Webinar – Identifying Raw Materials & Components of Novel Vaccines with Portable Raman


Good morning or good afternoon everyone, depending on where you’re joining us from and welcome to today’s webiner My name is Tarek O’Dali from Business Review, and I will be your host It is our pleasure to have B&W Tek with us today We’ll be discussing Portable Raman Analysis for Novel Vaccines Today’s guest speakers are Dr. Marina Kirkitadze from Sanofi Pasteur Analytical Research and Development, Toronto site And Dawn Yang, Applications Manager I’d like to welcome you to our webinar platform on twenty four You’ll notice that this webinar is browser based, so if you disconnect for any reason please just click on the link that you received via email to rejoin the session In order to ask questions, you can send them in via the questions widget So just type them into that box at the top left hand corner of your screen, and click submit We will allocate around 10-15 minutes at the end of the session to address any questions or thoughts you may have If you click on the survey widget there are a few questions in there to answer in order to provide feedback And you can do this during or immediately after the webinar If you click on the green resource list widget you’ll be able to view or download some PDF files relevant to this webinar Please use the yellow help widget if you require any assistance And you can move, re-size, and maximize any of the windows in front of you to get a better view of the slides But now, without any further ado, please allow me to welcome Dr. Marina Kirkitadze Good morning, good afternoon everybody, thank you very much for joining us today Today Dawn and I will introduce the capability of portable i-Raman instrument and applications developed so far So in Sanofi Pasteur Toronoto Site, we have analytical R&D and in it biochemisty platform I’m responsible for Biophysics unit in the Biochemistry platform and part of my responsibility is to bring new technology and development and find applications for current projects, ongoing projects and also planning for future, what to anticipate, potential needs that we can address in a timely manner So basically that’s the purpose of today’s presentation and the summary that we collected so far So basically, the contributors are Kamaljit Bhandal and Sasmit Deshmukh We started, basically an evaluation of i-Raman last year, and after two feasibilty studies with Dawn and Thomas, we got the instrument installed, and I think since October last year we’re generating our own results and learning as we go So basically before, just to get the outline, so today I would like to quickly touch base about principles of Raman spectroscopy What are the main business drivers, and then applications such as Biological raw materials identification Vaccine components identification, And also, characterization of aluminium adjuvant and raw material that is used to prepare it So, on slide three right now, basically an overview of Raman spectroscopy So as you know, a principle of Raman spectroscopy is based on the inelastic light scattering So basically, what it means inelastic light scattering, we’re all familiar with light scattering and we know that about 99.99% of scattering is rayleigh scattering, it’s what we really see But only 10 to minus 5 percent of it, so 1 in 10,000 part is the light that whilst reflected from the particle from the molecule is changing the frequency So there is a shift between the frequency of incident light and the scattered light by the molecule And that happens because the induced polarization of the dipole, of the molecule basically causes this shift It was predicted by Snahkhal in 1923, and in 1928 it was demonstrated experimentally by Raman So basically, after that I think until 1960’s, the spectroscopy was very hard to use and was mainly residing in the physics laboratories However, with the creation of laser and widespread use, it became more practical more available for many researchers, including industrial researchers And so now we see the benefits of old technology and development that’s done over the years and can apply relatively easily to most of our samples that are Raman active as molecules So basically, on the slide you can see the energy diagrams so basically after the oscillation of the molecule, excitation of the molecule it shifts to so-called virtual energy levels, so very quickly returns and that’s what generates Raman spectrum, Raman peaks So our main business driver of course is to identify raw materials because as you know pharmaceutical companies are responsible now to have their own means to prove the identity of raw materials not just rely solely on it from vendors, so it becomes more and more emphasized by regulators and so this is one of the motivations to increase the use of Raman spectroscopy And of course to apply for characterization of novel vaccines, novel components of vaccines that may contribute, complement to existing characterization packages we have And also, potentially address stability issues But for now we focus on the identity So on the next slide, and yes I forgot to say that Right in the corner you see the picture of the i-Raman spectrometer that we have It’s a 785 nanometer laser And above is is a schematic diagram of, basically