(DESCRIPTION) A woman with gloved hands holds a syringe to a vial. Logo, 3.M., Science, Applied to Life. Title, Enabling new bioprocess strategies using advanced process technology solutions. Alexei Voloshin, P.H.D.. (SPEECH) Good morning, good afternoon, and good evening, wherever you are. My name is Alexei Voloshin, and today I will tell you about how advanced bio process technology solutions from 3M help support development and deployment of new bioprocess strategies. (DESCRIPTION) Slide show. Bioprocess Simplifications and Intensification. A bulleted list. (SPEECH) If you look at the biopharma megatrends today, all of them center around acceleration of discovery, development, and manufacturing of advanced therapies to treat life threatening and life changing conditions, and making them available to the people worldwide. Two of these megatrends center around the bioprocess simplification and intensification. And both of them revolve around the same idea-- ability to do more with less. What that means is ability to be able to go much faster from discovery to the clinic, in terms of the candidate development, and to be able to produce more mass per the facility footprint. (DESCRIPTION) A chart with illustrations with three columns, pre-clinical, clinical, and commercial, depicting the difference between legacy and evolved. (SPEECH) If you do look at how bioprocess simplification and intensification megatrends translate into process development at every single stage of the molecule development from discovery, into commercial manufacturing, you can see the same trend. And this is the trend of process compression. For example, in the pre-clinical stage, you're seeing the processes which have traditionally been executed in either process lab scale, or pilot scale now being translated into high throughput lab environment. Instead of being able to scale just a few purification trajectories and process development trajectories, now you can do even now tens and hundreds different trajectories at the same time. If you go into clinical, the ability to manufacture material for clinical studies is now being concentrated from utilizing commercial scale systems into highly intensified pilot scale system. Same trend as the molecule keeps moving on. If you move to commercial scale, it's now the translation of very large stainless facilities into highly flexible manufacturing facilities, where the footprint can be very, very effectively utilized, the facility can be low balance, depending on the amount of mass of each product that needs to be produced. And if we are to enable our customers to be able to meet these calls, the actual technologies for bioprocessing need to also answer these trends and answer the challenges that exist in the transition. (DESCRIPTION) Slide, Translating Process Strategy into Process reality. Two flow charts show the process leading from legacy and evolved. (SPEECH) As we further look into the details of what that transition into much more intensified and much more simplified processes means, it's really the transition from large scale stainless steel and glass processes of many larger unit operations into much more evolved primarily, or even exclusively, single use monolithic systems that are able to do more with less at every single stage in the manufacturing process, from intensified cell culture reactors, to intensified purification trains. (DESCRIPTION) Slide, Process Efficiency is Defined by Purification Trajectory. A chart labeled legacy m.A.b. process, moving from cell culture through harvest, capture, and polish. Two lists of values are labeled HCP, ppm, and DNA, ppb. (SPEECH) The basic challenge of transitioning from these large processes into these small processes have to do with the purification trajectory of a molecule and its separation from the key process related contaminants. In this case, we can use a very simple example of the contaminant level as the manufacturing process, both the cell culture and purification, moves on, and to see how fast do we separate and do we decrease the level of the key process related contaminants as we move through the steps. And so you can see in this case, all of the processes that have been exercised until recently-- for example, in the monoclonal world, have essentially the same trajectory-- is that by the time you're done with harvest, you have hardly made a difference in terms of the clearance of the soluble key contaminants. And it's only in that tail of the high precision chromatographics separation do you really start to purify with every single step significant amounts, and decreasing the level significantly of both the host cell protein as well as genomic DNA from your product. If one is to create a process which is simpler and more intensified, that strategy needs to be qualitatively changed. You need to be able to purify the product much faster, which means that the purification itself, and the significant reduction, has to start much earlier. For example, you can no longer think of harvest as simply infiltration by size. The harvest, for example, must also become part of the purification at a level which is similar with chromatographic separation in the capture and polishing stages of the train. And so the technologies for bioprocessing that will drive the next generation systems must reflect that. Both their performance and the fidelity of separation must align with the new strategy. (DESCRIPTION) Slide, Moving Chromatography into Clarification. 