 Good morning, good afternoon, and maybe even good evening to the participants of today's webinar of our EMEA webinar range. Today, my colleague, Dr. Catherine Sheehan will talk about the importance of excipient testing and quality. I hope you can see the slides and I also hope you can hear us well. So please let us know in the chat quickly that this is the case so that we can see that we have no problem on our end. You can also raise your hands if that makes sense. But I see already that I get comments that you can hear us and that you can also see the slides. Excellent. So whenever you have a problem, that problem might be unfortunately then on your end. So welcome once again to our webinar today on Excipient Testing and Quality. And presenting those slides today will be my colleague, Dr. Catherine Sheehan. And Dr. Sheehan is currently the Senior Director of Science for the Excipients section at the United States Pharmacopayer. And in her current role, she co-leads the Excipient Science Program unit there. And responsibilities include beside a number of other activities, includes the development and update of the high priority excipient monographs and related general chapters. Supporting also the USP Council of Experts, of course, with the expert committees that are dealing with excipients. Her current further responsibilities also include the support of the PDG, the Pharmacopayer Discussion Group, that is comprising the USP and then European Pharmacopayer and Japanese Pharmacopayer, to successfully harmonize the excipient monographs and the related excipient chapters that are undergoing harmonization through PDG. And Dr. Sheehan is also active in AAPS and in RAPS, and she is holding a BSc in Science from the University of Cork, University College of Cork in Ireland. A Master of Science in Regulatory Science and a Master of Science in Molecular Biotechnology from the Johns Hopkins University. And then also a Doctoral in Regulatory Sciences from the International Center for Regulatory Science from the University of Southern California School of Pharmacy. And with that, Catherine, I would give the floor to you and yeah, all yours. Thank you, Christian. Good morning, afternoon and evening to all that I have planned to attend this presentation on the importance of excipient testing. So, today, what I would like to do is in the presentation, the objectives of the presentation would be to provide you with an overview of USP's mission and standards. Of course, their use around the world, their recognition in the US law and their application in secure quality across the entire supply chain. Understand that the quality of excipient ingredients impact the quality of finished products. Identify the value of USP excipient standards throughout the supply chain. And most importantly, understand the value of a comprehensive program for verifying the quality of an ingredient that can include performance to the USP excipient standard. And the documented evidence of ongoing product conformity to a certificate of analysis specification. And then finally, a look at some recent USFDA warning letters where there is an increase in letters, citing lack of excipient ID testing of every incoming lot and or overreliance on supplier certificate of analysis for a tribute testing. So hopefully you will come away with an understanding of these these important aspects when it relates to excipient testing. So I will begin with introducing USP and our mission. We have been around for 200 years. This is our 200th year anniversary. And we continue to improve global health through public standards and programs that help ensure the quality safety and benefit of medicines and foods. And how do we do that? How have we been successful to advance quality? We work and partner with experts in science and health throughout the world to develop quality standards that helps at the bar for manufacturing and distributing safe and effective medicines, supplements and foods. Our partnerships with FDA and other regulatory bodies help advance quality along every point of the supply chain. And today, our standards are available in more than 160 countries. So a little bit of background on our history. Bear with me. There is a box here in the way. I don't know if the audience has their slides interrupted. So our history, as I said, we were founded in 1820. So as you can see here, we were in the first culmination of the 1906 Pure Food and Drug Act. They recognize USP as the official companion under the federal law. And of course that was repealed and enacted in 1938. Food Drug and Cosmetic Act as we know today also recognizes USP and these standards remain connected to FDA through this legislative legislation today. So, okay. So a little bit further digging into the USP's role in the law. Most importantly, a drug recognized in the USP and F must comply with written identity standards or be deemed adulterated misbranded or both. So the identity is a very critical component of the companion specification in terms of its recognition in US law. But how are FDA and USP different in our functions enrolled? Well, of course FDA approves the drug, USP sets the standards and specifications. FDA enforces, whereas USP provides the drug standards enforced by FDA under the FDA and CF. FDA approves the manufacturing processes and plans that produce the drugs for the US market and both USP and abroad. USP does provide reference standards, chemical physical samples used in the tests and methods to measure conformance to written standards and today requirements. And FDA requires and enforces the GMPs whereas USP helps the manufacturers to satisfy this requirement. So, let's