how it’s designed Next slide is just briefly advantages of Raman spectroscopy So first, it doesn’t require special accessories, it doesn’t require cooling of the detector Although there are instruments that have that, and have more sensitivity But for portable you don’t need, and still you can record quite nice spectrum informative spectrum from the components that you intend to investigate Another good part is that you don’t need significant preparation sometimes you don’t prepare a sample at all, you just analyze as is in a glass vial, or in quartz And basically, in some cases you will see in the slides we did some preparation to increase the signal And so, potentially can be used for quantitation for concentration of the sample But of course, the main attraction is it’s a non-destructive method It can work on solid and on liquid raw material, and you can go directly through the glass and through the plastic And this is really the main attribute that for example that was quite attractive to us Here you see an example of Tylenol, we used it during the installation and qualification of instrument But on a regular basis, we would use cyclohexane to check the instrument before it works and test before every measurement, every experimental data So on the next slide, the business need as discussed, it’s to develop a robust method with raw materials identity So basically, to have a view to check and confirm identity of raw materials not just for commercialized vaccines that already usually done in quality labs, QC labs But also, to do so for the novel vaccines which are still in clinical trials but to introduce it very early on the controls for the raw materials Then examine the effect of raw materials coming from different vendors on the properties of vaccine components, to have predictability and to a anticipate potential issues And on the other hand, compare because as you know for buiness continuity you need see and compare the raw materials from different vendors so that you can always ensure you have sufficient supply and of course the identity of vaccine components itself, and you may ask why The main reason is to support formulation, because doing formulations very often the vials and the compounds look very similar, and so it’d mainly driven by procedure and by segregation of the components during formulation However, we thought that if we have a tool which can confirm identity of constituents of vaccine during formulation, that way we have an extra check to prevent mistakes and to make sure that everything is done correctly So again, part 1 is biological raw materials, bascially we’ll be showing examples of how to measure with this instrument of peptide and oligonucleotide raw material So for us, raw materials previously was mostly inorganic compounds and organic compunds But now, with modern vaccines, that in development pipelines we have a need to also look at their biological raw materials And as you know, not all the time you have capability to do it as is without and dilution, preparation, so forth So in this case, we were able to find conditions So basically conditions I mean in this case is exposure time, so how long you collect Raman spectrum and the laser power which you can vary, say between 60% to 100% And so here you see basically an array of a graph of spectra collected for the same peptide and different exposure times And at some point, at 100% laser power, you see that the signals saturate, completely saturate However, depending on the region on the spectrum, which you’re specifically interested and want to choose as identity, this part can be highlighted in this case you don’t concern yourself with the saturation However for us, since we’re still on the learning curve, we prefer to have full spectrum and to highlight three regions where we see peaks and those regions are between 3000 – 2800 reverse centimeters which is normally responsible for cH, cH stretch, c triple bond to cH2 And so that part, which is matching the structure of peptide And also the region between 1500 – 1700 reverse centimeters which again is double carbon-carbon bond and nH2 And also C double bond to N This is just one peak you can see, and there are five peaks between 1000 and 800 and this region is normally responsible for C, so carbon – oxygen-carbon bonds and carbon c2oH bonds So basically, we’re thinking that this region is more rich, however we still want to account for one peak around 1700 and also a few peaks between 3000 and 2800 So basically, this description we can put, and also specific peak position which I’m not showing here but exact peak positions that repeat from measurement to measurement So that would be identity for the compound And of course we’ll be using software, BWID, where we can collect three spectra of the same compound and have it in the library and compare it against any unknown to confirm identity So the same procedure was applied for oligonucleotide, and as you can see in this case there is almost no vibration occurring in the region between 3000 – 2800 and of these stretches However, you see that in the region closer to 800 reverse centimeters there is significant peaks And there are also a few peaks around 1100 reverse centimeters also So these peaks, again, can be interpreted as cH double bond, carbon-oxygen-carbon, carbon