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Fill-Finish Podcast 2 – “The Past, Present, and Future of Advanced Aseptic Facility Design”

Participants

  • Guests: Sterling Kline, RA, Vice President, Design and Jason Collins, AIA, Director of Process Architecture, IPS-Integrated Project Services
  • Hosted by: Rizwan Chaudhrey

Rizwan Chaudhrey: Hi everybody, this is Rizwan Chaudhrey, and you are listening to the Fill-Finish podcast sponsored by ApiJect. This show shares the expertise and all aspects of injectables, vaccines, and aseptic fill-finish.

Rizwan Chaudhrey: This season is offering 10 episodes focused on topics, including facility design, regulatory quality supply chain management, and AR/VR, to name just a few, and today I’m delighted to be joined by Jason Collins and Sterling Kline of IPS – Integrated Project Services. We’ll be talking about the past, the present. and future of advanced aseptic facility design. So, Jason, Sterling, I am delighted to speak to you. How are you?

Sterling Kline: Very good, thank you, good to meet you.

Jason Collins: It’s very nice to be here today.

Rizwan Chaudhrey: It’s great to meet you, gentlemen. Thank you for joining me for this podcast. My very first question is that, before we start talking about aseptic processing, would you mind giving me a quick overview of IPS and your own backgrounds? If you don’t mind, Jason, would you like to start?

Jason Collins: Sure, so again, my name is Jason Collins I’m the director of process architecture with IPS leading a group of architects focusing really on front-end design work, strategic planning, and really helping our clients with their business initiatives, solving their problems. Sometimes that’s through facility design and sometimes that’s through higher level analysis. IPS as a company is very much involved in helping our clients solve their problems and helping them make product and bring product to the patients that need them. We are a full-service architecture, engineering, and construction company. A global company with offices around the world and, as mentioned, we focus on everything from front-end design right through detailed design, commissioning, qualification, validation, construction. All services. And we offer those services independently or all together and ABC and D models as well.

Rizwan Chaudhrey: brilliant Thank you, Jason, and Sterling, would you want to give me a quick overview of your background as well, and your role?

Sterling Kline: My role in IPS is Vice President of Design. Currently, I am a subject matter expert in aseptic processing, and concentrating on front-end client relations and business development with aseptic projects background. I am an architect, licensed construction contractor and a degreed engineer. I have spent 55 years in those disciplines. The last 45 years have been, specifically in the pharmaceutical industry. The first 28 years working directly for pharmaceutical companies in various roles primarily in aseptic manufacturing and then last 17 years here at IPS as a consultant.

Rizwan Chaudhrey: So, thank you for that, and you are perfectly qualified to ask my very first question, which is…What was the state of aseptic processing when you started in the life science industry way back when?

Sterling Kline: It was way back when in 1978 that we started with aseptic processing. That was really at the beginning of the technology throughout the industry, and it has evolved over the past two generations. In the very beginning, we were all learning and so typically, from an architectural standpoint, we were building facilities that look like any other facility in the world and we really did not understand the technology of clean rooms and the technology involved with that. Both from an architectural standpoint and buildings, mechanical, the whole building process, but then also from an equipment side, and all of that has evolved.

Sterling Kline: Initially, through the learnings, I started out in a pharmaceutical company. We had an assignment to build our first aseptic facility to manufacture freeze-dried product. As a young architect, I use traditional technology, so that was used. Drywall construction, typical flooring systems, acoustic tiles to ceilings which over the generations, we found were totally inappropriate. We found historically mold grows in all the drywall facilities. The acoustic tiles particulates and causes issues from a clean room standpoint and flooring will discuss through this process, but I’ve never been satisfied with any of the flooring materials. Even currently there have always been issues. But initially, we learned from that first facility and the equipment was rather rudimentary as well, and so, at that time, some of the equipment companies were then evolving. TL in the United States did quite a bit of development, most of us in the States use that equipment as it was growing and protections started, but with the equipment and the facility. So, from a material standpoint, over the period of time I’ll say the early generation was from the late 70s into about 1995 through to 2000. During that process we ended up using basically drywall but adding new coatings to it, so there were vinyl surfaces that were developed that coated the walls and made them seamless. We learned that when you had seams, particles would come into the facility. So, you created the barriers. Basically, what we were building were clean rooms that were like inside out swimming pools. Instead of keeping things in, we kept bacteria and viruses out of the facility away from the product. Over time, through different products being introduced, we have made small improvements on that.

