Webinar: CMO/CDMO Facilities Gain Value with Single-Use Containment

In this webinar, Scott Patterson, Vice President of Commercial Sales at ILC Dover, delves into the value that Contract Manufacturing Organizations (CMOs) and Contract Development and Manufacturing Organizations (CDMOs) can gain from implementing single-use containment solutions. He outlines the evolution of flexible containment technology, its applications in oral solid dosage processes, and the benefits it offers in high-potency active pharmaceutical ingredient (HPAPI) manufacturing.

Scott emphasizes how these single-use technologies not only reduce capital expenditure but also streamline cleaning processes, minimize cross-contamination risks, and adapt to increasingly stringent regulatory requirements. He also shares insights from a case study on retrofitting flexible containment systems and discusses the cost savings and operational efficiencies achieved through their use.

[Garrett]
Good morning or good afternoon everyone, depending on where you are joining us from, and welcome to today’s webinar. My name is Garrett from Business Review, and I will be your host. It is our pleasure to have ILC Dover with us today, who are presenting this webinar titled “CMO CDMO Facilities Gain Value with Single-Use Containment.” Our guest speaker today is Scott Patterson, Vice President of Commercial Sales at ILC Dover.

Webinar Platform Instructions

[Garrett] 0:31
I’d like to welcome you to our webinar platform on 24. You’ll notice that this webinar is browser-based, so if you do disconnect, please just click on the link that you received via email to rejoin the session. If you would like to ask any questions for your post-webinar Q&A, please use the questions tab at the top left-hand corner of your screen. If you require any technical help during the webinar, please use the yellow help guide at the bottom of your screen for any assistance. For now, though, please allow me to welcome Scott.

Opening Remarks by Scott Patterson

[Scott Patterson] 1:00
Thank you, Garrett. Welcome, everyone. We’ve got a dynamic group of attendees today that are coming in from all over the world, so thank you all for taking the time to join this webinar. I hope everyone has good takeaways from the information that we’re going to present today. Supporting myself will be Stephanie Arthurs from our marketing department in our headquarters office, along with Wayne Fern from our technical sales department.

Webinar Focus & Agenda Overview

[Scott Patterson] 1:22
So, as Garrett said, our webinar today will focus on CDL CDMO facilities and how to gain value while using single-use containment. The program is including a definition of flexible containment, which will refer to both single-use and flexible containment as the same products. We’ll look at a case study in an oral solid dosage process, including some data of containment performance taken during an assessment. A big change in the regulatory landscape towards shared facilities such as CDMOs with changes in the health-based exposure limits and the ADE requirements.

Now, as part of the regulatory environment, we’ll take a look at the true benefits that CDMOs can realize in using flexible containment single-use products. And again, as stated, there’ll be time at the end for reviewing any questions. So, please, if you have questions, send those through, type those in, and send those through, and we’ll take time to address those.

Defining Flexible Containment

[Scott Patterson] 2:26
So, what is flexible containment? Putting a definition to flexible containment, it’s the application of single-use products to contain or transfer drug substances and drug products in the manufacturing processes. But we don’t want to confuse single-use with a product that is not robust. We develop these products so that they can be used for a batch or a campaign or, in some cases, even longer. And the key to this is when cleaning will have to be done. The value proposition of using flexible containment is not cleaning; it’s saving the cost and the time from cleaning and being able to dispose of it. So, it’s a very robust product not to be confused with use at one time and dispose because it’s not that robust.

History & Application of Flexible Containment

[Scott Patterson] 3:10
This is not a new technology. Beginning in 1997, Eli Lilly saw the cost of containment of HPAPI compounds rising rapidly, and they sought out ILC Dover to develop technology that could control those costs. And that’s where flexible containment and pharmaceutical processing started. So, this is not a new technology and, for the past 22 years, has been applied to hundreds and hundreds of applications throughout the industry.

Visual Classification of Flexible Containment

[Scott Patterson] 3:40
So, looking at visually what is flexible containment, we classify this in essentially two groupings. On the left is to contain a process, which usually is an isolator type of containment. So, you see examples of flexible isolators being used. And on the right, we talk about transfer. So, we transfer products, we contain the process as it’s being discharged, and then charged into another process. So, during that transfer, we maintain the containment. So, two fundamental buckets that we use: either we’re containing the process, which we will use a term “contain at the source,” which is a practice, or we’re transferring the product while maintaining that.

Case Study: Oral Solid Dosage Process

[Scott Patterson] 4:27
Let’s dive right into a case study for an oral solid dosage process. This is the part where we’ll show data performance data. So, a little bit of background of the case study. The project was to retrofit with flexible containment to existing systems in a pilot plant that processed the oral solid dosage process. The flexible containment systems were designed, and you’ll see pictures of that for each unit operation. Again, we use the “contain” part of it with flexible isolators and the “transfer” part of it, and we’ll look at that transfer process.

