 Let me greet you once again and today we will talk about the value of pharmacopayor reference standards and we will show you or show you how pharmacopayor reference standards say if you work and can increase also your efficiency and especially it's not even here on the question there especially how you can lower the risk of noncompliant results here of course. So our agenda will be that I will quickly give an introduction about the history of USP, we will talk then about conclusive results and what is meant by that. And then we look on uncertainty, try to understand that uncertainty is always there and how it also determines the risk of a noncompliant result, for example. And at the end we will have conclusions about the slides that we have discussed before of course. Okay, so let's talk about first of all about USP and when we talk about USP we talk about more than 200 years of building trust. USP as you probably all know from other presentations was founded in 80-20 by Liman Spaulding and his fellow physicians there and back then 200 years, 201 years ago it was just a single recipe book, well not just but it was a single recipe book. You can see here for example the tincture of opium, tincture of coesia, how it should have been prepared. That's not the case anymore nowadays in 2021. As you know we have procedures and acceptance criteria in place to support medicine and articles in the marketplace. You see here a few examples for biologic materials, the majority of our 4900 monographs with specifications for identity, for strength, for quality, for purity, packaging and labeling for drug substances and dosage form, the majority of those monographs are of course for small molecules still. And accomplishing that 4900 monographs are 350, approximately 350, 350 general chapters that are providing clear step-by-step guidance is also again for essays, for tests and for procedures. So and I also like very much to refer to the history of USP, so although it's not here in the slides please allow me to do that as well. So 1820 USP was founded as I mentioned already and then first mentioning in law that happened in the year 1848 with the drug importation act. And that act required imported drugs, so when US manufacturer wanted to bring material on the US market without approval back at that time. But nonetheless you needed to obey to that drug importation act so to say. Or you needed to acknowledge the drug importation act there. And that act was more or less saying you have to meet the standards for strength, for purity that are established and mentioned in the USP. That legislation really held at the beginning to solidify USP status as a national compendium and set a precedent for the future federal drug laws that came up. And the next important step was the 1906 was the pure food and drugs act. That was followed the publishing of a book which was called In the Jungle by a writer whose name was Upton Sinclair. And Upton Sinclair described in his publication in the book he described the practices in the meat industry, in the meat packing industry. And it must have been, I haven't read it so far, but I'm determined to and he described the practices in the meat industry and the meat packing industry in such a realistic way that the public was out crying and was demanding more regulation. And at the same time as the food was then more regulated and especially the meat part in the food but also food overall. At the same time also the drugs were more regulated with that law in 1906 with the pure food and drug act. And USP was being mentioned there as the compendium as well. And that was then even more compounded in the years in the year 1938 when the federal food drug and cosmetic act was set up. That also followed a scandal in 1937. The medicine elixir sulfanilamide from one manufacturer was poisoned with a solvent, with a poisonous as we know solvent, dieted to Tlingelkohl. And back then during that scandal 107 persons, many of them were children were killed at that, yeah, let's not say event but you know what I mean. And as a result of that the federal food drug and cosmetic act was set up and that one is still in place with a advancement up to now. And you can see here on that slide how USP's role in the United States law with its standards for drugs is then solidified in that federal food drug and cosmetic act. So when it comes to naming and identity to the strength, purity and quality and packaging and labeling and also compounding as a another topic here people need to refer to the to the USP need to look at the standards, the written standards, the compendial standards there in order to avoid that the drugs may be misbranded or adulterated here. And at that point I would also like you to note that although we have set up the standards or we are setting up the standards, we are an independent scientific nonprofit organization and we ourselves have no role in enforcement that role in the United States and also in other countries fells of course to the regulatory authorities and in the United States that is of course the FDA, the Food and Drug Administration. So with that let's leave the history of USP but let's talk about compendial standards now and how they are data driven and grounded in science. First of all they are set up compendial standards and I don't mean the reference standards now, I mean when I say compendial standards, I mean the combination of documentary standard and of reference standard we come to that in further slides. So that compendial standards are set up in a in a very transparent process and you all know that or probably all know that that before a USP compendial standard becomes official the draft is published in our Pharmacopayal