oH and cH2 is this case, and also double bond carbon So this basically correlates well with a structure of the oligonucleotide and so predictable that you would see basically the resonances of the peaks in that region And there are very small peaks closer to 1000 which we can also interpret as presence of p-o contribution So, on the next slide again we chose exposure time and laser power And so if we overlap now the two graphs, one from peptide and one from oligonucleotide you can see that definitely between the two vials with white powder you can differentiate between these two compounds, and this is essential for formulation because one of these compounds is a majority, it’s a major component during formulation and another one is added in much less quantities So, to prevent any mistakes it’s really important to confirm But of course, just aside from formulation the whole point of gathering and collecting so-called baselines of raw material from a given vendor, is to prevent in the future appearances of potential impurities and detect these impurities in the raw materials Also, it’s still more in the future, but also thinking forward about the stability of the raw materials to check through it’s lifetime how long it can last in our setting And basically when it’s the cut off time, when i’ts the shelf lifetime for it not to be used anymore So, from batch to batch obviously it can vary but nevertheless that could be a good to follow So the result, in conclusion for this part is that we’ve demonstrated that the i-Raman Plus is able to collect and we’ve found conditions where it’s collecting informative and distinguishable well-resolved spectrum for peptide and same can be said about oligonucleotide And so, as a result Raman spectra is applicable to identify raw materials and that can be used in the future for collecting baseline and also to monitor stability So we learned that 70% of laser power in the case of peptide, and exposure time of 40 seconds This is optimal conditions to collect peptide spectrum Then laser power of 80%, and 70 seconds was optimal to collect the spectrum for oligonucleotide So these conditions we continue to use What we also learned is that very often for each compound you have to select certain conditions And you may not be able to have the same conditions for say two or three different compounds for each, the conditions would be unique because the purpose really is to have each spectra with well defined peaks that can be identified, and again during the measurement So we’re basically learning that this is suitable technology, a suitable instrument and Raman spectroscopy a suitable technology to identify and characterize raw material going forward and specifically biological So if we move to the next part, the next part is the Raman spectroscopy examples to characterize vaccine components In this case, we look at drug substance, the buffer, a vaccine formulation And I think right now we’re on slide 11, at this point I’ll hand it back to Tarek And he will introduce you to the poll question Yes, thank you very much. So I think now is the time for the first poll in today’s session Thought, please audience members could you please select the option that’s most relevant for you and click submit So, I’ll just read the question The question is, what kind of spectrum would you expect to see the emulsion? And the options are: majority of peaks in the 500-1500cm-1 region No peaks in the 500-1500cm-1 region Few peaks in the2 500-3000cm-1 region No peaks below 500 cm-1 Few peaks below 500 cm-1 And Marina, what do you think the results of this poll will be? Just to give the audience some time to vote So, they need to probably guess what regions would be more prominent, and consider that as an option and the oils, so that’s a hint. But they also perhaps can draw on their experiences working with this compound Alright, lovely. I think that’s given them enough time to vote, so we can move on to the results now And there we go, we see that the majority have gone with the first option there Is that something you expected to see? Excellent, yes excellent thank you very much, we just thought that poll question would engage the audience and make this presentation more interactive So, if we could go to the next slide Here you can see that the we have basically stage groups, and stage two groups and indeed the stage 2 is mainly a small peak around 3000-2800 So, that’s all good. So basically we’re looking here at a Squalene this is our component, it’s not um, we sometimes call it vehicle as well And this is used for manufacturing of formulation of one vaccine component So as you can tell this spectrum is quite informative, but it’s not optimal So therefore, on the next slide we again go through the exercise of exposure time and laser power And basically, we’re learning that at certain regions, at certain conditions we have quite well a resolution well resolved peaks again in the region between 1500-1000 And again, around 1000 additionally two peaks which we can definitely count on And of course the region below 500, we see few peaks, however the less result but nevertheless can be taken into account, at least when we compare how this compound this Squalen compound, is mixed in with the others, and so trying to see