look at USP standards as I mentioned. So, you can see here from this slide that USP standards in terms of our general chapters, packaging and distribution dosage forms are examples in the literature and labeling. Standards, they're applicable as you can see across the entire supply chain. Our USP standards in terms of our general notices and general chapters or monographs and reference standards are applicable in certain aspects of the manufacturing. And then of course we have our USP healthcare quality standards, which are listed here that are applicable in the pharmacy and hospital setting and to healthcare providers. So, for the USP excipient standards, we'll start looking now specifically at excipient standards in the USP. These are public standards and they will define what food looks like for an article. And what I mean by that is they define the requirements for the asset purity contaminants and specific tests for performance and other quality of the tributes. They are continuously modernized to incorporate new technologies for testing and data. So I'll go into a little bit in the slide presentations on how USP is modernizing the excipient standards. In terms of excipient standards and the compliance with the monograph, it's based on the testing the article and meeting the limits in the monograph. And that the manufacturer of this article is under appropriate GMPs. And there'll be more on this in terms of the applicability that I will get into later on in the presentation. But just suffices to say that under section 310 of general analysis, the official products are prepared according to recognized principles of GMP and from ingredients that meet USP or NF standards where these standards exist. So when we're dealing with excipient ingredients and pharmaceutical products, we all should be aware that this is a complex global supply chain. And there are very, there is a lot of vulnerable areas for these materials to be subjected to adulteration. Our standards which constantly evolve through public input help detect adulteration and allow for rapid response in times of crisis. So I can't emphasize enough that in our collaboration with our stakeholders, we are able to have the ability to update the standards and make sure that they are a strong in the toolbox in excipient testing and quality control. So moving on to the application of compendial standards in secure quality. The next couple of slides will, you know, delve into different aspects of USP's general notices just to give you kind of an understanding of the terminologies that apply to excipients. And also familiarize you with our general notices section in terms of the applicability of these standards and what it means for to conform to these standards. So a little bit of background on section 2.2 official articles just to realize that official articles include both official substances and official products. And what we mean by that is that both the drug substance, the API and an excipient are considered official substances in USP. So in terms of these components or official substances, their applicability in terms of section 3.10. Most two important parts here are again emphasizing that these official substances are prepared according to GMP principles from ingredients-confined with specifications designed to ensure that the resultant substance meets the requirements of the compendial monograph. But also the applicable USP or NF standard applies to any article marketed in the US that is number one recognized in the compendium and secondly is intended or labeled for use as a drug or as an ingredient in the drug. So the applicable standard applies to such article whether or not the added designation USP or NF is used. So this is important to understand about the applicability of excipients that are intended for use in pharmaceuticals and then also to remember that the designation and performance if the designation is used on the label, it may be used on the label provided that the label also bears the statement such as meets the NF standard as published by USP and that indicates then which compendium you're referring to that you apply to. Additionally, some background information on definitions. We do have a definition within our general chapter. And it's a very straightforward one appropriately evaluated for safety and our intention included in the system. Within the statutes section 201, the term drug indicates articles intended for use as a component of any article meeting the drug definition. And then of course under the CFR regulations, any inactive ingredient is any component of a drug other than the active ingredient. So hopefully that gives you kind of a background and understanding of the laws and regulations that guide us with defining excipients in pharmaceutical products in the US. So now we look at the excipients from the perspective of their, their makeup, their origin. And of course, we all know that they have a very diverse space and see here. They are complex with the mixtures, multiple grades, multi source. So that definitely does create challenges when it comes to quality. And, you know, up until probably about 10 years ago, I'd say focus was on the active ingredients and the final product. But now we realize, you know, with recent activities that these excipients can cause a failure to your products as well. We have examples here that I show and we're all familiar with these in terms of what they have done to the drug supply chain. And then some of these components are more critical than others. So risk assessment strategies need to be tailored to ensure their quality. So again, just, you know, looking at the challenges