Forum where all the interested public has time to comment for a period of 90 days to to that draft. The comments are then considered after the closing the period the commenting period has closed the comments are then looked at considered for its relevance for the relevance maybe the monographs the compendial standard will be changed based on the comments maybe not maybe even another draft version will be published in Pharmacopayal Forum but it could also be that then the the official version will be published and six months later it's becoming then really official and is is in force. So that's quickly the transparent setup process that we have for the compendial standard and these compendial standards they are used by manufacturers and regulatory bodies to help ensure the quality of the pharmaceutical products and by ensuring the quality they also of course ensure the safety and efficacy or they can assume that the the generic products are also safe and efficacious. It can be assumed there because the compendial standards on quality are based on the manufacturer's application approved in the United States by the FDA where you also have then the discussion of safety and efficacy in the approval dossier. So they help to ensure the quality of the pharmaceutical products and to facilitate access to affordable medicines that was found out by a study of Dr. Murimi Wastel that you can see here referenced and that publication is available for free if I'm not completely mistaken available for free in the internet as well as the presentation sorry the publication of my USP colleague Ian Walden that you see also there who found out with he and his co-authors with the study and survey that compendial standards are of a high value to the pharmaceutical industry as well because they significantly decrease the development effort of pharmaceutical articles here. One word to compendial standards in in general as well there's also a white paper out since sometime last year from the World Health Organization from the World Health Organization's International Meeting of the World Pharmacopeias you can download that also from the WHO's website and there it's also mentioned about pharmaceutical standards that they facilitate the preparation and assessment of the regulatory submission and provide a public mechanism for an independent verification of the quality and by that safety and efficacy like we have mentioned before verification of the quality of a product at any time during its shelf life and we will come back to the shelf life in a second when we are talking about conclusive results that's what we are doing now in the in the next slides so as you as you all know and as we have mentioned already before that to ensure the safety and efficacy of active pharmaceutical ingredients and the finished dosage forms these articles need to be of a certain quality and what USP and other pharmacopeias are doing is they are establishing that public compendial standards to ensure exactly the quality requirements and we have discussed it already in the slides before that such compendial standards and their revisions are established in a very transparent process and we have two types of standards I mentioned that also before already the compendial standards consists of the documentary standard that can be the general chapters or monographs for example and then physical reference standards very very often physical reference standards as well and these physical pharmacopeia reference standards they are almost always primary reference standards why do I say almost always well there is a number of antibiotics that are that the pharmacopeias not just USP but also the other world pharmacopeias that the world pharmacopeias establish in comparison to the international standards of these antibiotics which are coming from the world health organization so so these are a small number of secondary reference standards but the majority of the more than 4000 reference standards that we have at USP for example they are primary reference standards when used in the books in the in in combination with the compendial standard and they are also like the it's not not a completely open process but it is an open process that's not done within USP it's they these reference standards are established by a robust collaborative approach what do I mean with that it's not mentioned here on the slides but to to to let you know that we discussed that also in a webinar a few weeks ago what you always wanted to know about USP reference standards so I quickly talk about that process here that approach here as well so we have dedicated reference standard scientists that are setting up the collaborative testing that are designing the protocol of their collaborative testing and that design testing is approved by the reference standard scientists peers and managers there and when it comes for example to essay standards that testing protocol is writing that we need at least three different laboratories let's say it like that and each laboratory is testing the material is generating and then reviewing their report before they give it back to the reference standard scientists and then the reference standard scientists are reviewing that laboratories reports they look on the agreement between tests within one laboratory they are looking then on the agreement between the collaborators that there is not too much difference in the values otherwise it needs to be rechecked and retested very often the mass balance approach is used to assign label values for the quantitative standards there the reference standards scientists they also generate the label text of the USP reference standards there and all that information that I