Raman results of the spectra So basically, on the next slide, we see how it’s now mixed So Squalen is added to another component, and that’s becoming one of the drug substances And so, as a result you can see that some peaks resemble the Squalen, and also appear new especially in the region around 1700, two very sharp peaks, this is new distinct peak and so if we overlay the spectrum, and at some point you will see that there is a difference So this is encouraging because that’s what you really need to see during formulation that there is some hints, a way you can recognize and differentiate between the substances as you go along So to prevent again mistakes during the steps So on the next one, just to illustrate, we overlay the vaccine component that you’ve seen just now so with the optimized spectrum, and also the raw material, and you see yes indeed the regions somewhat similar but there is some differences that you can count on, and differentiate between the two when working with them So, another example is Squalen again, and vaccine buffer which is different salt but nevertheless they contribute quite a lot, they also contain Peptide, so that makes a difference And so, again, that shows that yes even between the compounds we can differentiate again, this is important So on the next slide, there is an overlay of unadjuvated drug substance and formulated vaccines And I think this is the most important, because first of all for us we check how drug systems work but at the same time, we see that some of the peaks from drug substance are present in unadjuvated vaccine And also, the formulated vaccine has a resemblance of the previously stored raw materials and other drug substances And so, as a result it has features of both, but nevertheless it’s distinguishable and this is key So, as the conclusion for part 2, we learned that again i-Raman Plus is capable to collect the distinguishable well-resolved spectra for the buffer, raw material, vaccine component and drug product, and drug product is formulated vaccine And so, with the major contributions between 1200-1800cm-1 some of the peaks are quenched, but nevertheless it can distinguish between the compounds and different steps of formulation And you can use it as a fingerprint, and I think the word fingerprint and Raman I think is the strongest connection that we can differentiate between compounds in that field or not specifically with the thought about stability going forward, and of course lot to lot So that’s the next two important features that come into count, so formulation step first but then after it’s stability and lot to lot And so, basically in the next steps, I think it’s speaks to develop identity characterization tests for vaccine components to control the process So basically now, we’re moving to the compounds which are known since 1926, they are used as adjuvants This is aluminum based adjuvants, and some of you may be very familiar with it Mostly we used aluminum sulfate in the past, still used in some applications For the most part, at least in our company, we use aluminum phosphate and aluminum oxyhydoxide And today you will see the examples of aluminum phosphate and raw materials And so, on the next slide basically I’ll illustrate to the second panel; there are two panels So if you take aluminum phosphate suspension and measure it, this time we used quartz vials you see that basically retreated so just mixed sodium phosphate and aluminum chloride And after treatment, and also the aluminum phosphate commercial source purchase from a vendor they look very similar, they have similar features, it’s almost not possible to distinguish between them So, to increase the signal, we did dry the sample, and so for dry on the right-hand side you see the differences in spectra surface, here I show only part of the spectrum because the other part beyond 1500-3000 is not really informative, it’s flat And that’s why we focus on the part between 400-1500cm-1 So if I could again, yes you see the results overlay there in the signal lot but the purpose of that is to show there is differences in peak position in the region on 1000 so this is responsible for P-O vibrations, and so P-O 4, and so this basically shows that you can differentiate between pre-treated and after treatment aluminum phosphate the one that we prepared here internally in house, and also commercial lot, they’re all different And so we know that after treatment of it, the P-O bonds becomes stronger because it’s shift, and so that’s something that we learned as we observe But, how this information can be used, you can use it for lot to lot consistency, obviously You can use to redesign the process, and also more importantly to see how different source of raw materials may effect the output, the aluminum phosphate profile or Raman spectrum of aluminum phosphate in the future So that’s what we’re currently working on, so we have at least two or three we’re comparing And basically we’re building the data, so maybe at some point it would be interesting to compare And so, on the next slide, just to show example, this is the raw material of sodium phosphate and the raw material purchased from two different vendors And you can see that the full spectrum, again you can see that it’s only formative all the way up to 1500 