 To our webinar qualification of dissolution testers, USB performance verification test PVT. My name is Jan. I'll be one of the moderators hosts for today and welcome to our webinar. I would like to welcome our speaker for today is Alex Fierta, just to give you a quick information on him. So Alex's career includes seven years of experience as a pharmaceutical quality control chemist and eight years with the SOTAX group, working as a sales representative and then as a sales manager for Europe Asia Distributor Market Business Unit. He has been with us at USP since 2005 and he helped establish the first international office at the USP setup to US, which was here in Basel, Switzerland. So ever since he has supported USB customers on technical and commercial queries, organized regional user forums and educational courses and provided guidance to collaborators on the up-to-date monograph program. Since 2020, Alex has a coordinating role with the team covering EMEA Europe, Middle East and Africa, overseeing all sales supporting programs. So welcome. We just to give you some agenda outlines, we're gonna start. It's gonna finish in one hour. We're gonna have a 10 to 15 minute Q&A session at the very end. Please, when you have a question, select the Q&A box, which should pop up on your lower right half of your screen, where you can type in your questions and they will be fielded by our co-motorist, today, Mihail and Christian. We do ask you when you write your questions, please to write them in full sentences and please write them that they make sense so that we really understand what it is that you're asking because unfortunately we will not really have a time or opportunity to ask you to clarify that question again. So please try to write those questions in a clear manner so we can fully understand them. We will have a very short survey at the end. So if you'd be so kind to just take a minute or two to fill out that survey for us, to give us your honest and truthful feedback, we really appreciate it, it's very important for us and it will help us to build a better experience that you have with us. All right, with that. Thank you and please enjoy. Ask lots of questions. Alex is all yours. Thank you, Alex. Thank you very much, I appreciate the introduction. So if you wonder who of the three that you see there in the picture, that's me, just quickly raised the hand. To my right is Mihail Demen and Christian Seine are to the right, both helping me in the support of doing this webinar today, which I very warmly welcome to. Thank you very, very much for attending. I appreciate to see so many participants for today's webinar. I also would like to thank my colleagues who are obviously helping me to set this up and making sure that everything is working in the background smoothly. So let me jump right in and share my screen so that we can start with the presentation. And if I'm doing everything correctly right now, I will be doing this in the screen mode and have the opportunity to duplicate the slideshow and now with the confirmation of my colleagues, you should be able to see the full screen. So as Jan said, my name is Alex Fichter, which is probably more internationally pronounced. He already introduced my role within the USP. And today I'm going to speak about the qualification of the solution testers with the assessment of our standard called PBT performance verification testing. And before you do that, you have to go through several steps, which I'm explaining as well. Unfortunately, this webinar is going to be very short. We usually have one to two take classes that go more into that with the typical fundamentals in this solution and also the variables in play that this solution is often giving us challenges with. And I hope with this very short time to be able to give you a glimpse. And if we see each other again, maybe in a future opportunity with a full course that we are offering, that would be even perfect. For the sake of giving you an understanding already regarding the slides, unfortunately, we cannot share these slides. They are part of an educational program, which we are allowed to use for the webinar's sake, but we can unfortunately not hand them out. So I hope you understand. Again, let's dive into the outline for today's webinar is to discuss from the general chapter 711, the solution. The apparatus one and two, because they are essential part of the qualification using the PBT test procedure. Before we do that, we're trying to identify controlling sources of variabilities that play tricky roles in the performance and release of certain rocks, specifically with the prednisone tablet as they are designed to be variable so that you can detect the sources of variability when coming from the apparatus. The qualification of the dissolution test is where we start with the simple AIOQ principle, which is defined in the general chapters for instrument qualification, also in the USP. And then we go into more details with the performance verification test PBT. So the goals in general for this solution, the goals are, you know, varying obviously from what you aim to do with the dissolution itself. Obviously for those who want to identify changes in the formulation of the processing during the product development, they will see certain benefits that's coming from a rightly equipped and qualified dissolution tester. Differences thereafter that could be assessed and further up dated into the drug development. But if you want to also assess the drug performance during manufacturing as an impossessed test or a batch release test, the solution is the ideal quality and qualification test to go for. Variations in the manufacturing