Webinar: High Containment for Lyophilization Processes

Introduction

 [Kyle] 0:03 – Good morning or good afternoon, everyone, depending on where you’re joining us from, and welcome to today’s webinar.

My name is Kyle from Business Review, and I’ll be your host today. It’s a pleasure to have ILC Dover with us as they present their webinar entitled High Containment Lyophilization Processes.

Today’s guest speaker is Scott Patterson, Vice President of Pharma-Biopharma Technical Support. I’d like to welcome you to our webinar platform, On24.

You’ll notice that this webinar is browser-based, so if you disconnect for any reason, please just click on the link you received by email to rejoin the session.

If you want to ask any questions, you can send those in via the questions widget. Just type them into the box at the top left-hand corner of your screen, click Submit, and we’ll have some time at the very end to address any questions or thoughts you may have.

Please use the help widget if you require any assistance. You can move, resize, and maximize any of the windows in front of you to get a better view of the slides.

But for now, please allow me to welcome Scott Patterson. Over to you, Scott.

[Scott Patterson] 1:00 – Thank you, Kyle. Again, welcome, everyone, to our webinar.

Our webinar today is High Containment for Lyophilization Processes. We’re going to focus on the use of single-use isolation technology for high-containment purposes.

Program Overview
[Scott Patterson] 1:27 – Today in our program, we’ll cover a range of topics related to high containment, starting with the containment challenge when trying to work with a lyophilizer.

We’ll take a quick look at a single-use example so that we can clearly show what the technology looks like.

The purpose of using isolation technology is to protect the product, the operators, and the environment or the processing area. We’ll review that and give a few examples of actual solutions applied to lyophilizers and the specific containment designs.

As always, in using high containment, transfer technology for moving materials in and out is a critical part of it. So, we’ll take a look at options for transfer technology and then the real value of using single-use technology for high containment, including reduced cleaning, reduced validation, and cost savings.

As Kyle mentioned, we’ll leave time at the end for your thoughts and questions, so please, again, send those in using the box to type in your questions, and we’ll review those at the end of the webinar.

[Scott Patterson] 2:38 – So, here is the typical lyophilizer system and the challenge being: how do we contain this?

Particularly in this typical design, the door needs to open and close. For the most part, the containment system has to be retrofitted to the lyophilizer, so a lot of this is done in the field. However, new systems are often subject to containment, and the approach is about the same for how the high containment system can be adapted to the lyophilizer.

The key point, again, is the door and keeping the door contained while it’s opened and closed. But really, we’re looking at the ergonomics, and a serious issue when trying to contain a lyophilizer is maintaining good ergonomics for the operators to handle the trays and product and so forth.

The transfer points, which we’ll study a bit later in the webinar, are always critical. In this typical design, not all lyophilizers are the same.

This one is a little easier than a multi-tray type of lyophilizer in the last slide. The “pizza door,” as it’s often referred to, is somewhat easier to manage since the trays are handled in one location, if you will, at one height.

So, not all lyophilizers are the same. We’ll see a couple of different examples, including a very, very difficult lyophilizer system to contain, and then some of the easier, smaller ones with different approaches for the containment of these systems.

[Scott Patterson] 4:23 – So, here’s the basic concept of using a single-use isolator for containment in a lyophilizer.

This actual photo that we’re seeing on the right is of the sister of the lyophilizer, if you will—a tray dryer used in pharmaceutical API manufacturing. But the challenge is exactly the same. We have multiple trays, and we have a door that has to open and close.

You see how the operators are working inside the isolator through the gloves. The key to the picture that we’re showing here is where the operator is positioned. The operator is standing at 90 degrees to the actual single-use isolator.

This is to promote the idea of ergonomics and how easy it is for an operator to move using this type of technology. This is one of the absolute keys when considering containment in a lyophilizer—the ability for the operator to move about and handle the trays.

[Scott Patterson] 5:46 – So, a brief history on flexible containment and single-use: this is not a new technology.

