Webinar: Milling & Micronizing Pharmaceutical Powders in High Containment

Introduction

[Speaker] 0:05 – Today we are formally releasing to the North American marketplace the Atmospheric Control Module, the latest addition to the portfolio of products from ILC Dover that will enhance the performance of any ArmaFlex flexible isolator system. This reconfiguration and enhancement of our previously available jet vent is a plug-and-play module that can automatically manage process parameters and pressure within the flexible isolator.

We have redesigned this product specifically for the North American marketplace, but equivalent models are available for European and Asian regions. You will learn more about the performance of the Atmospheric Control Module during the course of this webinar, and if you have interest in further information, please reach out to your local ILC Dover contact or visit our website at ilcdover.com. Thank you and enjoy the webinar.

[Paul Bento] 1:07 – Hey, 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 and pharmaceutical industries.

My name is Paul Bento, and it’s a big pleasure for me to host today’s session where we will be talking about milling and micronizing pharmaceutical powders in high containment. The manufacturing of products containing micronized powders has been growing, especially for inhalation and injectable deliveries, and with particle sizes ranging generally from two to twenty microns. This creates a huge challenge in terms of containing such smaller particles.

Today we will look closely at dry micronization, which basically can be obtained using mechanical size reduction, for example, using conical or hammer mills, or by using fluid energy impact Jet Mills. Micronization is used from chemical synthesis up to oral solid dosage plants. This process requires a lot of energy and very often creates an overpressure inside the equipment. Adding to that the fact that the industry is increasing the use of potent drugs, the result is a very high risk of exposure for operational people.

During this webinar, we will be talking about how single-use containment technology can be used to easily upgrade existing processes. This technology has become a standard and facilitator in brand new applications, saving costs and time while making easier and faster scale-up processes.

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 and leading innovative advancements to the pharma and biopharma industries using single-use containment technology. We will have the pleasure to have with us David Howes, Product and New Business Development Manager. David has a very large background in powder handling and will talk about how to mitigate the risk using the Atmospheric Pressure Control Module.

Before starting, I would like to inform you that if you may need to ask some questions, please type them in the box and click submit. At the end of the presentation, we will take time to answer all of your questions. Now, welcome Scott. Talk to us about this technology.

[Scott Patterson] 4:01 – Thank you and welcome to the latest installment of the ILC Dover virtual trade show experience. Today, our subject matter is milling and micronizing pharmaceutical powders in high containment. This webinar program will focus on subjects including milling and micronizing systems and the containment challenges for each type.

We’ll do an evaluation of the critical issues that can impact the containment performance. We’ll do a first case study of a high containment combo process where we will use the  DoverPac® high containment FIBC feeding and taking the material away from the Comil process.

We’ll look at the advantages of flexible containment single-use systems for size reduction and milling and micronizing and then a second case study using the Atmospheric Control Module, which creates a negative pressure in an isolator for milling and micronizing applications. And finally, containment performance—what really is achievable when using flexible containment.

[Scott Patterson] 5:04 – Here’s our major issue when we get into containment challenges of size reduction systems. The first one is related to airflow. We have different styles of size reduction systems going from low-energy oscillator-type, conical mill-type, and then getting into more high-energy hammer mill, Fitzmill-type, pin mill, Jet Mills, and micronizers. So really, the difference here is the low-energy mills have a lower volume of air exchange during the process. Then as we get to the Fitzmill, the pin mill, and the micronizers, we have quite a bit of air that we have to handle, and this is a challenge.

Work with the process gas and release the process gas while not contaminating the area or releasing particulates. That also comes with the challenge of the particle size. When we’re looking at the low-energy mills—again, oscillators and conical mill types—we’re dealing with more of a granular material and a larger particle cut. First, in the high-energy mills, we end up with a fine powder that can be airborne and more difficult to contain.

So these are some of the basic challenges that we really look at in the beginning of a containment design for a size reduction system. Containment for size reduction applications is really seen as complex solutions in some cases, and these complex solutions—at least the perception—lead to often the reliance on PPE or ventilation-type controls. The ventilation being local exhaust ventilation or downflow booths.

But as we look at PPE and relate to the regulating body NIOSH in the United States—and there are similar regulating bodies in Europe and Asia—we see PPE is always at the bottom of the hierarchy of controls, meaning this is the least effective and the least acceptable method of control in a pharmaceutical process.

