In this webinar, Scott Patterson, Vice President of Pharma and Biopharma Technical Support at ILC Dover, and David Howes, Product and New Business Development Manager, delve into the transformative impact of flexible isolator technology on the pharmaceutical industry. Together, they explore how these advanced systems enhance operational efficiency and regulatory compliance, particularly in high-containment environments.
Scott provides an in-depth analysis of the design and application of flexible isolators, emphasizing their role in reducing traditional cleaning processes, minimizing cross-contamination risks, and supporting the safe production of highly potent compounds. David Howes complements this by discussing the integration of negative pressure control systems, showcasing how these innovations further strengthen containment and safety.
The webinar features real-world case studies, illustrating the practical benefits of flexible isolators, including shorter project timelines, lower capital expenditures, and improved adaptability to evolving industry standards.
Watch the video or explore the transcript below to learn more.
Transcript
[Paulo]
Good morning or good afternoon, depending on where you are joining us. I would like to thank and welcome all of you for participating in this webinar organized by ILC Dover. ILC Dover is a worldwide leader in the design and manufacturing of engineered flexible protective solutions for critical applications, from aerospace to pharmaceutical industries. My name is Paulo, and it’s a great pleasure for me to host this session today, where we will talk about flexible isolator technology—a containment solution that works in pharmaceutical processing.
The pharmaceutical industry has been challenged over the years with the processing of dangerous substances, such as hormones, steroids, cyclins, or other cytotoxic materials. Nowadays, processing products with OELs in the nanogram range is very common, and the manufacturing of ADCs is one of these examples. Additionally, pharmaceutical plants are being asked to produce more products at the same location and using the same process equipment in shared facilities, which brings a huge challenge in terms of cleaning and cross-contamination.
The speaker today will be Scott Patterson, Vice President of Pharma and Biopharma Technical Support. Scott has been with ILC Dover for over 14 years, leading innovative advancements in the pharma and biopharma industries using single-use containment technology. We also have the pleasure of having David Howes, Product and New Business Development Manager. David has a large background in other industries and will talk about how to mitigate risk in flexible isolators using the unique ArmorFlex® atmospheric control module.
Before we start, I would like to inform you that if you need any help or have questions during the presentation, please type them in the box and click submit. At the end of the presentation, we will try to address all of your questions. So now, welcome Scott, and please talk to us about this technology.
Flexible Isolator Technology
[Scott Patterson] 2:11
Thank you, Paulo, and thank you to all of our guests who are attending today. Just a quick note on connectivity—as we all may be challenged with broadband issues, if we disconnect for any reason, stay tuned; we’ll reconnect quickly. If you lose connection, please log back on.
Today’s program will cover a range of subjects related to flexible isolators and the single-use concept. I will begin with materials of construction and some of the design and manufacturing techniques that are used. We’ll go through a variety of applications in pharmaceutical processing and show real-time solutions that have been installed and proven. David Howes will join us to go through the benefits of the negative pressure control system and how that influences the performance of flexible containment. Then we’ll look at the risk assessment process in actual case studies for performance data, followed by the cost benefits and project management aspects when implementing a flexible isolator project.
Single-Use Concept & Problem Solving in Pharma Processing
So, beginning with flexible isolators and the single-use concept, isolators are used for high containment into the nanogram level. Single-use isolators are meant to eliminate costly cleaning and validation processes. With that, we have to ask: what is the problem in pharma processing that we are solving with this technology? Really, by using flexible isolators, we can apply high containment solutions to any process while making it economically feasible. That’s really the basis of it—looking at both the technical solution and making containment economical.
Just a note on single-use: a question that often comes up is whether single-use means it can only be used one time and then must be disposed of. But single-use isolators are robust and could be used multiple times while still maintaining risk elimination. We’re showing a quick example here of a simple flexible isolator used in an oral contraceptive tablet inspection process. Of course, during tablet inspection, the materials are destroyed and are not products to be sold, so in this case, many campaigns over many months could be processed using the same flexible isolators. Again, the idea of single-use is not about the robustness of the isolator but really about the cleaning requirements—when does an isolator need to be cleaned? Here we’ll see the benefits of disposal versus going through that cleaning and validation process, and that will be an underlying theme for today’s presentation.
