 Let me just move a couple of windows here. Oh, and while Nifer is still adjusting his screen to show the presentation mode, just to mention to you dear participants that you please put your questions in the question and answer box. You can also put it in the chat box, but then I think everybody can see who was posting the questions or the Q&A questions just come to us and we can answer them then after Nifer's presentation has ended. So now over to you, Nifer. Thank you, Christian. Well, let me start by saying good afternoon, good evening, good morning, depending where you log in. It's truly a pleasure to be able to bring this really hot topic to you guys this afternoon or today. As Christian mentioned, my name is Nifer Romero. I'm the scientific a fair manager responsible for the Latin American region. But also part of the team that it's working on the whole engagement with folks in industry and regulators around the topic of nitrosamine. So truly pleasure to be here. I want to encourage the questions. Hopefully we will have time. To address some of those questions. If there are some questions that we don't have answers for you, we're going to collect all those and we're going to follow up with each of you later. So no questions will remain unanswered so that I encourage everybody to send their questions. So nitrosamines really hot topic these days. I was just sharing with my colleague Christian that this last couple of weeks has been a lot of noise around here in the States with metformin. FDA has been starting to come out with a lot of market withdrawals around metformin. So a lot of companies have been on the media around this topic. So it's a topic that it's getting a lot of attention and I believe will continue to have a lot of attention. So a little bit of the agenda for today. We're going to talk a little bit about the background and regulatory concerns. Let's start from where all this started about beginning of 2018. Then we're going to dive a little deeper into the formation of nitrosamines, how they're formed, what are their sources? I think it's important that we understand these things can come from anywhere. And not just impurities, but the agents that can actually trigger the formations of these impurities. Then we're going to dedicate a little bit of time to defining limits, which has been probably one of those areas of more discrepancy between the different agencies of a little more discussions around how to define those limits. So we're going to touch base on that. Then we're going to look at a little bit of the regulatory approach. Let's see what are some of the strategies that FDA and EMEA. But ADQM has put to address these issues with nitrosamines. Then we're going to talk a little bit about the analytical part of this. I think this is probably one of the areas that has raised a lot of concerns about how we're going to go and analyze these materials, how I'm going to analyze my product against these impurities. Some of the challenges that we're going to face, and then we're going to introduce briefly the work that USP has been doing around the general chapter to address nitrosamine impurities, as well as some of the reference standards. A couple of disclaimers that I have to do at the beginning of the presentation. This presentation, it's really a conglomerate of information. This topic, it's constantly changing. So it cannot be taking the presentation as an interpretation of the guidance, the official guidance stand by itself. Any information that we have here might become irrelevant or might change tomorrow. So keep that in mind. We have included a lot of reference in the presentation. I know my colleagues are going to make available the presentation to you later. So you will have not just the material, but the references that are in there in case you want to dive a little deeper in certain areas. So that being said, let's start. So back in 2018, we start seeing this kind of news everywhere, not just from regulators, but around the press, the media. As I said, last week, we, a lot of attention got into this topic by CNN, ABC, the big network channels here in the States. Around the, the, the issue of nitrosamines or these impurities being present in pharmaceutical products. So, again, the nitrosamine presence in the pharmaceutical products emerge as a health concern back in 2018. When we learned that a particular product was contained in DMA and nitrosamine impurity at higher concentrations. This follow up with a series of investigations. Some of the agencies form a coalition to do some investigations around these topics. WHO, FTA, DQM, a lot of agencies around the world got into it. And we start learning about it was not just that product, but a series of product start emerging as risk products. So, let's, let's put a little bit in a timeline, the history of how this whole thing started. As I said, back in June of 2018, the European Agency comes aware of this issue for a particular product, Balsartan containing in DMA trigger, as I said, a series of agencies got together. And what we start learning throughout that year is that was not just that product, but a family of products. And it was, was not just the end DMA impurity was actually other impurities as well. Of course, that impacted a series of manufacturers, manufacturers have to do some investigations in some cases they have to do market withdrawals. So, again, I mean, it started to become a relevant or a concern topic for everybody in the industry. Back here in the States, the FDA about the same time issue a voluntary recall of Balsartan. Again, for the same reasons, right? High concentrations of DMA. Toward the end of 2018, they expanded this recall to not just Balsartan, but to all the family of Sartans. 