1:02
Yeah, thank you very much, Kathleen for the introduction and thanks, Martin for the great talk.
1:08
So as Martin said, the bar is set a little bit high.
1:11
I will try not to be boring.
1:16
And I hope I will share with you some findings.
1:20
So, let's start.
1:24
The title of today's talk is Green Peptide Chemistry and Beyond and the idea here is to look at holistic approaches to sustainable peptide manufacturing.
1:34
So you will see what we mean by this in a second.
1:40
I'm just opening up this talk by saying that we would like really to raise questions rather than answer questions and open up a discussion on looking at peptide manufacturing in a broader way.
1:56
So let's start with the agenda.
2:00
So during this talk I will divide the topics in two main areas.
2:06
The first one is green peptide chemistry. For this aspect, I will touch on our collaboration for microwave solid phase peptide synthesis.
2:17
We established a collaboration with CEM in 2021 for kilogramme scale cGMP production.
2:25
So we will touch on the main advantages of microwave SPPS and then we will move on to speak about solvent recycling and recovery initiatives.
2:35
So these are all the topics that we touched on this morning and before with Martin again.
2:41
So I will try to give you a different perspective on these and then we will move on to the more extensive part of the talk where we will speak about the holistic approach to peptide manufacturing.
2:56
And for holistic we meant the supply chain and transportation.
3:02
So in in our industry there are various CDMOs and each of them has a different business models which requires again a different supply chain.
3:13
And we will touch on the country of origin for amino acids used for peptide manufacturing and we will try to assess the CO2 footprint of transportation of raw materials and intermediates.
3:28
And then finally, we will have an example a little bit hands on and we will look at the case study of Liraglutide.
3:36
So starting from microwave solid phase peptide synthesis, as I briefly mentioned before, in 2021, AmbioPharm established a partnership with CEM because we've really foreseen in the microwave SPPS technology great advantages.
3:54
I'm going to touch on some of them now.
3:57
So the first one is the reduced energy consumption, and this drastically reduced the synthesis time.
4:06
We can do the coupling step in around 2 minutes and Fmoc removal from 15 we go down to 1-3 minutes.
4:15
So its a drastic reduction in synthesis time which is translated in a reduction in energy consumption.
4:24
But not only is this aspect covered by microwave SPPS, we can also drastically reduce solvents up to 90%.
4:34
And we spoke about PMI before.
4:36
So I think reduction of solvent waste is something that our industry is really looking at and we can achieve that by using microwave technology.
4:49
And then the use of greener solvent, we have John Lopeth in the in the audience here.
4:54
So the use of N-butyl-pyrrolidone it is possible only with at least as of now with microwave SPPS and this is due to its viscosity.
5:05
So by using microwave technology, we have the possibility of using greener solvents and then finally the scalability of this technology.
5:16
This is the beauty of using microwave that we can go up to kilogramme scale and we're pulling batches together.
5:25
We can really cover up to commercial production.
5:30
So this is something we are really proud of at AmbioPharm.
5:34
But moving on to the waste recovery project, this is really a very new initiative that we embark on.
5:45
And as you can see from the image we are working towards the recycling of solvents, and we started off with the acetonitrile.
5:59
This is recycling system has been set up in our newly built campus in Shanghai.
6:06
And we are at the final stages of qualifying our system where we will be able to recycle acetonitrile and in the near future, we have plans to another system to recycle also DMF and to recover process waste and water.
6:23
So this is something that we are really proud of.
6:26
And just as a side comment, we welcome everyone to come and see our facilities and see these newly built system.
6:37
So here is where we start with the holistic approach to peptide manufacturing and looking at the carbon footprint and the CO2 impact of the supply chain and transportation.
6:51
So we all know that manufacturing peptides generates a lot of CO2.
6:56
So this is not news for anyone.
6:59
We at AmbioPharm and are trying to address these issues in various ways.
7:04
So for sure, the use of novel technologies such as microwave SPPS to reduce energy and solvent consumption, but also the use of greener solvents such as TamiSolve or NBP.
7:19
We are also embarking on solvent recycling initiatives.
7:24
But what we have not touched on is the supply chain and transportation of raw materials.
