The Facility Master Planning Playbook With Herman Bozenhardt

In this episode of “Better Biopharma,” host Tyler Menichiello is joined by friend-of-the-show Herman Bozenhardt, a consultant and industry veteran who has spent decades advancing the fields of biopharmaceutical manufacturing, engineering, and regulatory compliance. Bozenhardt shares practical advice for teams planning a new biomanufacturing facility or retrofitting an existing one. He explains how thoughtful facility master planning can mitigate costly design mistakes and improve site flexibility, ensuring facilities remain adaptable to future technologies, new products, and evolving regulatory expectations.

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Transcript

SPEAKER_00 0:17

Hello and welcome back to Better Biopharma, the official podcast of Bioprocess Online. I'm your host, Tyler Minichello, and on today's episode, I'm joined by longtime friend of the show and contributor of Bioprocess Online, Herman Bosenhart, who's an expert on things from facility construction to CMC manufacturing and everything in between. Herman, did I miss anything out there?

SPEAKER_01 0:36

No, I just I've done just about everything, and I've seen it all. So you can't surprise me with anything.

SPEAKER_00 0:41

Amen. Longtime friend of the show and contributor. Thank you so much for joining me on this episode, Herman. Um, and so let's just dive right into it. We are going to talk about master planning today. And I wanted to maybe open up with just hearing from you why you thought we should talk about master planning, kind of what what spurred that that idea and that and that focus, and then we'll we'll move on into the discussion from there.

SPEAKER_01 1:04

Probably one of the most um necessary things you have when you run a facility or you maintain a facility is to have a master plan. What's gonna happen to the space? Where's it gonna go? What's gonna happen to the processes? What are they gonna be doing? And how are you going to maintain this space? You're gonna have to battle plan. I mean, it's just as if you bought a used house and you're gonna say you're gonna keep it that way with the person's old refrigerator and the old toilet and all this and all that. You gotta have a plan of what you're gonna be doing and where you're gonna be investing. Otherwise, you're gonna be lost and you're gonna be patching things day in and day out. So it's very, very important when you look at a facility and you know it's going to last for 20, 30 years, maybe even 40 years in some of these places. What's gonna happen to it? Where's it gonna go? And you have to kind of bring together some ideas of what are you gonna do with the space? Is it gonna always be the same? Of course not. You know it's not gonna be. What are you gonna do with the space? What are you gonna do with the HVAC systems? How are you gonna do the logistics? How are things gonna go in and out? Um, how are you gonna maintain the facility? Oh, I'm gonna build something with high ceilings. Well, that's a bad idea. How are you gonna clean those ceilings? Uh, you have wear and tear on the floors. Can you get machines and equipment in there to fix the floors? How are you going to maintain and control and modify and update as time goes on? Because you're not going to be there forever in doing that one thing. So it's important to look at that. And then the other aspect, which is very important, is what's going to happen with the GMPs. The GMPs are not going to get a, and the EU regulations, Annex one, are not going to get any looser. They're going to be they're going to be very, very strict, and they're going to focus on all the issues that are happening today. Cleaning, uh, waste disposal, uh, making sure that you don't have cross-contamination between one product and another. So there's a lot of drivers in this. So you must have a site master plan, and it's like a battle plan going into an action. You have to know what you're going to do, and you have to be able to respond. So that's kind of that's really why you want to do it. You can't just start from nothing.

SPEAKER_00 3:17

Yeah. Is there, are you, because you're a consultant, right? For the people who aren't unfamiliar, your last time on the show, we were talking about CDMOs kind of giving them a kick in the tuokass, so to speak, to uh in terms of quality and um and and talent and pipeline there. And then that was our last discussion. And that was for many people listening, probably their first time um coming into contact with you. So, what what else would you tell people about yourself? And and also it was this idea of today's topic of conversation born out of some work you're you're currently doing.