2018 was no difference with actually we started to do a lot more digging and start finding out that actually more products were impacted by the formation of these impurities. In 2018, Renitidine becomes again to the stage as a concern about the same time the FDA issue a series of warning letters to manufacturers around the process control. And we're going to see that why we start seeing a pickup in issues from FDA around control process controls on specifically around the topic of nitrosamines. By November of last year, we added a third product to the list of concerns and I said, then. And really to 2020 it's when it materialize a series of guidance, a series of documents that has trying to guide industry and how to move forward. And what to pay attention when we're trying to investigate or doing research assessments about these impurities in our products. FDA started to add more products. And again throughout this year we have seen the adding more and more products to that list of concerns around nitrosamines. So Renitidine comes into the list by first, first, third of the year. We see again more recalls around a series of products issued by the FDA. It's not until June of this year that we see for very first time a guide, right, an official document from the European agency that really guide us on what to do, what its expectations, what are the things that we probably should be doing as manufacturers or that we should be looking at. Most recently by August of this year, we add an additional product to the list of products of concern with rifamping. Around July regarding USP around around July of this year 2020 if USP release a series of nitrosamine reference standards, which can be used with a series of methods that are already out there from the different agencies. And September 1st for very first time USP make public the general chapter 1469 impurity nitrosamine impurities, which is now in PF. So now it's the opportunity that industry regulators really anybody has the opportunity to provide comments to USP around this chapter concerns recommendations feedback we want to hear from you. Again, I mean we want to shape these chapters and these standards around what industry needs. September 1st is, again, we see for very first time an official guide from the FDA. So now we have an official guide on the control of nitrosamine impurities for human drugs. So what are nitrosamines and again, I know I probably have a lot of experts on the on the call, but I think it's good to start from the very beginning. So nitrosamines are a class of chemical compounds. With a general structure as shown there on the right side of the of the slide. And basically it's any compound that has that nitrosa group. It raises a concern. Okay, these kind of compounds are classified as human carcinogens. Okay. And the, the guy that really classified this or define them as a cohort of concern. Is the ICH and 7. So this is really the guy that tell us be careful. This is, this is, this is serious. This impurities or this family of impurities. Nitrosamines as a compound. It's really not toxic. It doesn't cost anything to the to us, the humans. However, our beautiful liver likes to metabolize these compounds and when they are metabolized by the liver, they produce this highly reactive compound that we have with the DNA. So there, there you have it. That's really what caused this whole concern about mutagenic carcinogenic activity. So, in terms of regulations, we have had for many years regulations around impurities, right? We know we deal with them in the pharmaceutical industry. We deal with them in our manufacturing process. We know how to control. There's it's a pretty mature topic specifically genotoxic impurity is a topic that it's highly avoid. Especially companies that do R&D. Every time I raise a flag during my R&D process of a compound that might be mutagenic or it might have an impurity. I kind of walk around that. Okay. However, we don't really, if we really pay attention to this, we don't really have until until that whole thing started strong, robust guidance and how we deal with this kind of impurities. We know we should probably have prevented them. But once we had it, we didn't have clear guidance other than the ICHM7. So today that has changed, right? That picture has changed. And now we have a little more official guidance and official statements from the different agencies in how to do, how to approach and what's really the expectations and how to deal with these impurities. As we're going to see as well, these impurities are not new. We have known these nitrosamine impurities for more than 50 years. However, really the concern is concentrations, as we're going to see in some slides a little bit ahead. Some of the references I said you're going to have this material, these references so you can do a little more reading around this topic. So let's talk a little bit about the formation, how these nitrosamines are forming. So really the king here, it's a nitrosating reaction. So basically to form a nitrosamine impurity, I need two ingredients. I need a nitrate, a source of nitrate. I need a source of amine, right? A secondary mine and a ternary mine. I need acid conditions and boom, that really can trigger and form the nitrosamine impurity. Just as an example, we have an illustrated that in there as the second reaction on the left side. Common solvents as the DMF, which are used throughout the entire process. We use it in the lab to prepare our samples. We use it in our manufacturing process. We use it on the synthesis side of things. That solvent can suffer some minor decomposition to form a secondary mean. And that secondary mean is just waiting, right? To react with some sodium nitrate in an acid condition and boom, I have