3M Emphaze A.E.X. Hybrid Purifier. A illustration of a purifier. Parts are labeled Q-functional nonwoven and 0.2 micrometer membrane, with microscopic images of the material. A bulleted list of features. (SPEECH) Several years ago, we created and launched a solution that changed the purification trajectory in the monoclonal purification process. This is the 3M Emphaze AEX Hybrid Purifier. It brought the fibrous chromatography into the clarification space. So the clarification can now give you a similar result in terms of its performance and the fidelity of separation compared to any other chromatographic step. The product contains a few functional fibers woven in followed by a membrane, which distributes the flow across the non-woven bed. (DESCRIPTION) Slide, Complex, Size World of Biotech. A series of molecules are depicted with a line showing their size, with small molecules and enzymes at the small end, near 0.1 to 1 nanometer, up to mammalian cells, beyond 10 micrometers. (SPEECH) In order to understand the unique nature and the approach that the 3M Emphaze AEX Hybrid Purifier brings to bioprocessing, into clarification, one must consider various physical and chemical characteristics of the world of biotech. So if you look at the product, if you look at the contaminants, down the size axis, you can see that this world spends at least four orders of magnitude. And this makes it a very, very big challenge in order to be able to efficiently and precisely separate your product from the contaminants in the bioprocess stream by size. And this is the main reason why filtration, while being effective within an order of magnitude, remains ineffective as a very, very high precision tool for bioseparations. (DESCRIPTION) Slide, Simpler, Charge World of Biotech. A dotted arrow points to just beyond 7 on a line labeled negatively charged to the left, smaller numbers, and positively charged to the right, bigger numbers. The images of the molecules are depicted on the chart. (SPEECH) But if you look at the same world, down the charge axis, with respect to the pH and the harvest cell culture fluid, the world looks very different, and actually a lot simpler. Your product, such as an IgG antibody, or some other recombinant products, are either neutral, or positively charged. Most of the contaminants are negatively charged. So if you could devise, essentially, in an exchange system which is capable of capturing small contaminants, or large contaminants, soluble and insoluble by charge, you can actually have a very high fidelity separation very, very early on in the process and clarification. And this is what the Emphaze AEX Hybrid Purifier enabled the biopharmaceutical industry, to deploy an anion exchange, separation very, very early on in the process. (DESCRIPTION) Title, Moving Chromatography Upstream Changes Purification Trajectory. A chart labeled Emphaze A.E.X. Hybrid Purifier Process, m.A.b. Process, moving from cell culture through harvest, capture, and polish. Two lists of values are labeled HCP, ppm, and DNA, ppb. (SPEECH) As expected, doing something different also produces a different result. The 3M Emphaze AEX Hybrid Purifier, in its anion exchange approach to harvesting, changes the purification trajectory in terms of the key process related contaminants. So now, you can see that as the Emphaze AEX Hybrid Purifier is deployed as the second stage, or polishing state of clarification, you can now get significant reduction, chromatography-like reduction much earlier in the process at the clarification stage. Additionally, as we have discovered, removing key interfering contaminants, such as DNA, enables the rest of the chromatographic train in capture and polish stages of the process to work a lot more efficiently. And so now, you can get to your final purity, a product that is both safe and efficacious, much faster. For more information on the properties of the Emphaze AEX Hyrbid Purifier and these interesting effects they cause on bioprocessing, I encourage you to read the two papers referenced at the bottom of the slide. (DESCRIPTION) Sources are cited, Van de Velde et al, Chromatographic clarification overcomes chromatin mediated hitch-hiking interactions on Protein A capture column. And Gilgunn et al., Identification and tracking of problematic host cell proteins removed by a synthetic, highly functionalized nonwoven media in downstream bioprocessing of monoclonal antibodies. Slide, Enabling end-to-end Chromatographic separation. A chart of three cell cultures moving from harvest to polish, labeled Legacy m.A.b. Process, 3M Emphaze A.E.X. Hybrid Purifier Process, and Future Process. (SPEECH) If you now consider the trend an advantage for moving chromatographic separation upstream, closer and closer to the bioreactor, you can imagine that the next generation of this trend is to really have chromatography everywhere in the process. No longer do you need centrifugation, or other relatively low fidelity unit operations of the front of the process. You can simply chromatographically separate cells, cell debris, key soluble components, as well as even small molecules that are related to cell culture components as well. This will enable the next step in the process, compression and simplification, simply because you're capable of, again, once again shifting this trajectory towards much faster purification much earlier in the process. And so, this is one of the challenges that we've thought to solve as 3M using our advanced material platforms. (DESCRIPTION) Slide. Single Stage Extended Size Range Particle Chromatography, 3M Harvest R.C.. A footnote indicates Harvest R.C. will be available at a later date. A chart shows a cell culture moving through non-woven fiber media to C.C.C.F.. (SPEECH) In order to address the challenge of moving chromatography completely upstream and eliminating any type of filtration, and enabling separation straight out of the bioreactor, we use the same technology that we use in the AEX