Single-use technology really came to fruition in 1997, and it was the thought of Eli Lilly, who recognized in their pharmaceutical manufacturing that the compounds they were developing were becoming more and more potent. They had to apply more containment to protect the operators and the environment.

In the early days, the whole concept was really: how do we protect operators from exposure to highly potent compounds? Eli Lilly also took a look at the high costs of things like hard wall isolators, laminar flow booths, split butterfly valves, and this type of technology.

So, they also had a goal. The primary goal was to ensure operator safety, and the second goal was cost control. Through their processes, both the chemical synthesis process and oral solid dosage processing, this flexible containment technology—the single-use technology—came into the process for high containment.

So, it’s not a new technology and has been proven now for well over 20 years. But a lot has changed since 1997, when the thought was to apply single-use technology for high containment processes.

Certainly, from the definition of high containment in 1997, the gold standard was containment to less than one microgram per cubic meter. Today, the typical process is well under 0.1 micrograms, or 100 nanograms per cubic meter. We’re also starting to see companies talk about projects to contain within the picogram limit.

[Scott Patterson] 8:29 – So, one thing we know is that in any containment project or process, containment will be needed.

In a perfect process like lyophilization and freeze-drying, if it’s a perfect process, we really don’t need any containment. The product coming into the lyophilizer is in liquid form, so the risk of handling a liquid is very, very low.

The product is in, let’s say, a vial, and it has a stopper that is placed on top. So, we have a product in a closed container in liquid form, meaning extremely low risk. Even after the freeze-drying process, the product comes from the lyophilizer in the closed container—the vial—with a stopper on top, closed.

But that’s really not the reality. Nothing goes as planned, typically, in processes, and things can happen that will cause an upset condition.

Things like vials breaking inside the lyophilizer or vials falling over inside the lyophilizer can occur. Through the freeze-drying process, we now have solid particulates that get airborne, and now they cause a risk of operator exposure and exposure to the environment.

The containment system is in place to allow for controls during these upset conditions. We see this through using the ICH Q9 risk management system and conducting a risk assessment.

When we look at a risk assessment for handling product in the lyophilizer, it’s clear that the process will fail. It’s typical to have an upset condition, and so the containment system is designed for those particular risks identified during the risk assessment.

[Scott Patterson] 10:31 – So, single-use isolator technology—what is it really doing?

It’s multi-purpose. Initially, as product is going into a lyophilizer, it can be used to protect the product. Again, the product should be in a closed container, but we want to protect the product from contamination from the room, from operators, and so forth.

Our first goal in the process is to protect the product. Then, through the lyophilization process, now we have a potent compound in solid form. So, we’re no longer dealing with a liquid; we have a solid. Now, we’re looking at operator protection to protect them against that potent compound.

We do that through the environmental control of the isolator. In many cases, we use pressure control in the isolator—potentially both a positive pressure during the loading stage and a negative pressure in the unloading stage.

But the key here is really looking at the ergonomics and making sure that we’ve designed a containment system that allows the operator to work very ergonomically.

The alternative technology of using a restricted-area barrier system or just using the cleanroom is often much easier in terms of ergonomics than an isolator. But in both of these cases, they fall short of providing the total benefit that isolation technology really provides.

Certainly, a cleanroom really goes against the modern thinking of containment. When containment is needed, the concept is to contain as close to the source as possible—not to use the room as the containment device.

Certainly, a cleanroom without any containment technology or engineering solutions, and just using PPE, becomes the easiest thing for an operator to use. But it also creates a lot of risk when using that type of thought.

[Scott Patterson] 12:47 –  So, we’ve all seen in isolation technology the challenges that we get into with hard wall isolators.

Again, if you recall the first picture we looked at with the single-use isolator, the operator was easily able to work at 90 degrees to the isolator. Here, very typical, even through best practices of designing the isolator—using mock-ups and trials to mimic what the operations are going to be—things that can’t be controlled are the operators: the heights of the operators, the size of their hands, and different attributes from operators.

And so, oftentimes, we do end up with very poor ergonomic systems.

Then the other part of it is that we often see that a process will change—either a part of the process will change or the entire requirement in the isolator could change.

