Green Sustainable Chemistry: Better Solvents, Better Guidance

0:13 

I'd like to introduce you to today's discussion group leader for today, who is Alvaro Enriquez Garcia, who is an advisor of research at Eli Lilly. 

 
0:21 
And we are also joined by our two panellists, Wilfred Braje, who is a research fellow at AbbVie and Yi Yang, who is a principal scientist at Ferring Pharmaceuticals. 

 
0:30 
this session will begin with a short presentation from Alvaro and then we'll move on to a panel discussion. 

 
0:36 
you are welcome to use the chat function and pose any questions or comments you might have over the course of the session. 

 
0:42 
Some of you have submitted questions ahead of time during registration as well. 

 
0:45 
I’ll pass these on to our speakers, but please feel free to type any additional questions and comments or remarks you may have throughout the panel discussion because this will help our panellists keep this discussion going. 

 
0:55 
without further ado, I hope you all enjoyed the session, and I'd now like to hand over to Alvaro for his presentation. 

 
1:00 
thank you and over to Alvaro. 

 
1:04 
Hi, everyone. 

 
1:05 
Thank you so much for being here today. 

 
1:08 
I would like to talk about solvent sustainability in medicinal chemistry in early discovery. 

 
1:16 
this work is a work carried out by the Green Chemistry Institute Pharmaceutical Roundtable precisely the Med Chem sub team. 

 
1:26 
perhaps I should talk very briefly about this organisation so for whoever doesn't know very much, this is an American chemical society organisation is Green Chemistry Institute Pharmaceutical Roundtable. 

 
1:42 
As I said in there, as you can see, many of the big pharma companies, most of them are here contributing with funding and also with individuals who get together and are organised into all these sub teams. 

 
1:59 
And you can see here. 

 
2:00 
What we want to do is to come up with solutions and with strategies to improve the sustainability of our processes all the way from drug discovery all the way to all the phases and drug development until manufacture and ongoing research. 

 
2:19 
so this is what we do at the Roundtable, this is a company that has been growing very rapidly, in this group of companies, had been well from 2005 when it was born. 

 
2:35 
Now we count with 45 members in 2023, and we distribute ourselves into different groups. 

 
2:42 
And we try to improve the sustainability of all levels as you can see here. 

 
2:49 
I am leading the medicinal chemistry team. 

 
2:53 
At what we thought at this level it was to trying to improve solvent sustainability. 

 
3:00 
As you know, solvents are the substances and we use the most in our processes either for work ups, purifications, so we, think it's a very good start point to try to improve. 

 
3:15 
And move to solvents that are more benign. 

3:18 
As you can see here hexanes, dioxanes, dimethyl ethane, all these solvents here in the left are rated hazardous or highly hazardous. 

 
3:32 
And we use them very often in other processes. 

 
3:35 
just to introduce you very briefly, or what is a solvent selection guide? 

 
3:40 
You know, it’s a document where we brainstorm, and we try to give scores to every solvent and try to leverage or to evaluate their safety score, health score and environmental score. 

 
3:56 
then there is a discussion and a ranking after discussion and solvents line to three categories recommended, problematic, hazardous, or hardly hazardous. 

 
4:08 
from these solvents you could recognise, that there are a lot of them and that they are very common like chlorinated solvents, ethereal solvents, and polar protic. 

 
4:21 
Now we use them very often, and we shouldn't be doing so because they're hazard or highly hazardous. 

 
4:27 
in order to help this situation in order to improve, we thought to track metrics in the Journal of Medicinal Chemistry which is very representative of our activities at the Med Chem level, at the discovery level. There has been written a lot in process chemistry and scale up chemistry about solvent selection. 

 
4:48 
But really at the Med Chem level there are routes that are very long, that are the mobile synthesis that had not been optimised so solvent insulation was not must be not that good. 

 
5:01 
what can we do to improve it? 

 
5:03 
the idea here was to extract metrics from your analogue med chem on how solvent selection is conducted in reactions, work ups and purifications to structure metrics to see where we can help on solvent selection on where we are doing well, where we are doing bad and try to provide with some tips to help solvent action for medicinal chemists. 

 
5:33 
for reactions we first needed to identify which are the most common reactions just in medicinal chemistry. 

 
5:44 
This is something that appears to be some trivial you know, but we find it quite difficult. 

 
5:51 
We found this paper that already identified a lot of reactions that are very popular. 

 
5:59 
we adopt them, and we decide to look at solvent selection in all these reactions. 

 
6:07 
extracting metric, we obtain all these distributions of frequency. 

 
6:15 
These are the reactions that are more frequent in med chem is amide bone synthesis, heterocycle synthesis, and so on with all these entries. 

 
6:26 
we get the distributions of the frequency or the most recorded reactions in med chem. For each reaction class, we look at solvent selection. 

 
6:39 
Everything that you see here is for each reaction class, the percentage of solvents that are hazardous and highly hazardous that are used as solvents in those reactions. 

 
6:51 
There is not much time for discussion here, but you can see that there is room for improvement in most classes. 

 
6:58 
You know, there are reaction classes like for example, oxidation of an alcohol or sp2 halogenation when you use DCM or DMF like very broadly, and those are solvents that shouldn't be used. 

 
7:11 
Especially if there are other solvent selection choices. 

 
7:16 
From here we identify which are the reactions that are more recurrent in discovery and that at the same time don't have a such a nice solvent selection. 

 
7:28 
I mean they use solvents that are not benign. 

 
7:33 
We got extracting this data and reductive amination was the queen of unsustainability. 

 
7:41 
With 62,000 reactions run in unsustainable solvents then amine bond formation, BOC cleavage and so on. 

 
7:52 
We thought to make this nice poster with all this reaction categories to introduce the basic information that every chemist needs to launch a reaction. Like for example, reductive amination by using BF3, CO3 equivalents, formic acid, 2 equivalents, acetonitrile 05 molar 85°. 