Sterling Kline: From a classification system, we drew from electronics and from the radioactive industries in terms of clean environments and protection. We utilize the classification system with class 100, 10,000, and hundred thousand rooms. Throughout that time period, those two decades, that was primarily what we designed around and the central clean rooms for the product were formulation and filling were designed to class 100 rooms. It evolved over time, as to how do you design that to keep the particle levels down to those limits. Initially, we then put HEPA filters on the end of the ductwork for supplying the air. What comes into the room we’ve now shielded the room air comes into the room, so we’ve shielded the air with HEPA filters. Initially. It was maybe 30% of the room and we put that primarily over where the product would be.

Sterling Kline: What we found over time was that it was not adequate to get the airflow proper down to the level of the work surfaces. Ultimately, class 100 rooms, by the mid-1990s, were 100% of the room. Initially, where we transfer material, we actually put different floor colors, so operators would work walk under the HEPA filters on the colored floor to get to the next operation. You can see how it evolved from very rudimentary until we had clean rooms that we fine-tuned the HEPA filters, so that, in the middle of the room, we got much more air coming down, than the HEPA filters at the edge of the room. So that the air penetrated further down to the floor past the work surface and kept particles away from the product that we were injecting into patients. The problem, though, is, as I mentioned, the one item that came into the room was air.

Sterling Kline: The other thing was the operator and over those two decades, we found that the primary contamination to product was from the operators. Now we dress them in complete space suit type gowning, but particles still came through that. There were three holes through the gowning materials and that contaminated the product. From a technological standpoint, the FDA started getting involved at that point, setting up hundreds of SOPs that the operators had to follow to limit the contamination of the product. They had to move very slowly because, in reality, it was like the Peanuts cartoon with Pigpen. There were as many particles hanging around the person as that. That’s where the risk was. With the technologies we had, we got as fine as you could get at that point, using the operating procedures and the materials that we had available.

Sterling Kline: At that point, most people resisted any further change because of being risk-adverse and the regulatory agencies were also resistant to change. And so, in the mid 90s, three pharmaceutical companies, prior to that we were all operating separately and kept all information as a competitive advantage, so there wasn’t a lot of sharing. It was more people transferring from one company to the other that shared the information. But Lily, Upjohn, and Merck got together and decided, as a group, that they were more likely to get regulatory approval if they introduced the technology together. So that became known as the LUMs Project…Lily, Upjohn and Merck.

They developed with TL an isolator similar to what came out of the nuclear industry, where we were protecting the operators from the product. In this industry, we are having Isolated to protect the product from the operator who, as we remember, is the primary source of contamination. So, when that project was introduced, the weakness was that they claimed it was sterile inside the isolator not aseptic. They couldn’t prove that it was sterile to the FDA, and it created a barrier over probably the next decade and some resistance to go into that technology. But it was so logical that is how the industry wanted to proceed. What they did do then, at that point, created something called RABS, Restricted Access Barrier System. They did put a barrier up there, technically it wasn’t totally isolated, so the air flowed from one to the other.

Sterling Kline: But if there was a barrier that kept operators away. Unfortunately, there were various applications to it, and a lot of people open the doors, during operations, so the barrier disappeared. And there was still a weakness, but it was still better than what we had with no barriers prior to that point. That was working up into the year 2000, when isolators started in. The other disadvantage was isolators at that time could be cleaned internally. By multiple means. The one that became predominant was vaporized hydrogen peroxide, VHP. One company had a patent and they hadn’t developed that to a high degree, so the cycle time for cleaning was 10 hours. That wasn’t very viable for most pharmaceutical companies, you had to have a product that you could campaign and fill for a week with very large volume. So very few products. Vaccines were one. The three companies, I mentioned, they were vaccine companies and it made economic sense for them to go with the technology.