When we look at flexible isolators, it’s important to start with a design philosophy that’s applied across the containment technology market overall, and that’s to contain at the source. By containing at the source, we reduce the reliance on personal protective equipment (PPE), which, when we refer to the hierarchy of controls commonly published by regulatory bodies like NIOSH, PPE is considered to be the least effective method. We’re trying to reduce that reliance on PPE and instead use an engineering control, as stated in the hierarchy, to isolate people from the hazard. If we eliminate or reduce contamination, we keep the process room clean, which further benefits us with less cleaning and improved efficiency, as we’re not dealing with cleaning and hold times on equipment in the room. So, we refer to this hierarchy of controls and using a flexible isolator as an engineering control, which is key to the benefits of flexible technology.
Case Study: Application of Flexible Isolators
How do we apply flexible isolators? That’s always a question, so let’s look at a case study. On the left, we’re showing a picture of a roller compactor—this is a capital purchase process where new equipment, the roller compactor, is being prepared ahead of time for the application of a flexible isolator. In this case, a simple mounting flange is provided by the original equipment manufacturer. The picture on the right shows the flexible isolator attached to that mounting flange. Of course, there would be a frame that would further support the isolator to allow the operator to easily move about and so forth. In some cases, flexible isolator technology is prepared with the original equipment, but for the most part, we’re looking at retrofitting existing equipment with containment. The key is to adapt the containment to the equipment without requiring a lot of modifications that would necessitate requalification, which adds to the project’s cost in a retrofit situation
Material Construction & Manufacturing Considerations
Let’s take a look at the material construction and some of the design and manufacturing considerations. At ILC Dover, we provide all of our flexible isolators with ArmorFlex®—this is a trademark of ILC Dover. The key to the material is strength and integrity. A common question about flexible isolators is: will it fail, and how will it fail? When dealing with high-potent products, it cannot fail. The ArmorFlex® was a purpose-built film for pharmaceutical powder processing, developed by blending low-density polyethylene with a higher-strength material, linear low-density polyethylene. This blend was developed by Union Carbide Corporation to meet the need for higher-strength material, which we then applied to our flexible isolator film, ArmorFlex®. This is not a commodity film; it’s purpose-built and developed by ILC Dover for this industry, not available on the open market, and dedicated to the use of ILC Dover for these flexible isolators.
Let’s walk through the design process—there are many different applications in the pharmaceutical market, so looking at each one independently is important. Here, we’re showing a design iteration process for a tablet press, a Courtoy 100 tablet press. It’s key to develop this design based on the customer’s needs. One company may have different requirements for their Courtoy XL than another, so we first determine the area that will be in the containment zone—what are we going to contain? The key now is to minimize areas that do not need to be in the containment zone. As you can see in this design graphic, we’re keeping the technical cabinet below the tablet press out of the containment zone. We need to understand the material flow to integrate transfer systems—how we get material in, like granulated material into the hopper, and how we take tablets off, as seen in the final design to the far right, where we also have a transfer coming out for another tablet inspection process.
Here is the design realization of that iterative Courtoy XL100 design. As you can see, the design process produced an installation that looks very similar to what was developed in the 3D drawings. A key with flexible isolators is understanding that there can be a continuous improvement process. Operators, when getting a chance to work with these isolators, can find areas for improvement. Perhaps there’s a change in the process, and redesigning the consumable part—the flexible isolator part—is simple. The framework used is a skeleton type that doesn’t infringe much on the process, so changes and additions can be made easily and quickly, and most importantly, economically. This is very key as operators begin to interface and find ways to improve the process and suggest how to do that. The design realization can continue for continuous improvement as more input is allowed for the design.
