SGS SA (SGSN) Earnings Call Transcript & Summary

Welcome to our webinar Planning Your Testing To Identify Unexpected Impurities In Medicine. The webinar will be presented by Christoph Diefenbach, a Laboratory Manager, Research and Development, at SGS. At the bottom of your screen are multiple widgets that you can use. All the widgets are resizable and movable. If you have any questions during the webinar, you can submit them through the Q&A widget. We will answer them at the end of the presentation in our Q&A session. If we do not have time to answer them all, Christoph will contact you separately after the webinar. Christoph, the stage is yours now.

Many thanks, Arlee, and welcome to all participants. The reason why we talk about the impurity is that a lot of guidance are available which rules our company how to handle impurity during all the processes we have to handle. I listed on this slide 3 examples but please understand it, this list is not full, where you can read something about impurities in guidelines. And at the end of the slide, you see how important it is to understand when we have to elucidate an impurity, which is recommended during any process in our production line. And you can see which challenge is behind it when we have to purify a structure, often unknown, with less or around 0.1% content in a sample. On the next slide, I will give you a topic or an overview, which and where it could happen that an impurity will be present. And after that, I show you 2 examples from our laboratory, how we had handled this point of interest for our clients, one in a general information, and second, which is caused in the overview of our presentation. Thank you. I think most of you are familiar with the situation that an unknown lies during any process of your production line. This could happen during a quality control testing as well as in a laboratory of a supplier of you or during a long-term stress testing investigation. Good advice is now urgent you have to react fast, but not headless because all products of you bound a lot of money, resources of personnel and you have to solve this problem properly and fast because it decides what you can do with your product afterwards. At the beginning, I will give you an overview where an unexpected impurity can be arise. As I mentioned, the most important thing when you get an impurity is to keep a cool head, concentrate you on the important steps to elucidate the structure of your unknown, be aware of the regulations by the authority and don't do anything which don't bring you forward. Available time is the most important regular, which is aware. And sometimes, your product can stay in the store as long as you need to clarify the structure of the unknown. Start with the brainstorming, collect all the information you can get, even small details could bring you forward to understand the nature of the impurity. Discuss with the supplier of your products because sometimes, they change their production processes and could give you information which is helpful. Talk with the chemist and the synthesis laboratory. Very often, these people have information about the reaction processes, which could bring you forward. How many batches are affected? What is the worst of the affected batch? Calculate the sum and make it clear is it possible or necessary to solve the problem or sometimes it could be easier to destroy the batch because the money you can spend or must spend differ. Additionally, it is helpful to be aware of the reason of this event. Think about what has changed, the supplier, the quality of the products which you use? Is there a change in the reaction conditions? Has anything in the system been replaced? Could you clarify if the unknown is part as a byproduct of the synthesis product? Which analysis were used where the impurity arise? Is there an investigation of the materials used? Have you unusual influences? For example, the weather change or pH value is not constant. Collect all the information, this will help. On this slide, I will give you some helpful information, which could be respect. At first, how much time is available to clarify the unknown? Because if you don't have much time, it's not possible to clarify the structure of the unknown. Repeat how much is the goods worth because it's affected very less, don't implement an expensive structure elucidation process. The structure determination. You can see on the right side, what I mentioned with that. How detailed must a structure determined? Is a method transfer necessary? Have you got your own laboratory, which supports you with the determination of the unknown or must you look to a supplier laboratory and then you have to transfer the method first? Is the method where the impurity arise compatible to the technology, which is necessary for structure elucidation? And at the end, what information is required? All GMP laboratories are really familiar with risk analysis. In this case, a risk assessment could help you too. Do it to clarify the nature of the unknown, when it arise, where it arise and how it arise. You can collect all information, bring it together, and at the end, the best case, you have a result. A further step is to collect the information about the impurity. The analytical method, which was used, can give you a lot of information, and this could bring you forward to understand the impurity. Very important is also to make an orderly process or something like that to reproduce the result. An estimation about the quantity of the unknown substance is necessary. Think about the Slide 2, where the 0.1 percentage clarification is present. With the used method, you can get a lot of information. For example, the polarity of the substance or when you have a GC investigations, the boiling point, the color of the sample could help you, the substance class, whether it is [indiscernible], also the solubility of the unknown can give you an information or an estimation of the mass of the unknown substance. Have a certain evaluation process for your supplier because the quality of the raw materials is really important for the quality of the end product. Is there any process being expected during production process? Are the laboratories using suitable methods for the investigation? Does the method detail process material? Now the risk assessment is finished and the laboratory work can start. At first, you have to transfer the methods from the laboratory, where the impurity arise to that laboratory which support you for the structure elucidation. Important it is to readjust the results from, for example, the quality controllable in that laboratory which you support. It is absolutely necessary to ensure that the test result is verified. Product analysis methods are often in use which are not usable for structure determination. This can be for HPC method, for example, salts, solvents or ion-pair reagents and the eluent. Changing a unsuitable method into a suitable method could cost you a lot of time, and it's always a challenge. In addition, it could be very difficult to clarify the correct analytes. There is more than 1 method present on the marketplace to clarify the impurity. The choice of the method is crucial. The implemented equipment has an enormous influence on the cost. And you can see in the table, a quick roundup of some and the list is not full or complete of possible methods, the price and the information you can get. When the lab work is done, the analyst has to generate a structure proposal. It's clear that the reliability of this depends on the quality of existing