We also look at the top of the hierarchy where we have the elimination or substitution. Well, substitution, we’re really talking about the hazard—replace the hazard—and the drug substance or drug product is the hazard, and so we can’t substitute that, obviously; that’s the process. So, in the middle is the engineering control where we isolate people from the hazard. During this presentation, we’ll talk about that more and more.

The core philosophy is to contain at the source. Let’s not let the pharmaceutical substances get into the atmosphere. Let’s contain them through the milling and micronizing processes so that we can protect the operators and the environment.

Again, more issues around complexity of the containment solutions, and here we’re looking at typical examples of durable containment or hard-wall containment. The complexity starts with trying to install heavy mills through a door. It’s difficult to do—one operator, two operators to do this—and when that happens, the picture on the top right ends up with a permanent installation where the milling equipment has to be built into the isolator.

So this is a fixed system. It takes up valuable floor space, can’t be moved easily, and so forth. So, this is one of the reasons the complexity of doing a milling system in containment is perceived. Retrofitting existing mills, unless they’re a lab size, can be very complex, as you can see in the examples here, and the complexity always considers the operators.

The operators have limited access in some cases and bad ergonomics. And with the complexity is also considering final cleaning and maintenance. This can be complicated in these large isolators that have a lot of surfaces to be cleaned—not only the equipment but obviously the containment device, the isolator itself, has to be cleaned.

More containment considerations. In doing a risk assessment, either for existing size reduction applications or new size reduction applications, here we see the typical flow chart for ICH Q9—the accepted methodology for the pharmaceutical industry in a quality risk management process to evaluate the risk assessment.

First, we start with what is the containment performance target, which we get from the containment system. This is just not the OEL, which is focused on the operator. We look at sampling protocols—always a lot of sampling when we’re dealing with size reduction applications. And usually, it’s just not one sample; there are multiple samples, so the frequency of the sampling.

Does the powder have a low minimum ignition energy, and does that require inerting? That can complicate the process, from the exchange of gas that we talked about in our first slide to having to add nitrogen to ensure a safe environment is created when dealing with these low MIE powders.

We are always thinking in containment: where is the powder coming from? What was the process before, and what’s the process after? So, in this case, where did the powder come from? Where is it going to after milling? We think about the product contact materials, particularly with flexible containment, and we need the regulatory compliance of the product contact materials.

But we also have to think about non-product contact materials for compatibility to solvents and other issues. At the end of the day, it’s all about ergonomics, ergonomics, and ergonomics. We have to build containment systems that are less complex and easy for operators to use. We want those operators to have the minimum amount of change from working without a containment system, so ergonomics is key in the evaluation.

[Scott Patterson] 10:56 – Then we look at the actual product and the powder. How much powder are we going to deal with? In a lab or pilot plant system, we might be dealing with one, two, or three kilos—a small amount of material. Whereas in production runs, we could be dealing with hundreds of kilos. Are there any flow issues, dustiness, and friability of the material? These are key. Powders will flow differently and have different moisture contents. This can change the containment design and need to intervene if there are flow issues, and so forth.

The equipment for size reduction—that was our first slide—are we needing to do something where a low-energy mill can do the job, or do we need more of a high-energy mill for more of a micronized or finer powder? Lastly, it’s always considered to be in a containment system: how do we get the product in and how do we get the product out? This could be delivered in drums, bins, big bags, and so forth, and the same with takeaway. We’ll take a look at these transfers and how that can affect the overall containment but also the cross-contamination potential.

Looking at the aspect of the volume of powder, development in pilot plant-size mills is much easier to contain. Often, these size mills can fit into an isolator or into the containment system because they’re smaller. Typically, they’re manual-fed, so the powder is transferred into the isolator and easily fed into the hopper.

We’ll use the Fitzmill L1A example on the top right or a Jet Mill example on the bottom right. Here, we’re putting the size reduction device inside the isolator. In these smaller processes—again, development and pilot plant sizes—we have less of an issue with air exchange. Really, it’s a zero sum because air coming into the hopper, passing through the milling chamber, whatever that is, is discharged back into the environment. So really, we’re maintaining a constant volume of air, and we’re not having to deal with that real big air exchange that causes a lot of problems during size reduction.

