 That was not correct. So I think now it should work. Good morning, good afternoon, and maybe even good evening to you all. And welcome to our webinar today on biotherapeutics characterization. Well, yes, welcome once again, and thank you very much for joining us this morning, or your afternoons and evenings here for having a look what we are doing at USP there to develop new standards in that field. Before we start, let me introduce my colleagues that are also in the back today supporting me while I'm presenting the slides in a moment. So I have my colleague Dr. Ranjan Chagrabati with me, who is our Vice President for Scientific Outreach on the Biologics at USP. And I also have my colleague Dr. Anuupal with me backing me up today. She is with me in the Scientific Affairs team at USP, and she is the Scientific Affairs Manager for Southeast Asia with a focus, with a special focus on the on the biologics. My name is Christian Zeine. I am the Scientific Affairs Manager for the EMEA region, and I'm very happy to present these slides today to you and getting supported by Anu and by Dr. Anu and Dr. Ranjan from from my from my from our offices in in India. Okay, so I think let's go into into detail directly. Let's let's start. We will do a quick introduction of of use before we then dive directly into the characterization of of biotherapeutics, and there we will also talk a little bit about critical quality attributes, and then about the test methods that are closely connected then to those CQAs and also the USP resources that we have. And then afterwards I would like to introduce you to our new monoclonal antibody reference standards that we have set up three new monoclonal antibodies we have there. And we will also discuss about USP future standards then as well at the at the end. Okay, so yeah, let's let's start with with our USP and the 200 years of of building trust. So in 1820 we were founded as you as you will probably all know and back at that time when the USP was a single recipe book where recipes were set up how you can make certain medicines and 220 well yes 220 is a special year for all of us but for us now 220 marks our 200th anniversary 2020 sorry 2020 marks our 200th anniversary where we have now procedures and acceptance criterias in place in all the documentary standards together with the reference standards there to support the medicinal articles in the in the marketplace and of course not just in biologics but but also in the field and much more at the moment still in the field of small molecules which is also the area where I am coming from. So so that is how we evolved over time and also in the next years hopefully in the sense next centuries we will evolve further and go of course with what what the way medicine is progressing like the way that medicine progressing like is going we will evolve in the same in the same way. So with that quick introduction of USP let's go into into into detail here. So when we look at biotherapeutics characterization you will all know that that biotherapeutics and here we see a monoclonal antibody illustrated they are very very complex molecules so the characterization is involving a number of techniques at at all levels at which you can look on on such a such a molecule. For example when you look at the at the primary structure structure first then then comes the secondary and even the tertiary structure there the higher order structures so so so that is where we need to to look at that we also have a lot of modification that the protein is undergoing once it leaves the the the ribosomes and the reticulum when it is excreted from there and going then outside of the cell on this way there's a lot of so-called post translational modifications a few of those are also mentioned here on the slide and we will go to to that in a little bit detail afterwards once again so we have deamidation oxidation we have the carbon and the nitrogen variants like lysine truncation there and pyroglutamide formation and very very important is also we will come to that later once again as well the carbohydrate structure the composition the the glycolization so to say because that is very important for determining at the end the immunogenicity of your monoclonal antibody so it's it's very you see and then we come also to the biological activity which are total different beasts then all together and so we will not talk too much about biological activity tests today but go more into into other CQAs but CQAs I mentioned it now it's very important that you have CQAs in place that are describing what you want to achieve what your molecule is and and for that you need then standards which we provide documentary standards and to some extent then also reference standards a quick word to to critical quality attributes to CQAs when you look into the QA guideline from ICH then it is there the definition that it is a physical a chemical biological or microbiological property or a characteristic for which you have to set up an appropriate limit and arrange our distribution to make sure that your product is in the end always having the desired quality so so that's an important important feature not just for biologics also for small molecules but for biologics the list of CQAs is of course much much higher here is a kind of selection of common CQAs and and also then test methods for monoclonal antibodies so we would test on the aggregation we have the attribute of the aggregation and we will see later that this is done with size exclusion chromatography for example also maybe with gel electrophoresis and and even analytical ultracentrifugation but we will have an example for for size exclusion I mentioned already glycolization very important there is also sialic acid we will come to that once again later and then I mentioned the lysine truncation