So, the right panel is expanded view, and so you can see that although the peaks they are similar to a certain extent, but if you look closely there is differences in the peak positions in the overall shape, you can differentiate between them there are subtleties, and so it’s important now to learn how this settles this effect, and with the already differences in the size of the particular made this to different vendors in aluminum phosphate with that they react differently during the treatment So during the preparation steps, and so now we need to learn whether there is any impact on the binding That’s something we need to learn first, and basically the purpose here is to trace back all the way to raw materials in order to have a good understanding about the process and to support any changes in manufacturing, changes in vendors So that’s where the power of the Raman spectroscopy becomes apparent and that’s what we’re quite happy to learn because it gives you opportunities to help and to support process characterization Now, on the other hand it also introduces controls, and so basically the ultimate goal is to have different gates and I think the gateway, you check raw material systems first So basically you can call, in this case Raman application that checks the quality And, based on that, of course we’ve experienced what kind of spectrum you expect to see and the library, you can decide whether you want to push that further with raw material or just stop at the first gate So that’s where we see the technique and that’s where we want to evolve going forward So again, just to highlight the region we’re focusing, and in the summary I think we already spoke that we evaluated so really last March we brought it in house and in September we started collecting our own data in October, between October and now we had at least opportunities to contribute to three different projects and one of them is commercialized vaccine, and we’re very proud of that because this is giving us opportunities to work with our colleagues and also to see the impact and the needs for new technologies to be developed in house And I think the next steps is to develop further to build our library and to build experience with different vendors and see the impact on the output, working from the intermediate and the final product And I think at this point we’ll pass it to Dawn, and thank you very much Any questions, I guess Tarek will answer them after the session Thank you Yes, and also I forgot to say that this acknowledgment slide for people who contributed to the work So Bruce Carpick, he was instrumental to have this project added early last year in the pipeline of the technology development project Kamaljit and Sasmit as I already mentioned, two key contributors for collecting the data and developing the method Joan Bevilacqua, head of analytical R&D, and she helped us to acquire the instruments And Lilliana, Lillian, Ruby, Julie, Jin, and Roger those people they made materials for us So because of them we had the opportunity to screen so many samples and participate in three projects and learn as we go With that, now it’s to Dawn. Thank you So yeah, I’ll just go over this question here. So we’ve got another poll for the audience now And that’s just before Dawn takes over So the question is, what spectroscopic or analytical technologies do you currently use? And the options there are Raman, FTIR, NIR, NMR, GC/MS, HPLC, LIBS, Titration, or Other And, just to give the audience some time to vote, Dawn what do you expect to see from this question? I think I will see NIR, FTIR, GC/MS, HPLC, you know maybe there are the equivalent balance amoung the top Maybe, I would like to see some Raman, yeah Okay lovely, so I think that’s given the audience enough time to answer, so let’s move onto the results Well there you go, we can see that HPLC is sort of in second place but the most popular answer was indeed Raman Okay, I’m glad to see this Hello everyone, my name is Dawn Yang, I’m the Applications Manager with B&W Tek Today, I’m going to present a Raman application case using quantitative analysis for online reaction monitoring This work is done by our Application Scientist Phillip Zhou in collaboration with one of our customers The Raman quantitative analysis uses multi-variate chemometrics approach The basic workflow for chemometric model building is first to select samples with verified concentrations that cover the range of the possible changes With the sample selected, sample spectrum will be collected on Raman spectrometer Some pre-treatment might need to be done to the spectra, such as baseline correction smoothing, derivatives, or normalization The model can then be built using algorithms such as PLS regression, or PCA After the model is built, when an unknown sample Raman spectrum is collected and loaded into the model, a prediction of the concentration for the unknown sample will be given The reaction is from a Boron Refinement Operation It is a crystallizing stage involving the reaction solution containing borate, hot water, sulfuric acid, and other low concentration by-products During the reaction, two main chemicals are formed, boric acid and sodium sulfate The concentrations of boric acid and sodium sulfate are two important variables that need to be monitored