with the different sources, updating excipient standards are challenging. Again, just emphasizing that the grades, the multiple supplier, the lot variability, the desire to get better, more highly characterized excipients because of their use in specialized drug delivery systems. And then the concerns with the lack of supply chain integrity. This all creates challenges to USP in updating compendial standards. And this is just a snapshot going back a couple of years where our FDA colleague indicated that, you know, on review of excipient monographs, it's apparent that even if performing all tests, it might not be possible to deduct undesirable substances because of non-specific idea or assay methods or questionable acceptance criteria. And then just by the sheer, you know, volume of the excipient in the drug that can create a significant, you know, impact in terms of risk. So we have been since then, you know, updating our monographs and, you know, FDA was working with us since 2010 to that FDA modernization task group. And the first thing we looked at was the postpodone. This is a good example. We did not in the USP have a test for the limit of peroxides, whereas our colleagues, the European pharmacist did. What FDA were realizing was that peroxide levels were found in excess of 30 to 40 times the typical levels that would be controlled if the test was in the monograph. So USP updated and devised the monograph in 2011. So this is just an example of how USP is proactively working with regulators and industry to update the monographs in USP. I won't go through this, but this just gives you a snapshot of where we're focusing in terms of our efforts and resources to update the excipients. And as you can see, the first line of defense here for us to update the monographs is the identification followed by assay and impurities. We also have a suite of general chapters that are exist. And we're also adding to that. You can see here on the left, GMPs, certificate of analysis, a significant change, distribution. These are all critical in the, you know, ensuring the quality of excipients in your supply chain and it also helping with the verification and supply. And about a year ago, we were contacted by Xavier Health, who work very closely with FDA and they have agreed to work with USP to develop a chapter on supply chain practices. So stay tuned for that. That should be coming out in our form within the next six months, hopefully. So key messages that I would like to deliver from this is that public standards by across the entire supply chain. So that is very useful for our stakeholders and standardization of these people to allow to control consistency. And they can also provide tools for compliance with regulatory compliance. So moving on to the next section of our presentation. We're going to delve deeper now into the supply chain and the important aspects and things to look out for when qualifying incoming materials and what incoming material checking should look like. So again, going back in time, you know, USP has been, has been working on this actually since probably 2007, that was the time of the glycerin crisis, the Hepburn. But what we, what I want to focus on here is that back then component testing again, you know, was gaining prominence in drug GMP warning letters. So that was the beginning looking at components in general and FDA is concerned that each component is not being tested by dosage manufacturers for component conformity with all of its specifications and our specific ID tests. And this was definitely a concern because it was seeing that they were being accepted based on the supplier C of a as required by CFR 211 84. So looking at, you know, this perspective, and looking at incoming accident checking, two main aspects would be looking at it from verification, looking at verification of income. Excipients would be looking at it from the ID checking visual checks testing for the critical attributes so that the recipient can be released into production. But also looking at additional controls for your intended use. Because as we mentioned, different grades, different manufacturing sources, you need to understand if this exhibit is is suitable for for your intended use. So an additional purity, appropriate grade, physical attributes that can relate to how it will function in the drug product. These are all critical incoming exhibit checking parameters. And of course, it's the last line of defense for medical product safety. So I won't dwell much on this, but I just wanted to give you kind of a history of one of the most, I think, most prevailing of the adulterants that has occurred in the US. And it was actually the incentive behind introducing the 1938 drug and cosmetic act. The enactment of the drug and cosmetic act. So it this adulteration has been around for over 80 years. And what we did in the meantime, you know, in the late 1990s, we attempted to update the monograph. And what we did was we actually, you know, we thought by putting the limit of diet and glycol in the marketing section that this would be probably sufficient and then just put a the in the ID section of reference to the retention time to that method. However, as you saw, the adulterations kept happening. And then the horrible Panama crisis for over 400 deaths. Currently, the number keeps rising occurred. So, you know, we scratched our heads to understand what we put the limit test in there. So what is going on here? And so just to emphasize that there definitely should be appropriate procedures or measures to assure the identity of the content of each container of a starting material. So it's very the identity of the exhibit