SPEAKER_01 3:46

Oh, sure. Well, uh uh first of all, again, my name is Herman Bosenhardt. I've been in the industry for 50 years now. I started my career in Pfizer in 1976. And let me tell you something, it was a great facility. And uh, I have a bachelor's in chemical engineering, I have a master's in system engineering, and I was in the engineering end of the business for most of my career. I finished up in 2009, and then I was uh been doing uh independent work uh over the years. I worked for JJ, I worked for Biogen, and currently I still work for CSL Bering and for Fujifilm. And I built the uh the locust biosciences facility that was uh facility of the year for ISPE. Um, so I've been around for a while. Like I said, I've seen everything, I've done just about everything from monoclonal antibodies to uh antibiotics to BL1, BL2, BL3 facilities. Um, so I've got a pretty good perspective on all the things that people do wrong, as well as all the things that people do right. In some cases, you actually do you do have a little bit of forethought. Um, but you know, you you look at you look at the evolution of where we are. So, kind of the first area I want to talk about is you know, you know, what happens and what triggers a real serious look at a master planning. Well, you know, products don't last forever, you know, the patents run out. You know, you got a 17-year window, but by the time you really introduce a product and get into the market, a new monoclonal antibody, a new oncology, uh, gene therapy, you got about seven, five to seven years to really work with that and to reap the benefits. What happens is products go off patent. They go off patent, there's new competitors, and so what happens? You got to move it out to a CMO. Now, what do you do with it? You have other issues where you have uh yield changes. So if you look back uh in the old days, and they still do this today, you know, you have your phase one work, your phase two work, you're doing producing product in a in a clinical trial facility, and the RD scientists and the clinical areas say, well, you've got to get uh a yield of about one gram per liter. Oh, really? All right, well, I better design the new facility to do one gram per liter. But then you put it in industrial scale with with automation and really good cleaning and really good, very precise workings, and you start to use some single-use disposables. All of a sudden, what are you getting? Four grams per liter. Oh, geez, I overbuilt. Now what do I do? So there's there's one potential, and that's another area that that tends to come up, and then you got to deal with it. Or what do we do with the spare capacity? You know, can we keep using it? Well, this is unless the market is. There's some situations where the market explodes and you need extra capacity, and that's good. But today we we tend not to, you know, we give you capex to execute and build and design something. Um, sometimes product demand goes goes down the down the drain and nobody wants it anymore. So now you got to figure out how to repurpose the facility. Sometimes you have adverse effects from a particular product and you got to stop production. So there's a lot of different things that happen in the facility that kind of forces you to rethink in terms of consolidation. You got overcapacity, you have undercapacity. Uh, what am I gonna do with this? So you can't just say, oh, geez, we got to walk away. We have to have some plan of can we get in and take equipment out? Can we replace it? Can we do better? What if the market explodes? How can we expand? Maybe we have to shift our gears and we take out some of the old style things like all those uh filter housings and put in single-use disposables. Sometimes we have to look at a different way of working and maybe increasing our shift load. You know, it said one shift a day, two shift a day, three shift a day. If we do that, we're gonna have enough water, enough air. So we gotta have a good idea of what the basis of the facility is, and then what can we do? And we have to kind of prepare ourselves for the future. Um, you can't just leave it and say, oh, well, it'll take care of itself. We, the engineers and the operations people have to plan out what do we do with this space, or do we add to this space in anticipation for the future? So there's a lot of there's a lot of things that go on, Tyler, in in master planning, and it all has to do with what do we have and what do we have to look forward to and be prepared to move and to innovate as we go along.

SPEAKER_00 8:36

Thank you, Herman. That's great response, and you touched on a lot of what I wanted to talk about in in this recording here. So I'm not quite sure where the best place to start is, but maybe I mean you talked about what could trigger a master planning effort. I guess the natural next question for me would be how do you think sites should balance short-term needs and long-term vision? And kind of along with that, how do you avoid designs, facility designs that is, that limit your future adaptability? And and we can move from there into you know, kind of assessing infrastructure constraints and whatnot.

SPEAKER_01 9:15

Yeah, that's that's a good question. I mean, you know, we always are given a fick fixed amount of money, but there's some things that you can do and be some sm do some smart things when you look forward and you look at the design, and you have to be aware of long-term versus short term. So the first thing is is space. You know, we have a particular process area, a big facility. What are we going to do with that process facility? Um, we we have to know about it, but maybe what we should be doing is being smart about it and say, let's make sure we have some more gray space, some more flat concrete space that's enclosed in this whole area. Now, the the dollars per square foot for flat gray space with no process equipment is very, very cheap. You know, $100, $200 a square foot. So maybe we should put in some more flat space that's under this particular roof. So we don't have to worry about knocking out a wall and digging into dirt to and to to refurbish long term. So that's the first thing we got to do. Next thing we got to do is look at the utilities. What are we doing with utilities that we have to understand a little bit about and really get down to it? The big issue that always strikes people is water for injection. Okay, let's so let's let's go, let's let's delve into a real life situation. So a particular facility which will mean nameless in Pennsylvania, um, beautiful facility, gorgeous, it's state of the art in its time. It ran out of water. Soon did it start it up. Well, the the designers got the basis that they'll need 3,000 liters of WFI to flush out an entire train from essentially seeds seed train through all the main bioreactors all the way out to the harvest area. So 3,000 3,000 liters, they punched that in for each number of the trains, and we're good, right? Well, they misinterpreted it. What they wanted, what the the R what the RD folks and the operations folks said is they wanted 3,000 liters per vessel in the train. And guess what? There's five vessels in the train. So guess what? There was not enough water. So that's one of the biggest issues is to really understand what the process is going to be. And everybody always wants to focus on just the bio process. What do we need to fill the tank? It's a lot more than that. All the clean in place, clean out of place, all the flushing, all that water, the water feed to the the um clean steam still, you know, all those pieces in the puzzle. That's very, very important. Um, not enough air. Well, what we should do is we should make sure that we have multiple air compressors, and even if we don't need them right now, leave some pad space and leave a main for that. Another issue that comes up all the time. We're just going to do PF water for cleaning, cleaning, cleaning, and then the final little rinse is just going to be WFI. And then when we get into the actual cleaning operation, guess what? Oh, geez, the PFW, that PW water is not doing it. We're using ambient PW water. We've heated it up a little bit, it's not really doing it. What we really need is the 85-degree WFI to clean the vessels. So now all of a sudden we don't need as much PW water, we need a WFI. So again, we're getting to this constraint again, and now we have no capacity. So, you know, it's flat space and then capacity. Now, the capacities issues are not just WFI and PW and calculating them correctly, but it's air, it's nitrogen. Um, we always have one spot for the airlock key people or uh who's ever supplying air, liquid air people, and then we we blow it all through the whole facility. With all that space and all that line and all the manifolding and all the tubing, we have tend we tend to have a pressure drop problem at the other end. So, where do we go to locate that and how are we going to supply the the nitrogen grid? Um, one area that is becoming a big problem is the waste area, waste treatment. You know, you have you have the you have the production right now, we got to get rid of, but we have to get rid of not only the you know the flush from the media areas and whatever, but we also got to get rid of all that water that's done for the CIP, the COP, and so on. We can't just let it just go to a normal sewer. So there's a lot of volume that's got to come out. And so what we see today is the biggest constraint is in the utilities called the waste treatment and really understanding the volume that's going in and building for a large uptick in that uh that waste treatment, or at least doing it correctly. Um, so we see those are the biggest, biggest issues out there, and um those are what constrain facilities, then we have to quick, you know, patch up the facility later on. So when you're doing a master plan, you have to look at where are all my vulnerabilities? Waste treatment, water, and what about HVAC? Oh, but Herman, yeah, all the all the suites are taken care of. Well, what if uh we need to increase our capacity? Do we have enough flat space in the mechanical area for uh additional HVAC uh drives? And one of the biggest problems, especially legacy facilities, in mechanical space in the near the HVAC, what do they use them for, Tyler? Storage. They put all the junk, all the spares, all the stuff they don't know what to do with, all the old stuff that we don't want to get rid of. That if you typically go into a legacy facility today and you walk around and you go into the mechanical space, it looks like grandma's closet. It's just everything's there. And you know what? No one person knows where everything is. So the thought is is that we need to plan out even our gray space and our mechanical space, and we have to leave the space for that and also space for storage, too. So that's kind of the that's kind of some of the things that we really want to make sure we understand as we get into these these planning issues.