That’s the opposite when we’re dealing with production-size units. Here, we’re looking at more of a production-size Fitzmill—the D6 size or the D12 size—that’s commonly used in pharmaceutical size reduction. We’re showing both the example on the left of containing the feed hopper and scooping powder from a drum into the hopper that goes through the mill. It’s fairly straightforward, but again, we have to be concerned about airflow because, in the Fitzmill or any hammer mill-type process, you’re going to have a fan-type situation created by that rotor.

It wants to suck in air. Here, you can see on the isolator, we’ve added a high-flow HEPA filter to allow air to come in. If we don’t add that air, we can have an impact on the particle size distribution, and we can have overheating of the process. It’s really key to understand that this mill wants to run in a typical process like it didn’t have containment. Now that we’ve let the air in, we have to get the air out.

You can see on the right we’ve done the containment with a continuous liner on the discharge of the Fitzmill. We’ve added a high-volume HEPA filter below the milling chamber to allow that air to escape. There are all kinds of executions we can look to do with this. Really, when we’re dealing with high containment, particularly on the discharge of this high-flow HEPA filter, we really want to consider that the design should be a safe-change filter. So, as we have to remove the filter, the operators in the environment are still protected.

More critical issues that impact containment performance—and again, looking at the complexities. The containment system can be retrofitted to the equipment with minimal or no hardware changes. We see this idea of retrofitting as extremely important because if we have a lot of hardware changes, this could lead to changes in SOPs. It could lead to changes in validation. The cost of revalidation is very expensive. So we’re looking for ways to add flexible containment that’s going to give us the protection that’s needed without really impacting the system.

Here, we implement a floor pan design. The floor pan is essentially a cookie sheet with a raised edge on it. Same with a flange, which we add to the existing equipment easily. Then we attach a five-sided flexible isolator for the installation of containment.

We’ve used both the pan design and the flange design in this Jet Mill micronizer type of operation. A key point we want to highlight, which will be part of the subject in the next couple of slides, is the discharge of the powder. Here in the circle, we’ve shown the powder is being discharged through a continuous liner, also called an endless liner, into a fiber drum. That fiber drum and the continuous liner are external from the containment zone. This is very key to keep the containment package outside of the containment zone so that we don’t have any contamination on it, and we don’t have to go through any cleaning.

This is very key: to think about the discharge being external of the containment zone.

Here’s another example of a Jet Mill installed in a flexible isolator. This one has a cyclone receiver that separates the air from the micronized powder. The picture on the top right shows the components laid out without containment, and now we have the drawing where we laid everything out and put it inside the flexible isolator.

Here, we think about the transfers in and out, which include the product container. As we said in the last slide, we really want to keep that product container out of the containment zone, but sometimes you just can’t. In this type of cyclone receiver process, you often end up having the product receiver inside, so you have to go through a cleaning process to remove it from the isolator.

Again, different designs for different applications are part of the evaluation that needs to be done. Also, here we’re containing the process of feeding the hopper. In this process, powder from drums was hand-fed into the hopper of the micronizer, so that’s open to the atmosphere. We want to contain that.

A big part of Jet Milling and micronizing is the process gas. A high volume of process gas comes in through hard piping, and we have to ensure the containment system can allow the hard piping to come in and exit so we can have the gas in and out in a contained way.

We always plan on the sampling protocol. Typically, in micronized powder—just like all size reduction—there’s a sampling regime. So we consider how we’re going to take samples and keep everything contained within the isolator, always thinking about protecting the operator and the environment through the entire process.

We work on a protocol of how to do the cleaning and remove that flexible isolator while still maintaining the containment performance target.

Here we have the opposite, where a powder party has gone on inside the micronizing suite. A typical Jet Mill. I think probably a lot of us have seen rooms like this that are completely covered with powder. There’s a high reliance on personal protective equipment, and this really isn’t a good scenario at all.

Think about the cost of the lost product. How many safety issues can we count here—from operator exposure to slip hazards on the floor because of all the powder? How long does it take to clean this? What materials are needed to clean, including a high volume of contaminated water? How many days will the suite be unusable while cleaning and validation are done? It ends up being very costly to continue using a non-contained application here.

Thinking that it’s too complex to contain? Well, we break that down in the next slide here to show that you really have to take a modular approach to this and think about containing each portion, which has a little bit of a different dynamic.

Here, it’s the same type of process with a baghouse filter separating the air from the powder in this micronizer. In position one, we have a passive flexible isolator to contain the mill. In position two, we have an inlet to get the powder in. In this case, we would attach it to a DoverPac®. In position three, we’re simply containing the baghouse filter with an isolator, but that isolator is filling with the process gas coming through the filter.