 
8:16 
You don't need to know anything else but all these conditions and reagents for all these reactions that are very popular in journalism. 

 
8:24 
They use benign solvent so every time you want to improve your solvent selection of the reaction mixture, you can always look at this poster, and instruct information very quickly. 

 
8:37 
You know, we know medicinal chemists are very don't have much time to look up in chemistry deeply and nation. 

 
8:46 
We did this stapling our science. 

 
8:48 
we want to make things easy in the lab. 

 
8:51 
then we look at solvent selection in Word caps and purifications. 

 
8:58 
We took eighty articles from 2000 and 2020 and we just look at the AT8080 study Mentos where they were described solving usage in worker amplifications. 

 
9:14 
What you can see here is that for purification method most of them, they're realigning chromatographies. 

 
9:22 
I mean like more than 65% very unfortunately because it's a very unsustainable wave of purifying compounds. 

 
9:31 
They rely on chromatography if not HPLC and in very few more than only 11% we got telescoping techniques. 

 
9:41 
Now when you look at this insolvent choice in solvent support, modifications in chromatographies, most of the time ethyl acetate is the one that is being used together with exane. 

 
9:59 
ethyl acetate is fine. 

 
10:01 
It's a very benign solvent, but as you know, exane is hazardous is neurotoxic so there are other we recommend to use other solvents like heptane or cyclohexane for this purpose, which is more benign and is less hazardous OK for you. 

 
10:19 
Also, TCM and methanol is very the use is very expensive and we live with it. 

 
10:25 
We believe that the reason why is because solvents are scaffolds are very unsoluble so that's why people use these mixtures in order to improve solubility and be able to purify by some support chromatography. 

 
10:40 
concerning work apps and we always saw that ether acetate is very common. 

 
10:47 
It's the most common solvents. 

 
10:48 
That's good news. 

 
10:49 
But dichloromethane and chloroform even or even dieselester, which is very flammable are very popular choices as well. 

 
10:58 
that in the papers and the manuscript and we're writing, we are including some tips in order to get around this. 

 
11:09 
We also include some tables, what you can see your solvents and you want to replace. 

 
11:17 
This is like a polar approtic type of table. 

 
11:20 
You know which this is organised and range of polarity and you can see which solvents are hazardous in here, which has the DMF you know, and missile parallel leading on and etcetera and all the other solvents that you can replace with you have a lot of data that is very familiar to you like silo P like a boiling point, melting point flashpoint and so on enhancing solubility parameters. 

 
11:50 
you can make a solvent choice very easily. 

 
11:54 
But in here there are only included the solvents that are recommended or problematic. 

 
11:58 
so only the good solvents are offered in here. 

 
12:03 
you can just look at the data and choose a solvent and it will always be benign because we didn't include a harmful solvents in here. 

 
12:12 
 

 
12:14 
Moreover, we advertise this tool, which is a pretty quick tool is free of charge. 

 
12:21 
You can use it anytime in the Green Chemistry Institute Pharmaceutical Roundtable web page and it's a fantastic solvent selection tool. 

 
12:30 
You could combine properties of 243 solvents. 

 
12:35 
You can plot by principal component analysis or by physical properties. 

 
12:41 
that will help you can philtre off by health and safety and environmental scores and this will help you very easily to find a solvent of choice. 

 
12:57 
 

 
12:59 
Moreover, Paul Richardson from Pfizer also included the section in this manuscript where we talk of the past properties of solvents. 

 
13:10 
You know, the solvents that are hazardous, why the solvents are hazardous, which are disposal limits and which are the concerns for these materials. 

 
13:21 
 

 
13:22 
And to conclude, we'll write some words on automation and miniaturisation. 

 
13:26 
Since miniaturisation and automation always help solving selection, solving choice, and also reduce the amount of solvent per experiment. 

 
13:37 
you can very quickly find the optimal conditions for your process. 

 
13:41 
And this is always moving to improve the sustainability of our reactions. 

 
13:48 
And to conclude this acknowledgements to the groups that are leading with everyone including here that has been contributing to this work on solvent selection and are part of the meth cancer team. 

 
14:02 
And thank you so much for your attention and you have any questions I would be happy to answer. 

 
14:18 
Sorry, muted. 

 
14:19 
Thank you very much, Alvaro for your presentation. 

 
14:21 
If you do have any questions directly for Alvaro, please feel free to type them into the chat. 

 
14:25 
There might be a bit of a short delay on this. 

 
14:27 
perhaps we could begin just sort of hosting the panel discussion now when obviously Ben Ebony do come specifically for Alvaro, you can come to those. 

 
14:34 
Otherwise we could perhaps move on to the broader questions that people submitted beforehand that works for you guys. 

 
14:39 
what I'll do is again, I typed, so I'd like to begin sort of it will introduce the power discussion element of the session now. 

 
14:48 
perhaps Alvaro, you'd like to maybe give yourself a broad introduction, but then Wilfred as well and you and then obviously then you guys can tackle on the questions. 

 
14:55 
But I submitted beforehand if that works for you guys. 

 
14:58 
perhaps we could start with Alvaro with a short introduction. 

 
15:01 
Sure. 

 
15:02 
this is a further on a panel discussion on solving selection. 

 
15:06 
Mostly I am leading this parallel discussion. 

 
15:13 
I am from Eli Lilly. 

 
15:14 
I'm mainly a regional chemist with some expertise in the scale up chemistry. 

 
15:19 
But I am not a process chemist, and I passed the word to welfare. 

 
15:29 
Yeah. 

 
15:29 
Good afternoon, Vivlipaya. 

 
15:31 
I'm a director of medicinal chemistry at ABV Ludwigsenafen in Germany. 

 
15:36 
I also have the pleasure to represent ABV at the ACS Farmer Roundtable. 

 
15:41 
I'm involved in the chemistry and water team as well as in the grants team. 

 
15:45 
I also have the pleasure to represent ABV in the European consortia that's just being formed. 