SPEAKER_00 15:40

Yeah. And Herman, to be clear, are you who are you speaking to right now in our audience? Are you talking to people who are uh perhaps upgrading a facility, retrofitting one, refitting or building from the ground up, or does this apply across the board?

SPEAKER_01 15:54

I'm talking to you all, everybody. I mean, if you're if you're about to build a facility, make sure you listen to me in terms of extra gray space, extra black space, you need the process space, but get that get that cheap, dirty space in there so that you that under your roof so that you you have some capability. Secondly, is when you um when you're building a brand new facility, br the utilities, open your eyes. What do they really need for flushing? And we'll sort of anticipate what you're gonna have to do in the cleaning validation. What are these cleaning people gonna tell you? They're gonna probably want to put more water in there, flush it for a longer period of time because they can't get the TOC down. So think about some of those, and when you're doing that, because on the other side, what are we typically doing? We're looking at you know, capacity factor, service factor, uptime, downtime. And we sometimes want to reduce the size of what we're buying to save capital, but we really have to look at it from the standpoint of what is it gonna be when we're doing a peak demand. So, one of the things that I will, if you're building a brand new facility, the one thing I'm gonna stress for you to do is do a dynamic simulation. Don't don't don't tell me, oh, I got a nice spreadsheet that's static. So one time, best guess, wish on a static. Go to dynamic because you're gonna see the ebb and flow of the utilities, especially, and the utilization of the the process, the the waste coming off of it, and also something else that you're gonna find out. How many people are you gonna need to staff this? Changing filters, changing, you know, uh charging for the media, uh, operating, uh, weighing, dispensing. You start to really understand how many people, then you start to realize what you what you're gonna be getting in in terms of your teams and the training required. So dynamic simulation is probably one of your best tools if you're starting off. If you're if you're retrofitting, which is what everybody's doing, um, then it's pretty obvious. You have to look at, you know, what are your key areas in terms of your utilities? What flat space can you use? What flat space can you not use? You know, you have that old space that's used over there, and nobody paid it, clean it out. Maybe we could put something there. We need to add on additional compressors for air. We need to see if we can do something better with the maybe a new evaporator for our nitrogen area. Uh, do we have enough water? And if we don't, part of the master plan is to take a step back in the legacy facility and say, maybe, just maybe, we should go to single-use disposables rather than using, you know, I I there's one facility remained nameless, was not uh uh, you know, they had a particular problem where they did not have enough water and enough staffing to clean vessels, and the vessels they were cleaning and washing and sterilizing were five liter, ten liter, twenty-liter, and hundred liter. But why would you do that? Get rid of doing all that and go to single-use disposable bags. All of a sudden, now your capacity frees up, your staffing frees up, the water, the steam, everything frees up. So you got to start part of the master plan also for the legacy facility is what technology are we gonna take advantage of to the next level, to the next step? And the single use disposables is probably the most you know, save the day. And I think that's that's an important part because if you think about any any vessel that you may have, how are you gonna get out of this mess? Well, single-use disposables will do that, whether it's filters or it's vessels. How about another one? I got another one for you. Uh, they call they called me one time, they said, Herman, Herman, our our solution prep area is just maxed out. We have all the people working, we're doing this, we're doing that. Oh my goodness, we can't get another liter of stuff out of there. And I asked them, Well, what are you making? You have some complex, you know, sodium hydroxide and alcohol uh for chromatography. Oh no, we're making um phosphate buffer, we're making sodium chloride buffer. And I said, wait a minute, you're making 50 liters of salt water? Oh, yeah. Well, why don't you buy it? Why don't you buy rather than taking up four to six hours in your vessels, buy the sodium chloride solution, buy the buffer. Hey, I'm gonna tell you something. Thermal fissure, they'll sell it to you with no problem at all. A lot of times we we don't want to think out of the box. We're just stuck in, we have to do it this way. You don't. You could call, and I don't know, I'm not, I'm not an agent for thermal fissure, but you can call thermofisher and say, I want um five tote bins of sodium chloride, and you're gonna give it to me, sterile solution with a a certificate on it for sterilization, authentic, you know, all the analytical results, and they'll sell it to you. You pipe it up with uh aseptic quick connects, and you're you're on your way. And your vessels you can use for other things. So, master planning a legacy facility has a lot of opportunities, and you just got to sometimes just get out of your own way.