process can have critical influences obviously that you would be able to, you know, be view with the performance of the dosage form that is used for this particular test. And the link to bioavailability studies if you want to compare an already available market product to, you know, what you would do then in bio equivalence for the drug formulation that you are in developing procedures. The apparatus one we call the basket tester. It is comprising like the apparatus two, the paddle tester of a glass inert transparent material, which usually, you know, is clear. We have also seen some amber coated glass material in case, you know, your drug product is light sensitive, but in the most cases it is glass. If glass is an issue or, you know, if you think the material in terms of handling and cleaning is not the right thing, an alternative to plastic vessels is seen as well. All are comprising of a hemispherical bottom, which means the, it's a half round of a bowl. We know from the general chapter, vessel sizes of one liter, two liter and four liter, whereas a two liter is just an extended version of the one liter in terms of height, the four liter is also wider. The basket that is used here comprises of a 40 mesh wire opening that is can be cold coated. Again, it is stainless steel, electrically polished. So from that point of view, your drug product should not actually go into a chemical reaction with the material that it is exposed to, but if stainless steel is an issue, cold coating will be accepted by the general chapter as well. The steering for the typical tests given from the rotating steer and motor assembly on top of all that, we know of test procedures in monographs that typically have 50 to 100 RPM. The dosage form for the basket is placed obviously inside which has some flaws and cons for material that if you introduce it into the vessel that is floating you would have or is buoyant, you would have an opportunity to keep the dosage form immersed all the time. So that material is not coming up to the surface area of the media top and is also giving you a more constant release characteristic. Sometimes there are drawbacks with drug formulations that are falling into very, very small particle size below the 36, 44 millimeter wire opening. That means that material could flush out. Particles could flush out of the basket that still contain undissolved active principle and that will fall onto the bottom and there it actually doesn't really do a good and reproducible job in releasing the drug product. For the paddle assembly, we use the same glass. Instead of a basket, we use a paddle that is attached to a shaft. The same inert material is used here. We are also allowing the opportunity to coat it either with peflon or there are even, you know, shafts and paddles available that are fully out of peflon material made. Agitation with those methods used with the apparatus too in the monographs that we see are typically around 50 to 75 RPM. Now the sources for variability from a dissolution test system in general may result from its environment obviously where it is placed. So it would not do good use if you place the dissolution tester on a instable table, for example. If you have nearby equipment, you know, that because of their machinery and because of their design are, you know, applying variations in terms of vibration to the table which will be picked up during the dissolution test and the dissolution tester itself. So the devices from the dissolution test play a typical role ourselves when we do the sampling and the processing, the filtration, dilution and transfer we can play a critical role. This is not full and related of the dissolution tester but we have to consider that these are variabilities in general when doing the solution tests. We will talk about filtration and sampling at a later stage. Transfer of media is probably a good thing to talk about too. And the details of the testing procedure. You have your validated procedure. You follow those validated procedures from A to Z. So it is the case with the PBET. You have a test protocol that you ideally follow, you know, very close to what it is required and only then you are really able to assess any results that you obtain from that PBET test to the certificate that is giving you, you know, the range and limits of what you are supposed to achieve. The analytical instruments that are used on top of the dissolution tester obviously play a certain goal. As I said before, we all have, you know, our daily moods and daily, you know, stresses and so forth. So ourselves as analysts have to be very careful that we in a very reproducible way do the testing on a common basis. Now, last but not least, the specimen itself, I mean, every tablet, it's a formulation, including the one for prednisone PBT tablet has its inert intrinsic variability. But I can assure you when it comes to the prednisone tablet, in terms of bait variation, content variations, we have very, very strengthened and narrow specifications for the manufacturer who is producing the PBT tablet. I thought it is a good idea for you to show or understand the fluid dynamics that are happening during the test. What you see on the left-hand side is kind of a top-down bird view, a circulation of a typical apparatus to steering blade assembly. You see obviously from the heat map itself that, you know, the colourful it gets, the closer it is to the shaft outskirts that are, you know, in the highest in terms of hydrodynamics. To your right-hand side, you see the vessel with the shaft assembly, with a paddle here in the same sense. You don't see the paddle left and right. It is in rotation. But what you can see here is the