is so very important when you're qualifying this material. And, you know, this was kind of really emphasized with all the work that was done surrounding glycerin in the in the US. And it really drew emphasis to the sections of 211. And they are section 211, 8, 4, where it says at least one identity test should be conducted to verify the identity. And specific identity tests if they exist shall be used. So it was there in the regulations. And what it's saying there is that it requires manufacturers of drug products detected, quantify any day present. Both at the time of manufacture and upon receipt at the point of transfer to another party. And what we learned here was that manufacturers cannot deviate from the day limit. Since it is an aspect of identity. And essentially under the statutes, you cannot label away from identity. It has to be done. Whereas, you know, in the 1990s, we put this in as a limit test. In contrast, if dead section and part of patient is solely part of the, you know, the purity and purity test and manufacture need not include as part of its identity testing. So that was the key to why we needed to then go ahead and introduce this specific identity test into the identification section of the model. So again, the guidance reiterates to 1184 that it requires specific ID testing when not performing full usp testing and that the reliance on the COA is not sufficient to ensure quality of listening. So this was the learning that we got. And the guidance also emphasize this. So the key messages from this section is that incoming material must be verified to be the correct material of the specified quality before it can be released to be used in pharmaceutical manufacture. So now what we can do is let's let's move into looking at some, you know, testing deficiencies now that currently prevail and look at some recent activities in terms of FDA's deficiencies letters to applicants. And not only do they relate to the identity of the materials, but also we've seen recently that they're looking at functionality versus the quality. And also, you know, within recent years, the FDA warning letters are actually calling out with respect to the lack of identity testing conducted on incoming recipients. So it was it moves from a very general component to actually calling out the incoming recipients. And as I mentioned to you, you know, USP has been involved with industry regulatory bodies to update our excipient monographs. But, you know, there are monographs that are missing tests. And, you know, sometimes the users are not aware of these deficiencies. So it's important to understand that. And actually, if you feel that recipient monograph USP is deficient in terms of ID assay or impurities, you know, please contact us and work with us because we'll be more than happy to update these tests so that they are, you know, they are of value and they can help in the quality testing of their recipients. So going back to how does a verified ingredient help. Well, most importantly, it provides documented evidence of ongoing product conformity to a C of a specification. So it's not just a, you know, a one point in time, like a paper audit, or a physical audit, it's ongoing. The annual product testing ensures that these validated analytical methods are being used and produce reliable results. And it gives the user the, the, the manufacturing ability to scale supplier qualification procedures. And, you know, use those resources to some, you know, other aspects of the manufacturing and other internal resources. It also provides a way to identify quality conscious suppliers and for suppliers to differentiate themselves from competitors. So if, if anyone in the audience is interested in finding out more information on USP verification of ingredients, please contact us for more information. So I'm going to give a couple of examples here of FDA's warning letters and how, you know, they really are starting to look at the deficiencies that they're seeing in terms of testing on excipients as, as components. So the first one is from my home and in Ireland, and this was in around mace 2018. So here you can see FDA says you've, your firm failed to test samples of each component for conformity with all appropriate written specifications for ID pure to strengthen quality, according to the US regulations in 211 184. And it was specific to failure to analyze the lots of glycerin raw material from your supplier for the presence of day and prior to releasing it for use in your drug manufacturing. And so the issue was that they explained was your response. You know, when the, when the manufacturer responded your responses in adequate because a manufacturer as a manufacturer you're responsible for performing a specific ID test for all component blocks prior to release for use in drug product manufacturing. And you also failed to describe your interim actions to ensure that all raw material lots meet their specifications before used in manufacturing. So this is just one example of where, you know, FDA warning letters were focused on. And so in response to the warning letters. And their reply FDA instructed the firm to provide written procedures for how you will qualify your suppliers. Both initially and on ongoing basis and describe whether you intend to test each lot of incoming components for all attributes because remember in the glycerin guidance of 2007, it was on all each lot. Alternatively, if you intend to rely on the supplier certificate of analysis. Provide specifics on how you will verify each suppliers test result at regular intervals and include a commitment to test every incoming component block for identity at