And so, when using single-use systems, we deal with both of those.

First, from the ergonomics standpoint, we create a flexible wall with glove interfaces to allow ease of motion for the operators.

Again, we use a bungee cord system with this flexible isolator to allow that operator to have a full range of motion and so forth. So, really, the ergonomic issues that are seen in isolation are minimized when using a single-use flexible wall technology.

But really, then it gets to the second part: that the process can change or even the overall product and what is done in the isolator may be different. And that can go for the lyophilizer as well.

And so, in single-use technology, that can be adapted easily. Then, by definition, single-use—the isolator is used and then disposed of. The next version of the isolator could be modified for any changes that are needed, and that’s done extremely easily.

When using a hard wall isolator, trying to change a glove port, move glove positions, and so forth is extremely expensive, requiring revalidation and a high cost to do that.

So, the ergonomics and the ability to adapt and change in a single-use system is at a premium.

Here, we’re going to play a video just to show the ergonomics of a single-use system.

In this video, you’ll see the operator is essentially loading the powder into a milling system. We’re reviewing it through the isolator wall.

Also, with single-use isolators, again, the ability—the vision—to work through the wall and to see what’s going on inside is at a premium. But as you see, the operator is able to scoop material from a bag and easily load it into the isolator.

And you can see he’s not restricted at all as he moves around inside this isolator.

And this is really what we promote as a premium: ergonomics can be the same almost as working without isolation technology.

So, this is a very good example of how the operator can move around easily, manipulate products, and so forth.

Also, you can see here in this video that you physically can see the dust coming from the powder transfer and so forth.

So, when we start talking about high containment using a single-use isolator, we really have the ability to have that containment into the nanogram level.

And in this case, even when there’s a lot of visible powder that’s airborne, this can be maintained.

So, we’re going to pop to another video.

And getting back more directly to the lyophilizer: again, this is one of the challenges that we get to.

And we would sort of label this as “Don’t try this one at home,” because this one is one of the more complicated lyophilizers in terms of the size and the door to be able to have containment.

So, we have a very large door. We have trays that are in elevation, and it makes it difficult for the operator to work.

But we see in this operation, the operator has to take the tray from the lyophilizer after the freeze-drying process, and he’s going to move that to a laminar flow hood for further work.

So, again, in this strategy, they’re really using PPE as the primary mechanism for operator safety.

And then they’re really using the room primarily as the containment device, followed by putting the trays into the laminar flow hood.

[Scott Patterson] 17:50 – So, in this case, a very difficult application, we did come up with a unique solution that’s shown graphically here with this drawing. In this solution, you can get an idea of how single-use technology can be adapted very easily.

Although this is a complicated system, you see the operator is actually standing in, if you will, a box that completely separates him from the process. Inside that box, he reaches through the gloves to pull the trays out of the lyophilizer.

You see the series of gloves on both sides, particularly on the operator’s right-hand side, where he can then turn and hand the tray to another operator. That operator will then place it on the table behind the first operator.

So, we’re mimicking exactly what we saw in the video: trays being taken out of the lyophilizer and then placed in an area to do further work, unload the trays, and so forth. But it’s all being done in an isolator—not relying on the PPE or the room as the primary method of containment.

More Examples

There are all kinds of different lyophilizers. The last one we saw was a very difficult one with a very large door and multiple trays in an ergonomically challenging position.

Here’s the easier side of it: a small lab and formulation lyophilizer that we see in the picture on the left. In this case, this is probably not even a cGMP operation. We see it sitting in a lab environment, but again, the customer was interested in having some containment for an upset condition.

On the right, you can see a very simplistic static pressure isolator. There’s no positive or negative pressure being circulated inside the isolator, but the static pressure isolator is in place to allow for an upset condition. Any materials that might get into the environment are contained within the isolator.

So, a very simplistic, very simple design to meet that requirement.

Again, moving maybe to a slightly larger scale but possibly in the same realm, in terms of pilot plant size—something to make clinical supplies—we have a lyophilizer with a door and multiple trays.