Containment Assessment Protocol

[Scott Patterson] 5:08
The containment assessment was completed following the SMEPAC protocol. This is the standard industry protocol for understanding what the containment performance can be of a particular system. And in this case, the surrogate was used, and that surrogate was naproxen sodium. Also, in this case study, we had a containment performance target of 125 nanograms per cubic meter. The standard for accept-pass/fail, if you will, was used, the EN 689 standard. Now, this was done before 2018, so you’ll see in the data tables that the target was 25% of the containment performance target, or we needed to achieve containment of less than 31 nanograms per cubic meter.

Changing Regulatory Landscape

[Scott Patterson] 6:04
A note here of the changing regulatory landscape again. The EN 689 standard, which has always been a part of the containment assessment protocol, was changed in 2018. Where this case study used 25% of the CPT, the new EN 689 2018 standard requires that 10% of the CPT is calculated. So, this is a much tighter standard, and this was in recognition of the fact that compounds are getting more potent, and when using a small sampling set, there still is a risk. The 25% was seen to be too conservative, and so the 10% was adopted as the new standard in 2018.

Polling Question One

[Scott Patterson] 6:50
So, at this point, we have a polling question. I’m going to pass it back to Garrett, and he’s going to introduce a polling question to the audience.

[Garrett]
Thank you very much. So, the first question we have is, “Have you had a containment assessment performed on a process, and based on the results, have you changed your PPE requirements?” The answers are: never had a containment assessment performed, I’ve completed a containment assessment and the result required to maintain/increase PPE, had a containment assessment performed, and the result allowed us to reduce PPE, or we regularly monitor processes so that we can minimize PPE, which is a cost-saving and ergonomic benefit to the operators.

Scott, what results do you expect?

[Scott Patterson]
We typically see in the industry that most companies will perform a containment assessment on one or more processes and use that as a benchmark going forward. Each company has its own standards on how to treat PPE based on this, so it’ll be interesting to see what the audience reports.

[Garrett]
Well, let’s find out now. So, we have never had a containment assessment performed at 88.9%, and have completed a containment assessment and the results required to maintain/increase PPE at 11.1%. What do you make of these findings?

[Scott Patterson]
Interesting. It’s interesting because as we look at the containment assessments, it has become a key part of the Environmental Health and Safety departments for pharma companies that we work with. But that’s why we ask the question, to get the pulse of what the audience is doing currently.

Wonderful. Please continue when you’re ready.

Detailed Case Study Insights

[Scott Patterson] 8:46
Okay, so on to our case study. So here, again, looking at a few more details of the case study for the oral solid dosage process. In this case, the containment used static pressure flexible isolators. Often these will be referred to as passive isolators. This was chosen because of the need for a very fast delivery, quick installation, and immediate startup of the systems. In this case, the CDMO needed to begin processing HPAPIs that they had contracted, and so we had a very tight time frame to work with. And so by going with static pressure isolators, that reduces the time frame. Again, the core idea we are achieving here is “contain at the source.” This is a best-in-class practice where we want to be able to contain where the product is being handled so that we can reduce the exposure to operators and also reduce the exposure to the environment, which is going to be key as we look forward to some of the real value proposition offered in the reduction of cleaning.

Focus on Transfer Points & Connections

[Scott Patterson] 9:55
“Contain at the source” is always key, and by using flexible containment and being able to retrofit these existing systems, we were able to maintain that concept. We always look at transfer points and connections as the most critical parts of the containment design. Again, when we’re looking at a stainless steel box or a stainless steel bin, the same thing with a flexible single-use isolator or FIBC, particles are not going to pass through that wall. The areas of risk are at the transfer points and connection points. So, we’re going to look at that, and we’re going to look at the bag-in-bag-out technology that we designed into these systems. And bag-in-bag-out technology really provides a dual layer of containment. We’ll take a look at that, and also that the product bag, the bag-out sleeve, is clean to the outside so it can be handled without cleaning, whereas technology like a rapid transfer port or a pass box, there needs to be some cleaning at some point before the product can actually be handled.

Unit Operations Overview

[Scott Patterson] 10:58
So, here’s a rundown of the unit operations that were done. Starting to the left, there was a weighing and dispense operation. In this case, the customer understood that they would have to sieve some of the drug substance. So, again, in this operation, the surrogate, the naproxen sodium, was at a 100% concentrate to mimic the drug substance, so we truly were acting like we were handling the VHPAPI. From there, we transferred that out through bag-out technology and then bag-in technology to the blender. You see the bin blender here where the surrogate was added in full concentration, but then the excipients were also added under containment. So we were able to keep everything contained at the source as close to the connections as possible.

Mimicking Drug Product Process

[Scott Patterson] 12:04
Now for the first time, we’re mimicking the drug product with the drug loading similar to what their products would be, the surrogate being the API, and then the excipients involved. After blending, we went on to roller compaction and granulation. We’re preparing the product at this point in powder form into a granulation to go into encapsulation. An interesting thing about the roller compaction, along with a good containment design for having low exposure levels, we have to think about the actual process, and roller compaction can be unique in that we’re taking a powder and agglomerating that, pushing it together and essentially pushing all of the air out. And we’ve seen in examples that a positive pressure can come from that process.