already deamidation and pyroglutamide formation these are all charge variants we will see how we look on the charge variants as well with the with the slides later and then oxidation and also process related impurities about we will not talk too much today here but but CQAs these are CQAs here and it's very important to have then public standards for for the test methods that are supporting the the CQAs so that's where where we are heading to that is what what usp is always attempting to to set up public standards that you can use not just for biological medicinal products but here of course today we talk about that so the the benefits of of public standards for biological medicine product is that it promotes transparency there's then clearance about the whole region what what the quality should look like what the limits are there and it's also a first step towards international regulatory convergence there so so we are still in the farm area we're still far away from from getting something that is accepted and registered in Europe to get accepted also without any problem in in in America or in other parts of the world and we are getting to that but we are still somewhat apart from that but but these public standards are the first steps to to that and promote the international regulatory convergence and we also have then there the topics of quality because then quality is set and it should look like that always in the in the same way and in that way it's supporting really the access to to high quality products worldwide so in the way that we provide the the standards there and enable then multiple manufacturers to to follow that so not every manufacturer need to set up their own standards once again or that is what we do with the with the public standards and in the end as you can see it here also as the last sentence on the slide in the end it is all helping them to ensure patient access to to quality medicinal products and today we are talking about quality biological medicinal products so so coming back to the to the cqas and then now the usp resources that we that we have there we mentioned already the attribute of aggregation and when you look into q6p into the guideline therefore specification of of medicines also for biological medicines aggregation is in the field of identity and purity we have there is the usp resource and there's chapter 12 9 or 129 there on the analytical procedures for recombinant therapeutic monoclonal antibodies also in that area the glycolization 129 129 129 also talks about parts of of glycolization gives there and and and insight into into that but but the most specific glycolization chapters that we have is the chapter 212 on oligosaccharide analysis the chapter 210 for the monosecaride analysis we will touch these topics once once again a little bit later and also important is although it is above above 1000 and as you probably know all the general chapters below 1000 are so to say enforceable chapters the the FDA can can enforce these chapters those chapters above 1000 are so-called informational chapters but also very often the regulators are referring to that and a very important informational chapter is the chapter 1084 on the glycoprotein and the glycan analysis general considerations and and giving you also some ideas of of strategies how you can check on the glycolization on your molecules your monoclonal antibodies there in in more detail we will come to that also a little bit later once again with a with a specific slide and then we have some further chapters here the applications of mass spectrometry and in the peptide mapping mapping to to check here on the on the truncations on the deamidations pyroglutamase formation there these these things we have in the chapters 1055 explained and 1736 gives a vast overview about the applications of mass spectrometry also in the biological field and then about process related impurities we have the chapter on residue DNA testing below 1000 and then also about above 1000 for the host cell protein measurements so with that quick introduction into what we have already as as public standards for for biologics I would like now to to get into more detail and then talk about our new reference standards that we have for for monoclonal antibodies and they are out since since summer and they are standalone reference standards they are this time not associated with a monograph or a chapter you will see later that we have analyzed those and provide information that we have achieved by using these chapters on our antibodies there on our new antibodies but they themselves are not associated to a certain monograph or a chapter so they include a very detailed characterization package each one and I will send out later this presentation and there will be links to the certificates so that you can see what we are providing there and the customers can have then a look on those characterization packages and can choose then their the map which is best meeting their needs based on the characteristics of their own product that they that they have and these standards they can provide support for for yeah all almost all stages in not the clinical stages so much but but all stages during during drug development so especially of course qc release and the stability monitoring and developing methods for that for that testing that is of course the main features or the main main fields where our maps can be can be used so let's have a closer look into those into those monoclonal antibodies I mentioned already that I that I give the link so in the presentation here we have the links to the certificates there and you can you can later than ever have a look on those so we intend the what we want the the user to to utilize the maps for is as a qualitative standard in a in a broad range of applications so you see