In position four, we’ve got the connection that will go to a dust collector—a Donaldson-Torit type of dust collector or Camfil Farr—but it’s exhausting the gas away so that we’re not building a positive pressure in the isolator that’s containing the baghouse filter. In position five, we’re taking the powder away. So we’ve got the final product here, and we can take it away in an endless or continuous liner. That could be a DoverPac®, a split butterfly valve, or a powder bag.

Remember here, we have the opportunity that the packaging material is all external to the containment zone, so we don’t have any risk of exposure, contamination, and so forth from that package being inside the containment zone.

[Scott Patterson] 21:07 – Our first case study is with a Comil and using the DoverPac® technology. We referenced the DoverPac® technology a couple of times in the presentation. Here you see the DoverPac® feeding the Comil on top and receiving it from the bottom. This happens to be a U20 underdrive Comil. Again, the underdrive Comil is very simple to do a containment like this, and it’s simple because it’s set up with tri-clamp connections on top and bottom.

We set up our O-ring canister system, which is the connection hardware for the DoverPac®s. It’s a system with the O-ring canister, simple clamps, and a seal-separate system, the crimp-lock. You’ll see that it’s easy to maintain containment, and we can do up to ten DoverPac® connections while maintaining that high containment without any cleaning or any other activities that would have to go on in the line.

So just a little bit about the DoverPac® in containment as part of this case study and some of the benefits of this. High containment is absolutely proven to be 250 nanograms or less per cubic meter, and we have had applications where there needed to be a higher level of containment. For those, we have a COAX model of the DoverPac® that can go to less than 30 nanograms per cubic meter.

It comes in a full range of sizes, and we always connect with standard tri-clamps. It’s a simple lift system to position the DoverPac®. We don’t need anything complicated to lift, position, and dock. The flexible wall of the DoverPac® and any FIBC is very important when we’re dealing with poor-flowing powders that may have a tendency to bridge.

The DoverPac® is built with  ArmorFlex® film, which is very solvent-resistant and also anti-static. This is key in some of the processes. This anti-static film will comply with ATEX for the European requirements and is also rated for some of the models as a Type C FIBC. A great feature of the DoverPac® is its inline sampling sleeve, so sampling protocols are built right in. It’s easy to dispose of after use without exposure to the operators or the environment.

On with our case study. This was actually the summary table for the DoverPac® and the containment system on the Comil. We followed the SMEPAC protocol from ISPE and used the single-point transfer system methodology. A lactose standard was used as a surrogate for each iteration. You can see we did three iterations and used at least 25 kilograms of lactose each time. The test was done docking a DoverPac® on top and filling into another DoverPac® on the bottom.

A key point to understand here is that the lactose used was not loaded with excipients. This test was really a test of a drug substance containment with 100% drug loading. When we look at the results, we see very nice results. The operator breathing zones (OBZs) were monitored first, and we also had area samplers.

In the OBZs, the assistant operator, looking at the geometric mean analysis on the far right, was about 240 nanograms per cubic meter. That’s pretty good containment. But as we look at this, again, this is 100% drug loading, which is really not the case in most oral solid dosage processes using milling and micronizing. Often, drug loading could be as low as 10%. In that case, the results of this test would have been closer to 24 nanograms per cubic meter.

Now, through this, as we created the test plan for the Comil, we also thought about an upset condition that might require us to open up the milling chamber and access the screen and/or the impeller. The picture on the right is actually a flexible isolator integrated into the containment system. So in the middle of a process, if we had to access the milling chamber, we could do that in a highly contained way.

We’ve also done this with other types of mills. For example, we’re seeing a schematic here of the Frewitt MFH mill. This has a milling chamber that’s a unibody with a door on the front to access the rotor and the screen. We simply use a portable isolator that we roll up, dock, and access in a highly contained way.

Back to the Comil case study: you can see the data set again here, somewhat similar to the DoverPac® process data set from the last slide. We see the assistant operator was at about 350 nanograms per cubic meter. Again, remembering that this was 100% drug loading. If it were 10% drug loading, the actual containment would have been closer to 35 nanograms per cubic meter.

Looking at the advantages of flexible containment, we specifically focus on the market segment of multi-product facilities or contract manufacturing organizations. What are the benefits? First, low CAPEX for retrofits and new installations—a big financial benefit. Single-use consumables are purchased only when needed for campaigns, which aligns perfectly with CMOs that run campaigns a few times a year.