data. More data and better data will generate a better result. And it's really important that you have an analyst on hand who has the quality and has the necessarily expertise to fulfill all these things. In principle, the process of the determination of the structure can be broken into 5 essential steps. And on the next slide, I will give you an overview about this process. We can break down the process to determine the structure into 5 steps. First step is the method transfer. It takes up to a week for a successful choice there from 1 laboratory to the next laboratory. Second step is the choice of a suitable analysis method. Normally, this takes only 1 or 2 days to decide which type of method it will be. Gathering the analysis data is the next step and this takes from 1 week to 2 months. The next step is the assessment of the analysis data. It can take up to 2 weeks. At the end, the verification of the analysis data might be necessary. I can understand that the synthesis of a substance takes a lot of time and this process or the time of this process is open. Realistically, a timeframe from a few weeks to several months absolutely is standard. When the work is done, and I hope the unknown impurity is now a known substance, there must be a lot of work necessary. For example, is the toxicological assessment necessary? Did your quality department tell you [Audio Gap] the CAPA plan? Has you got update on SOPs? How many are [Audio Gap] personnel trained? If there is a quality of the process material insufficient, then you have to provide an extractable study to avoid the replacement of the item. A tip from my side. At the time of developing a method for quality control, it's important to already think of any problems which may arise, make a better method at the beginning of all processes. A mass spectrometer could not operate with a mobile phase that contains, for example, ion pair reagent. An NMR spectrometer requires greater substance quantity for testing [Technical Difficulty]. As a conclusion, I can say when an impurity arises, it's not possible to foresee the complexity of the problem. But when you follow the way I described, chance of success is present, but still there's no guarantee. For example, when the amount of impurity is not sufficient, can get a result. When the unknown is identified, source of the entry must be determined. Any anonymous process found must be counteracted. An impression of the workload will give you this slide but there is no claim for completeness. And I don't want to go in detail because I discussed all this points before and it's only a visible overview of the workload. Now let me show you 2 examples, which were present in our laboratory. Here you can see a typical HPLC chromatogram after 1 dimensional separation on a C18 column. But following an MS identification gave us an unclear result and then we tried to make a further separation. To our surprise, it was really big that a further separation on a C18 column gives us another eluent, gives us 2 impurities with nearly the same peak area. So we can say that the concentration of both is nearly identical. And now think back to Slide 2 that impurities up to 0.1% must be clarified. In this case, when the sum of both not higher than 0.2 percentage, you don't have to clarify any of that. So this can help you to decide as we go further on to clarify identification or can we finish the steps yet. And now the MS spectrum, it get very good. Here, you can see the MS spectrum of impurity A. The determined sum formula was C20H27N3O5S. The ionization was performed with ESI in positive mode. Here you can see the MS spectrum of impurity B, if you stay on my slide. The determined sum formula was C20H27N3O4S. And the ionization was [Audio Gap] ESI positive mode. Between impurity A and impurity B, there was [Audio Gap]. With both impurities, further MS/MS investigations were executed. And this MS/MS results gave us a deeper impression of the nature of the impurity. The data information were interpreted and with the information from the client, both structures could be proposed. And be aware, there was only a difference between both impurities by one oxygen. The LOQ of both impurities were the same in the first HPLC chromatography. And this might be a challenge. Very often that there's not only 1 unknown behind 1 peak. There could be several peaks behind 1 peak. Beware above that. And at the end, let me give you a short information about the used device. We have a couple, an HPLC systems, there's an ion trap mass spectrometer. We had used an ESI source using or operating under positive voltage. This was general information about the system. I think this system is a good compromise between cost and used amount of the impurities. For the first example, I couldn't give you more detailed information about the structure of the impurity because we have a clear security agreement with our client. For the second example, I can go a little bit deeper in detail. It's an example of Oxazolidinone drug product. We also start with an HPLC-UV chromatogram. This chromatogram was performed by our customer as a sample represents a stability test. Three impurities were assigned to identify and receive information, we start our work for SGS. We stressed the drug product with different conditions. And in the chromatogram, every color represents a stress under different conditions. In summary, we can say all impurities, which have to be clarified, were found and the method transfer was successful. As I suggested, very often, the method from our activities are not compatible with our equipment. And that was, in this case, too. The first step was to transfer the method from our client to an MS compatible method in our laboratory. We changed the mobile phase into an MS compatible mobile phase. And afterwards, the chromatograms are really different. For example, impurity 1 was a broad big peak and impurity 2 and 3 were outstanding. But now we are ready for structure elucidation. We collected the 3 impurities by an HPLC fraction collection system and measured all 3 extracts afterwards on a high risk MS device. Here you can see impurity 1 by an MS/MS investigation with 3 different collision energies and you can see that the first collision energy is too low to fragment the impurity but with a higher collision energy, you get more information about the molecule. The same was done with impurity 2, and you can imagine that with 30 volts collision energy, the amount of impurity was not really sufficient. At last, the investigation for impurity 3 was done. You can see on all 3 spectrums that the impurities are really close together. A stress test of linezolid generates a manifold structures of the degradation products. Take a deeper look on to impurity 2. The position of the hydroxylation of the degradation product could not be clarified final, but the toxicologist of our client gives it an all clear. So the client have all the information which is necessary and we have done our lab work properly. As summary, I can say, in this case, the investigation was successful. The client received all necessary information to close his process. The MS/MS investigation was sufficient enough in this case for a structure interpretation and a final toxicological assessment could be done based on this information. Now let me ask you, do you plan to outsource structure elucidation in the future? I hope you enjoyed the presentation and it helps you in the future. I hope you feel a little bit more confident with that background. And now I think we are ready for questions.