We set up the same kind of single-use isolator system here. Again, it’s simplistic as it uses static pressure. This may not be a cGMP environment, but again, we’re trying to ensure containment within the isolator during an upset condition.

You’ll see at the bottom right of the drawing of the containment system is the bag-in, bag-out system. That’s one of the transfer technologies we’ll look at briefly here.

So here we’ve got a polling question. I’ll hand it back to our host for the polling question.

[Kyle] 20:56 – Thank you, Scott. It’s now time for our first poll.

I’ll quickly read the question: Please select one option and click Submit. The next slide will display live results.

Our question is: Would you consider using a single-use isolator in an aseptic process to reduce the risk of any carryover particulate or bio-burden?

The options are:

• We already use single-use isolators in these processes.
• If using single-use isolators, do you mean reuse and sterilize the isolator?
• We do not use single-use isolators.
• We’re not using single-use products but will consider it.

Take a moment to think about your response. In the meantime, Scott, would you like to elaborate on this question as people vote?

[Scott Patterson] 21:46 – Yes, we see certainly one of the growth areas in the industry is aseptic processing. And the lyophilization process is often required to be done in aseptic conditions, so this is an interesting area.

Because there needs to be containment, there needs to be the aseptic condition, and there’s a further view on contamination and particulate and so forth. So, it’s interesting how different companies are viewing engineering controls for these types of processes.

[Kyle] 22:30 – Okay, very good. That should have given everyone enough time to think about it. Let’s take a look at how the responses turned out.

[Scott Patterson] 22:48 – It looks like we have a pretty even spread.

[Kyle] 22:55 – Yes, it does. Scott, is this result what you expected?

[Scott Patterson] 22:59 – Yes, I think with both aseptic processing and the choice of technology, it’s clear that traditionally hard-wall technology, like hard-wall isolators, has been the go-to solution. However, there’s a growing demand for single-use isolators.

[Scott Patterson] 23:19 – Okay, so we’ll keep going through the containment solutions that have been applied to lyophilizers. So here again, now we’re stepping up from the sort of non-cGMP type of process to an isolator that has a controlled environment inside. And so this would be, let’s say, a grade A or grade B environment inside. So it’s not considered aseptic, but it is a controlled environment to create that clean space.

This is done through either a negative pressure or positive pressure system. So typically, with the lyophilization process, we would be looking at a positive pressure, and we’re going through a HEPA-filtered system to exchange air inside and then create this low particulate level of as low as grade A. Again, there’s a small differential pressure from the inside of the isolator to the outside, but this is common technology to be able to control the environment inside to create that clean space.

So this is a step up from those static pressure examples that we gave that may or may not be really providing product in a GMP environment. Here is certainly something for the production mode.

And then the step up from that is creating an aseptic condition inside the single-use isolator. So this is becoming more and more common to have an aseptic side in the isolator for the lyophilization process. And the single-use system is the most common process for creating the aseptic condition, including the vapor of hydrogen peroxide (the VHP process) to do the sterilization.

And so, again, the same system that does the pressure control—a positive pressure inside—also assists in going through the cycles of the VHP process to go through and dehumidify and all of the cycles for creating that aseptic condition.

So here, the single-use isolator can have the benefit where it could be reused. It can go through multiple cycles, or, potentially, to reduce the risk of cross-contamination, it can truly be a single-use isolator and be disposed of after the use so that the risk of any cross-contamination is mitigated.

[Scott Patterson] 25:48 – So, going on to the transfer technology, it plays a key role in containment. It’s somewhat easy to put an isolator around the process and achieve high containment, but we do need to get the product in and out, obviously, since it’s a process. So we have to rely on different technologies to manage those transfers in and out.

The different technologies could be used for different reasons, again looking at, well, what is the next process for the materials in the transfer? When we bring the materials out of the lyophilizer, where does it go to next? What is the process? Will the transfer require containment again in transferring the product? We’ve seen applications where, because it’s in liquid form, there hasn’t been a lot of emphasis on the containment. So, is the transfer going to require containment? How large are the materials in the transfer? That can be key in determining what technology is used and how the transfer is done.