Proven high containment. The Comil case study we just presented is backed up by dozens of additional SMEPAC studies. We know we have high-containment solutions for a range of milling processes. Flexible containment systems also reduce cleaning time for faster campaign turnovers, which lowers the risk of cross-contamination.

Cross-contamination risk is especially reduced because flexible containment is disposable. Retention on surfaces between batches is the number one reason for cross-contamination after mix-ups. By eliminating the need to clean these surfaces, we eliminate that risk entirely.

Financially, there are clear benefits. Comparing durable and flexible isolators shows flexible systems have significantly lower CAPEX, operational costs, and maintenance requirements. For instance, a durable system may cost $775,000, while a flexible system, including consumables, may only cost $55,000. This is a significant cost-saving over time.

To take this further, let’s look at an example where a flexible system with a Comil and DoverPac® is used. This setup requires a simple lifting hoist system to dock the DoverPac®. Now, compare this to using a stainless steel bin in high containment. That would require a split butterfly valve, a precision lift and docking system, and potentially a CIP or washing system for the bins after use.

These additional requirements for stainless steel bins can add another half a million dollars in CAPEX and take up more fixed floor space. This highlights the financial and operational advantages of flexible containment systems.

Now I’m going to pass this on to Dave Howes as he takes us through the next section, starting with a case study.

[David Howes] 30:36 – Thank you, Scott. I am now going to present a couple more case studies for containment of milling operations. In these instances, the new Atmospheric Control Module (ACM) plays a key role—not just in providing additional containment risk mitigation but also in resolving particular operational issues associated with these specific mills and their applications.

Let me give a quick overview of the Atmospheric Control Module. The ACM, being formally launched today in a reconfigured, upgraded form, enhances the performance of any ILC Dover containment solution. A range of standard models is available, all of which provide plug-and-play operation for additional containment risk mitigation by maintaining the containment space under vacuum.

In addition, it delivers process parameter control, such as oxygen and relative humidity monitoring and management.

[David Howes] 31:59 – The basic function of the ACM is achieved by providing a regulated gas feed into the containment space and extracting this gas using a variable-speed fan. The extraction rate is controlled to reach and maintain a setpoint vacuum level.

ILC Dover strongly recommends a vacuum level of -15 Pascals. This allows retention of the ergonomics associated with soft goods used in forming the containment barrier. Control is provided by an onboard PLC, with an HMI interface for operator oversight and functional management.

[David Howes] 32:53 – This simple schematic captures the basic operation of the ACM. Note the three connections between the ACM and the containment space: gas feed, gas extraction, and differential pressure sensor. The setpoint vacuum mentioned earlier is actually a negative differential pressure compared to the ambient pressure of the isolator location. Detailed information and specifications are available on our website.

[David Howes] 33:36 – Our first ACM-empowered case study involves a Jet Mill. This is a widely used mill type available from multiple manufacturers, but it presents particular challenges for containment. This cutaway schematic offers a good summary of the design and operational principles of the Jet Mill. The airflow through this mill type is critical to its performance.

The schematic shows the air inlet points, the powder inlet (or feed point), and the powder outlet (or discharge point). It is the containment of both the powder feed and discharge points that must be designed for in any isolator system. These points present differing challenges that the ACM can help overcome.

This 3D model illustrates an ILC Dover flexible isolator solution for a Jet Mill. It has two distinct sections adapted to fit the specific mill design, containing the powder feed and discharge points, as highlighted here.

However, powder containment is not the only challenge with this application. The flexible isolator solution shown would not work without the ACM—or alternatively, some clumsy, labor-intensive manual management of the pressure regimes created by this type of mill.

The airflow through the Jet Mill creates a vacuum at the powder inlet point, which can suck down or deflate the flexible isolator. At the powder discharge point, the exiting gas pressure inflates the flexible isolator. Gas management is required at both points to avoid failure of the flexible isolator and subsequent loss of containment.

The ACM performs two functions in this instance. First, it maintains the isolator under vacuum, providing additional risk mitigation with respect to containment. Second, it manages gas flow automatically, freeing the operator to concentrate on the process rather than on managing the isolator.

At the feed point, the regulated gas feed from the ACM to the isolator is increased to balance the vacuum generated by the mill operation. The flow is set to manage the maximum vacuum generation condition. The extraction fan speed is then automatically controlled to maintain the setpoint vacuum level within the isolator.