more orange or the more red it is, you see more turbulence, more energy, more agitation than anywhere else. And what's interesting, if you look at the bottom of the shaft where it is blue, this is a zone where actually not much in terms of hydrodynamics is happening, which is where you usually have your tablet, your capsule or whatever is placed underneath the paddle. So imagine if you are in a situation where you are forced to dissolve active principle from a dosage form where it's seated and not really well agitated, probably the release rate is a little lower as if it were anywhere else in the vessel place. So considering that fact, for some of the developers in this solution method, this plays a critical role. Some of them are even using peak vessels, which means, you know, in the development still possible, you can use vessels that have kind of a glass peak or a glass bowl or whatever, just to distract, you know, the specimen to be sitting underneath the shaft and be exposed more to energies and fluid dynamics around that. Again, as I said, for development purposes, that is a great thing. If you want to start seeing some early results in terms of the release of the drug formulation, that's fine for routine and quality control batteries. This is no longer a dissolution vessel specifications that you use. As far as I am concerned, I haven't seen any monographs or any approved products from the FDA or other authorities, but I might be wrong there. So not only for the agitation here, but also considering when you take the sample, it is actually meant on purpose that you have to take a sample, how it is described in the General Chapter 711, in the so midway between the media surface and the back paddle top or the basket top, at least one centimeter from the vessel wall. Because with 50 RPMs and, you know, only 30 minutes in in the case of PBT or any immediate release drug product, or let's say it's likely modified and we have a longer release characteristic, you will see, you know, differences in homogeneity in concentration eventually, especially with 50RQM. So it is essential that you take the sample at a spot that you define on a regular basis at the same spot throughout the whole test-to-assembly, whether it's six vessels, seven vessels, or eight vessels you have in place. The specifications for drug release are based on six or 12 or 14, depending on the design of your instrument. But again, my aim here, my point here is to be reproducible with the position of the sample that you are taking. So this is very interesting. And of course we can go there into much more details. I am not the scientist and I'm not experienced enough to really tell you the details, but I thought those big ones that could contribute in terms of variability. And by the way, those of you who have witnessed the performance test already once, when the tablet starts to release, you know, the first couple of minutes when the tablet breaks apart down here, you see some material floating at the beginning, but suddenly then after, you know, five, six minutes, everything starts to relax and the material comes down to the bottom. But what is shaped is this kind of a peak. And this peak for PVT is wanted. You know, you want a reproducible surface area throughout the whole six vessel assembly to be able to have controlled release of the specimen in place and be able to extract any variability that may come from, you know, the surface area that is produced by this peak. If the peak is not formed the way you are used, you know, this powder peak, if it's kindly kind of left shaped, right shaped, or it is flat, these are all indication that something is going on within the tester itself. So our experience has shown that the more flat this peak is, the more vibration you have, either coming from the dissolution tester itself, the motor steering elements, a circulation pump or whatsoever, or nearby sources. In the worst case, you have a centrifuge, a product that's just next to the dissolution assembly that is really applying vibration to the tester. So you will see differences in results if just only by visually looking at how this shape is occurring and whether it's left centered, right centered, flat or whatever. In our experience, you can immediately stop the test because you will have variances in results. How big, it's a question mark whether it's still, you know, adjustable up to you to define, but as a variability, I'm giving you an alert here. This is essential. So, but before even doing the PVT, we are looking at the instrumental qualification, the AIQ. And we have a chapter for that that is called 1058, which is an informational chapter, all chapters above 1000 are for information purposes only. They are not regulated, nor are they enforced by the FDA, or shouldn't be by any other competent authority. Everything below 1000, so in the case of the general chapter 711, this is a mandatory chapter. So if a monograph that contains the dissolution procedure or dissolution test that calls out for the dissolution test to be done according to 711, it's a request to do that. It's mandatory to do that test accordingly to 711 and 711. Also describes the qualification of the instrument and is calling also for the system suitability or the performance verification test PVT. But the analytical instrument qualification starts out with the DQ, design qualification. Installation qualification is next operation qualification is the prerequisite for a performance qualification. Operational qualification OQ, what you also understand as the mechanical qualification, there are basic requirements coming from the general chapter 711, but ASTM and other guidelines are extending