Sterling Kline: The change came in 2002 when the patent disappeared, and competitors came on the field and instantly, the previous company that you talked with in the first podcast, SKAN, came out with a five-hour cycle time. All of a sudden, the market opened up and it became more viable. And, at that time, they claimed the inside of the machine was the same as the rooms historically have been that it was aseptic and not sterile. It gathered regulatory approvals very quickly. That was the early stages. What progressed, in terms of a facility and finished during that generation was, in 1995, closed cell modular panels came into being. They were typically an aluminum cell, closed cell that had a vinyl finish. And the adjacent panels were connected together mechanically, but then chemically welded together, so then as remember, get a smooth uniform seamless finish that also was connected to the ceilings so that worked out fine. That was a progression that still today is the cutting-edge. A lot of details have been improved slightly so that it’s easier to clean, then easier to operate in, but that technology is current. Between 1995 and 2000 was really the change of the old evolving to where we are at this point. Technically with a soul enters with architecture and finishes with the modular wall systems and sealant systems.

Rizwan Chaudhrey: Thank you for taking that sort of quick overview of the history of the development of aseptic processing. That’s been really interesting. Jason, will ask you when you join the industry and where was the focus of aseptic processing at that time?

Jason Collins: It’s actually a perfect segway from where Sterling was ending up because that’s pretty much when I got plugged in. I started in the life sciences industry in the late 90s, 97-98 I believe. Really started to focus more on aseptic facility design in the early 2000s, which was an interesting challenging and critical time for aseptic processing. In the early 2000s, we saw some things happening, which really created some chaos, but also gave us some direction. We had some new guidance coming out from the FDA, I believe in 2004, they had their newer guidance for industry for sterile facilities. Surely before that I think a year before that the European Commission also issued their version of sterile guidelines in their Annex One documentation.

Jason Collins: So now all of a sudden, you’re getting some direction. You’re getting some guidance. You’re not being told exactly what to do, because it’s guidance, but now all of a sudden there’s something to follow. So the big challenge at that time was you had you know hundreds or probably thousands of manufacturing facilities around the world that now were in a state of assessing where are we with this guidance. Are we in compliance? Are we out of compliance? How long are they going to allow us to operate the way we are operating? And I think they were starting to get some feedback from the auditors and inspectors saying hey you really need to be moving in this new direction, we’re smarter now, the science is better. We know where we have issues, and you should be starting to address those for better products and better patient safety.

Jason Collins: So a lot of what I was doing at that time did involve assessing existing facilities, understanding how they operated, and trying to align them with the new guidance. There were probably three areas that we focused on the most from facility design, especially. There was the identification and monitoring of every classification. Now we had a little more information on the environments, that we should be doing different unit operations and how you should transition from one environment to another, one cleanliness level to another. And so, a lot of assessing was done in existing footprints to say Okay, can we now divide this up to have a better flow of people materials to protect the products more, to get the right transitions through air locking and gowning procedures. Is there the space to do that, or what can we do as a compromise? So, a lot of thought put into that. And then there was assessing the technology. As Sterling was saying, a lot of good work had been done regarding isolators. They weren’t perfect, there were a number of installations, so you did have some benchmarking information and then companies had to decide; Do we want to go all in with isolators? Do we want to make it a little better and use restricted access barrier systems, the RABS? Or do we want to stay with a conventional filling line which has none of that?

Jason Collins: And I think there was there was enough information to drive folks to say all right, we need to move away from conventional filling. We do want some sort of barrier between the operators and the product that just makes too good sense, we should be doing that. And then, it was you know, do we really want to go forward with the isolators? At that time, we did a lot of analysis, you know, operating with an isolator versus, RABS? Which one’s better? How does it affect throughput? How does it affect my flexibility? Those were some of the challenges to be addressing. And then, lastly, from a facility design standpoint again, Sterling mentioned the cleanroom panel systems which were being adopted from electronics facilities and just made a lot of sense.