Will the transfers require aseptic control? Do we have to hold a sterile condition as we’re doing a transfer in and out of the engineered isolator? Looking at that, there are different technologies. One of the most common is the rapid transfer port (RTP). Here on the left, we’re showing a simple flexible isolator, a single-use isolator, that has the RTP, if you will.

In this case, just like on a hard wall system, the alpha flange is designed to be permanently mounted to the isolator. Then, as you see on the right, the containers that move the product in and out have the beta flange to connect to that alpha flange. So it’s multi-use, allowing for multiple transfers in and out of the isolator.

Additionally, there is the beta bag, shown in the lower right picture. The beta bag combines the technology of the rapid transfer port and the benefits of that, including the ability to do aseptic transfers, with the single-use flexible technology of the beta bag. The beta bag also has good value in terms of sizes and is a little lighter for transfers, so it offers some advantages.

Another option is pass box technology, which is extremely common on hard wall isolators, as shown on the right. You see this isolator on the right has a small box where materials are passed into it in a contained way, and then the door opens to move the product out. The same technology is shown on the left, but in the flexible single-use technology. The pass box uses zippers to pass the material in and out.

This is good technology, and a lot can be done with it. However, challenges include the size of the transfer, both dimensionally and in terms of weight. As you can see on the right-hand side, particularly, the transfer box on the isolators is relatively small and may make it difficult to move larger items that are heavy. These items might only be able to be handled with one glove while inside the isolator.

Additionally, with pass box systems, we have to be careful with multiple uses of the pass box. Each time we open it to the atmosphere, there is a risk. So, a risk analysis must be conducted to evaluate the potential exposure risks.

The next technology is the bag-in-bag-out technology, which is really the single-use technology. This is extremely effective for large sizes and doesn’t take up much space with the isolator system. On the left, you can see that it is essentially an extension of the single-use isolator. It’s a flexible sleeve that’s connected to the isolator system.

The picture in the center shows a transfer—in this case, of powder—into the sleeve. Then there’s a secure seal and separate crimping process, if you will, to separate the sleeve from the containment system. Now, this material can go into the next operation or whatever needs to be done.

The beauty of this system, compared to the pass box system, is that the sleeve, as seen on the left-hand side, has never been inside the containment area. The sleeve is completely clean and can be handled by operators on the outside, then taken and transferred wherever it needs to go. Using a secure seal and separate process like the crimping system, this can be done without the risk of exposure or having the product open to the environment at all.

Lastly, we look at the split butterfly valve technology. This is an interesting technology because it combines the idea of high containment with transfer. Some of the systems available now can also be used in an aseptic process, allowing for aseptic transfers.

In this case, we’re showing the split butterfly valve connected to a plastic bottle. One of the challenges, however, with split butterfly valves is the size of the transfer. By nature, they are butterfly valves, and as they open, the wafer—in this case, a two-wafer system—sits right in the middle of the transfer.

Instead of having, say, a 6-inch diameter split butterfly valve with a true 6-inch opening, you essentially have two half-moons split by the valve wafer sitting in the middle. It’s good technology and lends itself to certain types of transfers, but because of the size limitations and the wafer in the middle, it can be somewhat restrictive.

[Scott Patterson] 32:11 – So, here we’re going to take a look at cleaning validation when it comes to the lyophilization process and some of the cost savings associated with that.

The comparison we’re going to make in the next couple of slides is between the single-use isolator and a hard-wall isolator. However, we could do similar analyses when looking at other technologies commonly used in lyophilization, including RABs or just using the cleanroom.

In those cases, we would examine factors like energy costs and the maintenance of HEPA filter systems, rooms, and so forth. We’d also consider how to monitor and clean the cleanroom, the cleaning and maintenance of RABs, and the amount of PPE required—particularly when the cleanroom serves as the main containment mechanism.

Not only would we evaluate the cost of the PPE, but also the time required for gowning and related activities. These are the kinds of factors we would include in such comparisons.