the appearance of NDMA. So, in general, these nitrosamines are formed by the reaction of a secondary mean. As we're going to see, we can also induce the formations of nitrosamines with ternary and quaternary means. But in general, with secondary means with nitrates in acid conditions. Okay, so that means that whatever I have throughout my process, these 2 ingredients, I have potentially the risk of forming nitrosamines as we're going to see in when we move forward. So, let's make parentheses here and let's talk about Balsartan that it's really who started, right? What opened the kind of worms around all this issue of impurities of nitrosamine. So, by 2018, we knew that Balsartan was a part of the essential medicines for WHO. He had been on the market for more than 25 years, so it was a very well known and robust product. But by 2018, we faced with about more than 1200 batches recall of this product because this issue of nitrosamine. So everybody started wondering why now, right? We didn't see this kind of things before. Why now? Just for reference, there you can see the molecule of the Balsartan. They have the two impurities, right? We have the structure of the NDMA and the NDEA, which were the two impurities that were found in these products. Just for reference, the FDA limits accepted for these two impurities are 0.3 and 0.08 ppm. And in the investigations when this whole issue emerged, we found products with concentrations that vary from 0.15 ppm to 63 ppm. So we were talking about like sometimes 20 times the concentration that were supposed to be there. We found it in the product. So what caused all this issue? And really, no intention or judge anything on anybody, but really was a product of a change in the manufacturing process, specifically the formation of the tetrasol ring in the molecule. So historically, the method or the API was manufactured using these two components that you see on the upper side of the reaction to form the ring. However, a specific manufacturer decided to do some changes in the manufacturing process or in the synthesis to make the process more efficient and to make a higher yield, which is a common practice for API manufacturers. However, that reaction, it actually induced the formation of nitrosamines because I put together the two ingredients that I needed for forming nitrosamines. So the molecule at the end of the day was the same, but the remaining of the ingredients on that reactor or in that reaction or collaterals of that reaction was actually triggering the formation of nitrosamines. So let's learn here when we do changes in this manufacturing process, not just the synthesis, but throughout the process, the manufacturing itself, I can potentially introduce components that can trigger the formation of nitrosamines. So just for reference, we mentioned at the beginning of the presentation other products other than Balsartan, but then we have the Balsartan, we have the Renitidine, we have Nesatidine, and we have metformin. Now let's examine these molecules and see why might be a source of concern. If you look at the Renitidine and if you remember that those two ingredients that I need, right, I need a nitrate source and I need a secondary mean. If I inspect the Renitidine molecule, I have both components in the molecule. That means that a minor degradation of this molecule, and actually I can produce the two ingredients that I need to form in nitrosamine. And that's really why the Renitidine has been starting to become a really big of a concern. In the case of Nesatidine, same thing, right? I have a source of nitrate on the right side of the molecule and I have a secondary mean on the left side. So again, a minor degradation or the presence of impurities in my product from any source can actually trigger the formation of an nitrosamine. In the case of metformin, well, you can probably see we have secondary means, the entire molecules are secondary means. So again, it's a high risk product. So let's talk a little bit about the sources, okay, where I found the potential sources of nitrosamine. And for this, let's going to divide these sources into two buckets. Let's talk about upstream, right? Which is really the manufacturing of all my pharmaceutical ingredients, excipients, API, others. And then let's talk downstream, right? Once I get all these ingredients and I transform it into a pharmaceutical product. So upstream, downstream. I put the reference there of the reaction again. I need those two ingredients and acid conditions to trigger a form of nitrosamines. So upstream again, what are my potential sources of nitrates? So these nitrates are commonly used as quenching agents, okay? Every time I need to form a ring for a molecule, I use a series of reactions. One of the very commonly used reactions involves the use of acides. Acides are extremely active reagents. And at the end of that process or that step on my synthesis, I need to quench that reaction. Nitrates are normally used, right? Are added in an excess to quench and stop that reaction step or process. So that means that if I'm adding excess of this material, I'm actually introducing one of the ingredients that I need to form nitrosamines. Nitrates are also often present as impurities in a lot of reagents that I use throughout the process, throughout the synthesis. And as well, some of the solvents that I might be using during my synthesis can degrade and induce the formation of some of these compounds or can have impurities of nitrates in them itself. In terms of the source of amines, again, I have presence of secondary ternary and even quaternary amines throughout my entire synthesis. Amines are commonly used throughout the entire synthesis process of any API. Again, additionally to that, the sources