 
15:50 
we just submitted the proposal to the EU. 

 
15:52 
It's called Farm Eco, which is part of an IHI consortia though basically what we have learned from the US side and the American Chemical Society that it makes absolutely sense to work pre competitively together because we face universal problems. 

 
16:09 
Much looking forward to the panel discussion here. 

 
16:14 
Thank you, Will Gee, Hi, thank you. 

 
16:18 
This is E I'm working in Faring Pharmaceuticals in Denmark, Copenhagen. 

 
16:23 
I'm made responsible for peptide GMP manufacturing process development, process optimizations. 

 
16:28 
we have tried to initiate some process optimizations in terms of the sustainability and our peptide APM manufacturing. 

 
16:37 
when I'm not heavily involved in the regulatory involvements or this kind of things, but we're doing some process from the industry perspective to make the our process more sustainable. 

 
16:51 
Yeah. 

 
16:52 
All right. 

 
16:54 
Thank you very much, Jay. 

 
16:56 
if you like we could start dealing with all the questions that the audience posed. 

 
17:02 
 

 
17:03 
The first one would be what are metrics or key performance indicators should be analysed in suppliers due diligence programme. 

 
17:13 
 

 
17:15 
this is perhaps a question for G Yeah, it's actually I think PMI is one of the, yeah, most famous indexes. 

 
17:26 
And actually, as you introduce, we also try to consider the unhazard contribution for the PMI. 

 
17:34 
But if you decrease PMI by something not that detrimental, of course it's good, but it's not essential. 

 
17:43 
Would like to also measure the hazardous PMI contributions like TFA for examples, because we know that PFAS is also a issues of the European and yeah, the reach. 

 
17:56 
we also take that one into account. 

 
18:00 
Yeah, I think that's of course the type of the solvents and it's a category also matters. 

 
18:09 
Maybe to add on to me it's really I think that's where we need this consortia because we need to align on how we measure things. 

 
18:17 
To me it's something that still is ongoing. 

 
18:20 
We have different metrics is the PMI gal, you name it. 

 
18:24 
And I think every company at this point is more or less using their own metrics is and that's why I think it's important to work pre competitively that we align how across the industry we measure. 

 
18:37 
And I think that's ongoing. 

 
18:38 
And that's where I guess we will learn more about the outcome of the alignment in the industry to better understand how we measure greenness. 

 
18:49 
Because one other layer is also about when do we start measuring because often times we work with third parties. 

 
18:56 
And of course it can be tempting to buy your goods from other companies where you don't have the oversight over their metrics is how they do with the greenness and start in processes. 

 
19:10 
I think it's that's why it's a global problem. 

 
19:12 
That's why we need to solve this as a community. 

 
19:17 
Thank you, Will yes. 

 
19:19 
And I believe that the pharmaceutical Roundtable is the perfect scenario to meet all companies know and discuss these matters and get into an agreement, make the appropriate contacts know because it is true that you cannot improve what you cannot measure. 

 
19:36 
No. 

 
19:36 
And if everyone has a different Jarstick to measure their processes, then it's difficult to compare apples with apples. 

 
19:46 
No, let's call it like that. 

 
19:47 
it's one of the problems that this industry is facing when you want to improve on this field, on this space. 

 
19:57 
All right. 

 
19:58 
Thank you so much. 

 
20:01 
Second question, I don't know if I understand plainlist greener alternatives in the industry, both raw materials but also processes. 

 
20:11 
Maybe I can jump in just with the processes because I think that's a really important topic. 

 
20:18 
Which are the key technologies of the future? 

 
20:21 
For example, in the newly formed Farm Eco Consort that we will be investigating biocatalysis, electrochemistry, photo redox chemistry and water and also mechano chemistry. 

 
20:32 
And to us in this consortia, these are the key technologies of the future. 

 
20:38 
And of course, we have to make sure that what works on the lab scale can also ultimately be translated on scale. 

 
20:45 
For example, if you think about mechano chemistry, currently we do most of the mechano chemistry in batches. 

 
20:51 
But of course, eventually if we want to move something into manufacturing, we need to enable flow chemistry in forward state and that is reactive extrusion. 

 
21:00 
It's just an example where we have to fill the gaps and see what these new promising technologies, how they eventually play out when we go and think about larger scale and especially when we think about GMP or GLP manufacturing. 

 
21:17 
Absolutely, Yeah. 

 
21:19 
To supplement at fairing. 

 
21:21 
What we're doing is actually it's not so radical. 

 
21:23 
We're not totally the revolutionise the technologies, but we're doing something incremental. 

 
21:30 
For example, we have sometimes face a very big batch of manufacturing, which can cause a trouble for the productivity. 

 
21:38 
We have to produce a lot of batches per year. 

 
21:41 
that can also bring some troubles to the grain chemistry and sustainability. 

 
21:46 
And what have been doing at fairing is that we try to see what's the root causes of the low productivity. 

 
21:53 
If you can increase the productivity, it can also be greener. 

 
21:57 
It's not totally brand new of the organic solvent, but still, if you can produce the amount of the API in fewer batches, using fewer solvents and so on, you can also be greener and more sustainability. 

 
22:13 
And what have been doing here is that we try to produce the peptide without sitechain protecting groups because that can the sitechain protecting groups can bring a lot of the issues of the TFA consumptions have used a lot of solvents and even greater volume of anti solvents to precipitate peptide. 

 
22:30 
if you can assemble the peptide on the resin without sitechain protecting groups and then you can easily detach them from the CTC rising or silver rising with lower amount of TFA and then you can get your products without having to use a lot of the anti solvent and TFA. 

 
22:47 
we have A to some sometime success to introduce the site and unprotected arginine site and unprotected kerosene and so forth. 

 
22:58 
I think arginine introduction is very important because the PBF protecting groups is one of the most stubborn protecting groups to removed. 

 
23:05 
if you can manage to introduce the arginine without PPEF, then you could easily maybe detach a peptide without using high concentrated TFA. 