talked about before they collate that and more they collate into what is called a package a reference standard candidate evaluation package and that package the reference standard scientists are giving to the volunteers that we have in sitting in the expert committees and in the subcommittees and based on that package these volunteers and not USP themselves are balloting on the release of the reference standards there so that's the established sorry that's the robust collaborative approach we have mentioned here on the slide and of course you know that the reference standards assume the official status when they are connected to the documentary standard as it is outlined in the general chapter of of USP general chapter 11 on reference standards so let's have a look on the on on conclusive results here it's mentioned when in the pharmacopeias I have just put here the most important pharmacopeias up when assessing it's mentioned there that when assessing compliance with monographs that only the combination of the documentary standard and the reference standard is conclusive or authoritative that's for example excuse me that's for example mentioned in the European pharmacopeia in the general text 5.12 there where a European pharmacopeia reference standard is referred to in a monograph or a general chapter it represents the official standard that is a long authoritative in case of doubt or dispute and we have also the same not the same wording but with a similar outcome we have that in our general notices 580 where USP or NF tests or essays call out for the use of a USP reference standard only those results obtained using the specified USP reference standard are conclusive so and what is meant with with conclusive here in practice so it is that when authorities check a product for claimed compliance to USP for example or to any other pharmacopeia they pick the product from the shelf of the pharmacy for example or the drugstore and they check it against the combination in last consequence they check it against the combination of the USP documentary standard and the reference standard and that combination is the benchmark and that is and it is only that combination there and that is meant with with the conclusive result or the authoritative result like EP is mentioning here so and and also in in turn and consequently other combinations of drugs sorry not drug documentary standards and reference standards other combinations here are not conclusive and they may potentially increase risk here and let's talk about risk now a little bit in more detail and especially the role that uncertainty is playing there in understanding the risk and let's start doing that by looking at the measurement hierarchy so here in this figure on the top you see the defined unit of measurement that defined unit of measurement can be an SI unit for example it can be also dimensions derived from SI units for example with what is very relevant for us in the pharmaceutical area weight per weight percentage or as we have it on the label of our USP reference standards milligram per milligram material we are we are giving the purity values assigned values in that way so that's at the top of of a measurement hierarchy on the right you see here the procedures like here the primary reference measurement procedure which is the collaborative testing that we have discussed before which is assigning a value to the USP reference standard here we have other procedures down here for example the USP compendial procedure that you see below the primary measurement procedure on the left hand side we have the materials I mentioned already the USP reference standard there could be also the manufacturer's product sample then here and at the bottom we have always the result or the reportable value for example so what's happening is that with the USP reference standard you are calibrating the USP compendial procedure and normally you are directly checking the product sample with the procedure on the reportable result on the reportable value each of the steps are adding uncertainty and adding of course risk as well and what is sometimes happening or very often happening in the farm industry is that the in-house that the manufacturers are adding uncertainty and risk by that they set up for for convenience purposes for for cost purposes they set up so-called manufacturers house standards that are then used in turn to calibrate maybe once again the USP compendial procedure or another procedure here to check the product sample on the reportable result so and when you set up the secondary standards like that compared to the pharmacopale reference standard then as we have already mentioned it quickly but here it is also written then by that comparison you inevitably give or leave your secondary in-house standard a higher measurement uncertainty then the pharmacopale reference standard would have with the pharmacopale reference standard is always the lowest and of course also you introduce a higher measurement uncertainty for the testing result as well we will talk about that in the next slides and we will use the guardband principle there because with the guardband principle we can visualize uncertainties and the implications in a in a very evocative way in my opinion so let's have a look on guardbands first of all they are mentioned in more detailed in the urochem publication that is outlined here and we will only touch here the surface of the topic of guardbands but what we can say about guardbands is they are commonly used and they consider the expanded uncertainties of measurements and also when you want to know more about expanded uncertainties I would refer you either to the article that we have written