Here, however, we’ll focus on a quick comparison between single-use isolators and hard-wall isolators.

But before we dive into that, we have our second polling question. I’ll hand it back to our host to address this polling question.

[Kyle] 33:20 – Okay, thank you. Now for another poll. If anyone missed the first one, just click one option, click Submit, and wait for the next slide to view the live results.

The question is:

Do you find single-use products reduce cleaning validation SOPs in your processes?

• We do not use single-use products in our processes.
• Yes, we have found that single-use products are effective.
• No, we’re still required to perform cleaning on single-use products.

Once again, take a moment to think about that. Scott, would you like to elaborate a bit on this question?

[Scott Patterson] 34:06 – Yes. So, it’s an interesting topic, and somewhat always decided company by company, particularly within the quality department.

Decisions on how or when to apply single-use products—and how to evaluate cleaning, whether it’s decontamination for removal or complete cleaning—vary widely.

We do see a range of strategies implemented by the quality departments of different companies. It really becomes an education on how each process, and really how each company, approaches the implementation of single-use products with respect to cleaning.

[Kyle] 34:45 – Okay, very good. That’s enough time for everyone to vote, so let’s see how it turned out.

There we go. Once again, those are the results. Anything you notice about that, Scott?

[Scott Patterson] 34:57 – Yes, it’s clear. We have a big chunk of our attendees selecting that they have found single-use products to be effective.

This highlights the fact that single-use technology isn’t really that new. However, the range of processes it’s being applied to is expanding significantly.

This tells us that single-use technology is being implemented across a wide range of processes.

[Kyle] 35:31 – Okay, very good. We’ll move on to the final part of the webinar.

[Scott Patterson] 35:44 – And so here we’re back to the discussion about cleaning. In a recent publication by the Parenteral Drug Association, we see something that’s really being debated among experts in the industry—non-product contact surfaces.

Usually, it’s straightforward: a surface is either a product contact surface or a non-product contact surface. It’s generally black and white in that way.

However, in this publication by the Parenteral Drug Association, the discussion revolves around indirect product contact. This gets interesting because the definition of indirect product contact, as opposed to the black-and-white categorization of product contact or non-product contact, is surfaces with proximity to open products.

That’s a perfect definition, and as outlined in this guidance, this is directly applicable to situations with lyophilizers.

In a lyophilizer, the trays and the area within the lyophilizer are not technically product contact surfaces. However, they are in direct proximity to potentially open products. If a stopper comes out or something similar happens, the potential for airborne particulates to get into the product becomes very real.

With that in mind, when working with a lyophilizer, and the isolation technology that comes with it, all of these surfaces are considered areas that need to be cleaned to prevent the risk of cross-contamination.

That’s the whole purpose here. Even though, by definition, we could argue that the surfaces of the isolator are non-product contact, they are within close proximity to potentially open products.

As this guidance states, we must treat them as product contact surfaces with validated cleaning methods.

[Scott Patterson] 37:55 – So, here we take a look at what that means. With a lyophilizer, the surfaces will have to be cleaned—those are stainless steel surfaces, reusable surfaces.

However, when we look at the isolation technology that could be applied, we have a very different case.

In the picture shown, we have essentially identical isolators performing the same process. The hard-wall isolator is shown at the bottom left, and the flexible isolator is in the middle. These were identical isolators, but the flexible isolator was developed specifically to get validation done in the process, make validation batches of the product, and so forth.

You can see the difference in cleaning requirements. For the hard-wall isolator, the cleaning area—the surface that needs to be cleaned—is about 20,000 square inches. That’s a massive amount of cleaning, and this doesn’t include the glove surfaces, which can be some of the most difficult surfaces to clean.

In contrast, with the single-use isolator, we’re going to dispose of it after use. Fundamentally, there’s no cleaning required. There might be some minor wetting or preparation, but we’ve virtually eliminated all of the cleaning.

By eliminating the cleaning, we also eliminate the associated SOPs. As we all know, reducing SOPs is a huge advantage. Furthermore, we eliminate the validation processes tied to those SOPs.