Containment Design Considerations

[Scott Patterson] 12:56
So, a little bit hard to see in the roller compaction picture, but in the top right, there’s a large HEPA filter that allowed us to exhaust any buildup of pressure so that we kept an atmospheric pressure inside the isolator and did not build up a positive pressure. Lastly, there’s an encapsulation process. As you can see, we build the isolator frame around the system in a skeleton form to allow for the best ergonomics and for operators being able to perform their unit operations without interference of a superstructure. So this was the process that we looked at, and now we’ll look at the performance through the containment assessment.

Containment Assessment Data Analysis

[Scott Patterson] 13:32
This is a typical data table for a containment assessment. The number one thing to look at is we did have test run one, test run two, test run three. This is all part of the standard SMEPAC protocol. As you look at this, the numbers under the measured concentration in nanograms per cubic meter show all “less than” numbers. And so in this case, as often is the case in a containment assessment, we were below the level of detection. So in the samplers that were taken, and all of these were air samplings, including the bottom two lines, which were operator breathing zone samplers, we were below the level of detection. So that drives this away from being a sampler where we’re looking at the mass on the sampler, that we have to take the level of quantification of the surrogate, and we have to calculate that out with the volume of air that passed through the sampler to be able to then have a calculated microgram or nanogram per cubic meter.

Successful Containment Performance

[Scott Patterson] 14:42
So, here everything was very good in this weighing, dispensing, sieving operation. And on the right-hand side, in our gold circle, you can see that we calculated the geometric mean, which is also part of the SMEPAC analysis, and the result was very good. And you can see the bottom statement is the device passed. So, everything was well below the 31 nanograms per cubic meter, and in this case, even applying the 10% EN 689 standard that exists now, we would have had a pass.

Roller Compactor Containment Data

[Scott Patterson] 15:20
Moving on to another data table, this is for the roller compactor. So here we start to see some information where the samplers did find particulate. And this goes to, again, each process can be a little bit different, and each process and product has to be looked at. An interesting aspect here is in the test run one, we do have a reading at 34.2 nanograms per cubic meter, which is above the EN 689 CPT as we keep referring to 31 nanograms. But the analysis, the statistical analysis allows for readings to be above the 25% in this case, as long as it’s not above the containment performance target, which in this case was 125 nanograms. But then we refer back to what we have in the gold circle, which is we still have to have the geometric mean calculation that’s going to be below the 25% of the target. And in this case, we had basically an outlier at the 34.2 nanograms, so the calculation for the geometric mean allows to have a 95% confidence in the performance of the device. And so as you can see again, the bottom statement says pass, so the device passed.

Encapsulation Process Containment Data

[Scott Patterson] 16:58
And here we have the final process in the OSD chain, the encapsulator, and again we see different numbers here, but we see the lowest numbers here. And so that goes to the effect that each containment system has to be looked at for what is the process, what are the product characteristics, and what is the quantity of product being processed during each one of these runs. So the quantity part was easy to do. We developed a process here that we were processing at least two kilograms per run, so test run one, two, and three each had a minimum of two kilograms processed. Again, as you see, the processes are different. The roller compactor gave us some higher readings than we did on the weighing and on the encapsulation.

Importance of Process and Product Characteristics

[Scott Patterson] 17:48
So when you look at the process, something like a milling process, which fluidizes the material quite a bit, is more of a containment challenge. So we have to look at the process. And finally, we have to look at the product characteristics, and that’s what we’re seeing in this table, that we’re seeing extremely good results, but we’ve got a granulated material. As we were handling product before in the dispense of blending and roller compaction, we were handling a powder. So powder is a finer material versus the granulated form that goes into the encapsulator. So the process and the product characteristics have a lot to do with the overall performance.

Bag-In-Bag-Out Process

[Scott Patterson] 18:33
Lastly, we wanted to take a look at the bag-in-bag-out process that was used on all of these. So in the data tables, we did area monitoring around the transfer point because, as we’ve said, transfer points are a critical aspect of the containment design. You have to get that right. So here, internally inside the isolator, a product was collected in a product bag or container. In this case, we used a flexible product bag, and then that’s moved into the bag-out sleeve as shown in the picture on the left. That’s moved into the sleeve, so it’s completely contained. We have a secure connection so that that connection provides the containment, and then the really important thing is this product is now inside a clean sleeve, so the operators can handle this through the facility. They can move it through the facility; they haven’t had to clean it, so there’s no risk of transferring product from this sleeve onto anything else. The picture on the right is the seal and separate process, where we use the crimping process, which is a secure closure, essentially gas-tight and requires a tool to remove the crimp from the process. So this assures that the bag-out sleeve is not going to open and cause exposure at some point, and using the tool to open it, that allows you to access the material only when you want to access it.