Now, let’s delve into the manufacturing process. With flexible isolators, the idea that it cannot fail extends beyond the film itself to the entire assembly. Flexible isolators are made from piece parts, given the different shapes and sizes, with different gloves positioned around the isolator. All of this starts with automatic cutting, ensuring that the pieces are duplicated time after time for the same part, which is key to ensuring the assembly is always the same. When the flexible isolator is installed, operators can interface with it in the same way every time. Just as the cutting is automatic, so too is the welding, with CNC controls ensuring consistent temperatures and times. This whole concept develops processes that are repeatable and traceable within the quality program, leading to a high level of confidence that the process is duplicated time and again. Lastly, the inflation dwell test is the final study to assure that the film and the integrity of the assembly have been done correctly, ensuring there won’t be any leakage or any ability for the potent compound to escape.
Under the idea that it cannot fail, we use a unique process provided by ILC Dover when using this ArmorFlex® material: lapsing welding. Often, customers new to flexible technology and flexible isolators ask about the potential points of failure, with weld seams being a concern. The lapsing welding technique, as seen in the isolator’s front, where the stripe is less transparent than the rest, involves overlapping one inch of material and welding it. Compared to pinch seam weld technology, which has more risk as it becomes the weakest point of the assembly, lapsing weld is the strongest. This technique provides a product with high integrity, minimizing the possibility of failures.
Applications in Pharmaceutical Processes
Now, let’s look at some applications in pharmaceutical processes realized with flexible isolator technology. We’ll go through a range of examples to give an idea of how the products and isolators can be applied and attached to various processes. For example, we’re looking at weighing and subdividing chemicals—let’s say non-potent materials where flexible isolator technology could have a benefit. We’ll also look at chemical synthesis processes, then back to weighing and subdividing, but this time focusing on the drug substance and excipients. The drug substance is the key here when dealing with 100% of the API, then a few oral solid dosage processes, sampling, and a unique packaging example to show the process from the beginning to the end of the pharmaceutical value chain.
Here we’re looking at two milling operations—one in a pilot plant size and the other in more of a production scale. On the left, you can see an operator working easily through the gloves for a co-milling operation. The operator handles the materials, puts them into the feed hopper of the co-mill, and the material is collected at the discharge and transferred out of the isolator. On the right, a more production-scale operation features two levels of gloves, as materials must be charged higher into the hopper and processed through. The flexible isolator technology is adapted to the process as needed, with minimal frame work, providing easy access to the process for operators and allowing for future revisions, such as adding gloves in different positions.
Micronizing is another popular application, and here we can see a non-contained process on the left, which can be sophisticated when it comes to feeding materials into the feed hopper and then feeding the micronizer. The information and dimensions of the micronizer were used to create a 3D design concept, showing where gloves will be positioned to ensure all components can be reached for processing and cleaning. The final product is contained within a flexible isolator, where an inflation dwell test ensures the assembly meets the criteria for 100% containment. This design allows for high containment during sampling, breakdown, and cleaning processes, and provides high containment during upset situations that may not occur every batch but could be costly when containment is not available.
Next, we’ll look at the weighing and dispensing of a drug substance. Here, we treat the process a little differently because we’re dealing with 100% of the API, so every particle must be contained to prevent exposure to the operator or the environment. This is very typical, and the flexible isolator will often be used in these processes, providing containment levels of less than 50 nanograms per cubic meter. The high clarity of the flexible isolator allows for a precise and accurate process, minimizing waste material. A unique feature of flexible isolator technology is seen in the use of a scissor lift to lift the drum into the isolator, improving ergonomics for the operator.
Flexible isolator technology is used throughout the lifecycle of a process, from research and development to pilot plant processing and full production. Here, we have examples of wet granulation systems that have been highly contained using flexible isolators. Each system is different, but the key is adapting the isolator technology to the equipment with minimal modifications, avoiding requalification and revalidation costs, and allowing the technology to be applied across all processes.
