 Good morning, good afternoon, good evening, and thank you for attending my talk. The title is the value of open standards for vaccine manufacturing. And I will go through a number of topics, including our company's contributions in the fight against COVID-19. I'll talk about flexible manufacturing based on modular engineering and how that was a key engineering development to enable the rapid expansion of manufacturing capacity to produce vaccines in the hundreds of millions and into the billions to protect patients around the world. I'll talk about how open standards fit in within the concept of flexible manufacturing and modular engineering. And with time permitting, I will also talk about the distribution challenges in supplying vaccines, especially those that need to stay frozen. And so I'll be talking about frozen supply chain once a vaccine dose leaves the plant and the path it takes to get to a patient. So the CEO of our company, Ken Frazier said it very succinctly that nobody is safe until we are all safe. And as part of operation warp speed announced at the White House, as you see in the picture, our company has committed to contributing in the fight against the COVID-19 pandemic. And we'll be modifying a facility to produce hundreds of millions of doses of vaccine to help protect the patients around the world. We also have an oral therapy in clinical trials and that oral therapy is intended for the sickest COVID infected patients. So I'll detour first into how a class of vaccines, adenovirus based vaccines work, two of the more common vaccines from J&J and from AstraZeneca are actually based on this class of vaccine. It starts with a coronavirus and the spike proteins on the surface of the virus, which help itself attach the virus to the respiratory tract and cells and the respiratory tract of humans. And within the coronavirus is a spike protein gene that's been isolated by researchers. And then it was placed inside an adenovirus. Adenovirus is a class of viruses that causes the common cold and other respiratory illnesses. This particular adenovirus has been modified so it doesn't replicate and can't cause illness. But importantly, it hosts that fragment of DNA that produces the spike protein. So adenovase vaccines when injected subcutaneously into a patient, these little adenoviruses containing the DNA fragment for the spike protein enters cells in the body. The cells are quickly engulfed in a bubble. And then the adenovirus is able to find its way to the cell nucleus where it then deposits that DNA fragment. The DNA fragment is translated by messenger RNA. And the messenger RNA gets to work by producing spike proteins within that cell spike proteins and fragments then migrate to the outside of that vaccinated cells so that it protrudes out to the body. The body then encounters these cells with these spike proteins and develops antibodies against them. The antibodies have in the immune system have lasting memory. And so it still remains to be seen how long the lasting immunity will be for humans and these adenovirus based vaccines. But by being able to recognize these spike proteins and fragments and developing immunity, it provides protection against the actual COVID-19 virus. So I'm now going to take you to manufacturing from the past stainless steel tanks custom designed by my company process control code custom designed by my company. They are not flexible in that they tend to be dedicated to single products. They have extensive piping for cleaning and sterilization and that's how we manufacture vaccines in the past and it took years to construct and qualify these type facilities. The future and actually present design of manufacturing facilities for vaccines and biologics makes use of flexible. Single use modular pieces of equipment single use in the sense that rather than using stainless steel reactions happen within a plastic bag. Soft connections are used to connect unit operations such as chromatography filtration and each of these units are off the shelf purchased modular and highly interchangeable given their flexible nature and of the connections and the tubing. So it's this engineering development that of modular equipment enabled bio pharmaceutical companies to quickly scale up manufacturing capacity to meet the demand for COVID-19 vaccines. I'll highlight some more advantages of the module design. It's very much in tandem with our company's goals of how we construct new facilities. I have a quote from our vice president of capital facilities and engineering. He has a broad goal of 40% less capital expenditures with 80% of the work done off site. That forces us into broad acceptance of modular plant design using equipment that has been designed by our suppliers can be purchased off the shelf and can be quickly deployed in the timeline shown below. We have two timelines one based on modular engineering where much of the engineering work is done not only off site but in parallel by our supplier community. And because the engineering has been done. It's much faster to integrate the equipment as opposed to maybe a decade or two ago the traditional process plant design and engineering where it was done all in house. Construction was done largely and supervised by the company and it took many years to construct a vaccine or bio pharmaceutical plant by taking advantage of modular plant design. A lot of the work has been done up front. The equipment can be purchased off the shelf and the work of the manufacturer is more around integration engineering saving considerable time in the construction qualification of a bio pharmaceutical plant. As illustrated and in fact the time savings are even greater when during times of pandemic large amounts of resources can be put forth into building a plant very quickly. So, going again over the advantages of modular plant design. Flexible manufacturing the ability to change in and out equipment to accommodate new products or changes in the process. Cost savings due to smaller compact designs. The ability to reuse equipment for new products based on platform processes and modular equipment. Because there's far less time in engineering and new plants. We