The target concentration of boric acid is between 6% and 8% And the concentration for sodium sulfate is between 22% and 34% Among these two, the concentration of sodium sulfate is most important in order to achieve high reaction efficiency, and low waste If these two concentrations are not within the set control ranges it would raise the cost of the production The impact on the cost increase is in the millions of US dollars The Raman system used is B&W Tek i-Raman Plus, with 785 nanometer laser excitation The laser power can reach up to 350 milliwatts For assembling an industrial probe with immersion shaft and flow cell are used The integration time is three seconds because the reaction is very slow the spectral acquisition interval is once every hour Data collection software is BWSpec, and chemometric software, BWIQ, is used for model building For At-Line Process Monitoring, the entire instrumentation is put inside a NEMA enclosure for water a dust-proof, and working temperature stabilization The sampling is through industrial probe with immersion shaft coupled with a flow cell installed on the bypass line In the picture on the right side the red arrow points to the location where the flow cell and the immersion probe are installed The models buildings are done in two stages The first stage is to build a model based on data collected in the lab, or static sample data collection In this stage, about 80 samples from reaction solutions were obtained and their Raman spectra were collected inside the lab The actual concentrations of boric acid and sodium sulfate for these samples were measured by titration and gravimetric analysis as the primary analysis Chemometric models were then built using BWIQ In the second stage, which is at-line model building with samples from dynamic fluid More than 500 samples and their data were collected at-line Simultaneously, the real reaction solutions were sampled from the reaction line and the concentrations were measured by titration and gravimetric analysis In this second stage, the concentrations in the real reaction solutions are close to the target range The at-line models were then built off-line using BWIQ Some feasibility studies on the reaction solution and its components were done before model building In this slide, the Raman spectra for boric acid, which is the red line, sodium sulfate the green line And the reaction solution, the blue line, are displayed The peak at 880 is the Raman band for BO stretch bond for boric acid The peak at 993 is the Raman band for sulfate iron stretching The spectral regions around these two peaks are chosen to build the models for two variables as boric acid and sodium sulfate concentrations This slide shows the Raman spectra collected in the lab, which is used for the first stage model building The calibration curves of two variables PLS regression for the lab model are displayed here The algorithms include base line correction, so basically smoothing standard normal variate normalization and centering Both regression curb fittings achieved are squared higher than 0.99 and root mean square error at 0.034 for boric acid, and 0.066 for sulfate the picture in this slide shows how the at-line data collection was done for at-line models A large number of spectral data was collected for at-line model building Here it shows the at-line model regression curve for sodium sulfate The r-squared dropped to 0.82 and the root mean square error has increased to 0.58 Several factors may have contributed to this result One of the major differences between the lab sample and the real reaction solution is the complexity of the real reaction solution in terms of the number of by-products in the reaction process This should be the main reason to cause the difference between the lab model and the at-line model For over a month, the at-line predictions for sodium sulfate using the at-line model were carried out in parallel with the existing routine measurement using titration Both sets of data were plotted on the statistical process control chart The black dots are the at-line Raman measurements, and the red dots are the titration measurements As you can see, the Raman measurement gives the result very close to the existing measurement for both concentration mean and concentration range So in conclusion, the Raman quantitative analysis for at-line sodium sulfate concentration monitoring demonstrates that Raman can be used as an effective secondary quantitative analysis method Because Raman measurement is quick and non-destructive it is an ideal tool to use for reaction monitoring The the small portable Raman systems makes the method development and at-line installation very easy Thank you Lovely, thank you very much Dawn Now, I believe it’s time for the Q&A section So, just a reminder to the audience, you’re able to ask your questions by typing them into box at the top left hand corner of your screen and clicking submit So let’s start with a question addressed to either speaker I suppose As a user, what are the important user specifications that I should consider before purchasing an instrument? Do you want me to answer? I can take it I can answer from the instrumentation point of view, so i think for the application The several main important elements of the instrument would be