With single-use technology, another interesting benefit arises compared to hard-wall technology. In lyophilization isolation, there’s a tendency to perform glove testing and integrity testing on hard-wall systems, which requires another SOP.

With single-use technology, the entire assembly can be integrity-tested at the factory before being sent to the customer for use. This reduces the number of SOPs, validation requirements, and associated costs.

All of this contributes to cost reduction, risk reduction, and better efficiency in using the equipment and the technology.

Here we see the main benefit of single-use technology: the ability to dispose of the system rather than clean it, significantly reducing costs and improving overall efficiency.

[Scott Patterson] 40:24 – So, we also think about the performance of single-use technology. What is its capability?

Earlier in the webinar, we had a slide showing that containment projects currently aim for containment targets under 100 nanograms per cubic meter in terms of containment performance.

What about containment in the lyophilization process? Like our friend Sasquatch, data on lyophilization containment is very, very rare to find.

The reason for this is that obtaining data can be challenging. Can we get real-time data on these processes? Typically, there aren’t many assessments done on live or active products. Surrogate testing is usually the methodology, but here, how do we mimic the process?

In lyophilization, we start with a liquid. In the best-case scenario, we won’t have any exposure from that. So, the risk is quite low, and the containment in place is really to protect the product from outside contamination, bacteria, and so forth.

After the freeze-drying process, however, there is potential for airborne contamination and exposure. That’s where isolation containment becomes critical. But how do we mimic that scenario for testing?

It’s a very difficult process to replicate and gather data on. This makes it challenging to definitively say what the performance of an isolator is in a lyophilization process.

Instead, we rely on data sets from similar processes. For example, the ISPE SMEPAC protocol is typically applied to containment studies. We look for other data sets that can give us a high level of confidence.

At the end of the day, that’s what the SMEPAC test is designed to do—provide a high level of confidence that the containment system will perform as needed.

[Scott Patterson] 42:35 – So, one of the things we would reference is using a single-use isolator. In this case, this is a data set from a weigh and dispense system.

Here, in a weigh and dispense scenario, we’re openly handling the product. The powder inside, in this case, is a surrogate, and we’re observing airborne powder.

We can see that we have to isolate the operators from the process. I think the key here is in the gold box in the middle.

You can see that we measured the airborne particulate inside the isolator. In particular, we were using a negative pressure system, and at the extract filter, we observed 506 micrograms per cubic meter of product.

So, we know there was a challenge inside, and we know there was airborne particulate. On the right, you can see that the isolator passed the test, which required containment below 60 nanograms per cubic meter.

In terms of how the statistical analysis was applied, the isolator met all requirements.

We use data sets like this to compensate for the lack of data on lyophilizers. By examining the containment scenarios and challenges from similar processes, we can start to build a high level of confidence that the isolation technology will perform well—even in upset conditions.

This is especially true when we can prove that there was a measurable challenge of airborne particulate, as in this example.

[Scott Patterson] 44:15 – So, lastly, let’s take a look at this comparison of single-use systems to hard wall systems.

From a straight cost analysis, we focus on the capital expenditure (capex) and the operating expenditure (opex).

Here’s the analysis very quickly with just the key points.

On the capital expenditure side, single-use projects are typically implemented for 20% or less of the cost of a hard wall isolator. So, in that direct comparison, there’s a massive cost saving in capital spending.

We also know that the time to implement a single-use system is much faster. The engineering time is shorter, mock-ups aren’t as critical because the flexible systems are more adaptable for operators, and changes can even be made after the initial implementation of the isolator.

Project times are significantly reduced, and start-up and validation times are also much shorter. So, in terms of capex, there’s a major cost saving.

Rhetorically, there’s the thought: “Okay, but then I have consumables to buy.” However, there always needs to be a direct comparison of the cleaning costs for a hard wall isolator against the disposal costs of a single-use isolator.

We’ve worked on projects where customers literally complete a process, dispose of the isolator, install another flexible isolator, and are ready to run a different product within hours. That’s impossible to do with a hard wall isolator, given the cleaning validation, hold times, and other processes required.