At the discharge point, the extraction fan speed automatically increases to handle the additional gas generated by the mill operation. This ensures the setpoint vacuum level is maintained within the isolator, preventing over-pressurization or loss of containment.

[David Howes] 37:26 – Our second case study involves a pack-off system. Pack-off refers to any system where powder is discharged from a dryer and charged directly into packaging, such as drums. In this case, the powder requires in-line milling before being packed, and the drums must be filled to a precise weight—typically within one percent accuracy—all while maintaining high containment.

ILC Dover offers a unique solution for this application, one that integrates the ACM to resolve challenges like gas flow variability and weight measurement accuracy. Variations in system pressure can directly impact scale readings, so maintaining consistent pressure is critical.

The ACM automates gas flow management, ensuring the pressure remains constant, which eliminates weighing errors and maintains high containment. This approach provides a total but simple solution for complex pack-off operations.

[David Howes] 38:20 – This simple schematic captures the system for our example: dryer feeding mill, feeding drum. I’m sure many of you listening to this webinar have seen a system like this in some form. Highlighted is the containment challenge: both the mill inlet and outlet, and the charging of powder into multiple containers. The “multiple” aspect often makes it harder, although not for ILC Dover.

The second challenge is accurate weight measurement. This is particularly difficult because of the need for a closed system to maintain containment while also dealing with a varying amount of gas, typically from the dryer’s nitrogen inerting system. A varying gas volume in a set space means variations in pressure, which directly impacts the scale reading.

The previous simplified schematic looks like this when translated into a formal P&ID. There’s a lot of detail here to absorb, but on the next slide, we’ll highlight the key points of interest.

Key components include the rotary valve, fundamentally critical to the dosing system, and the mill—in this case, a cone mill installed in-line but designed to be accessed for routine maintenance activities. Another key element is the weight scale at the bottom, which is crucial for achieving accurate dosing into the packaging that receives the powder.

[David Howes] 40:02 – This is how the P&ID converts into a physical layout, as shown in this 3D model. The ACM delivers automated control of two critical aspects of this mill containment system: it keeps the containment space under vacuum, providing additional risk mitigation, and it manages gas flow entering and leaving the system to maintain a constant pressure. This ensures that weighing errors caused by pressure variations are eliminated.

In summary, this approach delivers a total but simple solution. Of course, there are a host of additional details associated with both case studies that could not be addressed in this short time. If you’ve heard anything today that you see as a challenge in your existing or planned operations, please reach out to your local ILC Dover representative or visit our website at ilcdover.com.

[Paul Bento Bento] 41:16 – Thank you, David, and now back over to Scott.

[Scott Patterson] 41:21 – Thank you, David. So, we’re going to finish up by looking at what is achievable in containment performance using these solutions we’ve shown today. The first thing to consider is containment banding. Typical operator exposure banding charts are used as a starting point. Here, for our purposes, we’re presenting the Safebridge Consulting four-level banding chart.

This chart is appropriate as we move into HPAPIs because it covers all the requirements we’re discussing today. Banding charts provide a starting place to classify containment solutions based on OELs. For example, we establish the OEL through toxicological analysis, evaluating the hazard—the drug product or drug substance itself—and then the containment performance target.

Once the risks are understood through methodologies like ICH Q9, we apply containment performance targets and acceptable pass/fail standards. For example, some companies might apply a 50% pass/fail standard, meaning if the target is 100 nanograms per cubic meter, the pass/fail threshold would be less than 50 nanograms per cubic meter. Alternatively, stricter standards like the EN 689:2018 might require a pass/fail threshold at 10% of the containment target.

As shown in our data, adding the ACM to a flexible isolator design improves performance, particularly in negative pressure systems. Flexible systems with the ACM can achieve containment performance comparable to or better than durable systems while providing additional risk mitigation during breaches.

It’s essential to conduct a containment assessment when implementing any system to verify performance. Operator training is also critical. Data shows that operators with significant training achieve better containment results, while poorly trained operators often experience issues with exposure. GMP guidelines for HPAPI handling explicitly require this level of training.

[Scott Patterson] 46:57 – In summary, we’ve evaluated that containment for size reduction applications can be complex, but there should never be a reliance on PPE. Engineering controls are essential. There are a multitude of mills and size reduction systems, so the right containment system must be selected for the specific process. Flexible containment systems provide a range of technical and financial advantages to the process.