Challenges for CDMO Operations

[Scott Patterson] 20:05
So, moving on a little bit, looking at some challenges for CDMO type of operations, which are referred to as shared facilities. When we look at the regulatory norms, and this landscape has changed quite a bit now. So recently, regulatory requirements driven by the EMA, the European Medicines Agency, have required that HPAPIs have a health-based exposure limit calculated, and they also then have to have an allowable daily exposure requirement calculated. Now again, there’s a big change in how this is being required because the HBEL is really for the patient. So now the EMA is recognizing that they’re putting this in place in the manufacturing facility to protect the patient. The ADE is in place to protect the operators and the environment within the manufacturing facilities.

Increasing Stringency in Containment Requirements

[Scott Patterson] 21:11
So yeah, the world has changed quite a bit for shared facilities and CDMO CMOs. Back in 2006, we regularly were asked to provide containment systems that achieve less than one microgram per cubic meter. Well, that’s changed a lot now. The majority of the URSs that we receive will have something less than 0.5 micrograms per cubic meter, and regularly we’re addressing needs that are less than 0.1 microgram per cubic meter, down to 100 nanograms. So what’s the future? We’ve already seen some customers requiring picogram levels of containment, and when you look at it, and particularly with the pass/fail test of the EN 689 and the 10% of target, we’re really starting to get to that picogram level of containment as pass/fail. So as time goes on, I’m sure we’ll see even more changes to this, but now with the HPAPIs, it’s becoming even more rigorous.

Regulatory Guidance Breakdown

[Scott Patterson] 22:22
So what does this really mean? So, starting in 2010, Risk-MaPP from ISPE, which was published in accordance with ICH Q9, started to address how to manage cross-contamination in a shared facility. So this was interesting guidance because it was needed guidance from the standpoint that regulatory bodies were looking at having all HPAPI in segregated facilities, which would have been a significant additional cost for the manufacturing processes to locate all of the HPAPIs in single facilities. But in this Risk-MaPP guide, there was an identification of the four main sources of cross-contamination, and cross-contamination is his product getting from one batch into another batch. And particularly, it’s bad if they’re different products—product A gets into product B.

Sources of Cross-Contamination

[Scott Patterson] 23:34
So the four main sources identified were mix-up, retention, mechanical transfer, and airborne transfer. Well, mix-up is something that a containment system really doesn’t address, but mix-up is really that the wrong material was brought in from the warehouse. So, something that wasn’t supposed to be in the process suite was brought into the process suite, opened up, and started to be used in the process. So, mix-up was found to be the number one reason for cross-contamination, but the next three, and really focusing on the second one, retention, were identified as problems for cross-contamination.

Risk-MaPP Process and Single-Use Technology

[Scott Patterson] 24:11
The Risk-MaPP process provides a way to mitigate that. It’s a database process where you collect data on what the real performance is. Retention, as a definition, is the residual material left on a surface after the cleaning has been completed. As you’ll see as we go on, the value that we’re offering for CDMO processes is all of the containment surfaces can be eliminated when using flexible containment single-use containment because instead of cleaning, we’re going to dispose of those surfaces.

Cross-Contamination Risk Reduction

[Scott Patterson] 24:51
Again, to reiterate, using Risk-MaPP, it’s really understanding the risk of cross-contamination and where it comes from. So by applying that and using single-use technology and a “contain at the source,” we can keep everything enclosed, we don’t let anything escape into the environment, we can reduce the cleaning that’s required of the containment system, and also the cleaning of a room. Using the database approach from Risk-MaPP, you can prove that the room is not contaminated to the levels that would require cleaning, and that is a tremendous cost saving in not being able or not having to clean the room after a process.

2015 Regulatory Changes & Impact

[Scott Patterson] 25:39
The next change in the regulatory landscape came in 2015 when the European Medicines Agency established the HP HPEL for shared facilities. So, this is a toxicological approach. So no longer were cleaning limits established based on what cleaning could be, but toxicologists had to evaluate the products to understand what the limits should be. And again, this is an evaluation and approach that is based on the patient. So, again, in a shared facility, if product A is being made on Monday and product B is being made on Tuesday, we can’t find any of product A in product B. And looking at it from a patient standpoint, this means that we can’t give a dose to a patient that’s going to cause any type of reaction and so forth of a drug that they didn’t mean to take.

So, this has become a very strict rule and is being addressed by industrial hygienists and so forth for applying containment systems. Now, to mimic that, PIC/S (the Pharmaceutical Inspection Convention Scheme) basically mimicked that in their 2018 guidance. They mimicked what EMA did to adopt the HPEL and what needs to be done to have the proper controls.

Benefits of Flexible Containment for CDMOs

[Scott Patterson] 27:15
Now we’ll go into what the real benefits are. What are we talking about benefits that CDMOs can get by using flexible containment? And in summary, they really are a tremendous reduction in capital expenditure to achieve high containment. As facilities are looking to bring in these HPAPI compounds, the investment into capital containment equipment could be massive with respect to isolators, bin systems, split butterfly valve systems, and so forth. And so, flexible containment offers a methodology to meet the containment levels required and have a greatly reduced capital expenditure, typically reducing capital by up to 80-85%.