of secondary amines can be impurities on reagents. It can be formed during the reactions. It can be formed as secondary species during the reactions, which I will need to control. So again, what I want to highlight here throughout the process of creating or synthesizing APIs and Excipients, I'm using these components. So I need to pay attention how I'm going to control and diminish the risk of bringing down those ingredients together to form nitrosamines. Other sources of these compounds are water. Water, we know it's the most used solvent throughout every old manufacturing process. So water can have impurities that can actually trigger the formation of nitrosamines, or in some cases water can be the source of nitrosamines. Solvents, and as you probably see in the slides, I have highlighted their fresh versus recovered solvents. And again, this is a topic that we're starting to see a lot of concern being raised by the agencies during inspections, during reviews of a lot of dossiers or a lot of registrations. How are manufacturers dealing with solvents? It's commonly used, right? It's commonly practiced to utilize, recover, or recycle solvents in the synthesis process. However, one of the observations or the things that we're starting to see is that the controls are not necessary there to control these impurities, to control these reagents that can be present or can be removed throughout the recovery process or the recycling process. So this is one area where we're going to start seeing a lot of attention from regulators, okay? And ultimately contamination, right? These components can be present from any component in the process. Now, let's talk now downstream, okay? I have my API, my XCPS, my ingredients supplier, now I get all those ingredients and I need to transform it. So, am I susceptible to nitrosamines? Of course, yes. So water, again, we utilize water throughout the entire process. So water can potentially be one of those sources of not just nitrosamine, but the impurities or one of those two ingredients that I need to form nitrosamines. Degradation products, of course, we can, as I mentioned before, some of these molecules can degrade and actually the product of that degradation are the base to form nitrosamines. So special attention to the degradation path for my products and highlighting the risk of forming nitrosamines. So interactions with my APIs, with the XCPS, this is something that now we need to start looking into it, okay? If I have an amino group in my API, I need to look now at my XCPS to see if there's any impurity or the XCPS itself can be a source of nitrate. And I can potentially have the risk of forming nitrosamines in my metrics, okay? Packaging materials. So we're starting to see a lot of studies around packaging materials, especially in the blister packing side, printing inks, lacquers that are used in the aluminum foils. Some of these materials contain amines or contain nitrates. So again, a lot of this, we need to start paying attention to this area as well. So in conclusion, these two ingredients can pop from anywhere, anywhere in the process I can find these two components. So again, if now it's becoming more and more relevant, the need for me to identify this risk throughout my entire manufacturing process from beginning to an end. So let's talk about the regulatory approach, okay? And I said we were going to talk a little bit about the defining limits. Really the two bodies that we follow around concentrations are about the limits for these impurities are the IARC, right? Which is the, this database of carcinogen data, okay? And the ICHM7. So these are really the two bodies that we follow when we define these impurities. Basically, we're not going to do a toxicology class here, but basically we have established through clinical data or through model data. What are the concentrations of maximum concentrations of the exposure for each of these impurities? In some of them, we don't have clinical data, so we assume or we apply the same concentration from impurities that have similar structure, okay? So for NDMA, we know this, we have this data, right? We have animal data, tox data. So basically what the approach that we see in general is we basically divide, we take this toxicology factor, let's call it toxicology factor, and we divide it by the maximum dose of that particular pharmaceutical product. And that's what give us the concentration, the maximum concentration that we should have in that product. So that's really what after doing that little calculation, this is the table that we're starting to see, right? In the FDA guidance, in the EDQM guidance, in every other regulatory body. So basically I have the maximum daily dosage for a particular drug. We had the acceptance intake, right? That toxicology factor. We divided that by the maximum dose and I get finally then the concentration that I can have of that product. What does that mean? That means that the concentration that my product can have of a particular nitrosamine impurity, it's given by the maximum dose of that product, okay? So that varies, that can vary. That doesn't mean that one impurity has the same limit for every product. And that's important to keep in mind. In terms of the FDA and the EMEA. So as I show you here, we have some of the FDA approach and the limit, the concentrations of the limit, the intake, allow limit for the FDA and on the right side you have what would be the EMEA approach with the allowed concentrations for EMEA. In the case of the FDA, it's expected that all chemical synthesized APIs, right? Carry out a sort of risk assessment for the nitrosamines. And as you can probably see said, all chemicals. So we're not limiting this just to a particular series of products. So it's