it here mentioned internal essay control is of course possible but but also as an independent control material later than all the time in the bracketing fields there you can you can use it as a as a control material for for method development but also later to see that it that the method is still running stable over the whole time of the of the analytical run and that can be for a lot of physical chemical testing here on the intact mass we come to that later again also charge heterogeneity the size variants and then very important also the glycan analysis of course and it can can standardize that about across laboratories so so that that you can see if one laboratory works well with the with the method and and the the reference standard in there then it can show that maybe that method was nicely transferred from from from the sending laboratory to the receiving one so so also for for method development validation but also for method transfer these reference standards can be can be used a lot i mentioned already that we did rigorously tested those materials by the chapters 129 and also 210 and 212 and then put that information on the certificates and we also did that in in an interlaboratory study here and so so that the materials are very very well characterized not on the certificates but there is also a technical note this is not shown which is not not shown on the on our website or not on our website yet but i will send that with the email out to you i will send that technical note as a pdf as well and to you where we have additional data for these for these three monoclonal antibodies such as the intact mass and then olicosecarides a little bit more information there on the olicosecarides and then also capillary isoelectric focusing there as well on and we have further applications under exploration as you can can see here and once we have data for that we will also then extend the certificate and and also issue new new tech notes that that's also what we what we have in mind for that so let's have a quick look into into some of the the features that the that the monoclonal antibodies have so here we you see the size exclusion chromatography example from the general chapter 129 here for all the the maps here so you can see them here based on what i said based on the on the chapter 129 and you can see when you look on the on the first map on on map zero one zero zero one you can see that this one is having the most complex high molecular weight species fraction here coming eluting before before the monomer for example so this is maybe a very good map that helps you to develop your method so that you can resolve and get that that same picture on your with with your method then on the on that map for example and the the map two and three is showing better resolution here between the monomer and the aggregate so that can also be very helpful there for you and i mentioned already how you can use this for example on the system suitability criteria that you check that the method that your method is running stable and consistent over the whole series in that you check in the bracketing injections always with that precision control or that performance verification control here on the the reference standards so basically the users here can can utilize their own methods and define also the systems suitability criteria here based on the chromatographic similarity so and then you can show the consistency of your of your chromatogram that is that is here for size exclusion chromatography it's also possible here with the capillary ecto ectophoresis here in this case we have the data for the reducing conditions so you see for example here again from chapter 12129 you see for example here on the on the map number one that the level of the non-glycolacid heavy chain here is is very very low so this material would would be ideal to to test the method sensitivity for example and and also you can you can check on the on the resolution of course with all of the maps between the non-glycolacid heavy chain and the heavy chain here after having reduced the the antibody of course and there you can use the materials for for system suitability criteria for example like the resolution but also the ratio of the non-glycolacid heavy chain to the total heavy chain for example right and then we have the same here for for capillary ectophoresis under non-reducing conditions here and you can see here on this one that the map number three is having the the lowest purity for the IGG main peak but has a very complex range of impurities and and to have a method that can can yeah resolve all all these impurity peaks here from the from the low molecular weight species side the fragment side and that is of course also a very important feature so so map number three can probably be used a lot for for method development and then also qualification then you know so so that's what we what we have here for for the product related impurities we we also have but that is not on the certificates yet but it's in the tech node we also have here capillary isoelectric focusing data in the in the tech node for all maps and and you can also see which is not in the tech node yet also the mirror image on the bottom here for imaged capillary isoelectric focusing so ICIF sorry I'm stumbling here ICIF there as well which is the the the the newer technique and is a quicker technique of course because you don't need anymore to to elude once again all the all the basic acidic peaks and all the charge variants from the from the column with the normal from the capillary from the from the normal CEIF technique and CEIF is also quite useful for checking on the on the stability so we we are recently undergoing these are preliminary data but we are undergoing here stability studies and and once finalized we will also make