Hybrid Purifier, and we modify it now to be able to deal with objects as large as hotels. Here we present to you the 3M Harvest RC. Because of its unique construction, and of its unique approach to separation, it also has some very unique properties in dealing with very wide PCV and cell density ranges of greater than 40 million cells per cenimeter cubed. It is completely synthetic with very low extractables and leachables. Just like chromatography, it scales exactly from screening into manufacturing, such that the data that you get throughout the entire product candidate development process, from discovery to manufacturing, is actually completely predictable, and it's completely the same. And because of was very, very high porosity, and very high product recovery, it has very high performance, and very small footprint. (DESCRIPTION) Slide, Advantages of Chromatography at Clarification. Two graphs. First, Clarified Product Recovery, showing product recovery for different m.A.b harvest. Then, discovery to manufacturing scalability, showing a normalized throughput in different stages. (SPEECH) I would like to give you a brief preview of the performance of 3M Harvest RC in key performance characteristics, which are critical at this part of the process, and at the clarification unit operation. The first is product recovery. Because of the synthetic nature, because of very, very simple interaction with your biopharmaceutical product, which is in an exchange only, we typically see product recovery or greater than 95%, and a lot of times greater than 98%. So even if your system is relatively large, which is expected, and clarification, because of the amount of cell mass that you deal with, you can still recover the same amount of product as you can out of a typical flow through chromatography system. The second is the scalability. So here is overlapping data of several runs that we've done with a range of products that are going to be launched as part of the Harvest RC lineup. And you can see the scalability is linear within the natural variation of both experimental conditions, as well as the cell cultures themselves. And so with this allows you to do, just like in other chromatography systems, is to predict the performance of very large scale by doing experiments at very small scale, and everywhere in between. (DESCRIPTION) Slide, Transition to Single Use Polishing Technology. The charts depicting the process to V.F. for legacy and evolved reappears. Now, two steps in the legacy chart are circled, depth plus membrane, and A.E.X. column. (SPEECH) The second topic that I would like to cover with respect to these megatrends of simplification, intensification, of being able to do more with less, is the translation of large scale reusable filtration in column unit operations into small, very high performance, simplified unit operations, which is a key component of this transition from legacy to evolved processing. One of the most important steps, and perhaps the most universal step in the polishing train, is the anion exchange rate operation. It is part of the bio flow strategy, it is responsible for key process related contaminant clearance, and is sometimes responsible even for product related contaminant clearance. (DESCRIPTION) Slide, High Performance Single Use A.E.X. Polishing, 3M Polisher S.T.. A footnote indicates production capsules will be available at a later date. An illustration of a man standing beside a reusable A.E.X. column. An arrow indicates a second illustration, a man standing with a similar, but smaller machine, the Polisher S.T.. Bullet points list features. (SPEECH) At 3M, we applied our advanced materials platforms to bring you 3M Polisher ST. This is a single-use anion exchange solution which enables you to replace your reusable anion exchange column at the polishing stage of the process with a single use system at any scale, ranging from discovery into commercial manufacture. The system has a number of unique properties, such as atypical mAb loading that's greater than 100 times over Q resin, scalability from laboratory to manufacturing scale, and predictability of its performance offered from very, very small to very, very large. It has a very high operating range in terms of salt tolerance and pH tolerance, and it has very robust viral clearance along a very large area of process conditions ranging from pH, to buffering ion systems, to salt. (DESCRIPTION) Slide, 3M Polisher S.T.. A graphic depicting the polisher. Two tiny sections are indicated, labeled with features and microscopic views, Q A.E.X. and Guanidinium A.E.X.. (SPEECH) The product itself is composed of two parts-- upstream is Q-functional non-woven. This is the same non-woven as utilized in Emphaze AEX Hybrid Purifier, and it's responsible for capturing insoluble particles, which means the system can clarify turbid streams-- for example, turbidity after the viral inactivation neutralization. It has very high performance in terms of DNA capture, and very high capacity for DNA, and also has some DNA capture capacity as is commensurate for Q-chemistry. Downstream of it is a functional membrane. The membrane is functionalized with a brand new ligand. The ligand is based on the side group of arginine, and the functional group is guanidinium. What this chemistry is responsible for is for HCP capture, as well as for viral clearance. This hybrid construction, in bringing together different materials and different ligands, gives you very high performance over a very wide process condition range. (DESCRIPTION) Slide, High Viral Clearance Robustness, data in Phosphate, Citrate. Four contour plots, each of four elements versus p.H. conductivity. P.R.V, Reo-3, X-MuLV, and M.V.M.. (SPEECH) There