SPEAKER_00 21:37

So, yeah, at this rate, I hope ThermoFisher is open to sponsoring the show because they're getting a lot of free promo right now.

SPEAKER_01 21:45

It came to my mind, but you know, there's a lot of other folks out there who'll do things. But my my point is that whether you're doing a brand new facility or a legacy facility, there's so many new angles that you can do in a legacy facility in terms of uh Terms of modifications. So if you know, even going back to the HVAC area, you could go ahead and when you retrofit, use fan wall technology. Fan walls have multiple fans, multiple drives in a single plenum. Now, why would you do that? Well, you don't need to have all the all the fans online all the time. You're getting your pressurization and your flow. All of a sudden, now you're expanding your process area. You're wanting to uh bolster the air pressure because you're taking on a going from uh BL1 to BL2 uh product. There's all sorts of opportunities, but there's so much mechanicals and single use disposables and very practical things to do that a legacy facility has lots of little lots of little levers to turn, to knobs to turn and levers to pull.

SPEAKER_00 22:50

Mm-hmm. It's funny that you you mentioned the single use because a couple episodes ago that was the focus was single use. We continued a conversation from from a live event. And I'm curious, you know, we didn't really talk about facility design in that in that episode, but when it comes to retrofitting uh a legacy facility and you're you're constrained by the legacy footprint, I'm curious. You know, you're you're highlighting a a great many benefits to to master planning here, but I'm curious if there are any specific challenges with incorporating things like single user automation or uh other advanced digital systems in these legacy footprints that you might not have with, say, uh a brand new facility.

SPEAKER_01 23:31

Yeah, I mean, one of the okay, there's uh I'll gonna deal with the elephant in the room, it's called automation. Okay, we'll start with that one. One of the biggest fallacies we've seen over the last couple of years is we have a legacy facility that's got a bare minimum of automation, you know, some small amount of closed loop control, it kind of worked with pH control, you know, weight control, very, very simple. And they want to take the jump to uh an MES system. So they roll out a two, three-year effort to put in complete MES. And one of the problems is getting the MES to match up exactly with the process and getting the operators on board and throwing them essentially in front of something that they were used to doing and working with. And all of a sudden, now they've got this monstrosity of an automation system in front of them that's never really been checked out on the real or pilot facility. It's we're live now on the new on the new system, and the operators understanding what's going on, understanding failure modes, and helping the operators to make decisions off of what the screen is telling me versus what they've known from the past. There is one of the biggest fallacies in our business. So, my philosophy, and I have worked with folks to do this, is to do it a step at a time. You want to um do an MES? Well, let's do an MES and we'll do maybe the way dispense area and we'll take care of that, produce a nice barcode, put it on that, and we'll go from there. Um, we need to do better control on heating, cooling, or whatever. Let's put a little automation pack on that. So the operators are familiar with it and they can work with it. And they also understand the familiar, uh, they become familiar with failure modes. The one of the biggest problems in our business, in any kind of industrial business, is human beings will believe what they see on the screen, not necessarily what they know. And so they'll see something on the screen. Perfect example. There was a situation where a a probe, uh, a level probe failed in a chromatography area. The failure on the mode came up to the operator, and the next step that the EBS said was to press this button, do that, and and they and the operators went ahead and did it, and they dumped the entire product down the drain right into the sewer. They lost probably two months worth of production because this was the final run on the chromatography. So on the, you know, do they believe that the probe went bad? Well, maybe, yeah, probably did. Did they understand if the probe was good or bad? Do they know what was going on in these tanks and in the chromatography uh column? Did they know the implications of doing what the MES recommended because it was working off of bad information from the bad probe? So, what you need to do is I'm not, I'm never going to say don't automate, but I'm gonna say automate in knowledgeable, consistent, cohesive packages so we thoroughly understand the instruments, the ultimate secondary valves or whatever, and the control system associated with it, and bring it on over time and bring it on so maybe you can bring on pieces of it earlier, then wait for the whole gigantic system to be deployed. And so, what are the so like I said, so automation is wonderful, but unless we know how to do it, and unless we have the operators on board, unless we know all the failure modes, then that's what's going to become very, very difficult. On the other side, single-use disposables. You know, I've faced many of these situations where all that was the design, we did this, we did that. Well, if you realize, for example, the biggest fallacy I see is the use of all the um uh filter housings. Well, these big, beautiful, lovely, what we're a lot to say, millipore filter houses. They're beautiful, they're wonderful, but they're sitting around and they've been in operation for years and years. They've been banged around, dropped, or whatever, and they get they're getting some rushing, some corrosion on them. The guys get and gals get really lazy and changing the gaskets out. And what happens? Yeah, we have a little environmental incident, we have a little contamination. The the smart thing to do is to really look at the piping layout and implement a single-use disposable. Put in a single-use cartridge right in line, pop it in line. Now, what it's going to require is a little bit of plumbing changes. It's going to require a um buying a fair amount of inventory of these and then bringing them on. But you can do and you will do better if you do something like, well, let's start with just the vents, just the atmospheric vents, start with the nitrogen, start with the air, start with the PW, then the WFI. Now we can start and take it on to the product end. So the the philosophy is if you're uh hesitant about single-use disposal, start small, but but do have a radical approach to change it all to single-use disposals. Then you have less washing, less sterilization, less playing around with the internals of a filter and filter housing, and less dealing with rouging and corrosion. So that's kind of that's kind of a little bit of the philosophy on both those two. But again, you know, to to embark on a massive change out on an existing facility that is running, there's where you're gonna you're you're gonna have all sorts of downtime associated with it, unless you plan it out and you do it incrementally. And you got to do it with the operators. If you don't do it with the operators and they're not part of this whole operation and turn or this project, then you're you're you're uh you're kidding yourself.