that data available but you can see already here that our our map especially that one but it is it is hopefully the same for for all maps that we have now that we have here room temperature for four weeks that the material is stable there and it is a solution I have not said that it was shown further on the slide but I didn't before on the slide and I haven't mentioned it but this is in in solution we have from those reference standards in solution directly it's not lyophilized so the materials at room temperature for four weeks are are quite stable here so this is about the charge variants where we have information here in the in the tech note and then let's come to the to the important section of of glycolization here and this is a topic of course as you know which is very complex and very variable it's it's not template directed the protein glycolization I mentioned already when the the template is running the protein setting up decoding and and excretion excretion is the wrong word here but but it's set up of course in the results in the reticulum but it's undergoing then post translational modification afterwards by the interaction of many enzymes and and substrates and also by chemical influences and it very very much depends on the cell line factors also on the culture conditions and even later by purification so the whole downstream process is also important there on the on the glycolization so that means that there's a large possibility of significant variability there batch to batch and if manufacturing is changing here and and even then and also on the on the important field of biosimilars that is of course also a very large topic how is the glycolization pattern of the reference product and and normally you want of course with the biosimilar product come as close to that localization pattern as it is to the to the reference product so what can you do to to check on on glycolization we have for that we have the chapter 1084 where analysis strategies can be can be set up with so you can analyze at the intact lycoprotein level for example the yeah the intact mass there with with Mali and easy mass spectrometry you see here those highlighted in in green we will explain this information a little bit so we will explain or we have data for our maps with with this techniques in our certificate and also in the in the tech notes here very important so however also not at the intact level but at the level of the cleaved glycans so with the chapter 212 that is telling you how to to cleave the glycans from your from your monoclonal antibody and then for example how to analyze that with the fluorophore labeling and then capillary electrophoresis that is what we what we do also in in our with our monoclonal antibodies there and then also very important on the cialic acid point for the cialic acid is the analysis on the on the monosaccharide level we will come to that also in a in a second once more so this is showing the data that we have on the certificates and also in the tech notes for the for the intact mass here i don't want to go into detail but when you assume n-terminal pyroglutamation and c-terminal lysine truncation then the pattern that you would get here the interpretation that you can can make here is shown there and and showing here that you have the different mixtures of the maps with the different glycolization patterns here so that's that's that is shown here and you can use that of course also to to check if you are if you are mass testing is this running in the in in the right way so i don't want to go too much into detail here this is also i mentioned this is here to to check that the releasing of the glycans is is working that you can evaluate that method in your laboratory for the for this technique and feature we have the following information on the certificates here and this was done by i mentioned already by capillary electrophoresis and then we have laser induced fluorescence there in order to make um yeah to make them visible the peaks and visible but that is a very normal technique so that's the glycan analysis we also have cialic acid on there and you see here that we are expressing that that cialic acid content as the molar ratio of cialic acid to the protein and we we check then on the level of of the new 5 ac and the new 5 gc both both cialic acid variants we we are checking on that and you can see that we have very low levels in our maps for the new 5 ac and could not detect the new 5 gc in in our in our maps here so and that is an important feature that is also very it's a very critical quality attribute because the the level of new 5 gc is is showing how much um so so you always want to have um i'm probably just stating the obvious but for me it's it's very interesting information so with a with a level of new 5 gc you can see how how how much immunogenicity you can expect because it is hinting to to a strong animal parts still in the in the cell lines um as you know we humans can cannot produce a new 5 gc but are just producing new 5 ac and have that in in our proteins in our maps itself as well so so a low level of new 5 gc is also very very important to have low immunogenicity characteristics on your on your molecule as well so so that is also a very important important feature here and then we have also of course the chapters itself with which we have tested the the maps and from that you have seen before so there's the chapter 212 that we discussed already a little bit it's here explained we have also to to check that the method is running in the right way we have also the system suitability mixtures that you can see here on the slides and also linked here um to to those um to those system suitability mixtures are the certificates the usp certificates so that you can have an idea um what we um what we provide there with