these steps and even narrowing the specifications to what you know from 711. Because remember, the general 711 has been developed many, many years ago with the solution apparatus that have not been designed the way they are engineered today. So everything is much tighter, much smoother, much, much better for those testers these days to comply to the standards in 711 is a given. So narrowing down the specifications for up-to-date equipment is only a logical procedure. Having said this, this is all fine, but this alone would give you the whole story of the performance of the dissolution tester. That's why we do on top a holistic test and so-called umbrella test, which is the performance qualification that makes sure that everything that is applied to the dissolution tester is working in accordance. The design qualification for you is a typical thing at the beginning before you buy an equipment or before you use an equipment that you already have for a new project, or you continuously verify whether the purpose for this dissolution tester for the test that it is addressed for is still good. So you describe everything, the parts over to whatever it is required to be doing, so it successfully is doing the dissolution for you for the drug product that you are assessing. The instrumental qualification is essential, especially when you have a new equipment. You would want to check every single part that you obtain. There are manual checks that you can do. There are visual checks that you can do. All equipment, all accessories supposed to be delivered to you according to the specifications of the Channel 711 and you usually get a certificate of compliance from your supplier. I encourage you to check that. Don't take this for granted. Check it please again, especially with the vessels. They have a very wide, I would say, specification. If you look at the inner diameter sticks for a vessel, a one-liter vessel, it's 98206 millimeters. So that's almost a centimeter variance that you have from a small vessel to a larger vessel. And if you go back to that fluid dynamic picture that I saw probably before, the variations, if you are at an extreme small within spec vessel or an extreme wide within spec vessel, the variances and we have shown this in studies can be different and can make a marginal difference to your distribution results. So please check your equipment, your accessories under IQ before you assist them with the mechanical qualification. A thorough mechanical qualification is important and with our recommendation before every PBT should be done again. There are customers who are doing the PBT on a yearly basis, other on a six-monthly basis. We always recommend how many times you have the equipment in use, how many batches you are releasing that should qualify for the number of the qualifications that you are doing. If you have a dissolution tester that releases batch, let's say on an unregular basis, it may satisfy to do this on a yearly basis. But if you do, you know, several batches a day, for example, which is obviously the other extreme, just think of the fact that, you know, as soon as something goes wrong, you know, and the dissolution tester is the faulty part of your product that is released not in the right way or is giving you results based on the performance of the dissolution test and not on the formulation. You identify this as an issue. How long ago or how much time ago has this started to go wrong already? And how many batches are in question that you have released based on this dissolution tester that you have now identified to be faulty? So the more regular you do the PBT test, the more insurance you have, you know, that the tester is really performing over the period of time that you have it in use. Why is PBT a requirement? As I said before, it's a holistic test. And it really, you know, encompasses all the metrological parts before that you do, but it's giving you a holistic answer of the test performance. It's also an ability to uncover influences and system variabilities in dissolution testing. The PBT is doing all that for you. Ability to compare intra and interlab variations. You can use PBT to do that, method transfer, for example. If I wanna mention just one way of doing. PBT is a globally recognized method for dissolution system. US Pharmacopeia is the only pharmacopeia that describes a specific formulation with specific test procedures. Other pharmacopeia who recommend you to do a similar systems suitability approach, but you are left there with your own interpretation on what to do with PBT and our way of giving you these type of recommendations and trainings. I think you are in a safe side in applying the performance assessment for dissolution tester for various requests from various competent authorities. Just before I dive into a little bit more in detail with the PBT itself, you can find lots of resources on our website as well. Lots of videos, lots of descriptions. We have a toolkit there that not only describes the essentials of the PBT, but the dissolution tests in general. We show you how to effectively degas the medium if your drug formulation is required for a medium to be discussed before you put it into, before you put the formulation into the media. For PBT and the drug product that is on tablet, it is essential to degas the media before it. And now you're telling me this is nothing to do with the performance of the dissolution tester itself, right you are, it is not related to that, but it is related to the sensitivity of the formulation itself that is releasing the drug differently if the media is degas or not degas. And the test protocol to do the test will ask you to degas