Cleaning Process Reduction or Elimination

[Scott Patterson] 28:03
We’re also going to reduce or eliminate the cleaning processes. As we talked about containing at the source, we’re going to eliminate cleaning and validating the containment system surfaces and possibly even eliminate or reduce the cleaning of the actual process suite as well. So, here’s the elimination of retention. A big point here is that in Risk-MaPP, it’s detailed that there is no such thing as perfectly clean; there always will be retention. And no matter what you do for cleaning, you will always leave some residue or retention.

CAPEX vs. OPEX: Cost Control

[Scott Patterson] 28:44
And this is an interesting thing that develops over time. Everyone has received brand new pharmaceutical equipment with a nice surface on it, a nice polish, and then as that changes with cleaning and use, it becomes a challenge to maintain that surface finish. And this is where residue can fit into the scratches and so forth of the surface.

Also, a benefit that CDMOs have realized is the cost control of knowing the specific cost of consumables used with flexible containment, single-use containment, because that becomes a fixed cost that they can identify on and understand versus the cleaning process, which can be a little bit random. And if for some reason the cleaning isn’t done correctly, and validation of that cleaning can’t be done, then cleaning has to be repeated. So again, there’s a lot of inefficient cleaning that goes on. And so being able to know what your containment costs are going to be versus a variable cleaning cost and so forth helps out with the whole cost model.

Comparative CAPEX Analysis: IBC vs. FIBC

[Scott Patterson] 28:54
So, looking at a couple of different applications for the benefits of reduced capital expenditure, we’re going to look at two products that do the same exact thing. The product on the left is an IBC, a stainless steel IBC, and the product on the right is an FIBC, a Flexible Intermediate Bulk Container, which is the  DoverPac® product.

So, looking at what the capital expenditure could be when looking at installing one of these technologies, the flowchart on the top is for the IBC technology. So, we’ve got to go out and buy the IBC. These are the stainless steel bins, but with that, to be able to achieve containment, and in this example, we’re saying that the containment level would be less than one microgram per cubic meter, so you do have to go buy high containment split butterfly valves to be used with these bins.

Cost of High-Containment Systems

[Scott Patterson] 30:54
So, that’s quite an expense. But now, these bins with the split butterfly valve have to be used with a precision lifting and positioning device, so this gets to be quite expensive as well to install that, to purchase and install that. If a precision device is not used, there’s a lot of risk of damaging the split butterfly valves, which again just go into more and more cost. And then there’s the cleaning of the bins. So, we’re going to reuse the bins, so we need to clean them. So, buying a washing machine, a tunnel, or a CIP system, you’ve got drying that goes into it. So, that’s a really big cost. It’s a big cost not only to acquire that in capital expenditure, but it’s always a fairly big footprint that takes up space in the manufacturing area.

So, that’s always a big thing as well. And then there is an intangible cost about having to store these IBCs and these split butterfly valves. They just can’t go out into the lot outside; they have to be stored somewhere within the plant environment and so forth, taking up space. So, we look at the same exact process but using the DoverPac®, the FIBC.

CAPEX Savings with FIBC

[Scott Patterson] 32:08
And here the CAPEX starts with a docking device. These are high containment systems that require a stainless steel docking device, which can be referred to as the O-ring canister system. But these docking devices are simple docking devices that are mounted with a tri-clamp or a bolt pattern. And so, in a CAPEX, you need one to discharge from a process into a DoverPac® and another one to charge into a process out of the DoverPac®. And so you’d expect a total CAPEX there of about $40,000. Again, we’re referring to equipment in both examples that would be stainless steel, 316 stainless steel. Obviously, if Hastelloy was needed, that would be a greater expense.

So next, docking of the DoverPac®. This is not a precision docking system. If we can get it within a couple of inches of where we’re going into the process, then that’s good. So, a much lower cost, a simple GMP hoisting system can be used. So, we estimated that at about $50,000. And then lastly, we have the consumable for the FIBC. And so, a high containment DoverPac® in roughly the 400-liter size costs in the area of $600.

CAPEX Comparison: IBC vs. FIBC

[Scott Patterson] 33:28
So, we went through this analysis and said, well, for the cost of capital here, the capital expense that would have to be put out and looking at a process that would have six batches per year, or let’s say in year one, and this would require five IBCs or five DoverPac® systems for each batch, you can see the difference between the $650,000 CAPEX and the $108,000 CAPEX for the DoverPac® system. So, a huge cost saving when it comes to using the FIBC, just a huge cost saving on the capital side.

Isolator Technology Cost Analysis

[Scott Patterson] 34:15
So, we’ll look at the same example using isolator technology. So, the example on the left and the example on the right are for the exact same process. Performance was at one microgram per cubic meter. The process performed inside was a co-milling operation with some weighing and sampling. So, you can see the hard-wall isolator on the left is a very expensive device with a CAPEX of $775,000, whereas the static isolator on the right, which achieved less than one microgram per cubic meter, is only $55,000 in a capital expenditure.