the expectation from the agency that from this point on, we're going to do this on a regular basis for any product, okay? To what impurities? Well, FDA has listed a six of impurities that they consider are impurities that they want to control or they would like to see industry controlling, okay? Some of the areas where we start seeing a little divergence between FDA and EMEA, it's probably in this impurities, as you can probably see on the right side. EMEA, well, it's expecting to control seven of these impurities. So an additional impurity than the FDA. And in the case of EMEA, it's expected that not just chemically synthesized product, but also biologic products needs to have this sort of assessment. And again, in both sides, you see that risk based approach or risk assessment. So risk assessment is something that came before we saw it before, but now when I trust them in, it came to stay, okay? So this is something that we're going to have to do on a regular basis for the entire lifecycle of the product. One of the references in both FDA and EMEA about how do I conduct this risk assessment, it's really given the framework by ICH Q9. So that guide really provides us a good core of how I conduct this analysis. Particularly the USP General Chapter provide a very general guidance of what are the areas that I need or that I should be looking at when I'm conducting this risk assessment. As we highlighted before, these impurities can raise from anywhere in the process. So a reflection of that risk, we see it here on the risk strategy that USP proposed where we need to do a risk assessment for the drug substance, the excipients, the manufacturing process, the solvents, the water, the packaging materials, stability. So it's really throughout the entire process. So what are some of the FDA recommendations for nitrosamine or dealing with nitrosamines? So basically some of the timelines. So basically it's expected that any manufacturer that has an approval from FDA have to conduct a risk assessment. Okay, this risk assessment should be conducted within 6 months of the issue of the guidance that put us by March of 2021. Every manufacturer with a registered product in the US should have a risk assessment. Okay, conducted for their products. If after conducting this risk assessment, I identify risk areas or risk steps where I can potentially have nitrosamines. So then the expectation is that I'm going to have to do some confirmatory testing. Okay, I need to prove that in that area where I highlighted the risk I have or not presence of nitrosamines. And it's expected as well from the agency that if I identify areas of risk, I most likely need to introduce changes to prevent right or mitigate that risk. Those changes need to happen and need to be documented and need to be notified through the agency. If it's on the API side of things that has to be done through a change under DMF or if it's a finished product. So then it has to be done through an amendment to the submission. Okay, those changes, those reports and the implementation of those changes needs to happen within a timeframe of 3 years. Okay, so the timeline that FDA has given us is September 2023 for us to do all these changes necessarily to mitigate the risk of having nitrosamine in our products. I encourage you to go and review the guidance. It's very has a lot of really good information, a lot of detail. And in that guidance, the FDA has highlighted the most common sources of nitrosamines. We already talk about most of them. Okay, but there are a couple of things here that I want to highlight. One, it's when the pillar here I'm highlighting, I don't know if you can see it, but one that call for lack of process and controls. And this is really connected to the solvents recover solvents. Again, guys, this is an area where we see a lot of concern from the agencies. And we're going to start seeing a lot of questions asked around how do they, you know, my API provider or supplier deals with recover solvents. Okay, the rest we have at some point, we have already discussed it. In the case of the EMEA, the expectations is pretty aligned with what FDA is doing. We're doing a risk evaluation. In the case of EMEA, as I highlighted before, we are including biological products. Then if we identify that risk, we have to move forward to do a confirmatory testing and then basically do an update on that marketing authorization, right? Based on those changes that are un-proposal. Let's talk about the analytical part. Okay, because as I said before, this is probably one of the areas where we get the most questions. In order to start looking at analytical, we need to see what is the expectations, right? The analytical expectations. What are those concentrations that we need to deal with? And I presented this table here that cannot give us an idea of what are those concentrations. So if we do a brief overview on the right side of those concentrations, we're looking at very low concentrations, right? We're looking at 0.3 ppm, 0.08 ppm. So we're talking out here about ppm, ppb level. Okay, so again, traditionally, we deal with the 0.5, with the 0.1% impurities. This is a whole new ball game. Okay, we're looking at concentrations on very, very, very low levels, which require the use of highly specialized instrumentations to be able to detect. And measure these values or these concentrations in a consistent way. In terms of analytical methods, what methods can I use to analyze this product? Well, we have a whole pipeline of analytical methods. FDA has issued a series of methods for the different products, different kind of instrumentation. Okay, EMEA has also in his website reference methods for the different products and the different impurities. Now we have the USP General