the medium. All those laboratories that helped us in the collaboration to establish the specifications have been doing this test. So the results obtained, the specs obtained have been on the basis that every time the media was discussed when the test. So only when you also degas the media you can really compare your results against the specifications. The certificate of the pre-neesone tablet, I hope this is the current one. Yes, it says September 30, 21, the current tablet formulation with the not RO8-OJ1 can be used until September 30, 2021. The last one that was in place actually expired just a year ago. So this is a year of expiry that this particular lot can be used. And if you look at other reference standards from USP, this is the only real reference standard at USP that has an expiry date applied. But it's also the only formulation as a reference standard. Everything else is an ingredient either an recipient or an API. So there you have a protocol. You are asked to follow that to the point how you discuss this in solution media. The procedure itself. And I really encourage you to follow that by heart. The gassing of the media, as I said, is essential. You would heat up the medium while gently staring here at the left-hand side up to 41 to 45 degrees centigrade. Why at that temperature? Because after you apply the medium with vacuum when you pull it over into that red flask through a filter mechanism and at 100 millibar vacuum, the temperature around 41 is simulating under degree which is usually the boiling point of water. And the boiling point of water would be the ideal scenario to decrease medium. But nobody's doing that because waiting for the temperature to come down to equilibrate the medium again is not what you want. So what you can do is simulating the boiling point because the solubility of gases is nearly zero at that temperature. So you simulate that procedure. And the other positive aspect is that once you transfer the media directly into the vessel because you have a gravimetrical method to do that or you put it first in a measuring cylinder in an old or room temperature measuring cylinder you will actually cool down the medium quite a bit before it's actually placed into the vessel. So consider the drop of temperature that you have because you would want to start the test with a degassed medium immediately. So that if it's exposed to environment the medium will not re-gas or re-erate again. So you would ideally define a temperature at the degassing of this medium that you know when you transfer the medium has exactly or let's say plus minus 0.1, 0.2, zero degrees centigrade so that you can immediately start with the test. There are other duration procedures. This one is used for the PBT and we encourage you to do the same thing not only because it is very efficient but it's also very inexpensive and probably can be used anywhere. What you will achieve when you do this test this medium degassing is rest oxygen concentration of about 4, 4.5 ppm. Everything that is below 6 ppm will stay in terms of results when you look at this charge. So left hand side percent dissolved and oxygen concentration to the right will result in the normal you know after 30 minutes released concentration of your sample pre-nezone. As soon as you know the ppm level of dissolved oxygen is going above six you will not only see much higher results but the variation of these results are much higher. So a medium non-degassed with pre-nezone will give you between 70 and 80% released after 30 minutes which is double the result. So no wonder why it is critical to do the medium degeneration here. When you do the basket test with PBT it is essential to dry the baskets and to put the tablet into a dry basket wide. Not only the pre-nezone formulation is sensitive to degassed medium or non-degassed medium it is also sensitive to picking up moisture. The longer you expose the tablet when you take it out to a blister to environment humid conditions or even to a wet basket the more different your results are going to be. So again for the sake of reproducibility make sure that your baskets are all dry and you put the tablet into a dry basket before you inverse it into the vessels you can do an immediate start by introducing all six baskets at the same time but you can also do a staggered input and then accordingly take the samples to the time differences to which you have inserted the baskets to. Timing is important because remember when we take a sample after 30 minutes the pre-nezone tablet has only released about 40% of its whole content. So it's in the verge of that the solution curve going up very shortly. So the time a tolerance of plus minus 2% at 30 minutes which is 36 seconds before and after 30 minutes you need to take the sample of all six if you have a seven station, eight station the solution test that you assess those stations as well but PBT the time gets even shorter. It's the recommendation to do it staggered as well. With the paddle again you allow the tablet to fall beneath the paddle blade. The paddle is not supposed to be moving when you introduce the tablet. The whole assembly is not supposed to be steered for equilibration purposes or whatever because you want to start especially with the paddle with reproducible start conditions. So you have the medium and again it's also important what I said before the medium degassing temperature that you have defined and the transfer that gives you a final temperature at the vessel should ideally be met at 37 degrees centigrade so that you can immediately start if you start to equilibrate the medium again because that's fallen below 37 or you need to wait for the temperature to come down imagine what happens especially for high head systems that may have coverage or not the exposure to environment air conditions is huge reirations can happen and the success of having the media discussed is fading away. But also the paddle is not supposed to be steered because when the tablet is falling down it potentially could be hit by one of the blades and could crack or fall apart and hence the disintegration part is much faster and the mechanical leg is different than from that one that was hit by the blades to the other ones that aren't there. So again, when you think of the coefficient variation that could be an instrumental part. Sampling is very essential as well. We recommend you to take as much as you can into a syringe. 