Cost Comparison: Hard-Wall vs. Flexible Isolator

[Scott Patterson] 34:52
So, dramatic difference. Now again, we could look at the flexible isolator and say, yeah, but that’s a static system. Our hard-wall isolator is a negative pressure system. Well, it’s possible then to add an automated negative pressure control to that flexible isolator. So, in this case, we’re showing the JetVent, a completely automated system, exactly how hard-wall isolators work, and which we have a variable speed fan and a pressure control system set up so that we can monitor fluctuations in the internal pressure, maintaining a negative pressure, and also preparing to go at a very fast speed, the fan going at a very fast speed, if we identify some upset condition, a glove failure, or something like that. So here, even if we added this to our example of the CAPEX, it’s a $60,000 estimated value. So we still have the difference of a hard-wall isolator, with an extreme $775,000 cost, and a negative pressure flexible isolator at less than $125,000 cost.

Benefits of Reduced Cleaning

[Scott Patterson] 36:09
The second thing we’ll look at is the benefit of reduced cleaning. We’ll look at the same examples again. So, when we look at cleaning of an IBC, we’ve got some problems to start off with because we don’t know what’s left inside the IBC. There’s always going to be retained powder in there, particularly if we have a poor flowing powder, maybe some stickiness, and so forth. So, the regular practice in the pharmaceutical market is that the first rinse of the IBC is captured because it has a rich content of whatever that HPAPI might have been. So, that’s typically captured and then gone off for disposal, which is typically an incineration. So, there’s time and cost just to get that first rinse done. And then we’ve got a detergent rinse, and then we’ve got a clean water rinse, WFI rinse if you will, and then drying. And then we’re only partway there. Now we have to disassemble the containment valve, assuming this is going to be a high containment split butterfly valve. There could be some additional cleaning on the seals there as well as maintenance, and then we have to go off and store it.

Simplified Cleaning with FIBC

[Scott Patterson] 37:12
Now we look at the FIBC and the DoverPac®, a very straightforward system. And starting with that idea of what’s left inside, well, you always know with a flexible intermediate bulk container that you’ve discharged everything else. You can see and/or feel to make sure that there’s not a blockage that left a couple of kilos inside or anything like that. Also, as a benefit, operators will typically, as their last operation, physically shake the FIBC and release any retained powder on the walls of the FIBC. So, literally, we’re getting everything but maybe 50 grams, 100 grams out, so we haven’t lost any product during this process, which oftentimes is the case with a stainless steel IBC.

So after we have all the product out of the DoverPac®, then we want to evacuate the gas because we’re going to do a seal and separate on it, and this seal and separate using the crimping process is basically a gas-tight process. So we don’t want to make a balloon, so we’re going to evacuate the gas, we’ve got the seal and separate, and now we just place that into a drum for disposal, and off it goes. So it’s a very simplistic, low-cost kind of process compared to the cost of cleaning an FIBC.

Polling Question Two

[Scott Patterson] 38:41
So here we’ve got our second and last polling question we want to run by you. So, I’ll hand it back to Garrett.

[Garrett]
Thank you very much. So that question is, “Does your company track the cost associated with cleaning, including labor, cleaning materials, disposal of materials, and validation?” The answers are: no, cleaning is performed as required, and the costs are not tracked; no, we have an SOP, and we can estimate the costs; yes, we have an SOP, and we follow the actual costs; yes, this cost is part of our manufacturing costs. While you answer, Scott, what results are you expecting?

[Scott Patterson]
Right. Our experience is that the cleaning process, whether that’s of the equipment and/or a process suite, is just considered to be part of the manufacturing cost and its cost of doing business, if you will, in the pharmaceutical industry. So, it’s been very hard for us to obtain specific numbers on cleaning costs. So, we think companies understand it, but we’re not sure that they actually collect those costs and track it.

[Garrett]
Thank you very much. We now move to the results. So, with number one, we have 27.3%, number two is 18.2%, and number four is 54.5%. What do you make of these results?

[Scott Patterson]
Well, that’s fascinating. So, our 54.5%, yes, this cost is part of our manufacturing costs, that’s very good. So, customers would understand what the cost of cleaning is, specifically, as they track these costs.

[Garrett]
Wonderful. When you’re ready, please continue.

Final Evaluation: Benefits of Reduced Cleaning

[Scott Patterson] 40:28
So, to finish up our evaluation of the benefits of reduced cleaning, we look at the isolator example again. So here, we’re looking at that same hard-wall isolator. The containment surfaces—not the surfaces of the mill inside or any equipment inside—but just the containment surfaces are roughly 20,000 square inches. So, this has to be cleaned through possibly CIP, but also there will be some manual cleaning required, so you’ve got a lot of time and labor involved here. Glove surfaces are not included in the 20,000 square inch estimate. These are surfaces that are critical because they’re actually in contact often with the product, and we know from discussions with customers that gloves tend to be a failure point because they’re used over and over and over again in these hard-wall systems.

