particular with the approval of peptides for obesity and diabetes.
3:57
But we shouldn't look at peptides only for metabolic disorders.
4:01
Actually there are many peptides approved for cancer disease, for example, and other indications.
4:07
I can give you the example of infectious diseases or respiratory tract disorders and other disorders.
4:15
When we look at the peptides in development, this is a work in collaboration with our market intelligence team at Bachem.
4:22
We saw that we have over 700 peptides in preclinical development and over 350 in clinical development.
4:31
So definitely not a niche market anymore.
4:34
And we look at in particular for the clinical programmes, peptides in phase one, phase two up to phase three development.
4:41
What are the main indications for these peptides?
4:44
So for sure, from this graph you can see clearly half of the peptides in clinical development are either for metabolic disorders or for cancer indications.
4:58
But then we have other indications as well, neurological being one of these cardiovascular, sensory, anti-infective.
5:06
And here I would like to mention also some, I wouldn't say outliers, but some very interesting molecules that we will probably see on the market very soon.
5:16
One being the molecule that J&J is developing in collaboration with the protagonist PN235 for inflammatory diseases and in particular for yeah, for psoriasis.
5:29
These cyclic molecules I'm seeing from PepTherDia and also looking at the peptide development space that more and more cyclic peptides are moving towards commercialisation.
5:44
So give you this example of PN235, but also very interesting.
5:49
We should watch the space molecules developed by Bicycle Therapeutics.
5:55
There is a phase three molecule for cancer therapy and I'm pretty sure this will move into the market very soon.
6:03
So the space starts being more crowded.
6:07
We will see more approvals in the upcoming year, which will make my job to keep up to date very difficult.
6:14
But yes, with a PhD supervisor and his team, we will do our best to keep it up to date.
6:22
So at Bachem we are a leading specialist for oligos and peptide therapeutics.
6:27
So we specialise on API drug substance only.
6:33
We have broad capabilities on both peptides and oligonucleotides.
6:36
And from the peptides I showed you that are on the market, we supply more than 40% of these.
6:42
So we focus on chemical synthesis and we like to say it is more of a commercial term trailblazing the CDMO.
6:51
What does this mean?
6:52
We really focus on innovation.
6:54
We worked on last year 40 R&D projects.
7:00
These really are outstanding for a CDMO because of course we work for clients, but we have our internal R&D projects.
7:08
We collaborate with university, with a small biotech to make sure we are always at the forefront of innovation.
7:15
And important also to say we work on more than 150 NCE projects, so new chemical entity project.
7:22
This is really a big number looking at the obesity rate because of course obesity now is you know why peptides became so famous over the past years.
7:35
But we still keep our portfolio, diverse to make sure that we make justice to our long standing history of peptide CDMO.
7:45
We started our business in 1971, our first GMP production 1978.
7:51
So really an outstanding history and development over the years.
7:56
So going to the main topic for today, CMC framework, what does it mean if we look at these slides really, we may feel a little bit overwhelmed.
8:07
I felt this way when I looked at it for the first time.
8:10
I have so many information packed in just one slide, but you should we look at this as a way to say, OK, Bachem CMC framework is a stage-wise approach.
8:21
When we develop peptides, we don't want our customers to invest too much at the very beginning, but at the same time they should be ready to go into the clinical phase.
8:30
They are so just really systematic and stage wise approach as we think this is the wise approach to face a project.
8:41
And at the same time being a CDMO, we always work before our client starts the development.
8:49
So if our clients is still in the preclinical development, we already work on the phase one activities.
8:56
When the client is in phase one, we already work on the phase two activities.
9:00
And this is really important that we know what we are doing.
9:03
We know our path towards commercialization and at Bachem we are one stop shop.
9:10
So it's not about only about production R&D and you know manufacturing, but it's also about ancillary activities that sometimes can be even more important than the manufacturing process itself.
9:24
So let's look at the scheme in the fragmented approach.
9:28
I'm sure you will feel much more comfortable in this way when we start the project.
9:33
Ideally, we start from the very beginning.
9:36
We start with preclinical work and with preclinical work we usually start from a feasibility study.
9:42
This is where we test our chemistry, we see if our platform strategy works and we kind of tweak our chemistry to make sure that we can support both, simple synthetic strategies, but also more complex molecules.
9:59
And then we move ahead with a tox batch.
10:03
This is a batch that is used for in animal studies, in vivo studies, non-human studies.
10:09
So it's all non GMP work.
10:11
Usually the purity of the tox batch is lower than the GMP batches.
10:15
Why?
10:16
Because we want to qualify impurities before injecting or before administering the molecule into humans.
10:23
We may do also some technical batches if our customer needs to develop the formulation for example.
10:30
But this is all like I would call it non GMP activities.
10:35
Then we move ahead, we move to clinical batches.
10:39
This is where you know before we go into the first GMP production, usually the process is not developed.
10:46
So we use our platform methods for the production of the batch, but we highly recommend to look at the analytical activities and start developing bespoke methods for the purity and assay to make sure we can quantify the peptides in an appropriate way.
11:06
Sometimes we do some design batches to prove the process development that we are going through, but these I will speak about in the next slide and then we move ahead with phase two manufacturing which usually are released with validated methods.
11:20
So here is where we start the validation of the analytical methods.
11:27
Here process development, I mentioned in the previous slide, this is very important part of the CMC concept.
11:33
We start with the process development, we call it part 1 is divided into work packages.
11:39
Work packages are usually specific for each part of the manufacturing process.
11:46
So we have, for example, work packages to optimise the SPPS process, where we look at coupling efficiencies, we look at different resins, different solvents.
11:58
This is for SPPS.
11:59
But then of course, we have packages for the cleavage part, the purification, the isolation and our recommendation then of course it depends on the project is to start at latest before phase two manufacturing, because we should always start to develop a bespoke process for our peptide that we are working on.
