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Podcast Series: Dr. Joanne Beck, Vice President of Process Development Shire What are the main challenges to the entry of new biologics into the market? Joanne: Well, there are economic, regulatory and various political challenges, as we all know, especially as entry of new biologics is in global markets – not just the US market. So, first of all, it’s getting more and more expensive to do research. The success rates for clinical drug development, especially in less understood diseases, are lower. It keeps getting lower over the past decade. The time required to take a drug through the development market has not really gotten any shorter in the last, let’s say, 10 years. It can be as high as 13-14 years. So, that’s an incredibly long development timeline. Capital costs keep going up. Also, in the global market there is pressure in every single country to control healthcare costs that keep rising. Regardless of whether a pharmaceutical or biological contributes to this increase in healthcare costs they are under a gun. All new drugs really need to demonstrate that they either have a therapeutic advantage or a cost advantage over a competitor product that is out there or other treatment options. As far as the regulatory environment, it has become more stringent and there are new hurdles – more demanding hurdles – that we need to clear to get approval for marketing. In the CMC area specifically, the requirements for an increase in process and product understanding keeps making our timelines – and, of course, the costs – higher and higher. We spend a lot of resources and time trying to prove that we understand our process and our product and that we can control the process. We also have to deal with a lot of misalignment – regulatory guidelines from different countries are not aligned with each other. For example, the risk management guidelines are applied unevenly not just from country to country, but also regulatory bodies within the same country. For example, the FDA, CDER and CBER apply regulatory risk management guidelines differently. Even between reviewers you get different responses. So, we can spend an endless amount of time and resources to eliminate risk and still not convince some regulators that the 1

BioProcess International Podcast Series Dr. Joanne Beck, Shire


risks are minimal to non-existent. I think in the past two to three to five years there has been a very conservative environment that does not tolerate risk. That is a really big challenge for us because there is always a little bit of risk. But, of course, I recognize that the regulators themselves are caught between a rock and a hard place. We all want to ensure that patient safety --- for us, patient safety is the most important thing. But, sometimes we are sent, of course, to chase wild geese. So, in general, the drug development process is very cumbersome and there are a lot of moving and interacting parts. Trying to evaluate the impact of a change in a certain quality attribute of a product to pharmacokinetic properties or biodistribution - is a challenge. And we are still learning how to use effectively and how to validate some of these new technologies that have come up over the last decade or so, like high-throughput screening, all the -omics tools, etc. So, there are all these great challenges, but how do we deal with them? I think in our industry, to be competitive, we are constantly striving to reduce the product development timelines. In the CMC we try to define the target product profile before we start work and then screen candidates against that product profile before they go too far along in development. That helps us control development costs and makes us more efficient. Then we try to design quality into the process and product starting with discovery. Always strive to increase manufacturing productivity, of course. We are also looking more and more to the outside to collaborate and we are looking to the outside for innovation and enhancing our core capabilities. So, we are focusing on our core capabilities and outsourcing things that we are not the best at. We’re looking for the best all around us to overcome some of these challenges. How do you assess and address issues of over- or under-capacity in today’s biopharmaceutical industry? Joanne: There was a lot of discussion around under-capacity, maybe 15 years or so, antibodies came along. But more recently, even not as recently as five or seven years ago or something like that, it became apparent that there were capacity under-utilization issues. So, it appeared that capacity-utilization was something that was not stable. There was a lot of noise around under-capacity, but then it turns out that we actually had over-capacity and many companies suffered with under-utilization of their very expensive facilities. So, really, you have to balance low utilization and the financial consequences of not being able to manufacture that critical clinical lot because there is no capacity and the financial consequences of that with under-utilization. So, to deal with this we have to be very flexible and utilize and manage effectively both internal and external capacity. So, the internal 2