Challenges of Hard-Wall Isolators

[Scott Patterson] 41:26
Again, we know that there are maintenance plans to replace gloves, but we often see that the failure of a glove is due to fatiguing and so forth from all of these cleanings that go on. Ergonomics is always an issue in the manual cleaning and something like this, trying to clean the roof, if you will, the top surface of the isolator, very difficult. Even reaching to the back of the isolator can be difficult ergonomically.

And just the point here that the work was done to go with a hard-wall isolator with a pass box, as you can see on the right, but on the left, the customer chose to go with the continuous liner technology or flexible containment. And as we said before, the critical point of containment is always at the transfer point. So here, the customer had confidence to use a continuous liner, despite the high capital expense of the hard-wall isolator.

Advantages of Flexible Isolators

[Scott Patterson] 42:20
So, the example that does the same job is the flexible isolator. So here we have a six-sided isolator—we often call it a balloon. And so, in this system, we can dispose of 100% of the containment surface, so that 20,000 square inches doesn’t need to be cleaned—dramatic savings here. We do recommend a specific wet-in-place process for the surfaces before we’re going to prepare for removal and disposal, and we do suggest a standard operating practice for the removal.

So, in this case, we’re showing a six-sided isolator. Often we’re working with five-sided isolators where it’s not going to have a bottom. And so, by following these SOPs, we’ve been finding that the overall exposure to the operators and to the environment still is absolutely minimized, even when removing something that has an open surface on it. But it requires a wet-in-place process and an SOP for removal.

Again, we use the bag-out system here versus the pass box used on the hard-wall system, which again facilitates the removal of product very easily that’s contained and safe to handle. And really, one of the tremendous benefits that are recognized from flexible containment when we’re using isolators is when any cleaning is needed. And so, in this case, the co-mill, which is on the back wall, the co-mill would need to be cleaned, and the flexible containment moves with the operator. The isolator is actually connected to this frame using bungee cords, so it allows the operator to move quite easily, perhaps disassemble and do cleaning on the communal parts and so forth. So, ergonomics are always a big benefit for flexible containment.

Summary & Key Takeaways

[Scott Patterson] 44:22
So, in summary, taking a look at what we’ve presented today, flexible containment, single-use products have been used in the pharma industry and now for HPAPI for over 20 years. The data from independent containment assessments, as we showed one, are showing containment performance in many cases of less than 10 nanograms per cubic meter. So these are very definite containment assessments, giving very good results. Regulatory guidelines are changing and impacting the cleaning requirements and the tox methods that will be used. And in CDMO facilities, this is becoming a more critical aspect of how to do the business, handling HPAPIs, and how to protect the operators and the environment. Lastly, the capital expense and operating costs—your CAPEX and your OPEX—are both reduced by using flexible containment systems, particularly on the operating costs: reduced cleaning, reduced risk of cross-contamination. This is part of the whole risk mitigation process shown by Risk-MaPP. Reduce that, and it’s a better value proposition.

[Scott Patterson] 45:37
So, Garrett, we’ve come to the end of the presentation, and if we have any questions, we can take those now.

[Garrett]
Wonderful. Thank you very much. As you said, we can now submit questions, so please just type them into the box at the top left-hand corner of your screen and click submit. But I have a few already here for you, and that first one is, “Is a flexible containment system at risk for a failure like a tear or puncture?”

Response to Question on Flexible Containment Failure

[Scott Patterson] 46:08
Right, Garrett, that’s a common question as customers look to use flexible containment for the first time. And our answer to that is, from an ILC Dover perspective, that we use the actual flexible part, the film part. We use a particular film that’s built for high strength and puncture resistance. The  ArmorFlex® film has been developed specifically for the pharmaceutical and biopharmaceutical market to not only meet the regulatory requirements but also these physical requirements. And so, in our experience and from customer surveys, there have been literally no reports of these types of failures. Now, we’ve heard from customers about FIBCs and questions like, “What if I run a forklift into my FIBC?” or “Aren’t I going to puncture it?” Well, of course, you’re probably going to do that, but if you’re going to puncture the FIBC and do the same thing to an IBC, you could also puncture that. You could damage a stainless steel IBC quite definitely, and I think the cost and the risks are even more there. So it’s possible, but again, we’ve developed a system to assure the maximum strength to minimize any risk of failure.

[Garrett]
Thank you very much. I have another question here for you: “Are single-use products considered a green solution, and can they be recycled?”

Discussion on Environmental Impact

[Scott Patterson] 47:44
Right, okay, so that almost sounds like it’s coming from a biopharmaceutical market, which has adopted so much of the single-use technology. There’s a massive amount of these single-use products out there. So as we look in the pharmaceutical market, there can’t be recycling of the products that we provide. They’ve been exposed to these toxic pharmaceutical compounds, and so the choice of how to handle this disposal is usually incineration. But we would look at that and compare it to the cleaning processes that go on with the hard-wall solutions, and in so many cases, we know that the cleaning solutions are taking large amounts of water. There’s a lot of energy put into the water because it just isn’t tap water, it’s WFI typically, and then in some cases, that’s collected and incinerated. And, you know, in the example of the IBC versus the FIBC, the FIBC is using no water. The IBC is using a significant amount of water, with that first perhaps couple of hundred liters having to go to incineration. So what is more green: the incineration of two or three kilos of polyethylene plastic film or having to incinerate water? And as we look at the global markets, there are a lot of areas where water is starting to be a premium, so we would suggest that a high use of water that can’t be filtered and returned into the environment is not a real green solution either.