the laser wavelength And also the resolution, and also the laser power The range that the instrument will cover at spectral range Yeah, but it’s a very general question, so it’s better to have some specifics about the application that we can give a better answer Okay lovely, thank you for that. So there’s a question specifically for Dawn here What is the laser spot size and shape on the sample? Okay, the laser spot size for i-Raman Plus is around 90 micron, and the shape is round Alright, lovely So the next question here, have you experimented with any SERS technology? For example, the use of P-SERS by diagnostic ANSERS, cellulose based P-SERS strips or Nano-SERS particle solutions for low-level detection? SERS, yes. We have other applications that use this kind of technology Okay. Next question is I have questions concerning to the effectiveness of the identification through the different materials used for packing of raw materials Can you repeat that again? Yeah I can, I’m just reading this verbatim I have questions concerning to the effectiveness of the identification through the different materials used for packing of raw materials Okay, so the packaging it would really depend on what kind of packaging you’re using So basically, Raman works with packages as long as it’s transparent, so the laser can penetrate through So it would really depend on what you’re using, and so far we’ve seen people We’ve seen our customers packaging that works with Raman is plastic bags, vials, plastic bags, vials, glass, even brown glass bottles Lovely, thanks for that, so here’s another question for you Has the i-Raman been used to measure components in a cell culture media Yes I believe so, yes Okay good, so the next question is Sorry, the next question is what type of technologies do you use for compound identity? Yeah, is this for Marina? Maybe Marina Sure, yeah, depending on the compound we can use mass spectrometry that works on that, so if you have peptide raw material for example you can confirm identity But of course if you’re talking about raw materials and others, you do different kind of tools you could use all that chemistry, and HPLC, and we use gas chromatography with mass spec We don’t have it in house, but we use it successfully, and so depending on the type of raw material That sounded good to me, next question is Can you probe through transparent plastic bags? I think you can, we’ve tried Yes, the answer should be yes. Thank you Marina I’m sorry, go ahead please I can only say that with a glass vial, depending on the thickness of the glass and also the intensity of the spectrum, you may see stronger signal or no signal at all For raw materials, perhaps it’s not an issue, I mean inorganic and organic But if you’re working with biological raw material, it can be an issue So you need to have the vial compatible with Raman For example, we take alcohol and put in our glass vial to measure, or we use quartz to measure So you need to take output of the raw material Lovely, thank you for that. So here’s another question Can you spot palm oil hidden in high cost or high value oils? That’s probably a question for Dawn I don’t have that experience, sorry Yeah, I think this is, this would depend on the concentration of the palm oil right in the So basically the Raman technology, if not without SERS, just the Raman technology, it can detect The limit of detection will be about 1%, so this question..the answer will really depend on the concentration of the palm oil Okay, lovely. So I’ve got another question here What is your experience from Raman spectroscopy? I think this is for Marina I would say, experience meaning it’s impressions or overall i think it’s positive We learned that we can basically avoid the glass signal in the spectrum if we switch to quartz cuvettes, and we found quartz cuvettes that fits ideally in the holder in the black holder where you have a way to which you connect the laser So that basically gives us better clarity so potentially in the future that’s what we will share with people and also I hope we can publish some of the data, so that gives better resolution Not so much resolution, just you don’t see the glass peak anymore so you don’t get destructive by that But, in many cases where we see strong signals from the compounds, glass peak is not an issue And so, it depends where we’re going, but right now I would say we only get more customers who want to have the samples to test and they’re challenging us with new projects which we’ll have a full idea what would work or not but we’re willing to try because in any case, you may see for example both components that could be indicative of good shelf life or issues, you can definitely help to define conditions by using Raman for the mixtures So we’ll see, right now we have at least two challenging questions that we have to answer But again, it will come with real data and with measurements, so we can only say yes we’ll be trying But, from what we’ve learned so far I think the idea to push Raman as a control factor during formulation And you can expand further vaccine life cycles, that’s really key because that’s something you could appreciate going forward, especially from quality control perspective That you build quality early on, it goes all the way with the process, and