30 milliliters is what we describe here 20 liter, 20 milliliters at least. Do not apply a filter to the syringe when you take the sample. Apply the filter once you have taken the sample and push through a certain aliquot two, three milliliters discard that and use the rest that you are filtering for the analytical part. Why? If you are attaching a filter directly in line by taking the sample, remember you have undissolved particles in the vessel. You might potentially pull in particles with undissolved, his own active principle and through the filter and the tribulation you will expand the dissolution to it. It is also recommended to immediately after filter the sample because what happens if you have undissolved material in your syringe and at the temperature of 37 degrees centigrade, it will statically continue to be strong. So again, you will not have the real results of that aliquot that you have taken right at the time of 30 minutes. That's basically what I said about filtration. The specifications are based on ISO principles that were defined many, many years ago. You have now a range of acceptable geometric means plus minus and you have only an upper limit for the percent CV both have to pass. The certificate allows you to perform the PVT either at a single stage or let's say the requirement allows you to do it at a single stage or optional two stage test. And for both tests you have specifications within the certificates through your right. Single stage means for a six, seven or eight position test assembly, you do one test with six, seven or eight tablets and you do a consecutive test of again, six, seven or eight tablets and statistically calculate the geometric mean and presented CV based out of this 12, 16 or 13 or 16 test results. And what you are happening to me is up here. If you have a 12 or 14 position tester, you know, a large equipment, you only have to do one test within that single stage test and apply all the six results or 14 results that you have to this specification. This is for apparatus one and apparatus two. The optional two stage test means that you do one test and for that allowance to stop after the first test you have different acceptance criterias to the right. If you compare, you see they are more narrow. This is actually the penalty that you have if you decide to go for that optional two stage test the results have to be more strings and more narrow as well as for the GM, geometry mean and the presented CV. Down here, you have a futility factor test that can be applied actually to both single stage and optional two stage test. If you receive results from a six, seven or eight position vessel, a presented CV that is 16 or higher for the paddle 11 or higher, then you can immediately stop the test because you know with the second run you will not come into the specification. So this is just for you to avoid going through a second round. If you have such results, obviously something terrible is going on that you need to assess first. What that is is really a thorough procedure to find out. We have an hour homepage and Excel file a dashboard or a spreadsheet that is available under our toolkit where you can quickly, you know, run raw data and get some results for your immediate visual. This is not a validated Excel file for your routine purposes if you wanna do an Excel spreadsheet based on the calculations as a result of the equations as provided in the certificate you have to validate this your own first. Troubleshooting, I failed my PVT, now what? The data fails to geometric mean. So it's usually high but passes the presented CV requirement usually indicate that something is affecting the post with the positions of the tester in a similar manner. That means that for example, you have not properly digassed the medium external sources like vibration could be the part. If you use the dissolution tester in an automated procedure by introducing the tablets automatically or taking the samples automatically consider this to be a variability because none of the labs that have done the tests for us in a collaboration to establish the specifications are supposed to use an automatic procedure. Procedure is based on a manual equipment. Everything is taken manual hence the results are only to be compared against the same procedure. If you assess this with an automatic sampling procedure you first have to verify whether or not you are within your self-defined within or out of range specs for the same system with devices and assemblies to be qualified as such. Errors from the stand solution or absorptability could be an issue for high geometric means. If the CV fails high obviously then it could be an indication as I said before the vessels despite they might all be within the acceptance criteria if you use a range of vessels that qualify but are varying in terms of design that could be an indication. Vibration could be a source and issues for other specific components. But