minimum. So that was just to be in compliance with the guidance. And of course, provide a comprehensive independent review of your lab practices methods equipment and analyst competencies. Based on this review, provide a detailed corrective action preventive action to fully remediate your lab system. Provide a detailed risk assessment for drug products that contain glycerin and are within expiry in the US market test retained samples for all lots. If you find that you released any batch for which results are out of spec indicate the corrective actions such as customer notifications and product reports. So this will give you a kind of a sense of the added cost that was incurred in response to the warning letters by this company. And this was just all plain in the guidance and everything in there was in the guidance. So the second warning letter is an example that I have again from 2018 is the that's where we have the data. It's from Foshan cities, China. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to establish the reliability of components prior analysis on which you rely in lieu of certain tests to appropriate validation of supplier test results at appropriate intervals. Instead, your firm relied on the certificate of analysis from unqualified suppliers. So again, the issue was when they responded to the warning letter, you fail to indicate testing plans for each component of the drug product and your timeline for initiating identity testing on all incoming component blocks. And your response also failed to indicate how you intend to establish the reliability of your suppliers if you plan to use their C of a to assess the adequacy of components. So, in summary, they wish them to provide a summary of your procedures for qualifying and overseeing the the adequacy of the contract facilities that test the OTC product. You manufacture and a comprehensive independent review of your material system to determine whether all ingredients from each supplier are adequately qualified. So hopefully this will give you kind of a feel for where these warning letters in relationship to excipients are focusing on, you know, focusing on identity, focusing on how you qualify your supplier. If you rely on the certificate of analysis. And just to kind of show where are what we discovered in looking at these warning letters, you can see definitely that there is a sharp increase in warning letters, citing lack of excipient ID testing for these incoming lots. And for the, you know, reliance on the supplier C of a or attribute testing. And again, you know, just looking at this from, you know, around the world. Over 25% of all FDA GMP drug manufacturer warning letters cited excipient testings in the period of 2017 to 18. So the key messages from these warning letters that I would like to emphasize here that were issued to form a manufacturing. Manufacturers marketing drugs in the United States was when they relied on the C of a for release of that material into production. They did not perform one ID test according to the regulations for in the recipients. And they did not verify the C of a information from their excipient supplier at regular interval. The contract manufacturers are responsible for quality regardless of agreements. That was another important aspect of the FDA warning letters and ingredient verification can provide documented evidence of conformity. So in summary, because, you know, excipients can comprise up to 90% of your medicine, the quality of these inactive ingredients is critical for the drug to be safe and effective. So usp documentary standards provide the appropriate validated test procedures to establish the identity purity quality of excipients. And then our reference standards are authentic specimens that have been proved as suitable for use as comparison standards in the use of usp and and tests and outsize. So just a little bit of information in terms of the, if you go on to the usp.org website and the landing page for excipients, you can find all of this information and lots more. But this is just some of our upcoming, you know, stakeholder forms open forums that are occurring over the next six to 12 months. So that concludes my presentation and question we can now open it up for questions. Yes, thank you very much Catherine for providing your slides here. Yeah, I can open up now the question and answer section. You can put your questions. It's best to put the questions into the question and answers field and not into the chat, but I will check both right now and we have already a number of questions. You can you can put into both but question and answers is the better one there because it's just that we can see it here. Catherine and myself. So, but we can we can go now through the questions. Let's start with the questions Catherine that I see here in the in the question and answers field. I can read it out to I can read it out to you so that the participants can hear it of course as well. So can you see my screen. I can see your screen in non presentation mode. I can see the PowerPoint in the non presentation. I see. Okay. All right. Great. Yeah. So the first question that we have in the question and answers section section is, should we make identification for all excipient containers in receiving or instead could we make identification identification for pooled samples only. That's a very good question. And I can give you an example of the glycerin in the glycerin 2007 guidance. It was specifically emphasized that glycerin should be an identification test should be tested on each lot. So, I think if you can assure that your, is it your pooled lot you're saying, if you can assure that you