 
23:16 
that's what we're doing at fairing to see whether the methodologies can be extrapolated to more peptide API. 

 
23:25 
this is the I would say it's the incremental methodology. 

 
23:30 
And I think that if I can add on to this, it's very important that we take our management along the path of change because I think an excellent incentive is lowering the waste that's being created because that always equals to lower costs. 

 
23:47 
I think that's it. 

 
23:48 
It's an excellent driver for the whole field and also to get everybody involved. 

 
23:53 
It's a win for the society. 

 
23:55 
It's safer, it's good for the metrics, it's for every metrics. 

 
23:58 
It's producing lower amounts of waste. 

 
24:01 
I think that's it can be incremental changes also like minimising. 

 
24:06 
That's also a topic the precious metal replacements or using less because we all know that Palladium reactions accord to pharma, but also we also noticed that the prices for Palladium are going up. 

 
24:21 
even if we can lower the amount of catalysts, that's another, it's a, it's not rocket science and it's not something that will change the industry manually, but it still has significant benefits because also you'll have less Palladium than or contamination of the metal in your products. 

 
24:40 
there are several wins always when you reduce the amount of what is needed, either it being the waste that's being created or the amount of capitalist or the amount of reagents that you need to use. 

 
24:53 
Ideally you only use stoichiometric amounts, the absolute minimum. 

 
24:58 
That's what's needed for the reaction. 

 
25:00 
Yes. 

 
25:01 
And I think you made a very good point because in order to move things forward, we need to have the, our management on board and they need to be convinced, you know. 

 
25:12 
I always, I think the money is a good excuse because sustainability of reducing amounts of reducing waste, reducing amount of catalyst, it always translates into savings. 

 
25:23 
And this is a driver,  

 
25:25 
And then another thing that I would like to add is that I like to look at sustainability at like health, safety and environment, because sometimes, oh, Greek chemistry, we're going to save the planet. 

 
25:36 
No, it's not only that is health, safety and environment. 

 
25:41 
 

 
25:42 
Of course environment is very important, but there are other two pilots that are very key that are safety. 

 
25:47 
You don't want to have an accident, of course and not even in process chemistry. 

 
25:54 
That would be more disastrous to have an accident there that will help people or cast cost issues. 

 
26:01 
that is what the green chemistry is all about as well, not only environment. 

 
26:08 
it's a because it's a good, let's call it, that's a good excuse to justify efforts. 

 
26:19 
And I think it's something that we sometimes need to convince upper management of this and it's a good strategy. 

 
26:28 
Thank you. 

 
26:30 
Yeah, it's also goes beyond actually I think they also involving the FDA because whatever we in manufacturing if we change the processes that also needs to be approved by the FDA. 

 
26:39 
I think that's also part of the ACS from our own table that we work with the agencies, also with the politics and also with the funding. 

 
26:48 
Because I think that all needs to be reflected that we move the field forward because if we don't have the regulation complementing what we are doing, then we are not In Sync and then it will take much longer to get the new processes implemented. 

 
27:05 
I think that's why it's very important as Alvaro was saying, not to focus only on greenness, but there are many other aspects, including politics and society, because of course it's very important also that we make the manufacturing less prone to accidents. 

 
27:23 
Oh yeah, absolutely very important. 

 
27:30 
All right, thank you guys. 

 
27:32 
Any, anything else in this question now. 

 
27:35 
let's jump to the next one. 

 
27:37 
All right, What progress has been made with water based chemical peptide synthesis? 

 
27:43 
Yeah, that's maybe I can start here because I actually presented in 2017 at the pharma wrong table because I initially worked with Bruce Lipschitz who to me is the hero about changing the mindset what you what kind of chemistry can do in what exactly in myself. 

 
28:01 
what really I thought was interesting when I saw the publication from Bruce Lipschitz about doing a negation reaction in water because that was so counter intuitive to everything that I learned in My Chemical. 

 
28:13 
And so we followed up on that and that's what we also found a sub team in the pharma round table and we have been investigating for the past seven years this methodology. 

 
28:23 
We also published a paper in OPR D very recently where we, with six companies, we investigated the different procedures, including the MI coupling to actually show the field that we can reproduce what is published. 

 
28:38 
I think that's another important field is that the new technologies are robust because that if you try something new and you fail, that's the best recipe for people not trying this technology again. 

 
28:50 
that's why what's driving me is to make these new technologies robust. 

 
28:55 
But coming back to the point of peptide chemistry, Novartis has done a great deal of showing data the advantages of doing amide and peptide couplings in particular in water. 

 
29:06 
Many on the matrixes you have disadvantages that you produce less waste. 

 
29:13 
But also what's I think is really important is about the purification and also that for some amino acids, you have the problem that they start to rasomize and that can also be minimised when you try these reactions in water. 

 
29:26 
I think that's it's a great field. 

 
29:28 
It's moving forward. 

 
29:29 
And in the European consortia, we'll be working with Oliver Cup and we're currently working on getting these micelles and also these polymers that are supporting the solubilizing properties to get that into flow because that's another important area. 

 
29:46 
I think that for a scale up that we enable the chemistry in water to be done in flow. 

 
29:55 
there's more to come. 

 
29:57 
Watch out for the new publications. 

 
29:58 
I think that's probably the best. 

 
30:02 
It is very exciting. 

 
30:04 
Thank you and very important development as well. 

 
30:09 
All right, thank you so much Wilfred. 

 
30:11 
This a coupling aspect of the team here. 

 
30:18 
He did with the question. 

 
30:19 
Thank you very much. 

 
30:21 
He can also offer his perspective since he work in the Tides field, right? 

 
30:26 
Yeah, No, I don't have a lot of experience as well, but I think I learned some of the innovations like the cell phone F mark and so forth. 

 
30:35 
I believe that the usage of the for the face thing that says we'll need a synchronical change is not only the rustling, but also the protecting groups and coupling rate and so forth. 