Chapter, what contains four additional analytical methods that can be utilized to analyze my product for these impurities. What all these methods have in common, it's highly sensitive detectors. Okay, my detection system in most of them are highly sensitive mass spectrometry. Again, given that those concentrations and the sensitivity necessary to measure these concentrations. Now, when we talk about analytical approach, right? Okay, I select the method, I have my product, now I'm going to measure it. This step, it's not foreign to the risk assessment. Actually a key part of the analytical approach of the analytical verification of the method has to be done first with the risk assessment. So now I need to conduct a risk assessment on my product for my analytical work. Why? Again, if I'm introducing somehow ingredients that can trigger the formation of nitrosamine, so then ultimately I'm going to be reporting levels of nitrosamine that are not on my product but that were formed during the sample preparation or the analysis of the sample. Okay, so again, we need to do a very educated exercise to understand what are the impurities that I'm looking for on my metrics? What are the reagents that I'm going to utilize to make sure I'm not introducing potentially nitrosamines or agents that trigger the formation of nitrosamines? And I need to look at the affinity of my molecule with the analytical technique. An example of this classic example of this was metforming. When we started this whole issue with metforming, a lot of manufacturers decided to do a GC method. Well, happens that GC use high temperature that actually degrade that molecule and potentially trigger the formation of nitrosamine. So my product didn't have nitrosamine, but my analytical work was actually producing that nitrosamine. So that's an example of why it's so important for me to identify the right method given the affinity of the molecule that I'm analyzing. One of the other things that it's going to come into place is the dilution. Do I want to dissolve in my entire sample and my entire metrics? Or do I want to do a selective solubility of my particular impurity? And again, this is given by the high risk or the induction that I can have of degrading my molecule or degrading one of those ingredients and triggering the formation of nitrosamine. So the analytical work now becomes a detective work, if you will. What we see here is the analytical methods that has been proposed in the USP General Chapter. Again, we have two methods. We have a liquid chromatography methods and we have GC methods. And again, in each of those, we have different approaches and different nature of mass spec analyzers. One of the beauties of our chapter is that we, because it's above a thousand chapter, it's an informational chapter. Meaning that we can add additional information, supplemental information that traditionally we don't include in a mandatory or a below a thousand chapter. So what you're going to see in these chapters, you're going to see a lot of detail about not just the conditions of the instrument, the conditions of the analyzer, recommendations about what to do sample preparation. We have been able to include a lot more information that we traditionally include in a method for a monograph or a below a thousand chapter. So really good information there. Additionally, all the reference standards that we have make available had been validated through these methods. So I have assurance that USP did all the pre-work of making sure that those reference standards work with these USP methods. Okay. Let's talk about what USP has been doing and where we continue working on this topic of nitrosamine. So really the USP work started back in the beginning of 2019 where once this became an issue of concern, the expert committee created, one of the expert committees created a subcommittee in charge of nitrosamine. So this subcommittee had members from the different areas, from an area of analytical, from toxicology, impurities, dosage forms, excipients. So it was really a multidisciplinary subcommittee and they were put in charge of creating the strategy for nitrosamine in USP. Their approach was basically created what we have today, basically having informational chapter first. As I said, it was not until September 1st that we had, we saw for first time the guidance from FDA. So that being said, the subcommittee decided to first put information that could be used by industry as an informational piece. And eventually, right, the expectations is to see how the whole regulatory requirements and expectations progress. Once that kind of has settled, we can then move forward to creating a below 1000 chapter that can potentially be referenced in monographs for particular products, particular ingredients. Okay. But not at this point. So this is a little bit of the timeline for that informational chapter. As I said, starting September 1st, anybody have access to this chapter in the Pharmacopile Forum. Actually, my invitation is that everybody on the call go to the USPPF and download the chapter so you can actually see all the information that we put in there and you can utilize as a reference. For those that are not too familiarized with our traditional standard process or creating process, anything that we want to include in the compendium has to go to the PF. It stayed there for 90 days. That's the commentary period. So again, we want to encourage everybody to submit their comments to meet their observations, their concerns, their feedback to us. That commentary period and some November 30 at November 30, then all those comments are gathered and presented to the subcommittee who wrote the chapter and they have the responsibility to address each of those comments. Okay. So