are a number of very unique characteristics of the solution, but perhaps the one that is the most striking is the viral clearance robustness. Here you can see a viral clearance of four established models in the CHO world, in terms of viruses, in either a phosphate or a citrate buffer, depending on the pH. Clearly, this is a different system, a difficult system, as both phosphate and citrate are polyvalent. And what you're looking at are contour graphs in terms of the viral clearance, for each virus is a function of pH on the y-axis, and conductivity on the x-axis. You can see that in all cases, except MVM, the control plot looks very monotonous, primarily because, in all condition space, the clearance is greater than six logs, and very often it's complete clearance to the limit of detection. In the case of MVM, because of MVM's medium to high isoelectric point, once you get low enough in pH, it is consistent with an anion exchange mechanism. You do start to get very gradual fall off of clearance. But you can see that in terms of the conductivity sweep, in terms of the pH sweep, even in the case of a difficult virus, such as MVM, the viral clearance is highly potent and highly predictable. (DESCRIPTION) Slide, Process Intensification Improves Yield and Lowers Manufacturing Cost. Four progressively shorter charts depicting the process from filter to Viral Filtration. 3M products are circled at various stages in the last three processes. (SPEECH) So after all of this, we can now look at how the solutions enable process intensification, and thus improve yield, and lower the manufacturing cost. In this case, we're looking at four different scenarios, starting from the conventional one, where you are utilizing conventional verification methods, large reusable columns, at your polishing stage. And then, we can start dialing in the investment. So process number two has only the Emphaze AEX Hybrid Purifier. Process number three has both the Emphaze AEX Hybrid Purifier and Polisher ST. Process number four has now the Harvest RC and the Polisher ST deployed. And as the processes get more advanced, they can get simpler. There are no less steps. Your product becomes more pure faster, and so we can use now a package, such as, in our case, the package from BioPharma Services in order to be able to model these scenarios and to see does this really make a difference-- are we driving down the cost? Are we improving yield? Where is the advantage? (DESCRIPTION) Slide, Process Simplicity Determines Yield and Manufacturing Cost. A flow chart moves from Advanced technology to simpler process to higher yield to lower cost. Three bar charts depicting relative value. The chart labeled COGs is circled. The other two are consumables and D.S.P. yield. (SPEECH) There are a number of different parameters that one can explore, but perhaps the three most interesting ones to look at are the cost of goods, the cost of consumables, and the yield of downstream processing trade. And so, as you look at this data, you can see a couple of very interesting trends. So, if you look at the overall cost, as the processes get more advanced, and thus simpler, the cost of goods decreases. Understandably, this decrease is not driven by the cost of consumables. The consumables actually become more expensive, because there are a lot more events, and there's a lot more both regulatory compliance, as well as the technology developments being put into these consumables. But what's really overriding most, or perhaps even nearly all considerations, is the yield. The process has become more compact. There are less losses. You're capable of making a lot more mass per the same footprint of the facility. This is the definition of intensification in a direct consequence of simplification. And so, you can see how these megatrends are now related towards being able to produce more material, move more candidates in your pipeline into the clinic faster, and doing it at lower cost, which enables you to be able to deliver these life saving, life changing therapies to more people around the world. (DESCRIPTION) Slide, Advanced Bioprocessing Technology Enables Doing More with Less. A bulleted list of text. (SPEECH) What I hope that you have learned in the last 20 minutes or so is that advanced by processing technology does enable one to do more with less. You can now start eliminating the line between filtration, and clarification, and purification through this expanded size chromatography, where you can now do all of these separations, not only with small molecules after clarification, but at clarification itself. So your entire process becomes this continuum chromatography where you're able to remove various contaminants at various stages with very, very high precision, and high degree of separation. What this enables you to do, obviously, is much faster purification. So the basic trajectory of how fast you are clearing the key contaminants is now much, much more advantageous. What I hope that you have also seen or learned is that the unique properties of these advanced materials and unique chemistries really drive this transition to very high performance, and robust unit operation-- the ones that give you the capability to now do things that you have not been able to before, the robustness of processes that was not possible before. And this, again, leads to being able to make processes deal with a lot more mass while having a smaller footprint. If you have any more questions regarding these technologies, either for information or evaluation purposes, I very much urge you to reach out either to me or to your local 3M representative. Thank you for your attention, and have a good rest of your morning, your afternoon, or your evening.