can trace it back to your original lot. You know that you can actually verify the identity of the lot that you have pulled into your sample. You know, I think if you can, if you can do that and justify it, you know, with your, with your local regulatory body, you should be fine. But again, it all goes back to documented evidence that you have done an ID test on the the excipient itself. That's that's that's the most important part that the regulatory, especially in the US, they want to make sure that it'll go back to the source of your suppliers material. And so, if those lots are coming from different sources or if the lots coming from the same source, your testing will have to demonstrate that you have, you know, you have done your due diligence to make sure that you have, you know, you've actually identified that individual lot. Thank you very much, Catherine. Another question is we we had the the federal code paragraph 211 84. And the attendee is saying here that this can can lead to misunderstandings that at least one test shall be conducted to verify ID when there is a combination of ID tests available for example in our monographs. And if that's the case, how should one be interpreted one of the ID tests or one container performing all the required tests. Okay, again, a very good question. And I think a lot of the confusion comes from the conformance to the USP monograph. And if you look again at general notices, our general notices, I believe it's section for we really give details on, you know, what identification testing means. And I think it's, I think it is section for but it means that you must conduct all the tests in the monograph. And then if the in the identification section, if it has more than one ID test. All those tests will need to be you will need to determine that you are in compliance or you conform with it. So, again, going back to conforming to, you know, the general notices section for what I would, you know, understand from the question is that if you have verified and you have documented evidence that your supplier needs all of the tests within the identification. Section of the monographs, just sometimes it can be three, four tests, because, you know, depending on the recipient, if it's a complex, it's simply a mixer recipient. You will use what they call orthogonal tests to give you specific aspects of the composition to make sure that if it's sodium chloride, well, it's not, you know, just in Florida. So you will do, you will have to have a couple tests in there to determine, you know, that it is the actual material. So, in part of your qualification and your verification, if you agree that all tests within the section of the monograph on identification that you meet them. You will do so by having in place a very good verification program and establishing that you meet you perform on a regular and routine basis with all of the tests in the identification section. Thank you, Catherine. There's a number of questions coming in right now. So we will definitely have a little bit more to to to test to tell here. There's one question about during verifying of the results of the COA with with the during testing there and with the testing when you verify the results of of the COA with testing is the FDA then expecting to establish limits about the variants of results or is it just acceptable that both results the COA and the own testing is within the specification. So, depending on, you know, sometimes for excipients, the COA will have additional tests beyond the monograph and sometimes, you know, they are those that are functionality and you notice that the FDA warning letters were also looking at those functionality tests. Sometimes they may not be in the monograph. So again, you know, you would have to you would have to demonstrate to FDA that, you know, these functionality tests on the COA you are in conformance with. So, in terms of those that would be. So again, that would be you would meet the COA, but if the tests are part of the monograph specification and there is an acceptance criteria there conformance as I mentioned under general notices, you would have to conform with those acceptance criteria limits or whatever. You know, whatever they would be in the monograph. Thank you. We have one question about very actual, very, very actual topic about nitrous amine impurities or other genotoxic impurities. The question is in in case that that excipients have genotoxic impurities or nitrous amine impurities in there, will they be made part of the excipient monograph as a kind of limit test or test on that GTIs. You know, that is a very good question and we're following closely. All the, you know, all the information that is going on in terms of the nitrous amines that are. You know, causing concern in the drug products. So, currently within USP our focus is and I will say FDA's focus as well is on the dosage forms. But we are paying close attention and we're monitoring, you know, that perhaps as they are, you know, finding out more and more information as to the source of these, you know, the sources of these nitrites and nitrates that are causing the problems. We will of course be working with our regulators industry. Once we have identified that if there are any excipients that could be at risk that we would be working to update the monographs into these these these nitrous means. Tests, but right now there, there has been no communication from either our, you know, FDA or our industry to update any of the. But again, I would emphasize that, you know, if there is any interest from the regulators or the drug manufacturers or excipient manufacturers to help us be. Update