12:23
Once the process starts, you know it's optimisation, it's a PD Part 1 is concluded.
12:30
What we recommend is a risk analysis, a very important part because there we look at the MBPR.
12:38
Here we're still speaking about developmental MBPR.
12:41
So the batch records where all the instructions for the manufacturing are written and we look line by line what are the risks for each part and how do we tackle these risks.
12:52
And we look at the normal operating ranges.
12:56
We look if we have to implement in process control.
13:01
And what is very important to say is that the risk should be reduced at this stage through two techniques.
13:09
Through process development, which can reduce the severity of an event and through detection.
13:17
Elevating the probability of detection is very important because if there is a problem, then we detect it early in the process.
13:25
Once these FMEA or the risk analysis is completed, usually our recommendation is to go into process development Part 2.
13:35
Here is where we address the challenges we, you know, we found with our FMEA and if needed we would go into an additional risk analysis.
13:47
But yeah, I would say this is a key part during our CMC framework, CMC concept.
13:56
Moving ahead, we of course when we are more advanced into the development, we want to produce a phase three batch.
14:03
Usually our approach is to use this phase three batch as what we call a PRE-PPQ.
14:10
So a pre validation batch to release a phase 3 batch, all the analytical methods should be validated.
14:18
So not only purity and assay, but all the analytical methods can be residual organic solvents can be AAA.
14:25
If there is a AAA, these are analytical methods to make sure we have a very robust analytical strategy for our peptide.
14:35
And yeah, as I said, probably this is the time where we work on a pre-PPQ batch in preparation of the process validation which I'm going to speak about in this slide.
14:46
So prior commercialization the process must be locked.
14:51
So we have a process that doesn't allow any changes.
14:55
Yeah, I would say any changes.
14:58
So it is important that we do a process validation protocol.
15:02
Well, we write down what we are going to do during process validation and then we run 3 batches with manufacture, 3 consecutive batches at full scale with no changes in between.
15:17
And then at the end if successful, we write a process validation report and one master report collating all the data from the validation.
15:29
As I said at the beginning, I wanted to reiterate this concept is the ancillary activities.
15:35
These are as important as the manufacturing activities at Bachem we have all of these in house.
15:41
We are kind of one stop shop for the drug substance.
15:45
We do not only yet produce but of course we need analysis, and we need regulatory support.
15:51
So this is where our CMC concept entails also the activities.
15:57
I would focus more on the green part, on the QC part where you know, for different stages of the development, we would recommend for example, the development of the purity method already in preclinical development and going ahead with the method validations, stability studies of course and the assessment for genotoxin and so on.
16:20
So yeah, this is part of the CMC concept and it is as important as the manufacturing part.
16:29
So now we said lots of things all about, theoretical and how we apply this concept that is important to apply it in the real life and in projects that we are working on with our clients.
16:42
We took this example of a client we work with, a mid-sized biotech.
16:47
For them we have two projects.
16:50
So you could tell, OK, you have two projects, you have applied similar concept for the two projects.
16:56
And this is where, you know, our CMC concept instead is really flexible as well.
17:02
We have a Glucagon analogue and we also have a hybrid, the GLP molecule with a fatty acid tail.
17:10
So for the Glucagon analogue this fits really well with Bachem experience and also with our really standard platform.
17:18
In this case we did very little process development.
17:22
We had a very robust process from the very beginning.
17:25
We didn't have to go into, you know the massive work packages for process development and in this case we run an FMEA, so a risk analysis very late into the process.
17:39
It was already as you see here phase three, so very late, just the prior starting PPQ activities.
17:46
This is because we knew we had a strong process.
17:49
We knew that the FMEA would have probably resulted in very small changes and indeed it was just about in process control.
17:58
So just the analytical and the detection part, we needed to do some tweaks and tricks while very different approach we took for the hybrid GLP molecule having a fatty acid modification.
18:11
We started PD work already in preclinical development so early on.
18:16
And the FMEA was initiated already as you can see already.
18:21
Yeah, Phase one, end of phase one.
18:23
But yeah, still early in the development process.
18:28
But in this case, we highly recommended our customer to move ahead with FMEA to understand the challenges of the process, to understand where we would have implemented the IPC methods.
18:39
So in process control methods.
18:41
And then we had plenty of time to, we will have actually plenty of time to move towards a process validation with a very robust process.
18:52
So finally, I promised I would be brief.
18:55
So this was the last slide and now some conclusions and take home messages.
19:00
The peptide market is booming.
19:02
I think everyone in this room is aware of this.
19:05
We have as I said from PepTherDia, 120 peptides already on the market, 315 clinical developments, 700 in preclinical developments.
19:16
I mean, we set an amazing path towards a market that is booming and will be booming in the upcoming years.
19:25
Bachem supplies over 40% of the approved peptides on the market, it is really impressive.
19:31
And we still keep our portfolio very diverse because we want to work on good platforms, good new projects.
19:41
Our success is also given by the CMC framework.
19:44
This is a framework that we have tailored over many years of experience in peptide chemistry and also oligo chemistry now, but it's not set in stone.
19:56
It can be tailored depending on the project that we work on and depending on the client needs as well.
20:03
Important part of the CMC is the process development and the risk analysis.
20:08
The FMEA is critical to make sure that we have a robust process before moving into phase three and then commercialisation.
20:16
And we look not only at the manufacturing, but also analytical, quality, regulatory aspects as a whole.
20:25
And finally, I presented a case study with two molecules where the CMC framework was applied in two very different ways, just to give you a flavour of how this can be tailored depending on the project.
20:39
And with this, I'm going to thank you for the attention and to stick around until the very end of this long day.
20:47
So thank you very much.