you have some checks and balances as you go, and less puzzles perhaps down the road So that’s something we introduce with new vaccine, but with existing commercial drugs is that raw materials is a big topic and will go beyond what raw material means for production Does it change, does it affect anything during the manufacuring, does it affect the quality of the adjuvants? Does this quality make a difference or not? So all these questions we ask and we learn as we go at the present, so that’s already two big things can be done by Raman So overall impressions are good, I think where we’re lacking is modeling that Dawn shows where we want to work perhaps and learn how to deploy it, how to build it in our system so we’ve become more familiar in that, this is something we don’t explore yet because we’re just learning on principle where we can put this technology to use That’s something next step we want to learn Lovely, thanks for that answer, so next question I have here is What libraries are available with the instrument? Dawn will answer that Okay, so for i-Raman Plus we actually have totally we have a library with more than 14,000 spectra But, the libraries they are packaged in different sub-groups So for specific applications we’ll have a specific sub-group of libraries for that For example, for the pharmaceutical we’ll have a pharmaceutical library for that And totally I think we have probably 12 to 15 sub-groups that’s categorized by applications and you’re welcome to send an info request to us and we will give you answers, yeah, specifically for your application Alright thanks. Okay, so the next question I have here is Why would you use dispersive Raman versus FT Raman for the Sanofi application? Marina, I think this is for you Maybe I can just say a few words about he dispersive Raman, so the dispersive Raman is is considered a little bit new, comparing with FT Raman, and the main advantage, I mean it’s the creation of it is because of the new technology in the CCD in the semiconductor industry and in the laser So the dispersive Raman has one big advantage is that it doesn’t have moving parts in it And it can be made very small hence our i-Raman Plus is a portable Raman And yeah, so I will let Marina say a few words about what she sees what she sees the advantage a portable Raman I would say our main attaraction was portable, the fact that this instrument is portable I think we had the opportunity to explore a few Raman and potentially still in this case and will do it in the future But I think Dawn mentioned a key point, it’s not portable, you need to have cooling of the detector, you do it only in the lab at the station, and so down the road, you don’t have flexibility to for example use exact same model at-line or in-line And that’s where the limitation is, so we wanted to see how much with portable we can do And to build that as a potential that this is the model if it works if we get well resolved spectrum, and it answers our questions we can recommend it to our industrial operation colleagues who can easily deploy it at-line and you know control the process at the key steps that they see important So that was the real reason, and I think also to exercise kind of new concepts we tried to invent, it’s the lab is where we are, so if we go and can do measurement in the field, and that’s something very kind of modulating I think at this point Alright, thank you very much I think we’ve run out of time, so thank you for everyone who asked a question If we haven’t had time to get through to that question, they’ll be passed on to the speakers and also to B&W Tek, and you’ll hopefully get a response from them in due course But now, that just leaves me to thank Marina and Dawn for their great presentation and of course to thank B&W Tek for sponsoring this session To the attendees, you’re going to receive an email very shortly that will tell you how to access the on-demand version of this webinar Also, you can access it directly through our website, and that website is www.business-review-webinars.com Once the webinar ends today, the survey will appear in its place and we would very much appreciate it if you could answer the questions in there Also, don’t forget the PDF file’s available in the resource list, which you’re free to download And we look forward to sharing further webinars with you so please do keep an eye out on the website that I just mentioned and also follow us twitter, that’s @brwebinars for daily updates And of course, join our Linkedin group at Business Review Webinars Speakers, do you have any last minute comments for the audience? I would just like to thank everyone who stayed online and asked questions I think that the questions were, some of them very interesting And some just really unexpected so it was really interesting to and entertaining to learn and to interact with the audience, I really appreciate the opportunity, thank you Yeah thank you from me as well, thank you for everyone’s attention and questions, thank you And just a last minute reminder to the audience as well you can follow B&W Tek on Facebook, Twitter, and Linkedin So go ahead an find that, but apart from that thank you very much everyone And I hope you will have a nice day, thank you!

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