whatever. Excipients are at risk. We will be more than happy to do so. Excellent. Thank you. One question that can be. Well, yeah, let's see. I will post. Post it here. I will ask you should the name of the supplier of an excipient be in the registration dossier so that any change in supplier. Has to be applied as a kind of that variation once again in the registration of the of the product. You know, this is an excellent question. And actually this is something that USP and actually a lot of our stakeholders. You know, have been following along for many years. I think going back 10, 15 years that I think it was with the supply chain security act. I think it was there was a move I think at the time going back then to get that type of information into the dossier or the application. But unfortunately, I don't believe, you know, there was much progress made there. But yeah, definitely it's a very, it's a very good question and it would be very helpful. But I don't think any progress has been made. Because my understanding is that it's just the drug product and the API's need to register. And I think that's the big gap there in terms of, you know, kind of getting that kind of information on an excipient supplier. And of course, I think it also has a lot to do with the complexity of the, you know, how excipients are supplied. You know, at the end of the day, there is no such thing as an excipient industry because it's, you know, these components, raw materials, ingredients are supplied to foods petroleum chemical. So it's a huge area of, you know, in terms of where you're going to source your materials. Thank you. Another question is about harmonization. When a monograph is harmonized, for example, USP together harmonized with European Pharmacopeia. Do we have to perform the essay with a USP reference standard or a European Pharmacopeia reference standard? Very good question. So if you follow along on each of the websites from the Pharmacopeal Discussion Group, there's three Pharmacopeias that comprise the Pharmacopeal Discussion Group. That basically, even to this day, are the only recognized harmonized standards in the laws and regulations of these three regions. And on their websites, and if you go into USP as well, there is a whole section on the Pharmacopeal harmonization. And if you dig down, you can see that at the point when a monograph has been signed off by the three partners in PDG, there is a sign off document that accompanies the signed off or harmonized documentary standard. So there's two parts to it. And the sign off document provides you with very useful information in terms of what has basically been established as outside of harmonization. That it will never be considered as part of the harmonization effort. And one of those things is the reference standard. So it's clearly said that the agents and reference standards are those of the local jurisdiction. So that is something that is that was never part of the PDG's limit. So you'll use your local loan in other words. Thank you Catherine. Another question is him. Yeah, we should discuss that I think it's important is HPLC okay to use as ID test instead of the tests in the monograph. Instead of the tests in the monograph. Okay, well, so that there's a couple of layers to that. So, so as I had explained in the slides that, you know, the applicability and conformance under general notices, you know, in order to meet the requirements, then under our laws, you have to do the tests in the monograph. But there is a section in our general notices called alternative procedures. So if you're going about it as an alternative procedure, you want to use a different procedure to that in the monograph. That section of general notices will clearly indicate that if you do go that route. You need to show and demonstrate that it is equal or better. So determine equivalency to the existing compendial method that is validated and, you know, approved for intended use. So again, you'd have to validate that and you have to demonstrate equivalency. In terms of the identification section. As I said, there are several sometimes we do several tests in the ID section and some of those actually will. Well, you know, actually refer to the assay or impurity section where it has a HPLH PLC procedure. And what we will do is we'll use it in the ID as say it meets the retention time of the, you know, of the. We say listen, it meets the retention time. So we'll use that in conjunction with 1 or 2 other tests in the ID. So we do use the HPLC procedure in there because they would refer actually to other requirements in the monograph. And it's just an added assurance that you can demonstrate that this actually is it is the material. So hopefully that answers the question. We will, I think it does. I think it does. So we can follow up afterwards if it didn't answer. Yeah, we definitely can. Yeah. We have 1 question about co-processed excipients where at least 2 excipients are included. Only ID for each of excipients is not sufficient. The questioner is the same as there is no measurement of the ratio between the individual excipients. Is that something where we would agree to to that standpoint? Can you repeat that question? Yeah, it's I read it directly out here how it is written co-processed excipients where at least 2 excipients are included. Only ID for each of excipient is not sufficient as there is no measurement of the ratio between the individual excipients. Do you agree? Okay, so, so, so I this is just my interpretation. So we recently had a workshop at USP. It was May 2018 and 19 and it was on nomenclature. You know, the basically what's in the name and it focused on, you