 
30:49 
everything has to come together to promote this technology in the future. 

 
30:53 
Yeah, thank you. 

 
30:57 
Yup. 

 
30:58 
All right, let's jump to the next question. 

 
31:00 
What are the technical and regulatory barriers to solving recycling for ties and how can we overcome this? 

 
31:17 
Actually, I don't have a lot of experience of the recycle store because we're always using the, yeah, the original DMF and so forth. 

 
31:29 
actually, I know there's a lot of improvements and progressing on that fuse and a lot of the DMF can be recycled. 

 
31:37 
Maybe also the acetone nitrol. 

 
31:39 
What actually concerns me is of the invisible things, because you know, there's a lot of things in the DMF solutions and a lot of the reactions are invisible and this is not that predictable. 

 
31:52 
if something of course you can predict like the formaldehyde, acetaldehyde, diamethyl domain and so forth, but some are not so recycled DMF for examples, you should have a very robust engage to ensure the quality of the recycle DMF to make sure that EU process is robust and consistent. 

 
32:19 
but I just expressed my concern. 

 
32:24 
But of course, I think this can be used for example, rising rinsing faces. 

 
32:31 
And maybe this is more practical than using it what it as the solvent for the coupling, for example, right. 

 
32:39 
But otherwise, I don't have a lot of experience on the recycled DMR and so forth. 

 
32:48 
Yeah, me neither. 

 
32:49 
But what we try for the amide and peptide companies, for example, is that we try to crash out at the end of the reaction when we do these reactions in water, when we just add a little more water. 

 
32:59 
And then depending on the properties of your product, but mostly in our cases, it crashes out and then we don't need any organic serving for the extraction process. 

 
33:09 
And in most cases, the products are very clean. 

 
33:13 
That's another advantage of the chemistry in water. 

 
33:15 
If it works, usually the MI couplings that we did are done in less than a minute I would say. 

 
33:23 
it's really surprising how fast these reactions are. 

 
33:26 
But if you think about how nature is doing chemistry, it's probably not a surprise how efficient and how fast these reactions are because if you in our bodies, we do chemistry in water. 

 
33:37 
that to me is the biggest inspiration. 

 
33:39 
Also, nature is doing in all the plants. 

 
33:42 
Most of the plants consist also the majority of the weight is reflected by its water content. 

 
33:48 
it just I think it's proof concept to me that the chemistry that has been optimised by nature has been done for billions of years. 

 
33:56 
It's very efficient and there's almost no waste created. 

 
34:00 
That should be a source of inspiration how we should do our chemistry in the lab, hopefully in the future. 

 
34:06 
Absolutely. 

 
34:07 
I concerning solvent recycling and water and reactions in water. 

 
34:12 
I think Novartis was developing a process for cleaning up water, but I think that water came from a cleaning UPS reactors. 

 
34:23 
I believe I correct me if I'm wrong and they developed a process that could really clean water and then sent to certain levels that were, was easier to dispose or easier didn't need to be burn. 

 
34:40 
So, and burning water is an issue I mean taking water from 0° to 100°, it takes 100 calories per millilitre but then when you evaporate that from 100 millilitres to vapour, it takes a huge amount. 

 
35:02 
It like takes like twice the amount of heat that it took to go to front zero to 100, you know. 

 
35:08 
So you don't want to be evaporating water because you will have to spend a lot of energy and that of course, it's a footprint that is highly undesirable. 

 
35:18 
So, but there are more strategies and we will also more publish on it. 

 
35:22 
We have, I think another layer is also how you can use membranes, I think to avoid exactly like getting water off a reaction. 

 
35:30 
I think there are many new strategies how you can clean up wastewater. 

 
35:36 
I think that's another important, I think area for the field is how we can be more efficient if there are better in more simple ways and more robust ways how we can clean up wastewater. 

 
35:47 
Because as you were saying, Alvaro, the worst case scenario is that you have to burn or that you have to dispose contaminated water. 

 
35:54 
That's the most costly and painful part of such an equation. 

 
36:01 
Yeah, exactly. 

 
36:01 
exactly. 

 
36:03 
You don't. 

 
36:03 
You do that when you cannot do anything else. 

 
36:06 
No. 

 
36:07 
Right. 

 
36:07 
And of course, dump it in the river is not an option. 

 
36:09 
you need to burn it, of course. 

 
36:11 
All right. 

 
36:12 
what are the technical OK? 

 
36:18 
Which is considered the most environmentally friendly verification method and why? 

 
36:23 
That's an easy one. 

 
36:26 
anyone. 

 
36:31 
when we have the really big manufacturing and if the candidates looks appropriate, which we firstly try crystallizations of the peptide, it works for some saccade peptide and this is very good technology for scaling up and have a yeah, environmentally friendly purifications. 

 
36:52 
But of course, most of the peptide cannot be crystallised. 

 
36:56 
But we have some experience, we have some successful experience of crystallising cyclic peptide, mostly rigid peptide get from organic solvents and that's very, I would say are cost friendly and also very big productivity. 

 
37:14 
Yeah, this is my recommendations, my experience. 

 
37:19 
It's just a question. 

 
37:20 
Are peptides often oils or liquids or not or they can be isolated as a solid form. 

 
37:29 
so that yeah, solid form it crystallise out of the organic solvents. 

 
37:34 
Of course we have to do a lot of screening of the pure API in different organic solvent to the screen, the solubility and then you have a different strategies to crystallise and we have one successful or two successful cases of crystallising the peptides products API. 

 
37:50 
Yeah, of course. 

 
37:51 
That's the great power of crystallisation or I mean we have on mind this crystallisation. 

 
37:58 
Do they sell everything? 

 
38:00 
You philtre it, then you crystallise, then you philtre again. 

 
38:04 
But really industry it's not really like that. 

 
38:07 
You often 3 to rate the compound. 

 
38:09 
Not everything goes in solution, but you skin an array of solvents and you are able to find one that will clean up your brother. 