Jason Collins: That was the other thing to assess, should we go down the direction of modular panels? Well, now, okay I’ve got to get all the panels from a vendor. I can’t just get a carpenter from down the road to fix a hole in the wall. When someone drives a fork truck through my wall, you know I don’t I don’t know if that’s going to work for me. Yet, you couldn’t deny the clean ability and the way that the modular systems didn’t generate particles like traditional stick-built stuff. So there was that analysis and then, of course, the only analysis that ever really counts is the cost, right? It’s forever evaluating which one is more cost effective? Which one can go in quicker? Time is money, all of those sorts of things. I think at those three levels, just the flows of the facility and adhering to guidelines, assessing the technology, and then the fit and finish of the facility that was a constant evaluation on projects at that time.

Rizwan Chaudhrey: Right. So, where or what does aseptic processing look like today, and what are the two main challenges that people face within that space?

Jason Collins: So I can have a go at that I think this is an exciting time. It’s really exciting, for a number of reasons. All of those or many of those challenges that I was just talking about have been somewhat mainstream for a number of years. Most people are well aware of the challenges, a lot of folks like Sterling and I have come up with very sound ways of providing global compliance to facilities. So, you do a design once you do it right and you’re good to go, for you know 99% of the market. So, some of those things are well-known and well-established.

Jason Collins: The issue with cleanroom technology, I almost never have that debate anymore. Everyone knows you’re putting in in aseptic suite, use a modular cleanroom system that’s the best. That’s state of the industry at this point. It’s just what you do. Isolators versus RABS continues to be a challenge. However, not so much as it was before. We are finding that it is an important decision and our clients often either have already decided whether they want it or not. And it’s often difficult to convince them, otherwise, because you can make a case, if you really want it one way or the other. I mean you can justify it because they’re so close now in total cost. They’re so close now in operability. It’s really splitting hair and you know what I often say if a company really wants a RABS-based system because they believe it’s the best for their business it’s going to be hard to change their minds. But we are seeing definitely, and then there’s been recent surveys by a number of organizations, that the shift is really going towards isolator technology and that’s pretty exciting, because you really that’s the most robust way to protect the products and the patients they serve.

Rizwan Chaudhrey: Sterling, have you got anything to add to that?

Sterling Kline: Along the line with the isolators, I’m seeing the same as Jason. Had conversation with the FDA a week ago and they said they’re very excited because they prefer isolator technology and they’re excited that they’re rarely seeing RABS at this point. From their view, quality is the most important and there’s not a lot of arguments opposed to that. There’s some operational issues once in a while. There’s some processes like ophthalmic bottles. It’s very difficult to get bottles into an isolator so from that standpoint, there’s a lot a logic of going to a RABS because that is the best solution, in that case. Predominantly with vials and syringes, at this point, the technology is well-established, and it took about 20 years to get everybody to accept that. Large pharma initially because they were the ones it’s all economics and they were willing to take the gamble. From an operating standpoint, some of the others were not. Because they had to retrain all their operators, so remember, we were talking about the SOPs. Folks knew how they do it, there was risk to them to change the technology. Big pharma typically had gone to that point. Contract manufacturers are now using the isolator technologies. Primarily, driven by their customers because big pharma will use CMOs as backup. And they’re looking for them to have the same technology, especially if multiple clients are in that facility and they have competitors in the facility that they don’t know what they’re making and their products next on the machine.

Sterling Kline: They want to make sure there’s the least risk, and from that perspective that’s what the isolator technology. Now, from an economic standpoint, it’s gotten, to the point where generics are now using it. It got to the point generics costs are the most important to them from an operating standpoint, because their sales are at a much tighter margin sure. The economics is now there. The isolator machine costs a little bit more. But the savings in the facility are going to a lower class. So, that isolators can be done in ISO 7 grade C environment where the RABS takes a grade B environment. You have to wear the space suits. The economics of that operating costs has driven people to isolator technology. So as Jason said, the industry is really matured at this point and the drive to get to this point is fairly well achieved.