[Garrett]
Thank you very much. Just a reminder, you can still ask questions using the top left-hand corner box. I have another one here for you, though: “Slides 23 quoted $55,000 for the flexible isolator. Does this include the cost for the frame?”

Cost Inquiry for Flexible Isolator

[Scott Patterson] 49:50
Yes, yes. So that was, the $55,000 was a turnkey cost for the frame. You saw the bag-in-bag-out system, and actually, in this system, on the backside was a superstructure of the frame to hold the Quadro Comil. So yeah, that was an all-in cost on the $55,000, and typically, it will also include two consumables for the flexible isolator, but yeah, that’s an all-in cost.

[Garrett]
Thank you very much. Another one here for you: “Do the product contact materials meet the regulatory compliance norms?”

Regulatory Compliance of Product Contact Materials

[Scott Patterson] 50:38
Right, this is one of the critical aspects of using single-use products, and in the pharmaceutical industry, it’s critical. In the biopharmaceutical industry, I’d even say it’s more critical. So, right, the minimum level needed to use a single-use flexible containment product would be FDA compliance and then also compliance to the European Food Safety Authority and their food contact requirements. There are other global requirements as well, and that’s sort of the minimum. Then we step up, and now we have standards for the U.S. Pharmacopoeia, the Europe Pharmacopoeia, so we have to address those. Again, Japan has some standards to meet as well. And then once we get beyond that, we get into more specific standards of no heavy metals, no animal-derived materials, and so forth. So as we put these all together, the regulatory landscape requires a very highly characterized film, which has to be proven through these tests and through extractable and leachable tests. So yes, there is a high standard that’s required for these films.

[Garrett]
Thank you very much. I have another one here for you: “Can we use the flexible isolator and the canopy set for multiple times, but the whole set would be dedicated to one product?”

Reusability of Flexible Isolator Systems

[Scott Patterson] 52:10
So we have had that experience, yes. This goes to some of the opening comments about robustness. The example that I will give is that we provided an isolator system to a company that was making an oral contraceptive. So, the system was being dedicated to that. Now, the isolator system was being used for analytics of tablets coming off the tablet press. So, as they would take samples every 15 minutes, they’d transfer them into the flexible isolator. We knew their production levels were high, and following up with the customer, initially six months after we did the installation, and they hadn’t asked for any additional consumables or a replacement flexible isolator in that case, because they were disposing of the tablets afterward because they were testing them for thickness, hardness, weight, and so forth. The tablets were scrapped. So, if you do have a dedicated product, it is possible to use these over and over and over again. It’s, again, not a matter of robustness; it’s a matter of cleaning. So, we would suggest them for this question to go back and look at whatever the quality department requires from a cleaning protocol, and as long as it’s on the same product, if cleaning isn’t required, then we would fully suggest continuing to use the flexible isolator system.

[Garrett]
Thank you very much. I have one final question here for you: “Can a flexible isolator be removed and disposed of and maintain containment?”

SOPs for Safe Removal of Flexible Isolators

[Scott Patterson] 53:54
Right, so, we’ve been studying this now through our containment assessments, and we’ve found through the containment assessments that the containment performance target is somewhat missed during the cleaning and removal process, but also we found that the cleaning protocols weren’t really being followed quite well. In one case, it was clear that there was visible powder on equipment inside the isolator, so when the isolator was removed, again, there was some amount of exposure, an excursion of the containment level. So again, cleaning is part of the whole process, and that’s why we say an SOP has to be developed to be able to minimize that. The second round of that test was really interesting. After we had done the containment assessment, we had gone back to do some additional training with the company, and they had decided to show the operators what they were missing. So, the surrogate that we used in the training process had a fluorescing powder mixed in, a Glow Germ, and so then after the process was done and the cleaning process started before the removal of the isolator, we went in with a black light or a UV light, and we were able to show the operators where they had missed the powder. So, it can be done. We’ve also seen a study done in Japan where they went as far as not only the swab surfaces inside the isolator but they swabbed the floor of the process suite. So, it can be done, but it requires a proper SOP.

[Garrett] 55:44
Thank you very much, everyone, for your questions. However, if your question was not answered, do not worry, as the team will be in contact with you with any answers to your queries. That just leaves me to thank you, Scott, for what was a great webinar and to ILC Dover for sponsoring this session. To the attendees, you will receive an email shortly telling you how you can access the on-demand version of this webinar, or you can access it through our website, which is business-review-webinars.com. We look forward to sharing further webinars with you, so please do keep an eye out on the website just mentioned, and follow us on Twitter at BRWebinars for daily updates, and join our LinkedIn group, Business Review Webinars. Thank you once again, and I hope you all have a lovely day.