again, this is really just a very, very general and small indication of what could go wrong with the dissolution tester nearby sources or analytics. There are more details explained on our website as well but as I mentioned before if you ever get a chance to do a course with us we go into much more details from that conclusions. Recommendations is follow the protocol make sure you read the certificate do this step by step and you are fine. Designated vessels mean keep the vessels always at the same position. If you always switch them around then you don't really know which vessel was at which position at a test even at your regular routine testing and something goes wrong, specifically within the PVT. You don't really have an opportunity to assess the vessels as a faulty part because they've always been at a different place. Wigorous mechanical qualification again is really essential but it doesn't tell you the whole story. Property aeration of the dissolution medium might be critical for a certain drug formulation. It is critical for the peri-zone reference standard tablet. The test should start as soon as possible after mediated aeration. The reasons I've given to you re-aeration is possible and you have not reproducible start conditions for all vessels. By the filtration of the sample immediately is important. Again, we only have taken a sample after 30 minutes where only 40% of the active principle is dissolved. So potentially we might pull undissolved material into the syringe at which it can continue with a certain static dissolution and results filtered an hour after the sample has been taken may give you different results. I hope you have been able to capture my email address especially if you are residing or working in EMEA which our office is responsible for so I can address for you any questions related to the dissolution if you like. The general mastermind or let's say guru or however you wanna pronounce Margaret Marcus to be she is responsible for all product monographs and all monographs that we have at USPNF. She's responsible for the general chapter 7-11, 7-24. She is working with our expert committees on these chapters not only that but also she has the column database. Margaret Marcus is the person that you would want to go to for any type of dissolution questions that you have. So mark her email address MRM at usb.org. If you ever have an issue with reference standards in general or in this case with the PVT, please send your email you're with the technical concern question to rstech at usp.org. Why Lisa Corbin who is managing this email address is funneling all requests, all concerns all questions in one database. And so we'll be able to ID identify any issues occurring from reference standards if they're coming in on a multiple basis which is a good indication for us to make sure we maintain the quality of the products. So with that I am a little bit over of what I promised to use as time but I hope we still have an opportunity to go through questions. Thank you for listening. I hope this was interesting for you. I stay available for the questions that you have. Alex, we have several questions in the chat box and the Q&A so what do you prefer? I will formulate it by voice or to send you in the chat message. If I open the chat myself, I see from Marta Mollins from Tunde, Cisla, Samuel Kuzi, I see questions. Are these the questions that you are referring to or do you see them? That's correct. Also Constantine Vierland has asked us. Okay, so let me read the first one. To ensure a good fluid dynamic in vessel what do you recommend about sampling probe? Should we perform the test with the sampling probe inside the vessel or is it better to introduce it at the sampling time? A latter please. Please introduce them at the sampling time because any other device that is inside the vessel during this solution test will cause you trouble in terms of variances. Not all the solution procedures are affected and are sensitive by that but definitely the PBTA. So remove the sampling probe while you do the test and only insert it at the time of sampling. Next question. We perform preventive. Is correct to perform MQ twice a year and PBTA one a year when we perform the preventive A? There is this general recommendation of USP that you have to look at it from the number of tests you do with this test equipment. If you think once a year PBTA is OK this is really up to you to defining your SOP. During the mechanical qualification more often really makes sense. Sorry I sent the question by error. We perform MQ twice a year and preventive maintenance once a year when one of the MQ is performed is correct to perform the only once a year after performing the preventive maintenance. I would always do the MQ before if that's what you call preventive maintenance. Yes, twice a year is definitely a good start but again look at the amount of the solutions that you do with this equipment. How many different people are working on the dissolution equipment itself? How often you have to replace accessories because of the speed you have to perform these tests too and we all know that the more stressed we are the less we take care of any accessories that are in use which we actually should do because cracks in vessels or irritations in vessels that are coming from a wrong cleaning procedure or baskets that are worn because we just drop them into the sink clean them and they get bent and whatever I would really recommend to do the mechanical qualification as often as you can. And enhance mechanical calibration replace PVT not in our opinion but that's for everyone else to design. Again PVT for us is a holistic test. You can do the