can go to market faster. A significant reduction in investment risk by starting out with small production capacities. And then building out or scaling out as demand for a product grows. And capacity expansions are easily facilitated by copying and existing design. And constructing additional modules to to supply additional product. Which brings us to a problem in the process control and standard space. We have equipment that is modular and purchase quickly off the shelf and comes with its own OEM controls. How do you get equipment to talk to other intelligent devices within a production facility. If you choose to go the root of custom development. You lose flexibility in your ability to move equipment in and out because you're tied together in essence by those custom APIs and drivers. The time it takes to write custom drivers extend schedules. There's a higher cost in integrating the equipment through the custom APIs and drivers and a long term maintenance expense around maintaining those drivers. So where open standards can come and enhance this modular equipment modular design of these facilities is through open standards stated another way. Flexible facilities requiring flexible automation to enable manufacturing of the future require open standards to help facilitate interchange of information between intelligent devices in the facility. So delving deeper into a typical drug substance plant for vaccine manufacturing. Cell multiplication starts with bioreactors. And then viruses need to be inactivated. And then downstream purification to isolate the cells like the adenovirus in adenovirus based vaccines require downstream purification technology such as chromatography and filtration. And our company has moved forward with full modular design, including platform processes to enable speed to commercialization. We start with a platform and where necessary we swap in and swap out different pieces of equipment. Say we use bioreactor a from from one vendor. If we choose to switch to a different bioreactor, we don't have to rebuild or reengineer the whole facility we swap swap it out because of the flexible nature of the connections. And that's true of all equipment within the vaccine manufacturing plan. Here's a typical process flow diagram. Of the facility. The unit operations are can be purchased off the shelf. They're pre engineered buyer supplier, and they come with their own OEM controls. And the nature of the problem is how to connect up intelligent devices represented by the OEM controls with a supervisory control system. Knowing that we need flexibility to be able to swap in and out those pieces of equipment depending on the process and depending on the product being manufactured. So, I'll take you through the journey of 1 of our facilities through this past pandemic year to demonstrate the flexibility of these designs. Over the course of less than the year, there were 5 products that were tried out in a single facility. The 1st 2 candidates were our internal vaccine candidates, which did not prove to be as effective as the ones currently in the market. So those efforts were abandoned. We were able to quickly pivot to 2 other therapies all within the period of a year. Whereas in the past with stainless steel facilities, it would not have been possible. But with modular off the shelf single use equipment, we're able to use a platform process and then make small changes to the process by moving equipment in and out in a flexible manner to be able to quickly change over to a new product. So to further highlight the challenge in a pharmaceutical plant. It starts with. OEM controllers on the on the processing skids. And a supervisory plant controller that runs the entire facility. All are capable of running. An S 88 state machine and all of them require data to be exchanged via standard communication protocols. Typically, that's OPC UA. We spoke about the state machines and that's based on the is a 88 batch standard. On the right is the procedural model, the batch engine run by the supervisory control system in the plant. And that will be set up to run with the physical equipment. The OEM units providing the process operations. Bioreactor chromatography filtration to manufacture the vaccine or pharmaceutical product. The skid controllers themselves run their own controls with equipment modules and control modules. So the challenge is to set up a system so that the supervisory control batch engine can drive operations at the unit operations level. And to do that, there's numerous standards that are being proposed to help the industry adopt and quickly develop the flexible automation needed to match the flexible equipment in the factory. One particular one sponsored by the open group is the open process automation standard Opas. Opas is a standard of standards, allowing the integration of best in class components from disparate vendors, the standards and compass compute. Configuration, connectivity, system management, security just to name a few. And universal adoption of a standard such as Opas would certainly facilitate the flexible automation required to run a modular plant, modular biopharmaceutical plant. Other standards being proposed and considered by the industry are also based on OPC UA. One other proposed standard to connect unit operations in a biopharmaceutical plant is the more MTP or module type packaging. The more offers a framework through the MTP for data structures as interfaces. It offers a state machine. And it also offers services so that a supervisory control system can interact with modular equipment represented by the OEM control systems. And so multiple industry groups have built upon OPC UA and MTP. The ISPE has a plug and produce work stream, which brings in GMP requirements, data storage, data integrity, time synchronization, user management standards to the problem. The biopharm has developed a set of profiles and functions for the various unit operations. Essentially a data model so that a supervisory control system can talk to a unit operation and be able to exchange all relevant operation needed to run that particular unit operation. So expanding further on some of the