Now we look at an encapsulation process using a flexible isolator. This system was part of a containment performance test that achieved less than 30 nanograms per cubic meter. One interesting feature is the use of an air sweep, which is different from a negative pressure control but still helps with containment. The technical cabinet below the encapsulation area is kept out of the containment zone, isolating it from the product and protecting maintenance workers. The flexible isolator’s skeleton frame allows gloves to be positioned around the encapsulator for ergonomic operation, eliminating the need for additional lighting and offering more flexibility than stainless steel hardware isolators.
We bring up tablet encoding as a quick example, containing the process on both a small tablet press and an O’Hara tablet coater. The key is not only to contain the process but also to manage the transfer of materials from one process to the next. The flexible isolator technology, typically used in ILC Dover systems, allows for high containment and ergonomic transfer using bag-in, bag-out systems, split butterfly valves, or rapid transfer ports.
Here’s a unique design for a packaging line, specifically a bottle filler that applies lids and torques them, with the possibility of adding labels. The risk assessment determined that the exposure risk was low, but there was still some risk, so gloves were added at every operator interaction point. This system can be reused, as it’s dealing with the same product from batch to batch, allowing the isolator to be in place for a long period before removal and disposal. The design considered both technical and economic solutions, resulting in a sophisticated packaging line system.
We also wanted to show a unique application for prototyping a new drug delivery concept. The flexible isolator provided a low-cost way to do all the prototyping, design considerations, and then transition to production. The system was integrated with hardware, including a unique hopper-shaped discharge with vibration to move particles, showing how flexible isolator technology can be adapted and provide a complete design solution.
Benefits of Negative Pressure Control System
[David Howes] 37:39
Thank you, Scott. I want to take some time now to talk briefly about the benefits of negative pressure control for your flexible isolator. The picture on the screen is an example of such a system, consisting of two key components: the flexible isolator and a device that generates and controls the vacuum inside the flexible isolator. In this instance, the picture shows the ILC Dover ArmorFlex® Atmospheric Control Module.
The first and most fundamental benefit is additional risk mitigation. Put simply, if you keep the process operational space, where your hazardous powder is present, at a pressure below that of where the operator is located, any flaw in the containment barrier will result in airflow—and hence hazardous powder—away from the operator. This makes the operation fundamentally safer.
Secondly, a correctly designed system will provide automatic breach response. This means that any breach in the containment barrier will be immediately detected by the atmospheric control module or an equivalent device, initiating a series of response actions, such as ramping up fan speed to maintain vacuum levels within the isolator and issuing alarms to alert operators.
The third benefit is not necessarily so self-evident: enhanced containment performance. Every isolator, be it hard wall or flexible, has weak spots in maintaining the containment barrier. These are any devices or arrangements that pass material through this barrier, such as split butterfly valves, rapid transfer ports, and bag-in, bag-out sleeves. A correctly designed isolator will create unidirectional gas flow within the isolated volume, always away from these weak spots, enhancing containment performance.
The fourth benefit is more of an important consideration for negative pressure operation. Excessive pressure differential across the flexible film barrier can cause the film to become rigid, losing its intrinsic flexibility and resultant ergonomics. ILC Dover recommends, and ensures with their own device—the ArmorFlex® Atmospheric Control Module—a vacuum within the isolator of minus 15 pascals. This is a sufficient differential to deliver risk mitigation benefits while maintaining the ergonomic performance of the flexible isolator.
Key Components & Installation
To fully highlight the benefits of a negative pressure isolator system and how these are achieved and maintained, I’ll take the next few slides to explain the key components’ design and installation. The first key component is the flexible isolator itself. Without being connected to a vacuum-generating device, this isolator can still provide excellent containment performance in a mode we refer to as static.
Adding the next component, such as the ArmorFlex® Atmospheric Control Module, changes this to a dynamic isolator system. We offer a pre-engineered, fully automated system that is truly plug-and-play, allowing operators to focus on the key element of the system: the flexible isolator.