information there's also some more information about where the oligosaccharides are are coming from um so um we have here you see it here mixture is coming from a polyclonal ig g oligosaccharide mixture b is coming from um so we release that from from air nazi b mixture c is from alpha acid from an alpha acid glucoprotein and the mixture d is from from phytoine you see the properties mentioned here i don't want to to go too much into detail here um you can see that later once again um also one information this link at the bottom is going to um to an article that we have recently published or just in august it was it was published and it's showing additional n-glycans um um identified in the mixtures for a and b so so there we have um let me just have a look again we have there um um from we went from from nine identified glycan pants we went up to um to to um assigning 30 overall now so from nine we went up to 30 n-glycans connected to 32 peaks that we have there and in the case of mixture b um we have there 16 n-glycan isoforms newly assigned where it was five before here so um that is that is very interesting so i can i can very much recommend to to read that article and maybe um apply the same methods there um so um so we could show with that um with that um article with the techniques that we used that we used their helix and uh plc coupled with um qtof here and could show there that the um usb mix a number a is showing um a very nice and and good representation of of cili cilillated galactosylated and fruco related n-linked lichens and a better representation broader representation than than we have on comparable commercial glycan libraries that is what we are saying in that in that article so so please have a look there as well if you if you're interested in that and then the chapter 210 uh once again we mentioned it already um um that the information is on the certificate here as well and um we have there also for um for that chapter um on the mono cigarette level um the reference then it's available that i is used together with that the chapter the two um for the for the more human um new g new ac new five ac and the u five gc um reference standards here okay and with that i am already at the future standards and i don't want to go too much into into detail here um we consider um um to expand our focus beyond the specific product classes so um we we are evaluating right now a lot of standards for technologies and essays with a broad application um and also a broad broad impact you can see the technologies and the essays um mentioned here um i don't want to to read through them right now also in the in the interest of time to have time enough for question and answers in which anu and dr randran are supporting here um we also just one mentioning here with that slide um we also are exploring multi-attribute methods here um to um to get provide more efficient and comprehensive for that protein characterization so marmes is um a very important technique you can monitor multiple cqas there in in one single essay with mass spectrometry and it's it's very very important and we are currently evaluating several mob materials using this approach and uh and and hope that we have a standard for that in the future available um as well but that is still a long um long way down before we before we come to that so um thank you very much for for for joining me today um i i hope i could make it a little bit clear that that biotherapeutic standards from usp can can work for you we have developed them using a rigorous scientific process and multi-lab collaborative studies here um and i hope um it will provide a consistent benchmark for our users in the analytical testing throughout the the product lifecycle and um what i would also like to to make you aware of is our recent quality methods block i have linked um here to to that one as well where my colleague um dr anu upal who is also supporting me in the question um session now here will um is also together with a colleague is talking about the very important glycolization issues so and with that um i thank you already for your um attention and um would like to um to um get your questions so i forgot to mention that please type your questions in the in the question field um so that we can um can address them right so um let's see if there are already some questions in let me go to the so we haven't received any questions yet question i was checking into and i posted in the chat box as well okay yeah i see it also here but here we have now there's one question ah yeah there's one question coming in now um anu um what are the inn the international non-proprietary names of the of the maps um would you like to um to say something about that i can i can do it as well we don't um let me let me start first we um we don't mention um the inns um of the maps that were used for creating um the three monoclonal antibodies um we provide however the cast number in the certificates and also on the on the webshop um you can see already the certificates so from there you can conclude but it is um our policy not to name them um directly so that was one of the questions there exactly it was just one question so far anu would you like to um to um add something to to that information yeah um thank you so i would just encourage participants to ask more questions because this is the time you can clarify your doubts if you have anything related to these map standards but what i would like to say is that uh these standards are basically broadly applicable standards they are not though they are not related to any of the usp chapter or monograph but these these standards have been verified using the chapter 129 uh chapter 212 and 210 for glycan analysis so if you have some methods starting methods to work on using these standards but you are free