biopharm work, some published papers around interface specifications that are protocol agnostic, it can run any standard that's out there. But is particular to a certain class of unit operations. In this case, this stirred tank reactor is applicable to a wide array of equipment, including fermenters, cell culture systems, mixers, buffer systems. And this information model can be embedded in the transport protocol of whatever standard chosen. These interface specifications as designed by the biopharm is meant to be protocol agnostic. Okay, changing direction again, I'm going to talk about distribution challenges for vaccines which need to be kept at very cold temperatures. The class of adenovirus based vaccines, which I spoke of earlier, tend to be hardier and to temperature sensitivity. So all vaccines will degrade when they are outside of certain temperature zones. The messenger RNA based vaccines like the ones from Pfizer and Moderna are specially sensitive to temperatures and need to be stored at minus 40 to minus 70 degrees C in order to not lose potency. The adenovirus based vaccines can withstand refrigerator temperatures and degrade less quickly and typically can be used put in 2 to 8 degree C refrigeration and still be effective once it reaches the patient. But the challenges around frozen supply chain will be highlighted in the next set of slides. It requires a heavy investment in the supply chain and at each stage of the supply chain, these very expensive minus 40 minus 70 degree maintaining freezers need to be purchased. The volumes for distributing these vaccines in the tens of millions, hundreds of millions adds to the talent challenge. I'll be talking about an important concept called talks time out of controlled storage and how that's relevant to the supply chain. You'll see in the set of pictures at the bottom. It starts with a carton, a 10 dose carton of vaccines. These cartons are placed in a box and then that box is put in an insulated container and then packed in dry ice. In some cases where they are available, they are palletized for easy transport to storage. But in the case that the palletized system and a refrigerator that can can allow pallets to be put in there is not available. These are done by hand. So this slide shows the various steps. Once a vaccine, a carton of vaccines is produced and the number of stages in which shown by the star that you are out of control storage and the vaccines are rapidly losing potency. It starts with the light blue boxes. At a vaccine manufacturer after it is packaged into those cartons, it is then stored at onsite. Freezers prior to a pickup and load into a set of trailers. So every time you're doing this load, whether into the freezer or out of the freezer into the next step of the transportation, you are incurring time out of controlled storage and your vaccine product is losing potency. From the manufacturer, it gets shipped as representative boxes in yellow to third party distribution partners like a UPS. When it arrives there, it needs to be unloaded from the special trucks, the refrigerated trucks and again undergoes time out of controlled storage. And when the trucks are ready to go out to the customers, again, the loading process introduces time out of controlled storage. And finally, when it reaches the customer and to the injection site, there are numerous other opportunities to be in a state of out of controlled storage, meaning vaccines again are losing potency. So these are the distribution challenges around minus 40 and minus 70 degrees C requiring vaccines. Looking at it in another view, we ship out from our plants like the one I'm based out of at West Point. And they'll go to either the third party logistics providers or the CDC. Now, those two nodes have invested substantially in these freezers and have capacity to take large quantities of vaccines and be able to keep them cold at the required temperatures. And even in the shipping process, special planes, special cargo holds and the trucks delivering them to their next location have the refrigeration freezing capacity needed to keep the vaccines at the required temperatures. But at the destination sites, whether it's public health departments, hospitals, doctors, offices, pharmacies, they may have very limited capacity to hold these vaccines. And that's what highlights the challenges of getting vaccines out to a broad population. If there's limited storage capacity, these vaccines then quickly degrade at improper storage temperatures. And so this slide highlights the challenges of getting vaccines out to a wide population because of the dearth of refrigerated equipment needed to maintain the vaccines at their desired potency. Fortunately, in the United States, we have a very strong network and there are enough doctors, offices, hospitals, pharmacies with capabilities and read out over time. By and large, we're able to vaccinate the entire population. But the problem gets amplified in other parts of the world that don't have the required infrastructure to distribute these vaccines. And so frozen supply chain, refrigerated supply chain is a great challenge in trying to reach all the patients around the world. To wrap up my presentation, I've described some of our companies' contributions in the fight against the COVID-19 pandemic. I've talked about modular equipment and modular engineering to create flexible manufacturing facilities based on platforms. And it's through the use of these modular developments that the biopharmaceutical industry has been able to scale up very quickly to produce mass quantities of vaccines to meet the needs of unvaccinated people and to protect as many people as possible around the planet. Modular equipment and modular engineering enables speed to market through faster facility builds. And these need to be supported by open standards in process control, like the OPAS, facilitated by industry forums and standards groups. And finally, I talked about some of the distribution challenges in supplying vaccines, especially during a pandemic where speed is of the essence. So that wraps up my talk, and I thank you for your attention during this presentation.