Jason Collins: I almost feel like in some aspects, we did too good of a job hyper sensitizing ourselves to all of the risks. We’ve gotten to a point of belts and suspenders and straps in our approach to facility design and there was so much that was known about open processing and the risks that we really strove towards going in a direction to mitigate risk as much as possible, and especially as the isolators were being developed. We kind of wanted to have a bit of a backup plan in a bit of again the belts and suspenders. And so, we implemented a lot of very conservative facility designs with full unidirectional flows and sometimes separate flows out for waste and going above and beyond, from a segregation standpoint. Now that we have really good technology and closed systems and really good transfer systems, we’re struggling as an industry to accept the science and say it’s going to be okay, and we don’t need to apply all the other measures on top of that, which is quite frankly been driving the facility costs up astronomically. We’re at a point where, finally, the regulators are saying, have a risk-based approach and make decisions based on that. You don’t have to go crazy as long as you can prove to us that you’re safe and so getting folks to kind of back off from the real extremes I’ve seen as a challenge now.

Sterling Kline: Well it’s more a challenge with big pharmaceutical companies than it is for the small ones, because where the cost is driven, they’ll do smart risk and willing to accept that. A lot of startups that we’re dealing with at this point are really the cutting-edge and where the industry should be. It’s not that historic big pharma that has driven the industry over the past three, four decades. So it’s interesting from that standpoint and fun working with the startups.

Jason Collins: Totally agree.

Rizwan Chaudhrey: With that leads nicely actually to my next question, which is what does the future hold? What does the future look like then going forward?

Jason Collins: Well, I think, as I mentioned, the technology is pretty sound. We’re always pushing the boundaries from that standpoint and it’s a bit of a segway into what I was saying previously. I am hoping we can get into more of a situation where the designs and the facility requirements are more cost effective. And that’s, certainly where we need to be going. We will see more advanced technology in regard to robotics and how robots are used Right now, it’s how far that should be taken and is it really appropriate in certain areas. I think we’ll continue to see that to help keep people out of the process by having things more automated and it’s just going to continue to make things safer. From a design standpoint and facility standpoint, our challenges, how do we go faster? It’s something that we’ve been working through for decades as well with different types of facility delivery options, whether module or whether stick built that sort of thing. That’s continuing to be addressed on a case-by-case basis. I think a lot of times clients come to us with a with a preconception of what they want. They want a modular building, one that’s completely modular constructed off-site and erected on site. And they just want it, because they feel that’s what’s right for them, but I think what we bring to the table is helping folks assess what that right delivery is for them, because sometimes it’s modular and sometimes it’s not. Modular systems are great if you have your process well-defined and you can rush the design process because it’s already established because the whole thing is about going fast. If you still need to spend a lot of time developing your process, then there’s really no benefit in doing that because you could be building your facility in a fast-track way in parallel. Those are the things you want to assess. Modular has a higher premium so you’re paying more money, but you’re trying to get that speed so again, you have to align that with what you know about your project and how fast can you really go. I know some Sterling has some other thoughts about that as well right.

Sterling Kline: Yes, I do. We’re now going into the future of worldwide economy and focus. Especially with COVID, we’ve seen that. How do you get drugs to the rest of the world? Fortunately, there are a number of benevolent organizations that are now getting involved and where Third World countries cannot afford drugs, they’re being supported by the super wealthy. Folks like Gates Foundation and some of the others are doing phenomenal jobs along those lines They’re looking at a number of these companies or organizations are looking at modular as well. How can they come up with a design that they can put in many localities but have a technology that in the Third World country that these facilities can be built. Clean room technology is fairly sophisticated, so how do you do that? We’ve been looking at a modular design that they don’t have to repeat and redesign the building every time. We have a very large pharma company looking at it as well. How can they do a similar design? And where, in the past, everybody thought they were unique in their machine had to be taken their products were unique. Well, now with biologics they’re getting very much the same, with just differences and in terms of their potency level BSL 2 or 3, but the facilities can be very similar. Jason and I and others in the industry have come up with designs that are very similar for both technologies now, especially with isolation and containment, the facility can be very similar with just some slight modifications to handle the complexities. With a very similar design, you can put buildings all over the world, and so we’ve come up with systems where there will be a superstructure that can be built, that the localities have built warehouses similar to that. What we’ll do is put a sub structure that can be containerized, which was a really good idea about two years ago, until we had the container issue. I think we’ll get through that and were in a developed country you can put the components together, keep them standardized, your ductwork is the same size. We have come up with the Baron Dale truss subsystem, that’s a possibility. All the materials can fit within the truss and that fits within the building as a standard module. We’ve looked at all the different components within. Jason and I looked at this totally separately and then came together and the module we came up with was exactly the same dimension. So, there’s some logic to it with the equipment and we can pretty much fit every manufacturer’s equipment within this module with all different technologies, whether it’s syringe or vial or blow-fill-seal or lyophilized components or bottles. It all works within the standard system. So, if we can do that, then all of a sudden, you can stockpile the substructures in pieces and get them out. It speeds up the design time because you can take components.