to use any of your in-house validated standards so what's the advantage of using these standards is that uh these are map standards you can use for uh you know optimizing your methods i mean whenever you are you know transferring your method for r and d to qc lab or you are doing any tech transfer to a third party uh you are outsourcing your sample analysis often you you know you feel uh challenges that whether the data been shared whether it's replicated or not is your method optimized are you facing any challenges so these these standards can work as an external independent control which can help you in optimizing these conditions especially when you are doing you know multi-lab study or transferring your method from one lab to another and these are not specific to just one technique like what christian has already showed multiple techniques like uh size exclusion uh csds under reduced non-reduced conditions for impurity profiling for intact mass uh the mass spectrometric analysis and i would just like to add in there is that this is just the preliminary data we are working on uh getting more of the data but that doesn't restrict you in using these standards for other techniques so right now like what christian has showed is the data for intact mass but this can also be used for reduced map or peptide mapping so you you are free to optimize or use your own methods using these standards thank you very much for more questions yes i see that as well so we also have one question or maybe even two questions in the chat in the chat box that came in so so maybe i can read that out to you anu um there's one question how does our standards or these standards meet other national standards such as those from the um world health organization as far as i know uh for these antibody standards there is uh no WHO standard for physiochemical characterization the standard what we have is for potency assays and those are product specific ones so this is a general IgG class one applicable standards and we have got three standards so that you can choose the molecule based on the charge variant analysis and impurity profile like which one is more suitable to to your molecule so but WHO mainly they don't have these physiochemical standards as far as i know uh they do have some potency standards maybe Dr Ranjan if you would like to add it there yeah i think uh uh you know WHO what an AVSC does for WHO are mostly the potency standard and uh there is uh they don't develop physiochemical standard because i was a part of those WHO committees who are working on this biosimilar standard so uh that's a discussion we have so WHO left it for uh pharmacopoeians to develop these standards for physiochemical analysis and another question where you i think kristin there is a question where i see that how are usp working in partnership with epjp chp uh and uh uh do you want to give that answer or do you mean do you mean me Ranjan yeah so i can answer that uh see we have a from a pdg group where all of these pharmacopoeians work together usp epjp are very active member of that group and chp has recently joined there and they are also now an active member so we try to discuss among ourselves and see how much uh what we call i think you use the word align what is called as the harmonized methods but i think it is easy to say uh this harmonization because you understand the requirement of each region uh many times has come out are different and thereby the pharmacopoeians also want to stick to their region's requirement because the regulatory requirements are not seen in all the places so that's why you will see a difference although we are trying we meet regularly and try to see how much we can harmonize but if you are talking about the testing methods uh generally the methods which are used are common because as kristin has mentioned because these methods are based on the cqs so based on the the cq you want to figure it you want to analyze you have the standard methods there so i don't think that you will see a big difference in the methods for specific cqs but of course the the specifications and acceptance criteria they vary based on the regulatory uh requirements of each region thank you very much dr dr ronjan there's there's another question sorry about the training you can respond yes yeah it was it was also talked uh we i see that the question as well showing up here um about training on the on the methods like we do the solution training um i i am not not um i cannot answer that question at this point do you have any information dr ronjan or anu if we provide training for our thinking about providing training so basically uh there i mean we do have different training programs but related to specifically the analytical characterization what methods you have shown in your presentation right now we don't have any plans for that training program but we do have uh other training programs related to qc so i mean they can visit our website for that so there are some training programs available other thing is the methods what you showed uh are listed in the chapter one two nine which is the analytical procedures for monoclonal antibody characterization so they can always refer to those chapters for for the the details yeah i think i just add up a little bit there are some i think on demand training on 129 uh and also we are developing a training on the glycan analysis as per chapter 210 so i think uh christian can um work with us and then see that how we can uh take it to your region uh and and and the second thing is we are in the final stage of developing a training on method development and validation for biotherapeutics which also i think will be available so in next uh two to three months i think couple of these will be available and so christian you can follow up with your stakeholders and