Step one in the installation is connecting the electrical power supply to the atmospheric control module cabinet, where the fan generates the vacuum for the isolator. Next is the connection of a gas supply—this can be compressed air, though nitrogen is frequently used so that the atmosphere inside the isolator can be fully inerted.
There are three connections between the atmospheric control module and the flexible isolator: the gas feed, the differential pressure sensor, and the gas outlet. The gas feed is regulated inside the atmospheric control module cabinet. The differential pressure sensor, also inside the cabinet, connects using plastic tubing with a push-fit connector.
An important design detail is the provision of a HEPA filter at the connection point of the tubing to the isolator. This permits the removal of the tubing at any time without loss of containment. The HEPA filter, in a stainless steel housing, is attached to the isolator and supported by the frame. The location of this gas outlet filter, with respect to the gas feed inlet, is an extremely important design detail, enhancing containment performance through unidirectional gas flow away from transfer devices through the containment barrier.
Finally, the gas is vented from the atmospheric control module cabinet. This is another important detail, and ILC Dover can assist with how vent gas is managed.
This slide schematically portrays the complete flexible isolator system under steady state conditions. There will be a constant flow of gas into the isolator, with the same volume being extracted via the HEPA filter. The gas flow through the isolator will be optimally configured by the design of the isolator itself, focusing on the isolated design as the critical point of any project.
Risk Assessment & Performance Data
[Scott Patterson] 45:44
Thank you, Dave. That was very interesting—the simplicity of the atmospheric control module and the plug-and-play method. We’ll move on to the risk assessment and performance data that apply to both the static isolators and the negative pressure isolators that Dave just presented.
On the right, we see the typical ICH Q9 quality risk management system applied when evaluating what is needed in terms of a containment project. The risk assessment evaluates the risk and selects the containment system needed. This is very important to avoid under-designing or over-designing a system, which risks capital and needed floor space. The risk assessment provides direction on which containment system to purchase. Different product forms and processes will change the level of risk, even with the same hazard or compound. We’ll see that in the case study next. Within the industry, a developing standardized approach is useful in determining the containment system selected for the process.
Case Study: Dispensing & Sieving Process
Let’s run through a quick case study and show data on the performance of flexible isolator systems. The first example is a dispensing and sieving process. Here, the drug substance (100% API) is being sieved. In a typical process, we conduct area sampling and operator breathing zone samples, which are shown at the bottom of the data table. In the final right-hand column, we’ve calculated the geometric mean of three standard test runs using a surrogate test—naproxen sodium. The flexible isolator system provided containment levels of less than seven nanograms per cubic meter. This was a static pressure system, but as Dave presented, the negative pressure system can improve performance and help in upset or breach conditions.
In the second part of the study, we looked at roller compactor containment. Again, we conducted the same type of studies with the material, but now we have an excipient with the API. The roller compactor process is more complicated than dispensing, so our numbers are a little higher, which makes sense. We’re still dealing with the same hazard, but the process has changed. Even with that, the containment levels are still below 20 nanograms per cubic meter in the roller compactor process.
Moving downstream, we look at the encapsulator application with a flexible isolator. Here, the material is very granular, with little dust. Again, even though our hazard is the same as in the roller compactor, the form of that hazard is different, leading to lower exposure levels. The encapsulation process resulted in levels of around 2.25 nanograms per cubic meter, which completely makes sense. In a risk assessment, we must consider not just the hazard but also other components, like the process and mass flow, to determine the right containment system application.
Cost Benefits & Project Management Time
Now, let’s briefly look at the cost benefits and project management time for an isolation process project, comparing a flexible isolator system to a hardwall system. More companies are evaluating containment as a business case with an ROI. The ROSHI tool, developed around 1995 by 15 Fortune 500 companies, looks at safety and environmental costs to lead to a return on investment. This analysis can be applied to containment projects, showing real costs that can be calculated, such as reduced cleaning and validation, less PPE, reduced materials, less maintenance, and eliminated product loss. All of these lead to a lower CAPEX and faster ROI.