they will either incorporate, they will add additional pieces of information to the chapter and they will have at the end of that process a decision to make. Either they move that chapter as it is with the changes to the next step, which is to make it incorporate into the USPNF or based on the number of comments that we receive, if there's a need to reassess the chapter, read, write, include more information. So then they can take that step, right? They can actually don't move the chapter to the publication and continue working on the chapter and go through this process all over again. So that's really a decision point that the committee will have to make once we receive all those comments. That's why it's so important that we receive your comments that you send us your feedback about the chapter, about the methods, about the approach. We want to hear from you. This is a little bit of the structure of the chapter. We have pretty much a little bit of what we have talked today. That's pretty much the structure of the chapter. As I said, the analytical part is really rich in information. It's really rich in details. Okay. So I encourage for you to go and check it out. What are some of the other areas where we're working or we're doing additional work? USP, it's actually working in an additional standard. This is, I want to believe it's the first time we are working on a deteriorated standard, which actually it's using a lot of the FDA methods. So we're actually working on developing and making that standard available for industry. We are working in a series of methods as well for the monograph when we potentially move that direction. We will have the methods worked out so we can apply it into the different monograph. We continue monitoring the impurities with the issue of refamping. It was new nitrosamines impurities that we haven't seen in other products that came out with that particular product. So we continue monitoring that impurities and working to our methods or developing method for those new impurities. Number 5, it's probably one that costs a lot more questions and it's really the comedy realized that the analytical techniques of the analytical requirements for fulfill all these requirements are expensive are highly specialized techniques. So we're looking for options. We're looking to see what other techniques we're looking to see what other approach we can take to identify this sort of impurities. Again, maintaining always the quality and maintaining the consistency of the results that we need for this for the severity of this impurities. Working in some testing for metformin. And again, we are starting the conversations with the different agencies and PDG around the topic of harmonization. Again, this is just at the beginning of the conversations. As I mentioned before, these are the reference standards that USP have made available to the industry. These reference standards has undergone the traditional development process of USP reference standards. And really the intention of these reference standards is to be able to analyze those trace levels of these impurities utilizing any methods. Again, I mean, the reference standards were validated with the USP methods, but really these reference standards can be utilized with any analytical methods out there. We know nitrosamine. It's a topic of constant change. So we created within the USP website, we have a dedicated hub just for the topic of nitrosamine. And this is where we're going to continue the adding information, adding resources that around the topic of nitrosamine. So here's my action, right? This is my act now. This is my invitation for you as we come to the end of the presentation. Go to the PF, download the chapter, submit your comments before November 11. We really want to hear from you. We want to see if this information that it's there, it's useful. If it's a concern, if you have additional methods, if you have additional information that can be useful for the chapter, we want to hear from you. And this webinar that you attended today, it's part of a series of webinars that we're doing around the different regions of the world. So really the invitation is to keep an eye for a follow up invite to our webinar too, where we're going to do a deep dive into the chapter. So this webinar was really an overview of the current status quo of the nitrosamine topic where webinar two will be a deep dive into the chapter. So we're going to really deep dive into the analytical part, the analytical expectations, the challenges, the sample preps, the conditions, the different nature of detectors that you might have in your laboratory. Some of the analytical strategies. So again, really good information is coming up on that second webinar. And again, if you want to engage with us more, I encourage you to reach out to your SED managers, to Christian, which is my counterpart there in Europe on the scientific efforts side. I encourage everybody to engage with us in this topic, since this is something that is constantly changing. On the lower part of the slide, as I pointed out there, it's the link, the direct link to the PF. So once you get this material, you can actually click it there and it will take you directly to the PF online version. As I mentioned before, the PF, it's free. So everybody have access to this information on the Pharmacopial Forum. With that, that comes to an end. I want to thank everybody for spending these 45-50 minutes with me. Thank you for my colleagues in Europe for the invite. I hope I did a good job and they invite me to come and do the second webinar as well. So that means I thank you, Christian. Thank you, everybody. Thank you very much, Nifer, for this excellent presentation and this very broad overview, yet