mechanical calibration which is an assessment of all tolerances that you test against with a mechanical assessment device you can confirm that it is within specs but when you actually look at studies that we did on a maximum exposure test I don't know how to call it in a different way but there is a study from us where we have done several tests where we used vessels always in the extreme within the specs of 98 and 106 we have tilted the shaft slightly so it's still okay so we have these done tests against each other with different exposure variations and we have found variabilities especially for vessels and devices that are bent that can contribute to you know an overall change in term metric mean and coefficient variation so if the mechanical calibration is telling you that everything is within spec it still doesn't tell you how statistically these contributions these potential variations are meeting as an essential role within the whole test description of assessing six tablets which is what you have acceptance criteria for in your model graphs Hi, please join the event to internet connectivity could you please share with me the video recording and the slides the video has been recorded and as far as I understand will be the link to which will be sent to you soon after we are ready with publishing the recording and I think YouTube if I remember well is what we use there the last question that I can see can we change percent recovery acceptance criteria in exceptional cases like oil based formulation in the solution method for the sake of the topic that we have discussed here I wouldn't want to go into that into detail we can take this offline and see who is much better qualified than I am to answer questions like this if there are any other questions please let me know we still have time let's have one more question from the question and answers box that we see here the question is the question asks that she has done a two stage PVT in five equipments and all of them failed the pedal test but they all passed the basket test and all mechanical criterias were also met what do you think about this what can be the reason for failing of the pedal test I think that's pretty much what you just explained also before and what was discussed with the fluid dynamics in the presentation but please can you maybe expand once more on that difficult to say from a distance without looking at the results but if you look at normally it is the basket test that gives you a headache or challenges and the pedal test is less of a situation because the conditions are much more controlled there and we use this type of apparatus in a more routine basis but if you are remembering what I said before regarding the hydrodynamics in below the paddle with the paddle test the formulation is sitting underneath the paddle what I recommend you to do is to look at the behavior of this pattern is on tablet is disintegrating and how quickly it is forming that particular peak and if this is consistent throughout the six vessels and similarly to be seen with the other dissolution equipment as well that could be indicative to eventually how you do the medium degassing and maybe look at you know the performance of the degassing procedure there but it also could be what I said before are these dissolution testers placed all at the same bench do we actually operate them at the same time when we do the PVT hitting on the bench working with other equipment while this test is running is all applying vibration and the extent of vibration as minimal sometimes it is but again from distance it is really difficult to assist but I would start with investigating on the points I just described medium degassing and vibration okay I think we have some more questions but we are already up to the hour but we have a protocol and will try to answer the questions if you still have questions and you feel your questions were not answered then please reach out to us again but I think with that we are ending the Q&A session and hand over to Jan again yes thank you very much I'm sorry we have to be on time we need to close if you have any questions please forward them to us anyways and we'll try to get back to you individually just a couple of more quick updates before we go we have a number of other webinars lined up for you next one is going to be on 11th of May by Christian who is here with us today it's called what you always wanted to know about USP reference standards and then we have got the next one on 20th of May with general chapters by Dr. Rassio Papa and please check our calendar on our homepage www.usp.org we will find a calendar with all the other webinars we have lined up as well as educational courses and other events if you go on our homepage you will see on the top right side of the tab it's called events and training and there is the calendar alright well thank you so much Christian do you just want to maybe just share a quick line about your webinar just coming up next for those who might be interested yes I can do that quickly so that's in two weeks and we will talk about the process how we set up why we set up reference standards and how we set up reference standards that will be included in the presentation there that's it in short perfect thank you so much alright everyone well thank you we hope you had a great time there will be a very brief survey afterwards if you could just take a minute or two to please give us your feedback we really appreciate it and yes thank you again to Alex for his welcome hope you enjoyed it, Miha and Christian as well and yes hope to see you soon please take good care and stay safe thank you thanks everyone see you later bye bye bye