Sterling Kline: For example, component prep. It’s either one parts component washer or two and one autoclave over two and it’s the same in any facility. The dimensions and through plugs are very much the same. You could have the same design and have that set as a tool in your toolbox. The FDA we’ve done some trainings with them, they’ve accepted the design and so your risk from approval once your buildings done is limited. As much as you can do it the design the exact same way and as Jason said we spent a lot of time doing compliance with all the regulations of the most cost-effective version. That’s where I think the industry should be going. I think, from an equipment standpoint, we should be using similar pieces and not have every equipment line customized because that is on the critical path. The buildings are not on the critical path. At this point, it’s always the equipment. And so, if we can get it standardized enough so that the project doesn’t start when you request a quotation on some custom piece of equipment, if they stockpile and, as an example, several manufacturers at a clinical scale have come up with a standard modular isolated unit and have cut the delivery time and less than half using that. I see that would be the intention going forward. Whether we can get there or not, that will be up to the suppliers.

Jason Collins: What I think is important is when you’re talking about facility or the future, which is a common topic these days, the important thing is not to have preconceptions of what that is. I think what we’ve learned in the last five- or six-years doing facility of the future designs for folks is that everybody has their own opinion on what the facility of the future. So what we’ve come up with is what I would refer to as a very robust design process for taking our clients through that process and figuring out what it means to them through a series of discussions and interviews in establishing design philosophies. What’s important is not to think of the solutions just yet, but what do you want the facility to do for you? Flexibility for one person could be being able to erect a facility, take it down next year, ship it across the world and re-erect someplace else. For another person, it could be well, I want to be able to be doing one product for the next five years and then wipe the slate clean and do something totally different in this space. By spending a little bit of time in the beginning to figure out what’s right for you and establishing those guidelines and design philosophies that can tremendously accelerate the design process from then out and the construction process because you won’t be second guessing yourself the whole way.

Rizwan Chaudhrey: Gentlemen, we could talk about this I’m sure for a lot longer than the time we’ve got left so. All I’ve got to say thank you very much for talking to me. It’s been a really fascinating discussion. I’ve learned so much listening to both of you today, so thank you for sharing your experiences and your knowledge with me today. If people like to know more about this, though, where can we get more information about IPS?

Jason Collins: Sure. Anyone can find more information about either myself or Sterling or the company by visiting our website at ipsdb.com. You can also find us through LinkedIn and any of the usual social media venues from that standpoint. I’d like to say, it’s been it’s been a pleasure talking with you, Rizwan, and it’s always a joy speaking with Sterling and sharing our experiences.

Rizwan Chaudhrey: There you go. I hope you found that useful. To learn more, check out the Fill-Finish Podcast, go to our website, which is www.fillfinishpodcast.com. To check out all the podcasts we’ve got there in the future podcasts will be coming up. If you’ve got any topics you think we should be covering in the podcast feel free to go to the website and put it there as well. We’ll just have to say thank you very much, gentlemen, once again, for sharing your knowledge and your experiences and thank you viewers or I say viewers, but listeners for listening to me, and until next time goodbye. Thanks very much. Bye.


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