and that is on the mentioned on the last slide or to the urochem publications there as well so but but let's stick here to to the slide so they consider guardbands are considering the expanded uncertainties and they should be in fact they should be as wide as the expanded uncertainties even we will come in a second to to why that is so. Guardbands are when I say commonly used and they are very often used in the food industry in environmental testing however they have also been suggested by Chris Burgess for example to be used in the pharmaceutical quality control by the publications that you see outlined here and also our draft general new general chapter 1220 on the analytical procedure life cycle is also referring and discussing guardbands there and their help for release control for example and analytical target profile and all the all the terms that are mentioned in in in chapter 1220 have a look into the chapter 1220 please as well it's it's very very very important and relevant and very interesting to read too so about guardbands a little bit more again so let's go to the to the figure that's shown here with the lower limit and the upper limit showing the specification zone or making up the specific specification zone and then we have guardbands set on the lower limit here and on the upper limit here and these guardbands are defining the overall acceptance zone then so and what what is now the function of the guardband it's somewhat simple it considers the expanded uncertainty that you see here symbolically shown by the Gauss curve so and the idea is that when you have a result right on the edge of the guardband to the acceptance zone that with the buffer introduced by the guardband you can still be sure it always depends what confidence level you have chosen for your analytical methods but normally you use a confidence level of 95 percent then you can be sure with that confidence level that the result is still somewhere the real result that you have measured here but the real result is still somewhere here or maybe also even here but that's not not bothering us so much when it's here that it is still with some probability you can assume that your result is here within the guardband not outside of the specification zone that is the important thing and what you should deal with with guardbands here so and to come to the monograph situation we all know of course when I say monograph situation I mean combination again here of the documentary standard and the pharmacopeia reference standard and we all know that uncertainties are not needed for the compendial purpose so what you see here is of course theoretical but it is nonetheless interesting to see what's happening the next step when you would would use an in-house standard here so for the monograph situation it is as you know the uncertainties are not needed for the compendial purpose so and so that's a theoretical situation here but we have nonetheless calculated it through to to show it to you and we use here the word surrogate in hydrochloride so that's an a code name for an API that is really having an actual usp monograph and respective reference standard and we have calculated the uncertainties here and added it as guardbands into the acceptance zone here as it is a theoretical situation as I mentioned we have still left the acceptance zone identical with the specification zone and you see also the guardbands are shown here in dotted lines so they don't apply correct really but they are there and they are interesting to to be used for the for the next slide here um we discussed that all in the in the publication in in more detail as you can see it here the link to the publication as well so so please have a look um there if you want to know more so that's that's now the uncertainty and risk for for surrogate monograph surrogate in hydrochloride monograph situation and what is happening now when we come to using a secondary standard for for surrogate in hydrochloride so that scenario is changing then there of course when you use a secondary standard that was compared for its assigned value to the pharmacopale like we have discussed before and of course as we have also discussed already on the on the slides before that insertion of the in-house standard is an additional measurement step and that additional measurement step is adding a larger uncertainty for the secondary reference standard and consequently then of course also for the expanded uncertainty of the overall measurement result of the reportable value that is it's increasing increasing as well so the outcome then is then here an extension of of the guard pin you can see here that part added that the secondary standard is introducing and it would of course narrow down the acceptance stone here so however per definition only results obtained with the original pharmacopale reference standard are conclusive there is now a real risk of obtaining an auto specification result without realizing it when you would work with an unchanged acceptance stone so let's let's assume you would be here where we have been before on the slide exactly on the edge of the guard band and the former acceptance stone the uncertainty now it's not shown here the uncertainty now would be bigger and we have a much larger probability that the result would lie outside here so therefore you should adopt the acceptance stone here and should not work with an unchanged acceptance stone and that is what we have done here to illustrate that risk we have added the additional measurement uncertainty reaching to the guard band so that it's reached further into acceptance stone there and now also the full guard band should be considered because we have not the combination