7:30
And just to give you an idea of how this even started, like why we started looking at supply chain and transportation, a valid challenge that was brought up by some of our customers was that our traditional business model relied on doing the synthesis in Shanghai and then shipping the crude peptide to our US headquarters to do the downstream processing and the release.
7:58
So one of the challenges was acknowledging that we have this model, but what's the impact on the carbon footprint of shipping the crude peptide from Shanghai to US.
8:10
So we really started thinking about it and we wanted to give an answer to our customers.
8:17
So we started asking ourselves what is the impact on the life cycle analysis for supply chain and transportation?
8:25
So in the next 10 to 15 minutes we will look at our traditional and simplified business models.
8:33
And I will tell you what this means in a second.
8:37
And our goal here is to open the door to assessing the CO2 impact of transporting raw materials.
8:44
And here I'm not saying that our findings are set in stone.
8:50
I would rather start a conversation on this topic and your input would be much appreciated.
8:59
But at least these are some findings from our calculations.
9:04
And we will take Liraglutide as an example and as a benchmark to calculate the impact of the CO2 on various manufacturing models.
9:18
So the very typical CDMO model, it works as it is represented in this image.
9:28
So majority of the amino acids, I would say a large majority of amino acids are supplied from China.
9:35
We cannot escape that the source of amino acids for each and every CDMO is in China.
9:43
And a very typical model is to transport these amino acids and raw materials long distance from the from the reagent supplier to the CDMO facility that is based in Europe, in India or in the US. In the CDMO facility, then we have the upstream processing and then the downstream processing obtaining the final peptide and then there is another transport to the customer various destination.
10:16
But the AmbioPharrm model is a little bit different.
10:19
So our traditional model really is to of course supply amino acid from China as everyone does.
10:27
But then we have a very short transport there because our Shanghai campus is located very close to the reagent suppliers and there we can do the upstream processing.
10:39
So we have our crude peptide which is then shipped as I mentioned before to our US headquarters.
10:48
There we do the downstream processing, release the peptide and the peptide is shipped to the customer.
10:54
So as you can see, the bulk of amino acids are transported long distance by truck instead of being transported by air, boat and truck as well.
11:06
Our simplified model though is a little bit different from the previous one.
11:11
So here what we do is we purchase amino acids again from China but transport them a short distance to our Shanghai campus.
11:21
And there the difference is that we can do both the upstream and the downstream processing, obtaining the final peptide during the releasing in our campus in Shanghai and then transport these final peptides to the customer.
11:36
And as you can see again, the bulk of amino acids are transported only short distance to our Shanghai campus.
11:45
So as I said, we will look at Liraglutide this is a peptide that is manufactured by majority of the CDMOs.
11:56
So we will look at the solid phase peptide manufacturing of this peptide in different regions.
12:03
And to do so, we use the geodis tool to calculate and predict the impact of CO2.
12:13
And we compared three different models: shipping protected amino acids from China to Europe, US or India, shipping just the crude peptide to the US, which is our traditional model or manufacturing on site in Shanghai, which is our simplified model.
12:32
And we looked at three different scales to have a little bit of comparison.
12:37
So we looked at 100 gramme final API scale, one kilogramme or 10 kilogrammes.
12:44
And then of course, we had to do some assumptions.
12:47
And this is where I say this is not something set in stone because some assumptions were needed.
12:54
So the scope of this study covers only amino acids used for synthesis.
12:59
We considered that all the amino acids originated from China, that raw materials are shipped all together as a single pack from China to the CDMO facility and that packaging is not included in the prediction and that we have a similar carbon footprint for shipping the final product to the customer.
13:23
So as I said, we started with 100 grammes, 1 kilogramme and 10 kilogrammes of final API.
13:31
And to do so as we consider Liraglutide at 20% yield, we started with 500 grammes, 5 kilogrammes and 50 kilogrammes at crude scale.
13:44
So Liraglutide is a 31 amino acid peptide, and we had to calculate how much of each protected amino acid and raw material was needed at each scale.
13:58
You can, you can see here that we did some calculations, we obtained the final total grammes needed in each case.
14:09
So and then we calculated what is the impact of moving these materials from China to the destination of the CDMO.