 
38:17 
Your brother often stays crystalline. 

 
38:21 
It crystallises into some crystalline form during the process and then impurities remain, in the modern liquors. 

 
38:30 
You can easily philtre task fantastic way of and it's under used in discovery in process chemistry. 

 
38:37 
You have to do that. 

 
38:38 
You cannot do a column of a tunnel product but chromatography. 

 
38:42 
But it's really convenient and we always try to encourage we were thinking in the roundtable even to develop something, some type of a tool to predict the solubility of compounds. 

 
38:53 
You know, that would be fantastic. 

 
38:54 
So you could predict a few 510 solvents where your company is going to be insoluble and try those in a small scale. 

 
39:05 
I have done that 100 mils 100 microliters or 200 microliters with 20 milligrammes of compound to a small situation and then find out very quickly how you can purify your product. 

 
39:17 
Not many people do this and they realise mostly in chromatography which is of course an standard in our discovery side. 

 
39:25 
When he says first in mobile synthesis but the synthesis and you guys work on it's been they've been there for a long time so you the compound that you need to do we do 3800 compounds so it's just a different scenario. 

 
39:42 
It's always very convenient. 

 
39:44 
Yeah. 

 
39:44 
And the good thing is that if you look at the FDA approved Teptide products in these two years, a lot of them are actually cyclic peptide and they can't have some rigid rigidity and maybe appropriate for the crystallisation technology. 

 
40:01 
Of course you have the GLP one, this is forget about that, but they have the bicosporine and this kind of things, cyclic peptide rigid. 

 
40:11 
I think the chance, the probability of the crystallisation can be higher than the flexible linear peptide, right? 

 
40:20 
But people of course, they have inertia that go directly thinking of using HPLC because it's not nice and easy and for most of the PET projects relatively smaller than those small molecules and they don't see the benefits. 

 
40:33 
they just go for HPLC. 

 
40:35 
But if you have a really gigantic projects and crystallisation can contribute a lot of the cost reductions. 

 
40:43 
Absolutely. 

 
40:44 
But it's also a matter of I think cultural change and training. 

 
40:47 
we had actually training courses on using crystallisation as a tool for purifying even in Med chem. 

 
40:56 
And I think that's another layer is that we enable also the early new and next generation of chemist about the principles of sustainability and about learning these technologies. 

 
41:10 
Because what I learned is that at university levels, most of the upbringing is also that you use an HPLC or that you use column chromatography, but that it's required also. 

 
41:23 
It's a skill in the end. 

 
41:24 
And as Alan was saying, it would be great if we have tools for prediction that again would really be helping the field. 

 
41:32 
But I think it's also, it needs to be in the mindset of chemists to even try this as an option. 

 
41:40 
Yeah, absolutely. 

 
41:43 
Even in some process routes have been described with a protecting group or with something that you place like a nut tile side chain or something that will provide with cristianality, let's call it like that for many intermediates. 

 
41:59 
that would ease the purification and then you clear it off at the end. 

 
42:03 
It's a synthesis of something that has been that strategy has been pursued for compounds or synthesis and return oils, which is not very common in pharma. 

 
42:12 
No, it took me a while to change the chip when I was coming from academia because CLP of compounds have very high in academia but really in general, but the compounds in pharma are very insoluble. 

 
42:29 
that's why you take advantage of three iterations. 

 
42:33 
And sometimes this is very difficult for chromatography. 

 
42:36 
I cannot chromatography sometimes this is a problem. 

 
42:41 
But anyway, this is another plan. 

 
42:43 
 

 
42:44 
Anything else? 

 
42:48 
What are the current DMF restrictions in Europe and what are the future solvents at risk? 

 
42:58 
Yeah, unfortunately, we don't have Barry Dillon here from Pfizer. 

 
43:01 
He's leading the Pharma Roundtable, this issue about solvents at risk and I think it's a moving field in Europe at risk definitely our NMP, dimethyl acetamide and DMF. 

 
43:16 
These are the three solvents, the polar aprotic solvents that are very popular for peptide and MI couplings. 

 
43:24 
I think they are at greatest risk, but I think there are negotiations ongoing with the regulators if there are no alternatives to these solvents for certain processes that needs to be balanced also by the regulators because we provide life saving drugs. 

 
43:42 
And if we if there's no other way for producing these drugs then at least for the time being that should still be recognised that we need the solvents at this point. 

 
43:52 
But I think longer term that definitely we should try to avoid because of our was showing nice very nicely about how unfavourable these three solvents are from safety and other metrics is. 

 
44:06 
I think also the industry, it's not that we need the regulators to change. 

 
44:12 
I think we also recognise the need for change. 

 
44:14 
But of course we need to find a balance by still being able to produce the drugs that are important for our patients. 

 
44:23 
Yeah. 

 
44:23 
And we know that the MF is actually the European Commission has already published some I don't know what is ACT or something to minimising the DMF use it from the December of the last year. 

 
44:36 
Actually, yes, one second I think yeah, I think DMF replacement can be relatively easily found. 

 
44:44 
We would know that it's love of green solvents can replace DMF like a DMSOF acetate is very famous. 

 
44:51 
The drawback, the problems related to that is actually maybe it's increasing cost because you have to use a more expensive solvent sometimes which is not very supply chain is this can be questionable and sometimes you have to use more equivalent because by default we're using 1.5 equivalent in our GMP manufacturing. 

 
45:12 
I would try DMSOF acetate and some residues. 

 
45:16 
You cannot incorporate them with 1.5. 

 
45:19 
We have increased them to two or three. 

 
45:22 
Of course this can increase the cost, but I don't think it's a killer. 

 
45:25 
we can still survive and expect especially pharmaceuticals because the cost of the API is only a very small portion of the list price of the drugs. 

 
45:38 
We know that the SO4 year the GOP is a semaglutite. 

 
45:42 
It's only less than 5 five U.S. 

 
45:45 
dollars for the monthly it's reported. 