Thank you, Christoph, for the presentation. We will now start the Q&A. So we have a first question, which is which amount of sample is necessary for structure test investigation?

Yes. First, let me thank you to you all. And I have heard that the sound was not really good during all the presentation. So I have to apologize my -- for this bad news. But yes, thanks to you all. And now to the questions. Yes, the first question is which amount of sample is necessary for structure test investigation. And this is a really important and manifold question because it depends on several points. At first, you have to decide which equipment do you want to need for structure elucidation. For example, when you want to use an NMR device, you need at least 2 or 3 milligrams of purified substance when you want to make a 30C experiment. For the test I showed in the presentation, the 2 examples, there only were a few microgram substance necessary for all the MS and MS/MS investigations. And you can see there's a big difference between the 2 different techniques. But let me make a further comment. This is valid for small molecules. In case of your molecule is very heavy, you have to need more substance because the count of molecules per milligram is corresponding lower. In addition for an MS investigation and mostly, this will happen, you generate multi-loaded molecules, and this results in a complex data interpretation and in a higher necessary substance amount. And it could be that you need further cleanup steps in this case and this even results in a loss of substance and you need more substance. And I can give you a tip. When you have an estimation about the molecule rate of the impurity, think about it, very small molecules are volatile or semi volatile. And this can also happen with molecule with 250 or 270 dalton. And when you have spent a lot of time in sample preparation, you're really disappointed when your substance is blowing in the wind. So be careful in this process and work really careful.

Thanks, Christoph. We have the next question. At which levels do impurities have to be labeled as specified impurities?

Yes. Thank you for this question. I think in principle, there is no limitation, but there are parameters available which reduce the chance of success. And I have to repeat that there is no guarantee for positive results. For example, an insufficient sample amount or a bad ionizable molecule can reduce the chance of a success or the molecule is not stable during the preparation of them or the molecule is not soluble in a solvent, which is proper to use for the experiments. And so there are a lot of points which can, yes, reduce the chance of success. But in principle, there's no limitation.

Thanks. There is also a question which says are there limits to investigation. I guess it's kind of answered at some point.

Yes. So let me comment that we -- laboratory who are working for other clients, so we have -- we don't have to decide which impurity have to be clarified. This is a point where the client tell us do this or do that. So normally, our clients are under regulation for ICH Q3. But very often, they have further information which are not available in our laboratory. So we are a little bit pending on the information of our clients, and they tell us do this or do that. So yes, this is a process, for every client is very special.