SPEAKER_00 29:58

Thank you, Erman. Thank you. And um I guess it my natural question to that would be when you are trying to figure out exactly what to what to refit or or improve here, when you are working in your master planning, what would be what would be your advice to companies doing that or you know, organizations and and performing data-driven assessments to find bottlenecks or or areas to to refit? Like what when it comes to looking at your facility to figure out the next logical step in this in this master planning, what do you think is the is the best start?

SPEAKER_01 30:38

Yeah, I think you know, you actually you gotta be smart about it and go back to fundamentals, fundamentals of chemical engineering, about a mass and energy balance around what you're doing. That's the first thing. And that mass and energy balance may surprise you with the amount of water that you're using, uh utilities that you're using, and some of the flow paths. So that's the first thing you need to do. In some cases, you calculations may not be enough. You may have to put some meters in and really start to meter and do a mass balance on what you have. So that's the first thing. Secondly, is almost we'll go back to what I had said before about dynamic simulation. You really need to start looking at where your bottlenecks are, and the dynamic simulation will tell you that where you're constrained, where you got to stop. Anytime somebody says, Hey, I got to stop production because I don't have this or I can't get that. Now it may be I don't have enough water, or the utility folks call you and say, Hey, we're overloading the waste treatment. Don't send, don't wash another vessel, don't send anything down here. That could happen. Um, it could be either one of those those areas. Um, it could also be a a hold time or some kind of a um transfer issue between uh one vessel to another vessel. It may be uh can't get the media into the vessels fast enough. Um, and because we went from a liquid media to a solid powdered media, and we have to figure out how we're gonna do that. So there's a bunch of things like that. There's also a logistical media component to this whole thing, and the logistical issue is I can't get enough stuff from A to B just by transporting it. I can't get enough drums of this year, I can't get the waste out of the facility. You know, if you look at some of the um, you know, the uh 2021 uh series 483, which will remain nameless, but the company is in was in the Baltimore area, part of the constraint was they couldn't get the waste material out in time. And they were they were essentially falling over themselves. So how are you gonna get the waste out, Tyler? I mean, you gotta get you got to move it out, but if you move it out, and especially in a BL1 or BL2 environment, does it cross path with new material coming in? Does it cross is a BL2 waste? Does it cross path with uh personnel coming in? So there are there are logistical, there's utilities, a lot far more than process. Um those are some of the key aspects of that. Um and the other aspect which is which we cannot uh forget is the point in which you must always consider as your top priority is the GMP constraints. Do what 483s do you have? Oh, well, we're gonna take care of that. Well, no, no, no, no. Let's take care of that now so that it doesn't roll over to the next inspection. What kappas did you write about the 483s to get us out of that? Oh, okay, we got that one. What upgrades are we needed to meet annex one? Hmm. And lastly but not leastly, what do we have to do to implement unidirectional flow? Oh, Herman, that's a big one. Well, we we have to we have to face again, I'll call the elephant in the room. How we have there's some ugly situations we have to face. And so the reality is that the compliance aspect should be always be in the forefront, and we should try to see every time we make a change, a logistical change, great, but does it meet annex one? Is it and is it unidirectional flow? Simple, simple things that go on. We're gonna do way dispense in a warehouse, then we're gonna drag that material through an unclassified area, then through a CNC, and then we're gonna bring it inside. Well, you know, you know the the the danger associated with that is so we've got to start being smarter about how we handle materials and the logistics as such, and we got to be careful about our waste handling. So those are all the aspects. So, you know, let's start at GMPs, start with a process, utilities, and logistics. Those are the those are the steps, those are the priorities.