of the documentary and pharmacopale reference standard anymore but another one and only that combination allows as we have shown on the slide before allows theoretically for congruent specification and acceptance stone for the user however it's not really possible to estimate how much narrowing of the acceptance stone is necessary as they don't know the uncertainty of the pharmacopale reference standard we have discussed it before that uncertainty for the for the pharmacopale reference standard is not needed for the compendial purpose and it's therefore not provided so that's the that the risk that you are introducing with with a secondary reference standard compared to the pharmacopale material okay and that risk can also be compounded it depends on the on the method precision of course to a certain extent and I'm telling the the experts of you that are listening here I am telling those experts of course nothing new so when you come from the pharmacopale reference standard to the secondary by the comparison and we have seen it then the reference standard the uncertainties of reportable results the expanded uncertainties of reportable results are increasing these are the values that were shown in the slides before they are also increasing when the method that you would use would be less precise and would have a larger relative standard deviation for example that's also nothing new it would also it's not shown here on the slides of course but it would also further increase when you go from a secondary reference standard even to a tertiary reference standard that's something that is normally not considered in the regulatory environment at all really but we know from evidence that this is happening sometimes that people are setting up their own in-house standards against what is already a secondary reference standard creating a tertiary reference standard increasing more risk even there then as well so to to keep your eyes here on that and and come with the with the message here which is not a surprise as I mentioned already inevitably the guard bands they are widened up with transition from pharmacopale to secondary to maybe even for further lower grades there and of course they are also widened up with increasing measurement with increasing relative standard deviation of the measurement so and with that we are already coming to to our conclusions here so let's let's talk about that and from our point of view here the setup and use of secondary in-house reference standards is of challenging complexity I mean we should maybe put here a disclaimer in users are always advised to consult with the regulatory authorities where the products are marketed for guidance on the qualification of in-house standards and the use of a non-usb reference material or reference standard but so we have as I mentioned before we have no role in enforcement there and it's up to the regulatory authorities but that is here what we think and what we take as a conclusion here so the setup and use of secondary in-house reference standards is of challenging complexity and might be more complex than you than you think at the first glance here so if you would use directly on pharmacopale reference standards wherever possible that saves you a lot of time and energy that are related to all the points that we have mentioned already before here we have the inherently larger measurement uncertainties of the assigned values of secondary standards when they were compared to primary pharmacopale reference standards we have then also of course the larger uncertainty to consider that would be obtained the larger measurement uncertainty of the measurements of the reportable value that that would be obtained with those secondary in-house reference standards and and also you need to to look and give time and energy to the to the question of the difficulty of and the effort related to correctly adapting the range of the acceptance zone the rejection zone compared with the range that you have maybe found for yourself with the pharmacopale reference standard and what should be definitely kept in mind that it is inappropriate to work with with the unchanged zones there so establishing secondary reference standards always leads to more risks and the approach that I described here may increase some risks there are other approaches that might introduce lesser risks but normally such approaches and we touch on one also in our in our publication in in Phamtech which is on the side below once again and which we will also mention again on the on the last slide we touch on that also in in our publication but but it is it's safer work but it's it's more elaborate there and is also introducing a lot of of work and time and energy that you need to to look on the to to use on the secondary standard and last but not least please remember that only pharmacopale reference standards in combination with the documentary standards in the end deliver conclusive results like we have mentioned that before and like it is written in the usp general notices and with that I come to the final remarks and acknowledgments so I would like to thank my co-authors here Stephen Walfish Ravi Reddy and Doug Podolsky these are all colleagues from from usp but we also have Jane Weitzel as a co-author here on the publication where you see the link to and Jane is a usp volunteer and right now in this cycle she is sharing our expert committee on data quality and and measurement so here you find our article that I referred to before and here you see some other useful links and also the link to our EMEA webinar playlist on on usp's youtube channel and with that I say thank you let's let's stay connected and I will close now the presentation