know, how to, you know, appropriately name excipients. But it also focused on how excipients were being labeled as part of a drug product. Because one of the things that we are seeing now is that there are on the labels of drug products, you have multiple excipients. When in some of the cases, they are actually co-processed excipients. And this was something that has come to FDA's attention that, you know, if, if, if you're, if you're putting on your label an excipient, while that excipient must meet if there is a compendium monograph there or intended, you know, that it's going to be in a drug product, it must meet that individual standard. So, so I think what we're, what we're trying to get at here is that I think there's confusion between, you know, individual excipients on a label, if they're called out, well, they must meet that standard for that individual material. Whereas a co-processed excipient is a very different, you know, totally different in terms of how you would label it and how you would characterize it. And for USP, unfortunately, the whole area of co-processed excipients is, is a very new area for us. Coincidentally, we did develop standards for excipients 20 plus years ago, satisfied MCC, sugar spheres, compressible sugars, these were examples, but at the time you, the, the, the whole concept of co-processed was not understood. And the fact that these co-processed excipients had additional components in there that was providing the added, you know, functionality. And so what we did in order to kind of, you know, understand how a co-processed excipient is different to say individual excipients, you know, in a drug product that should be labeled as part of the drug product. And what we did was we developed a kind of a concept or a criteria that USP will consider for inclusion of the co-processed excipient in USP. We published that in a STEM article, but unfortunately we have not advanced that to the level of a guideline. But, you know, the important point to that I'm trying to make here is that co-processed excipients will have, you know, multiple excipients in there, but they will be at very low levels compared to the nominal component and versus individual excipients that appear on a label of a drug product that by virtue of the fact that they're appearing on the label would need to meet that individual excipient margarine. So I can provide what I can do is I can send a copy of the STEM article where we put forward the criteria for what USP would consider the definition of a co-processed excipient and what we would be asking for to develop a standard for the excipient. And what we would need at minimum is a test, an identity test that can look at demonstrating how this co-processed excipient is different from a regular excipient. So meaning that, you know, it can show what additional properties that this co-processed excipient lends to the material. And what the additional components are in there because they usually do have additional components. So I don't know if that answers the question, but we are very, you know, we're in the beginning stages of developing admission guidelines for co-processed excipients and we welcome any support and help from our stakeholders and of course FDA as well. Thank you, Catherine. I think if you can forward that document you were talking about, I can forward it to the person that asked the question. Excellent. We are already at three o'clock Central European time here. Maybe one more question, Catherine, if I may. There are a couple of others and we cannot answer them all today, unfortunately. But we can follow up offline. But one question here, our materials used one, our last question here. Our materials used for production of a vaccine where the vaccine is the drug substance deemed as excipients as well, even if only traces later may remain in the final product. So in terms of traces of it being the final product, I think what you would have to do is refer to the section six hundreds of the regulations in, I'm talking about the US. But, you know, understanding from the drug side and the definitions I gave you earlier on in our presentation. You know that if it is part of the drug product, it must meet the standard if a standard is available, or if it's intended for use in the drug product. So if, yeah, if there is, if it is intended for use, a general notices section two and section three, I believe will give you the information you need there. You would need to meet the standard. Excellent. Thank you very much. I am getting a few comments here that this document that we were talking about for the for the question before is also of interest for others. So what I will do is I will send together with the slides. I mentioned that already that that we will provide the slides as a PDF together with the slides. I will send once I receive it. And also that document to all participants. So, so I don't think there's any, any issue with with that. So we are up against the time. I say once again, thank you very much Catherine. And also, thank you very much to to the participants to share that one hour with us here and providing all that interesting questions. We cannot answer them all today. But, but we try as much to follow them up online. So, thanks Catherine. Thanks to the participants. And I look forward. Thank you. And I look forward to to meet a number of participants, maybe all of you in our webinar in two weeks when my colleague ratio papa is talking about the general chapters 1224 1225 and 1226 on verification validation and transfer of analytical methods. So thank you very much everybody and have a good day further on. Thank you. And bye bye.