SPEAKER_00 35:24

Thank you for the succinct outline, Herman. That makes sense.

SPEAKER_01 35:27

There's a lot of interesting aspects that we really have to we have to be very, very careful about. And you know, and then you know, part of the um you know, part of what we're we're we're always trying to figure out, going to, as we said before, you know, single-use disposables, we're actually upgrading ourselves and we're doing better from a GMP environment if we're going to single-use disposables. Think with the handling and all the and all the matrinations and all the stuff that goes on with doing CIP in a room and then moving something in, doing COP and moving it around. Especially if you look at the size of the vessel that you're dealing with, whether it's an IBC or a tank or whatever, going to a single-use disposable gets rid of a lot of the issues in terms of cleaning, washing, rinsing, and sterilizing. You buy it, you know, gamma radiator, you put it in place, whatever. And yes, it's going to require a change of a little bit of a philosophy, but quite frankly, um, the benefits always outweigh the cost and whatever ever retraining you're gonna have to do.

SPEAKER_00 36:33

So yeah, that's a good case for single-use folks. Oh, absolutely. And if you haven't already, go listen to that episode and live and lunch processing.

SPEAKER_01 36:43

Yeah.

SPEAKER_00 36:44

Um I had a question for you, Herman, about and I don't know, maybe this is maybe this is uh gonna reveal reveal my naivete, but is it do you see a fundamental difference in patchwork upgrades versus refitting an entire facility or site to be fit for purpose? How would you describe that difference? Uh, and what what do you prescribe to folks?

SPEAKER_01 37:08

The problem with patchwork, and you know, I've seen plenty of it, and there's facilities out here in the US that have been doing patchwork for 30, 40 years, is they're like, oh, we have a new process. Let's see if we can find a little corner to shove it in. Okay, and and when you do things like that, you're you're hurting yourself. You've you know, put it in this corner, put it in that corner, stick it here, stick it there. And a lot of times you say, Oh, yeah, I got plenty of room. We could go ahead and do it. There's the there's the what another another fallacy of our business. If we had a master plan and we understood the logistics of how things moved from warehouse to non-cla, non-classified to CNC, then to D and to C, and then we work. We have to understand that primarily first before we start stuffing things in corners. Because what we do is we always violate them. We always like, uh, well, we'll just bring it in through the non-classified area, and we'll just do it extra clean when we get inside the airlock. Well, that doesn't really work. All you're doing is you're bringing in junk into the where into the airlock, and we're going to be having EM hits later on. So the the proper the proper master plan facility, whether it's brand new, relatively new versus old, is really understanding a lot of the logistics associated with it. And and you know, when we do this again, remember I said GMP's at the top? Well, that's always going to be that. Because a lot of times we go ahead and we just we don't have that enough forefront and we make compromises. And every time you compromise, and take it for a guy who's been in the business for 50 years, every time you compromise, oh we'll just get this will be fine. That'll be good enough. Don't worry about that. We'll take care of that, we'll write an SOP on that, then you're making a mistake. You're actively, cognitively making a mistake and making the new facility or the retrofitted facility vulnerable to GMPs and vulnerable to the next inspection. And there is where the issues will evolve. So if you do a good master plan andor you follow the four steps of Herman, you'll be okay. Either way, you're gonna have to do something. And the four steps of Herman basically force you into a master plan. So my the patchwork idea is dangerous, and you give you could see all the um all the different scenarios that we've had over the years with the um uh people stuffing things into an area to pick up capacity or to change capacity, whatever. Um but there are tools, there are things that you can do, and sometimes you have to change your philosophy. I'll give you a give you a perfect example um that helps. We deal with facilities, and you say to yourself, Oh, geez, I I have to go from non-classified to CNC and then to D. I don't have enough room and I gotta fit it in there. One of the biggest fallacies we've had is the locker rooms. Now, this may sound like who cares about locker rooms? It's an important point. Lock, how do we build locker rooms today? Well, we figure we're there is there's gonna be a hundred operators in this particular area. We will build for 75 men and 75 women. And then we have to put the lockers and the benches and all the amenities around, and we have a bathroom here and a bathroom there, and a bathroom, and everything's all laid all out, and it's a lot of space. One of the things that we're doing today in the modern philosophy is getting rid of uh the separate locker rooms and doing a unisex approach. Now, don't be scared when I say unisex approach. It's very simple. You go into you, you you go for you um go from street clothes into a uh a single area, you pick up your scrubs, and there in front of you are five uh booths. Booths are 10 by 10, 8 by 10, whatever. And inside those booths are lockers. You go in there, you lock a door, you change your clothes, you put them in one of those lockers, you're assigned to booth one and locker 15, you put your stuff in there, you open the door, and now you're into a CNC area. And by going to the unisex booth approach, you're not putting lockers for 150 people, you're putting lockers for 100 people. You're also the the amount of logistical space and the flow path of the people going in and out and in and out around. Guess what? It's much reduced. And when people come out, they come out into those booths, they change their clothes and they walk out. We wanna spend about saving about 50% of the whole space by going to this unisex approach. And so that's one way of helping uh consolidate on to get more free space for your next step. Um, the other thing we we also should always be thinking about is um using modular wall systems. You put down the track, you put the modular wall systems, you get everything all together, you're in good shape. You need to make a change later on. We go to we we we take the modular wall systems apart, we pick up the the track that it's been sitting in, and we move it. Stick building today is gone the way of the dodo bird. Okay, the way of the dodo bird. You want to go to modular walls, modular, all everything should be modular in some sense. So um, and then when you also do something else that's helped quite a bit in uh in retrofitting is um visibility. That's the best way for it. When we in the old days, you know, we just put doors up, doors up, a little window, whatever, but now we're starting to use things like infinity walls, all glass. We're doing the the um uh personnel airlocks and personal airlocks, all glass, material airlocks, half glass, half um um solid. So when when the forklift smacks it or whatever, it doesn't break. But visibility helps because you could see the people, you can you can get a little bit of maybe some some light in there, and it helps people with the day to day uh uh application, and it makes it feel like it's not closed in as much. Uh, it does help. Um, and the other thing we've been doing to help with training and help with when we modify a legacy facility is we paint the floors. You're gonna say, What? Give you a perfect. Example and something I did in my one of my past builds is the the um the non-classified dirty walkways where you can have visitors or whatever for street clothes we paint that like a sparkly black then the CNC it's a dark gray now you go through an airlock and when you get into the airlock for grade D it's a light gray and when you go to the grade C, it's a whitish silverish. Does a couple of things for you. One, it immediately tells you, and with the visibility, immediately tells you what grade you're in, it tells you what you should be gowned in as, and it shows the FDA that you know about the grade gradation, and when you walk them through on the non-classified side, you can show here's our D, C, and interior areas. This is how we do it, and so you combine visibility with the grade change on the floors, it makes the operators quickly recognize what they've got to do. And secondly, it demonstrates to management and the FDA that you have a control of the flow of uh the people and the materials, and that you're adherent to very strict uh guidelines on the classifications. So that's uh that's something that we've been doing in legacy facilities that helps at least prop up the GMP compliance and make it very, very obvious for people who are working there, people who are looking at it, quality assurance, and of course, our friends of the EU and the FDA. In the end, we have to satisfy everybody, it's a tough job, but that's what we're here for.