deep and some aspects here. Thank you also from my side to the participants already now. It's already five minutes before the full hour, so we only have five minutes time for questions. And I will bring up here a few. Nifer, do you have any idea? One of the questions that came to us was, are biologics also necessary to check? We have seen that this is the case in EMA, that it is not yet the case in FDA, it seems. And there was one question about if we know why the FDA exclude biologics from the scope. Do we have there any rational available? Do we know what's the reason behind that? No, Christian. Unfortunately, I don't have any insights as to why the FDA didn't include biologics. Again, as I said before, this is a constant changing topic. It would surprise me in a future or near future, we'll see FDA adding biologics. But I don't really have information of the rationale of why wasn't included at first when the guidance was first issue. Yeah, I thought so. Another question that we have quite interesting, if we use analytical methods included, oops, where it is now going, included in EMA or in USP to test on the nitrosamines. When we use that for our finished drug products, do we need to do a full validation of the method in our metrics? Or is just a mini verification sufficient? I think it's, I wouldn't say that we have to do a full validation, okay. But the traditional method verification that we do for any other product, it's not enough. As I highlighted on the analytical part, the metrics, the nature of the analytical technique that we're using, it can become a problem for us at the end of the day. We're giving us a false high concentrations of these impurities. So I think a little more due diligence needs to be done around the analytical conditions, the sample preparation. And some of that validation probably needs to take place to make sure that the results I'm reporting are actually true to what it is. I see. Thank you. We have also one question. Because I may add as well, because this is, it's a follow up questions that I normally get. What methodology that I can use, really I can use any methodology. The FDA doesn't say use only the FDA methods. The USP have just make available these methods. EME has similar approach. So I really, I can use any method, any method that works for my sample, it works for my metrics, it works for my, for my ingredients that I'm trying to analyze and impurities that I'm trying to identify. I see. Yeah. Thank you. Another question has to do with excipients, Naifa. If, if I would do the question is if I would do upfront screening of excipients on the presence of nitrogen mean impurities without doing a risk assessment before, which such as screening already be rated as confirmatory testing. I mean, we can probably follow up offline with that. It all depends. I mean, I don't know if these questions come from the exception manufacturer or come from the drug product manufacturer. If it's from the exception, that's an information that I'm going to have to start providing with to my, my customers, because they're going to start asking me to, to show that I conducted that risk assessment and that I have strict controls on my process. If we're talking for the drug product manufacturer. Yes, that's a piece of the, of the puzzle. Right. I know that once I get the ingredient that ingredient probably is. Let's, let's call it nitrosamine safe. But then I'm going to transform that. Right. I'm going to mix it with other things that I'm going to need to assess if that transformation. And bring again a race of forming nitrosamines. So it's just a piece of the puzzle. Yeah, yeah, exactly. It's that, that, that mixture later that can, can really bring up the risk of, of the nitrosamine generation. Of course, there was also one question and I think that is the last question that we can, can take because it is now already the full hour. Can nitrosamines also result from primary amines and primary amines? That's another question there are very reactive. Is it, is it necessary to check on, on those as well? No, primary amines we don't cause nitrosamines again. I mean, it will, let's go back to what the nitrosamines are. Right. So, you need that those 2 groups attached to that nitrogen and then to the nitrosa group to really be in presence of a nitrosamine impurity. So, primaries are not a concern. Now, those primaries can react and, you know, subsequent reactions cause a secondary mean or induct the formation of a nitrosamine. That's a different story. But by itself, no, it doesn't represent a risk. Okay. Thank you very much, Nifer. We have lots of other questions here. We will follow up with the majority of those on offline here. I will check later what, what questions came in there. And we will probably contact the persons that asked them then offline here. We don't have time anymore. But let me take the last seconds here once again to thank you, Nifer. Thank you very much for getting up that early and have a tie on for us here in EMEA. And we will also make the information available about the webinar to so far that Nifer mentioned so far. There is no, no date yet here in that region there, but we will work on that and then let you let you know then. And yeah, and once again, thank you to all the participants to all the attendees to join us for this this hour. Our next webinar will be in two weeks again that time, then it will be around Excipients. It's the first day, the 29th of October about Excipients from our colleague Catherine Sheehan in also coming to us from from America online there. So yeah, thank you very much once again, Nifer and all the participants and have a great rest of the day. Thank you very much and see you in two weeks. Bye bye. Thank you everybody. Bye bye.