 
45:47 
It's not my rumour it's $5 cost. 

 
45:50 
it can be less problematic for increasing lipid cost of the API manufacturing. 

 
45:55 
But if the regulatory say ban on TFA, for example, the PFAS, I would say it's a very big challenge for peptide industry because TFA is almost indispensable. 

 
46:08 
You have to use CFA to remove, to cleave and remove. 

 
46:11 
And it can be that the TFA can be banned from 2027 in Europe 27 I heard about that as a reach discussion and so forth. 

 
46:24 
if TFA is banned in Europe, that's going to be a really big challenge for peptide industry. 

 
46:35 
we have to find alternative to TFA and that's not a lot. 

 
46:39 
but we're doing something to see whether we can get rid of TFA for the peptide API manufacturing. 

 
46:45 
But I see personally as a big challenge, it's even bigger challenge than DMF. 

 
46:51 
I think there are a lot of the peers are also working on that to find replacement for TFA, to have the TFA free peptide synthesis. 

 
47:01 
But it's not easy. 

 
47:03 
We have 4 years, three years, Yeah, three years. 

 
47:06 
Yeah. 

 
47:06 
Someone has to take the initiation. 

 
47:08 
I think it's also a hot topic nowadays, become training to see whether TFA can be replaced. 

 
47:16 
Yeah. 

 
47:17 
It's a it's tricky. 

 
47:19 
It's a threat. 

 
47:19 
It's a threat for it's a threat for peptide industry. 

 
47:24 
There is not any other carboxylic acid that has APK -1 or so like TFA. 

 
47:30 
No, Yeah, no, not so many that same contain 2 fluorines in alpha which is, I think this is the best thing for environment. 

 
47:41 
Well, yeah. 

 
47:42 
It's not only TFA, but also the PFAS. 

 
47:45 
It's a big threat not only for the peptide industry, but also for others like Teflon manufacturer and so forth. 

 
47:53 
it's absolutely, but it's coming is separate section that there are other efforts like the premier effort where we are well most of the pharmaceuticals, the API itself, it is consumed and then that is created and everything goes to the river, what I mean. 

 
48:11 
it's a lot of mass of pharmaceuticals and that has been monitored as well. 

 
48:17 
And fluorinated pharmaceuticals, especially methylene F2 with 262 ends, that's really bad It and it perceives like really well in the environment. 

 
48:32 
And it's, is it's not a good thing but it is true that as Wilfred was saying that you need to deliver a key pharmaceuticals to patients. 

 
48:44 
You know, sometimes you need to leverage what is, which are the cost of cleaning money of cleaning those waters or get or disposing that. 

 
48:56 
And then the costs of hospitalisation of people that are not receiving those medicines as well are very high and have an impact or I cannot use the MF, but I have to use five equivalents of my often of these coupling peptides or whatever and then things become even more sustainable. 

 
49:14 
But my question is concerning the MF, which are really the restrictions. 

 
49:20 
I mean, I can buy the MF, I use the MF,  

 
49:25 
And this has been restricted since December. 

 
49:27 
And what I read in the rich statement, which is very short and very simple, I guess that is a lot more than that. 

 
49:36 
You cannot manufacture the MF for synthesis or for producers. 

 
49:42 
You're going to produce  

 
49:43 
you cannot use it, you cannot buy it. 

 
49:46 
But is that really true? 

 
49:48 
I mean, can you still justify, I cannot produce anyway my peptide. 

 
49:53 
I need to do this. 

 
49:55 
We are not delivering this pharmaceutical that is needed or the other option is 10 times worse. 

 
50:02 
Can you still justify in your the use of DMF or no? 

 
50:08 
It's completely forbidden in to be used in process chemistry because I didn't understand very well the rule. 

 
50:15 
It is banned. 

 
50:16 
It cannot be produced, but I can still buy it and use it. 

 
50:21 
I used the MF yesterday Yeah, I don't feel it. 

 
50:25 
I don't feel the restriction, but I just read it that it has been valid since last September, December. 

 
50:32 
So. 

 
50:33 
But yeah, I don't know how it's going to be evolved to be really affected or under which circumstances. 

 
50:42 
Well, I guess that is the driver for reducing a lot the amount of BMF in especially manufacturing processes or I mean and for the products has already sorry, I'm sorry to look for alternatives. 

 
50:57 
I think that is the task for the future, to look for alternatives. 

 
51:02 
I mean, something what I found for example, really interesting is like fluorination methods, because that's also something that's very difficult because as was saying, most of the pharmaceutical drugs contain some sort of fluorine. 

 
51:16 
we have to think about how we can be more sustainable when we do this fluorination reactions. 

 
51:21 
And I think one example that I thought was really cool was because it's involving a new technology, mechano chemistry. 

 
51:29 
When you use calcium fluoride, which is something that's earth abundant, it's non-toxic, it's very stable. 

 
51:37 
But using mechano chemistry, you can use it for fluorination reactions. 

 
51:40 
And I think that's why it's so important that we as an industry also collaborate very closely with academic partners because I think this is a very fruitful future for the whole field if we collaborate on these important questions. 

 
51:56 
I think important is and like in the pharma on table, we give out grants to certain research group that come up with cool ideas how to tackle a really difficult problem. 

 
52:05 
I'm also involved in this ignition grants as part of the grants team. 

 
52:10 
there we give 4 high. 

 
52:14 
Yeah, really highly innovative approaches money. 

 
52:20 
Otherwise you will not get any other funding money. 

 
52:23 
we give it's called an ignition grant. 

 
52:25 
If something comes out, you can look for another source to fund your research. 

 
52:30 
But if nothing comes out because it's a high risk area but high reward, then that's also fine. 

 
52:36 
So, but I think we need to work on these important topics as a community, industry and academia. 

 
52:43 
Sure, absolutely. 

 
52:46 
you guys think that dymethylacetamide and MP are going to suffer the same fate in the following years because DMF where you can use just DMF or could use dymethylacetamide or an MP or DMSODMSO is fine under the perspective of environment. 