SPEAKER_00 45:46

Yeah, yeah, that's a good idea about painting the floors. I never, I don't think I've heard of or seen that before, but it makes perfect sense to me.

SPEAKER_01 45:55

I do it all the time. And if you if you want to see a pretty facility that does exactly that, go to YouTube and uh put in locus biosciences manufacturing, and they'll show you the combination of light from the outside all the way through, and the and the the color changes on the floor. It it it believe me, operators do not make the mistake of not of not gowning properly with uh with the because it's become so stark. Our eyes tend to focus down, we're looking down, it changes the color scheme in the room, and it becomes very obvious what you should be doing. And you know, it's it doesn't cost anything. You've got to redo the floors anyway at some point in time. So when you do the legacy facilities, paint the floors, use modular walls, think about what you're doing.

SPEAKER_00 46:50

That's great, that's great for me. I could vouch that video is cool to watch. I've seen the one you're talking about on YouTube about the locust build. So I'd encourage you guys to go check that. Um, and I had one kind of last question here about as it relates to you, you mentioned something with regulators before. I think it was in the context of a facility um inspection, I imagine. But I'm curious, Herman, if you could speak to the current regulatory expectations around refitting uh and the challenges around site design and compliance. What would your advice be there? What if what are your observations? Um, maybe some good and bad stories or anecdotes to well, I'll start with what you should do, and then I'll tell you some ugly stories.