14:20
So let's start with the first set of findings.
14:28
So comparing regional solid phase peptide manufacturing of Liraglutide, you can see clearly from this graph, the first thing that catches your eye is that different scales have a different impact on the carbon footprint.
14:43
But this is not really surprising.
14:46
So we have a scale of 500 grammes, 5 kilogrammes and 50 kilogrammes.
14:52
And of course this has a different impact.
14:54
But what is more interesting is that we considered the different CDMO business model starting from in grey shipping amino acids and raw materials from China to Switzerland as a base for Europe and then shipping from China to California, US and shipping to Mumbai, India.
15:18
And then our traditional US release model and our simplified Shanghai release model.
15:26
And if we look at the 50 kilogramme crude scale just for ease of reading the graph, we can clearly see that there is a massive difference between the let's say more typical business models and our models.
15:43
So you can see that yes, it is true, we are shipping the crude peptide from China to the US, but the impact on the carbon footprint is much lower than shipping the bulk of amino acids.
15:59
But I think what was even more interesting and we wanted really to take this a step further was when we looked at coupling excesses.
16:11
So here what we thought was we are manufacturing Liraglutide at 1.5 fold excess, which is normal for Liraglutide.
16:23
But let's assume that we are manufacturing Liraglutide at threefold excess and this is already in the literature or if we face another peptide which needs higher excess to ensure that the coupling is driven to completion.
16:44
So we look at this graph here now and we clearly see that the different models of course have a different impact and that the higher the coupling excess, the higher the impact on the supply chain, transportation and the carbon footprint.
17:03
So we also have to say that as a CDMO in in many cases, we have to do re coupling or double coupling because we do in process testing.
17:16
And in some cases, if we see that the coupling has not been driven to completion, we have to re-couple or double-couple.
17:23
And this will have an impact again on the generation of CO2.
17:29
So the final bit was going a little bit further again.
17:35
And so we looked at yield and we looked at what is the impact of a higher yield, so having a better process in place.
17:45
And again we looked at Liraglutide of course and we compared the classical and standard 20% overall yield which requires then for a10 kilogramme final API, A50 kilogramme crude scale.
18:01
And we compared this to a 60% overall yield in the case in which we did some process development.
18:08
So we were so lucky and we have a very good process chemist, we achieved an overall yield of 60% which translates to a 16.7 kilogramme of crude scale.
18:22
And in this case, as you can see from this graph, so the grey bar is our standard 20% yield and the blue bar is the post process development result.
18:35
And you can clearly see that the impact on the carbon footprint has gone right down.
18:42
And I think this the most interesting part of this study because it really showed us that the process development is very important and not only does it help to save costs, but it also has a huge impact on the generation of CO2.
19:03
So by investing in process development, we can really achieve a reduction in carbon footprint.
19:13
So from this small study on the supply chain and transportation and on the effect on the generation of CO2, we really discovered that the region of the manufacturing site strongly influences the CO2 impacts, but also that the transportation at different stages.
19:35
So if we are transporting protected amino acids or if we are transporting the crude peptide is highly impactful.
19:44
But also we understood the importance of the process efficiency.
19:48
So if we need larger excesses for coupling, then this will translate in greater volumes of raw materials transported and so higher generation of CO2 if we have a higher yield.
20:04
Because we have invested in process development, then we can reduce the volumes of raw material transported and so we can reduce the generation of CO2.
20:14
So we can really say that investing in process development is worthy and it's worth it to save money and to reduce the CO2 generated by the process.
20:27
So some take home messages here.
20:30
There is an industry wide focus on chemistry and technology initiatives.
20:36
We at AmbioPharm are viewing this challenge as a real concern.
20:41
So our contribution is our partnership with CEM for microwave solid phase vetted synthesis, but also our solvent recycling initiatives.
20:52
And regarding supply chain and transportation, we can really say that transporting raw materials and intermediates generates lots of CO2 and that location of the facility versus the source of raw material has a large impact on the CO2 generation.
21:08
And finally, that efficiency of the manufacturing process is very important and has the potential to reduce CO2 generated from the raw material in the intermediate supply chain.