then figure it out how you can get it uh and deliver those yeah i think i thank you dr ranjan for mentioning that i forgot to mention about that so basically i'm working on that uh course for method development so that is specifically for uh highlighting the analytical considerations for the method development and validation for biotherapeutics yeah um we have another question here um if we plan to extend our standards also to different antibody isotype classes in the near future or to maybe more complex biologics as well yeah we are thinking about that considering the different types like i gg2 i gg4 but uh it's really i mean we are thinking and in the planning stage for that so right now it's uh difficult to say that uh by when they will be available but yes the plan is there yeah thank you very much christian you missed uh there were a few more questions above this question uh basically someone asked uh mr thomas has asked that other standards lyophilized and how others how are they stored to 28 degree how much do you have in stock considering availability of the same standard exactly that that would have been my next question i ask to you but please go ahead so uh these standards are uh provided in the formulation buffer and information about the formulation buffer is given in the certificates so uh question will be sharing the presentation which has linked to all these certificates so you can get the information about the formulation buffer and um and storage also is given there so what we recommend is that you can aliquot that and then store it in minus 20 if you want to use it for long um and yes we do have a huge quantity of stock available with us and it is from the same lot so you really don't have to worry about the uh lot to lot variability so in future this will be available i think for next 5 10 years something like that yeah we also have one one more question i can see here um what are health authorities expectations towards companies already producing biologics when a new usp standard is available for this specific biological probably is there internal evaluation of newly established usp standards toward in house standards obligatory yeah so that's a very good question and uh one thing i would like to clarify that when you are doing a biosimilar uh development or characterization you anyways need to show the biosimilarity with the innovator product so and you will have to have your in house difference standard for showing the comparison uh for establishing the biosimilarity and comparability studies the usp standard these usp standards are basically the system suitability standard which you can use uh to demonstrate the you know uh i mean this will help you in establishing whether the differences what you are getting is because of the experimental differences or because of the product differences because even if you're working uh with your innovator molecule and you're establishing biosimilarity over a longer period of time even innovative molecule tends to undergo changes right so uh then in certain scenarios it becomes difficult to explain whether the differences observed are because of the experimental variation or because of the product variation so in that case these are standards will help you in establishing the uh system suitability criteria over a longer period of time without undergoing modification and uh even these are standards you can use for completely characterizing your in house difference standard so please do not uh consider this that these are standards will replace your innovator molecule with which you need to show the comparability uh regulators demand that you need to establish your biosimilarity with the innovator molecule that is for there but these usp standards will help you in minimizing the experimental variations in generating the data over a longer period of time which will help you in you know uh convincing regulators that whatever variations or uh these type specifications you are setting those are very well meeting with with these standards thank you Anu I see one more question here um I think I can answer that one are the biotherapeutic standards aligned with other standards from from other geographies um when it is about um the um the documentary standards that I explained in um in the um presentation 129 to 10 and to 12 for example and also the other ones above 1000 these are at this stage not aligned with standards from other geographies from from other pharmacopayers for example that um that could be in the future could be one of our goals depends on um what what other pharmacopayers would do but at the moment they are not um they are not um aligned so they are not harmonized um um Dr Ranjan mentioned already um pharmacopayer discussion group before but this is so far um not um not done yeah I think with that I can see no more no there is uh one question uh I think these two are linked yeah yeah I see this one invalidating rates are high in biolabs further investment in its standardization of method is asked yeah and if survey was run on the QC bio methods and the rate of invalidating could be understood and training via WebEx develop the pharmacopayers need to developed into video yeah that's um I saw this comment as well that are very nice comments thank you very much to the participant who answered it or who post the questions or the comment the comment not sorry the comment not the question um I will get in contact with uh with the participant that um that gave these comments and um and maybe we can start some cooperation um from from there these are very valid comments I I um I yeah I can only uh agree to to that um there's also one more question I think we can not answer that really very well but but let's try um how much variation is allowed or accepted between a biosimilar and an innovator product