BioProcess International Podcast Series Dr. Joanne Beck, Shire


capacity, we cannot really operate 100% ever if we want to be able to deal effectively with the clinical pipeline, which is always uncertain. We need to decrease the change-over time between products in a multi-product facility and, in general, the ramp-up time needs to be as short as possible. So, tech transfer and new product introduction needs to be very efficient and then using the same platform across products helps with that. Also having an external partner that can absorb projects in times of internal under-capacity is a solution, but of course that usually requires advanced planning. You need longer lead times, you need to negotiate financial terms and then that can be quite expensive. So, then we have to be careful to outsource projects that are a good fit for the capabilities, both the facility capabilities and the skills of the staff of our partners. Otherwise, the risk of the failure can be high. So, all of these things need to be thought about and assessed in addressing issues of capacity. Which product and process areas appear to be lacking the kind of expertise required? Joanne: In general, I think it’s very hard to outsource anything but cookie-cutter processes and methods. For example, effective outsourcing of process and method development in manufacturing of proteins and enzymes is very challenging. The skill set is just not there and it takes many, many years to build. Shire’s products are biological enzyme products, which is a good example of that. It takes many, many years to figure out how to purify enzymes and develop appropriate assays. On the other hand, if you have monoclonal antibodies that are mostly platform it’s much easier to outsource those projects. I think that the biggest gap across the industry is actually analytics. It’s not just one discipline. It covers several scientific disciplines. You have chemistry, protein chemistry, molecular biology, enzymology and physical chemistry aspects to analytical method development. But it also takes tremendous focus and attention to detail and there just isn’t a lot of glory associated with developing an amazing analytical method. In fact, the rest of the organization is asking the analytical folks to stop looking for things! So, there are very, very few people out there that are interested in a career in analytical development and who are really good at it. It’s really not one field, as I said. Analytical development is not really one field, but many. Another gap is formulation and delivery. I think most companies, even large pharma, end up outsourcing or in-licensing technologies – breakthrough technologies. We still don’t see the formulation and delivery technologies fostered in the traditional process development organization. They almost come like an afterthought – after you’ve developed your product, then you think about the formulation and delivery method. So, that’s one area – formulation and delivery – that I would like to see my organization excel in. We are already pretty good at 3

BioProcess International Podcast Series Dr. Joanne Beck, Shire


upstream and downstream development, but I’d like to see us really strengthen our formulation and delivery platforms. Where in the world is the expertise appearing or very likely to appear? Where are the manufacturing “hubs” of the future? Joanne: That’s an interesting question. I think that – when we speak about manufacturing – manufacturing plants, albeit they are not the huge mega-plants of the past, I think they will appear in many places. Many countries are now requiring that you manufacture at least part of your supply chain on their soil in order to allow you to sell your drug in their country. So, we are going to have a lot more smaller facilities all over the world. On the other hand, process development hubs, especially processes that require some innovation, will not move very much. You have to have a critical mass to foster innovation and the required expertise to develop new processes and technologies. So, take Massachusetts, for example. You may not have huge commercial manufacturing plants. So, you would not call it a manufacturing hub, but we certainly have a very robust development community and significant clinical manufacturing capabilities. So, we can find scientists that can develop state-of-the art analytical methods and formulation and delivery breakthroughs. There is also a very robust and very active network of industry, academia and vendor leaders that meet regularly and we work together. We have been very fortunate that several of our politicians, current and past, saw biopharmaceutical technology as a growth area for Massachusetts and fostered and helped fund it. So, anywhere where there is such an environment, either a state in the US or a country that sponsors and encourages this sort of biomanufacturing/process development hub, you’re going to have hubs like that. For example, take the Research Triangle Park in North Carolina, the Bay area has a huge hub, San Diego, and Singapore is there as well, and places like the Shanghai area also developing into hubs. We know that Shire has embraced single-use in its processing. What will it take for the rest of the industry to adopt single-use? Clearly, the advantages in cleaning, validation, costs, etc. are known, but some companies are not yet implementing disposables. What is it going to take to broaden that adoption and make it truly “industrialized?” Joanne: I think the question of balancing cost -capital vs. consumables- with speed to build a facility or to changeover a suite with robustness and compliance. Recently Abhinav Shukla and Uwe Gottschalk published a pretty comprehensive review of single-use technologies that I think summarizes the advantages and disadvantages or challenges of disposables very well. It gives a very balanced review of the state of disposables. For example, prior investment in fixed 4