SPEAKER_01 47:35

The the reality is we've been through a number of inspections, and I've helped out folks with inspections and remediating and the good and the bad and the ugly. I think the first thing that everybody is looking for is from a regular station is unidirectional flow. They're looking for unidirectional flow from people coming in, doing their work, and then leaving separate exit. Then they're looking for unidirectional flow for materials, bringing materials in, working with them, and then whatever empties from there. Unidirectional flow on product, unidirectional flow on an equipment. And the most important and the most violent one that you will get yourself in trouble with is unidirectional flow of waste. We cannot, we cannot have, and I've seen it. You cannot have a pallet of drippy waste in a on a pallet, and you have brand new material coming in on top of it. Just can't do it. I will tell you that you'll get a 483 on that, and the EU will jump up and down and yell at you. So unidirectional flow is very, very important. Second thing is proper HVAC gradation and the concept of going from CNC, airlock D, Airlock, C. Can't get away from that. Okay. People do, and there's and I've plenty of places around, they have that magical black and yellow stripe tape in the middle of a room, and on one side it's D and the other side is C. Let me tell you something. That's not going to happen anymore. You think you you've been going like that and been using it for a while, you've been lucky, and your luck is gonna run out. All the new EU inspections have tell them get rid of the tape, do something with airlocks, put an additional door in there. And oh, by the way, the air to the next level should be of the higher level. Don't play games. And you cannot have two grades in one room. That's just dumb. Because people say, hey, wait a minute. So the micros know not to go on that side, but they stay on this side. Come on, let's let's actually think about some of the stupid stuff that we actually tell ourselves. So unidirectional flow is important. Gradations ongoing in and out. We have to have gradations on the way out. We can maybe potentially skip an airlock on the way out, but never on the way in. Proper pressurization. We have to maintain the proper pressurization between the grades. There's no getting away from that. And the fact is that goes back to 1976, where they have to maintain the proper gradations on pressure. And you cannot get around that. And if you don't have it, or if the air is flowing in the wrong direction, you and you, and it's somehow it's documented on the maintenance, you will get a 483 associated with it. So I think that's very, very important. Um, and the next thing I think that it's uh we've been seeing more and more of, and again, this is going to scare a few people who are gonna say it, is we cannot have water and washing in higher grades. And what I mean is C grade C or grow higher. You just can't have it. You know, we have wash pits in grade C. It doesn't work very well anymore. People will then that the FDA will come back and say, How do you maintain the pressure so that there's none of that moisture comes out? How do you keep the people from tracking the wet from a wash pit on out? How do you um can you know how do you control the pressure? How do you monitor the humidity? And they will ask you so many more questions that eventually you're just gonna go, all right, we give up. So if you have water in grade C, better watch out. Now, what do we do? Well, we're gonna have to come up with some some some uh you know a buffer zone in that pit area where we have to change into new booties, change off an apron to get rid of some of that stuff. But we got to make sure that any area that has water that's classified has a strong exhaust system, and the so that's always gonna be negatively pressured, and the area right up against it has to be what we call an air bubble. So water, air sink, adjacent, air bubble. What if you have an area that's got a lot of stuff going on, a lot of wrapping and unwrapping or whatever, and it's generating particles. Guess what? Air sync and everything around it, air bubble to pressurize into it. So, so for you know, a facility that we're worrying about for GMPs, those are the basic guidelines that I would give you today. Um, in terms of working with it. Uh, I would be very cautious about how I bring my people in because they're the big source of contamination and cross-contamination with waste. So people in waste. And we deal if we deal with the logistics of that, we'll be okay uh for now.

SPEAKER_00 52:59

Yeah. Very great advice, Herman. Thank you so much. Um, we're nearing the end of our episode, but I was curious if there's any last tips, tricks, advice, uh, messaging you want to give to our audience as it relates to master planning, site retrofitting, refitting, building, design, etc. Everything we've talked about.

SPEAKER_01 53:20

Is there anything you want to drill down on or convey to our audience before we I think it's incumbent upon the engineering andor maintenance department of every pharmaceutical plant to have a site master plan? It doesn't have to be, you don't have to be have a big SOP on master planning. You don't have to have, but a document that says this is what we do today, these are our vulnerabilities today, and this is our plan to either reduce the vulnerabilities and then to expand or uh innovate on what we have. Every facility has to have it. I don't care if it's even if it's a single page, you have to have that because when are you going to get questioned by the FDA about what are you doing about that? Why is there water in here? How can you have EN hits in here? Your plan needs to reflect what you're going to do to get out of that. And so the master plan is an evergreen document. It probably needs to be updated every year, and it will have a profound impact on how you answer the FDA, how you answer 483s, because it's going to be obvious to the FDA, oh, geez, they don't have a plan, but they've got to go make it up in the next couple of weeks. But if you say, look, we recognize there's a problem, and here's what we're going to do about it, and this is when it's due, then you can go ahead and tell them about it. But a master plan must exist, and that's you, all those people who don't have one. That means you got to put one together, start simple, start simple with the things that we talked about already, and keep it evergreen and update it every year. And after every inspection, EU, FDA, if you're doing work for another folks or whatever, you know, Russia, China, uh, Japan, whatever, and you get feedback from them, include their ideas into the master plan and see if you can make them mesh to where you're going to be. Now, you don't have to get that all that work done tomorrow, but you need to have a master plan that says when these things happen, we will trigger them and then we will implement them. So, my point is get it done. Just don't sit on your laurels.

SPEAKER_00 55:29

It's great, great piece of advice there, Herman. Thank you. And last but not least, the Hallmark question of the show. I ask every guest, and you've been asked before, but that is Herman, in your opinion, big or small, how do you think we can better biopharma?

SPEAKER_01 55:43

I think we can better biopharma by being a lot truer to ourselves with the regulations and not trying to kick the can down the street. We need to realize the issues I mentioned, the unidirectional flow and the people and the air and the pressurization. We need to we need to come to grips with that. And we need to do something about it and not just wait for the chips to fall. Because sometimes those chips fall and they're going to land right on your head. And when they land on your head, those are all going to be career-limiting moves. And that not only not only the plant manager, the engineer, but all the way up and down the line. We've seen situations in facilities where um the chips fall, they hit, and a whole rash of people get sent out the door. Now, yet a bunch of money comes in to fix it up, but those the people who fix it up, they're all different. So don't kick the can down the lane. Do your job. Let's get this thing going and let's make sure that we have the best products for the market and for our patients who really are uh really depend upon us delivering to them the quality and the timeliness.

SPEAKER_00 57:04

Well said, my friend. Thank you so much for joining me on this episode of Better Biopharma, the official podcast of Bioprocess Online. Thank you out there in the audience for tuning in. For more, head on over to bioprocessonline.com to see all our archived episodes as well as a variety of other content. I'm Tyler Minichello, and I will see you next time.