is that something you want to comment on yeah I can yeah uh see uh I mean this is really a difficult question to ask and this is something it depends on the manufacturer it depends on the uh processes employed it depends upon molecule to molecule so you really need to understand your molecule uh what kind of processes you are putting into place uh the innovator molecule specifications so that is where you know people say process defines the product so based on that only you need to you know set up these specifications develop the molecule and depending on that only we can consider that how much variation can be allowed in there so this is something like we really can't comment on that but as a manufacturer you need to understand your processes and molecule and define the acceptance limits or specifications, criteria's yeah I had add on to that that's it this is something which you need to talk to the regulators because you know this is based on the regulator's expectation where you have to decide but one thing as an who was telling you know if you are a biosimilar developer the first thing what you do is you collect several batches of innovator product at different uh what do you call that different stages of that I mean some are at the early stage some are near to expiry date and like that because you know very well there are several publications that we change in the manufacturing process change in manufacturing side and based on how close it is to the expiry date the innovator products also vary and so that's why that's where you need to collect those huge number of samples and then go ahead and do a full study of each of the CQAs and then figure it out what kind of variation you are seeing with the innovative product and based on that you decide on the space that what are the what are the kind of variation you see in the innovative product and based on that you take your product and then try to convince the regulator that I have seen this kind of variation in the innovative product this is in the market it didn't show any kind of uh huge toxicity or immunogenicity or any kind of thing because end of the day regulator want they are concerned on the safety and efficacy so if you can prove with that that yes my variation my product variation is within that range and we know very well it is in the market it's synthetic and there is no issues so far reported then maybe you can convince the regulator but this is as Anu said this is of your understanding of the innovative product range and also place it properly to the regulator and convince regulator that your product lies within the range and it will not uh there is no difference in the in the efficacy and there is no safety concern yeah and just to add in there I mean if you're working on a biosimilar molecule just remember the inverted triangle the more you invest in the anal collecting the analytical data the more you characterize your molecule better you understand your molecule better it will be easy I mean it's a database evidence approach so the more you know a number of batches the the different analytical techniques characterizing your molecule better uh it will be easy for you to convince the regulators okay I don't think we have too much more time for for questions we are almost out of questions anyway the other questions I will address from directly to to those that are asked have asked for maybe to to go back to one question in the chat where do I find detailed analytical report in the usp store I will you will find the certificates of course of all the reference standards also when you go into the usp store and click through there to the to the specific reference standards I will however provide the presentation to the participants you will also find the links there to to the map certificates in there you will also find the link to the to the article that I explained and to the quality matters block from from dr annu that is in there and I will also add the technical note which I mentioned I will add to the email because that technical note is not yet on the on our website as far as I know last week it was not yet not yet on and yeah and and that answers also the other question that we had there still in the chat function in the checkbox if we are able to provide that presentation yes we are able to provide that presentation and I will share it with with the participants either today or tomorrow and there you have then all the links and also the technical note and yeah one more thing maybe I just thought to share that we are planning to do a round robin study where we want to work with several laboratories across the globe to generate more data because I could see one question on that of each of these techniques and also some of the additional uses of these monochrome antibodies so if any of these people who are today as participant here if they are interested in that they can reach out to you and then you can get it out how exactly they can take part in that round of instance yes thank you for for pointing that out run run yes absolutely if you if you are interested in that please reach out to me my email is mentioned my email address is mentioned at the end of the presentation so please reach out to me and I will see that I connect you to the to the right people in order to participate there with having said that yeah we have filled that hour thank you very much to the participants for joining us today and uh investing the time of one hour to to go um with us through this webinar and the question and answer section and thank you also um Dr Ranjan and Dr Anu once again for participating from India and supporting our EMEA office here in doing that webinar thank you very much thank you thank you and bye bye all see you at the next webinar in two weeks fully bye bye everybody bye bye thank you