BioProcess International Podcast Series Dr. Joanne Beck, Shire


equipment is something that is inhibiting more broad adoption of disposables. So, years will have to go by until the investment in stainless steel bioreactors can be written off and they are just going to be over their useful lifecycle and may be replaced by disposables. Another thing is right now the maximum bioreactor capacity is at 2000 liters, pretty much, for disposables. So, that’s a pretty limited scale. If you need more, you have to have more of these reactors. Leachables and extractables, also absorption of product and our media components. The plastic continues to be an issue. We have to do studies and we have to do studies with each product with disposables vs. stainless steel, which is pretty inert – or glass – which is pretty inert and you don’t have do leachable and extractable studies with every single product or media preparation. The lead time for any modification in the disposable bag can also be an issue. You have to stock a very large number of parts. If you have a failure, you can’t just clean and start over. You have to have that part in stock. So, we tend to stock a large number of parts. The vendors, of course, are limited. The vendors don’t have universal standards. So, that’s tough for us as buyers. So, we don’t have a back-up buyer vendor that has exactly the same standards as our main vendor. Honestly, disposables continue to be pretty expensive. Then, of course, you have the solid waste disposal. So, those are some of the challenges that I think are stopping broader adoption of disposables. What are the current expectations of the role of single-use technologies in downstream processing – meaning, what are the current limitations of single-use materials and technologies that still need to be addressed? What opportunities exist for developers of those technologies? Joanne: It seems that the opportunity for disposable use in downstream is more with flowthrough and filter cartridges or viral filters have been pretty broadly adopted and they are disposable. I think the availability of disposables in a variety of sizes and functionalities is an opportunity for downstream. I can’t imagine ever being able to use resin from just one vendor, for example, to purify all proteins and antibodies that come through our shop. There is just too

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BioProcess International Podcast Series Dr. Joanne Beck, Shire


much product variability to allow this. So, we need that very large variety of functionality in resins for downstream. Also, it has to make financial sense. Right now, a disposable Protein A column or a MEP column is way too expensive. You can’t just throw thousands of dollars of raw materials out after one or two uses. Then, of course, there is a lot-to-lot variability issue. I think there is a lot of opportunity there to show that from a lot-to-lot, disposable, affordable chromatography column is robust. There is a lot of opportunity with that. Finally, have you been a part of past BPI Conferences? What has been your experience over the years? Joanne: Yes, I’ve been attending BPI Conferences for probably over a decade, I would say. As an attendee, as a Speaker, as a Conference Chair, Organizer, etc. I love the variety of sessions and concurrent sessions and being able to go to an analytical talk in the morning, a formulation talk in the afternoon and a purification or upstream talk the following day. My experience has been one of meeting a lot of different people, including going to the vendor shows and being able to just relax, talk about shop and catch up. Listen to the talks but also network afterwards in a very open environment. And there is a variety of people presenting both from academia, from industry and also vendors – select vendor talks. So, it’s been a very positive experience. That’s really what I’m looking forward to at this year’s BPI Event is to get together with colleagues that I haven’t seen since last year and have an opportunity to network with them, listen to talks and just find out what’s new. Thank you for joining us today, Joanne. Joanne: You’re welcome. Thank you.

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BioProcess International Podcast Series Dr. Joanne Beck, Shire

BioProcess International Podcast Transcript: Dr. Joanne Beck, Shire  

In this podcast transcript, Dr. Joanne Beck previews biologics and the capacity of the biopharmaceutical industruy.

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