Hard Wall vs. Flexible Isolator System
Let’s compare a hard wall isolator system to a flexible wall isolator system. The flexible isolator was deployed to ensure that engineering and validation batches were made on time, while the hard wall system was perceived as permanent for processing drug substances. The cost difference is dramatic—the hard wall system can cost up to $775,000 and take up to 28 weeks to implement, while the flexible isolator system, even with the addition of the negative pressure kit, costs around $125,000 and takes 12 to 14 weeks. This project, completed by a multinational pharmaceutical company, showed that the flexible isolator system met the containment performance target, stayed within budget, and was easily moved by one person from storage to the process area, unlike the bulky and heavy hard wall systems.
Closing Remarks & Q&A
That concludes our presentation today. We thank you very much for attending. This is part of the webinar series or virtual trade show experience that ILC Dover is presenting to our customers. We hope you visit the future webinars that we’ll be hosting, and please, if you have requests or need more information, contact our marketing department. They will be sending everyone a link to this program after the webinar is complete. With that, I’ll throw it back to our host, Paulo.
[Paulo] 57:08
Thanks, Scott. Thanks, David, for explaining this technology. Now it’s time for some questions.
The first one is: How do you perceive the use of single-use technology in pharmaceuticals, and in which part of the process does it bring the biggest benefit?
[Scott Patterson] 57:28
We’ve applied single-use technology, both from single-use isolators to single-use FIBCs, throughout the value chain in pharmaceutical processes, starting with chemical synthesis all the way through. It’s hard to pinpoint where it brings the most value. The value can be analyzed, but we find that in processes that require regular cleaning, especially driven by CMOs running different products or by quality requirements, the benefits are increased.
[Paulo] 58:21
The next question is: How can these solutions be installed in ATEX areas or other parts of the world in rated areas?
[Scott Patterson] 58:28
Particularly with ATEX, the key is using a static dissipative film. Simply inerting the process area is not sufficient to achieve the ATEX rating. The ArmorFlex® material has been tested by a third party to meet the IEC TR 679-32 requirement, qualifying it as a static dissipative material in ATEX areas. Additionally, the Chilworth Incendivity test, a globally recognized test, proves static dissipation, making it safe in explosion-proof or higher-rated areas.
[Paulo] 59:45
The next question is about the complexity of upgrading an existing process. Scott, maybe you can discuss this from a containment process perspective, and David, you can address upgrading an existing static isolator with the ArmorFlex® Atmospheric Control Module.
[Scott Patterson] 59:52
The complexity of implementing a containment solution using flexible containment depends on the process. Some processes, like a co-mill, are relatively straightforward, with minimal changes to the equipment, process area, and SOPs. More sophisticated processes, like fluid bed drying, require more detail and time. The goal of flexible isolator technology is to minimize the impact on the process equipment, avoiding modifications that would require requalification and revalidation, thus eliminating that time and cost from the project.
[David Howes] 1:01:41
Upgrading an existing flexible isolator to a negative pressure system is really easy. The isolator itself will need some adaptation and changes, but once those are made, the complete system can be set up with minimal effort. The atmospheric control module connects to the new isolator, and the system is ready to go. It’s an exceedingly simple upgrade.
[Paulo] 1:02:26
We are running out of time, and we have a couple of questions left to answer, but we will be happy to send you written answers by email shortly.
Today, we’ve seen that flexible isolators are robust and suitable for multiple applications and long-term campaigns. The association of the ArmorFlex®® material with a strong manufacturing and quality control program makes ILC Dover flexible isolators unique in terms of reliability and robustness. Flexible isolators can be used to easily upgrade existing processes, as we were just discussing when producing a new important drug or just to comply with industry guidelines.
I would like to finalize by saying a big thank you for joining us in this webinar. It was a great pleasure for Scott, Dave, and me to share this presentation with all of you. If you have any further questions, comments, or just want to share some of your experiences, please feel free to contact us through your regional sales manager or by using our webpage www.ilcdover.com. Thanks again and have a great day or evening. Goodbye.