Beyond the measurable costs in capex and opex, we also look at risk mitigation.

Risk mitigation with a single-use isolator primarily addresses cross-contamination. There’s always the potential for retention, which is defined as product that wasn’t completely cleaned from a surface.

Thinking back to the lyophilization process, those non-product or indirect product contact surfaces, in this case, need to be treated as product contact surfaces. We want to avoid having residual powder or retained powder moving from Batch 1 to Batch 2 or from Product A to Product B.

There’s a range of risks that are completely mitigated by using single-use technology. With single-use systems, contamination is managed by decontaminating and then disposing of the isolator.

[Kyle] 47:55 – Thank you very much.

So, everyone watching, send your questions in. Just type into the box in the top left-hand corner of your screen, click Submit, and wait to hear if they’re read aloud.

There’s quite a few coming in, so we can just get started with: is a flexible wall isolator only single-use, or can it be used multiple times?

[Scott Patterson] 48:11 – Right, that’s always the question because it seems, after use, it looks brand new. It’s not an issue of robustness.

Flexible technology, executed correctly, has the ability, in terms of robustness, to be used for many operations. The question goes back to: why clean it? There’s a cost to cleaning versus disposal. And why have the risk of cross-contamination?

The general industry thinking is single use and dispose of, to avoid the cost and risk of cleaning.

But it’s not because of robustness. A well-executed isolator, made with the right materials, could be used for many, many batches of the process.

[Kyle] 49:16 – Okay, thank you. On to the next question: after using a single-use isolator, how is it disposed, and is it considered a sustainable technology?

[Scott Patterson] 49:22 – The typical disposal method for a single-use system—and for reference, the typical isolator is made from polyethylene-based flexible material—is incineration.

The more potent the material, the more likely it is to go to incineration. The polyethylene material can be incinerated without environmental risk.

There’s also the option to dispose of it in a landfill, depending on the contamination and material inside.

In terms of sustainability, this is a fascinating subject being explored quite a bit in the biopharm area. Since we’re using literally thousands of tons of single-use products, it raises the question of what happens to them.

Studies show that the cleaning process—which uses a lot of water, solvents, and energy—creates a very large waste stream. Often, that contaminated water also goes to incineration.

The studies indicate that, from a sustainability standpoint, it’s more efficient to use a single-use product and incinerate it than to create WFI water, use it for cleaning, contaminate it, and then incinerate the water.

So, more and more studies are showing that single-use products are sustainable.

[Kyle] 51:06 – Okay, I’ve got a very nice question here: is PPE still required for operators when using an isolator?

[Scott Patterson] 51:14 – We work with customers on this a lot. The decision is always up to each company and their safety requirements.

It also depends on how the employees feel and the level of risk they’re comfortable with.

The reality is: data, data, data.

We’ve worked with customers who start off with full PPE, including powered air-purifying respirators (PAPRs). Through training, monitoring, and data collection, they’ve been able to downgrade that to lesser PPE.

It’s possible to reduce PPE requirements, but what we typically see is a progression. Companies begin with full PPE to contain any risk, then scale back as they gather data.

Some companies prefer a belt-and-suspenders approach, keeping isolation technology for room safety and operator safety while still using PPE as an added layer of protection.

[Kyle] 53:03 – Okay, thank you. Someone here has asked: how do you decontaminate the flexible isolator after unloading freeze-dried products?

[Scott Patterson] 53:10 – There’s a range of methods, depending on the compound.

It can be as simple as wetting with water using a spray wand or spray bottles. Some companies go further with solvent-based wetting or even complete cleaning.

Single-use isolators made from polyethylene are generally solvent-resistant. If decontamination or destruction requires a solvent, it’s fine to spray that inside the isolator.

The solvent can then be captured inside the isolator or drained away. Afterward, the isolator removal process ensures the room and operators are not exposed.

[Kyle] 54:28 – Okay, very good. I’m afraid that’s all the time we have for today, which just leaves a big thanks to Scott for the great presentation and, of course, to ILC Dover for sponsoring this session.

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