 
53:07 
There are many perspectives. 

 
53:08 
The only issue is hazard reactions. 

 
53:12 
You know, it's reacts with bases violently at high temperatures and you have to monitor that. 

 
53:19 
But those are a few reactions. 

 
53:20 
I would say that's minor concern. 

 
53:24 
You just have to assess the safety of your process in that solvent but for the other words, and I believe there are a lot of replacements. 

 
53:34 
I mean, we have been really doing a good job on the scientific community. 

 
53:40 
Think about 20 years ago when we started studying chemistry, how we were doing chemistry. 

 
53:46 
I just heard about that. 

 
53:47 
And then we don't have photochemistry, we don't have those disconnections. 

 
53:54 
Synthetic Ralphs Burma lengthy and everything was less efficient and less sustainable by I would say probably no. 

 
54:06 
And so but we our activities increase by an order of magnitude too. 

 
54:10 
you need to balance that very easily. 

 
54:16 
All right, in last question and we have 5 minutes. 

 
54:19 
we are doing very well on time and in light of significant investments and time consuming studies, what changes are a must and what changes are nice to have in chemistry? 

 
54:35 
Chemistry, I guess no service selection or process chemistry. 

 
54:39 
That's a difficult one Actually that's a difficult question. 

 
54:56 
If we would know, we would do, but I think as I said before on that direction, then we are pulling research. 

 
55:07 
You know, it's solvent selection I think is critical because it's what we use the most and you know, volumes and we use process much intensity. 

 
55:17 
I think we are doing that. 

 
55:19 
I think communication is key and This is why these organisations are like the Roundtable and the American Chemical Society are very important so we can all together find solutions and get homogeneous and concerns serve knowledge and that. 

 
55:39 
And also I think it's very important all the great development on synthetic methods that we are witnessing and especially in the area of photochemistry or photo radios, bio biocatalysis. 

 
55:53 
I think electrochemistry is more difficult to translate into process because it's difficult to scale up. 

 
56:04 
let's put it like that, then let's throw the surface and that I only run two or three reactions in my life, but I believe that is going to be very difficult to scale up as well. 

 
56:14 
And I would say those are some of the most areas of interest for in the chemistry, in development, in green chemistry. 

 
56:28 
You know, to, I mean, to me since 60 to 80% of the waste that's being created in pharma is related to solvent. 

 
56:36 
That's why and we come now full circle to what you presented, Alvaro, it's about the solvents. 

 
56:41 
That to me is the key area where we should be focusing on because that's the biggest contributor to waste and that creates the biggest impact on the environment and to safety and also on the financial aspects. 

 
56:55 
to me that would be where we need to have good answers, better answers in the future, better answers in the future. 

 
57:03 
And that is something, well, despite the fact that we have, we're finding new methods and synthesis are getting short and all of that. 

 
57:12 
And you can, you have more technology to get to the final product to do what you want to do, to produce, to achieve your goals. 

 
57:20 
When you take a synthetic route and you see step 123 and you come up to the end and you see the final yield, you see 5% total yield or 15% and you have 8 steps. 

 
57:33 
You know, that's the challenge. 

 
57:36 
I think that's something in chemistry that I always looked at that, oh, I got 80%, but my reaction went peak to peak. 

 
57:43 
What happened with my brother 19% conversion and at the end, it's difficult to move all the material to harness of the material through and it's really difficult to do a very efficient synthesis. 

 
57:57 
And when you think of a synthesis of 10 steps with 40% yield overall, that's fantastic. 

 
58:04 
You know what I mean? 

 
58:05 
And very difficult to achieve, especially at the process scale you see. 

 
58:10 
And this is what we do. 

 
58:12 
So I think that what that's what is a challenge on getting those numbers higher with new technologies. 

 
58:22 
I would like to make a supplement in terms of the changes they what is the must and what is the nice to have. 

 
58:28 
I would say a regulation is very good, very important drives because a lot of things are actually driven by the regulations. 

 
58:35 
Regulatory ask you to replace the EMF, ask you to ban the ATF and the so forth. 

 
58:40 
this is even a lot of you push and this is, I would say this is a must you have to survive first with the in compliance with regulations and then be more innovative. 

 
58:50 
That's a fantastic point. 

 
58:51 
Yes, yeah, absolutely. 

 
58:54 
Identify what it hurts and regulate it and then try to fix it. 

 
58:58 
And this is how we are getting, we are improving every year. 

 
59:03 
Yeah, absolutely. 

 
59:09 
Yeah, No, Brilliant. 

 
59:10 
Thank you very much guys. 

 
59:11 
I think we actually have just reached time benefit. 

 
59:12 
We've asked some questions anyway, so I think now will be a good time to sort of conclude the session. 

 
59:16 
I'd like to say a massive thank you again to Alvaro for your presentation and also thank you again to Yi and Wilfred for your contributions. 

 
59:23 
It was a really engaging discussion. 

 
59:24 
hope you enjoyed yourselves and thank you to everyone who attended as well. 

 
59:27 
It's much appreciated. 

 
59:29 
All that's left to be said. 

 
59:30 
It really is. 

 
59:30 
Thank you for joining and I hope you have a great rest of your day. 

 
59:33 
And also when you close the Zoom session, I'll pop up for a feedback survey will appear. 

 
59:37 
if you can fill all that in, that'd be great just because we're trying to tweak the format of these sessions and see how they run. 

 
59:42 
otherwise, yeah, thank you. 

 
59:43 
Thank you to our panellists and moderate Alvaro, thank you as much. 

 
59:47 
Appreciated. 

 
59:48 
Thank you, Declan. 

 
59:49 
Thank you. 

 
59:49 
We will put it again. 

 
59:51 
Nice to meet you all. 

 
59:52 
Thank you, everyone. 

 
59:52 
Take care in the future. 

 
59:54 
Bye. 

 
59:54 
Bye.