In David’s presentation, we learned about the Atmospheric Control Module, which improves containment performance and provides critical risk mitigation in the event of a breach. Lastly, flexible containment systems can be applied to milling and micronizing processes to achieve the same performance as durable systems, but data must always confirm performance. Data is the foundation of everything we do. Thank you very much for your participation. We’ll now address any questions you may have.

[Paul Bento] 48:02 – Many thanks, Scott and David, for the presentation. We now have time for some questions. The first question is, “Do you have proven containment for Jet Milling?”

[Scott Patterson] 48:18 – Yes, we do. Several containment assessments have been conducted for Jet Milling processes, and the data shows containment levels consistently in the nanogram range. We have data for both lab-scale and production-scale processes. Jet Milling can be effectively contained throughout the process, typically achieving levels below 100 nanograms per cubic meter.

[Paul Bento] 49:12 – Thank you. The second question is, “How can we sample the process if we need to collect a sample?”

[Scott Patterson] 49:19 – Sampling is an integral part of milling and micronizing processes, especially for verifying particle size distribution. If adjustments to the process are needed—such as changes to rotor speed or feed rate—sampling provides that feedback. The sampling method depends on the type of size reduction equipment. For example, in a micronizer, sampling is typically conducted at the discharge point, where a continuous liner or a small sampling bag can be used.

Sometimes the process may need to be paused for sampling, which is not ideal, as you want continuous operation once the system has reached a steady state. Manual and automated sampling methods exist, but the key is designing the system to ensure that containment is maintained during the sampling process. For example, a small sample of a couple of hundred grams can be collected from the discharge using a contained setup.

[Paul Bento] 51:28 – Thank you. The next question is, “Can flexible containment be installed in ATEX-rated areas?”

[Scott Patterson] 51:34 – Yes, flexible containment can be installed in ATEX-rated areas. It’s essential to ensure compliance with the zone’s requirements. For example, ILC Dover’s ArmorFlex® film is an anti-static material that meets ATEX standards. Additionally, regulations may require limiting the amount of non-antistatic material in the zone, typically to 100 square centimeters or less. A proper risk assessment helps ensure compliance.

In some cases, introducing nitrogen to create an inert atmosphere may also be necessary. David, would you like to elaborate on the ACM in ATEX zones?

[David Howes] 52:58 – Certainly. While the ACM itself isn’t electrically rated for ATEX zones, it can be installed up to 100 feet or 30 meters away from the isolator. We provide an upgraded electrical panel that meets ATEX requirements and can be mounted near the isolator. The ACM also includes atmospheric monitoring, such as oxygen level monitoring, which enables both measurement and control to ensure compliance with ATEX regulations.

[Paul Bento] 53:48 – Thank you. The next question is, “How do you handle overpressure or blowback issues in Jet Mills, and are there visibility concerns inside the isolator?”

[David Howes] 53:57 – The Atmospheric Control Module continuously monitors and controls differential pressure between the isolator and the ambient environment. If overpressure or blowback occurs, the ACM automatically adjusts the extraction fan speed to maintain the set vacuum level. This prevents isolator failure and ensures containment. For visibility, proper airflow management and cleaning protocols are part of the design to keep the workspace clear for operators.

[Paul Bento] 55:15 – Thank you. Does the containment data include monitoring of the entire process, including disconnecting the isolator from the ACM after milling is complete?

[Scott Patterson] 55:22 – Yes, the containment data covers the entire process, including cleaning and isolator removal. In recent years, ILC Dover has also included monitoring inside the isolator at critical points, such as transfer areas, to assess particulate levels and movement. For processes with airborne particulates, we may recommend negative pressure systems like the ACM to create unidirectional airflow, directing particulates away from transfer points into extract filters.

[Paul Bento] 57:24 – We are running out of time, but we still have several unanswered questions. We will be glad to provide written responses via email or contact you directly to address them. Thank you for all your thoughtful questions.

[Paul Bento] 57:44 – Today, we’ve seen that containment processes involve much more than simply placing an enclosure around a mill. Challenges such as charging and offloading powders, sampling, disassembling equipment for maintenance, or dealing with overpressure during milling require robust and reliable solutions. Flexible containment can easily retrofit and adapt to existing equipment or integrate with new manufacturing processes. This enhances production capabilities, especially for potent drugs.

This technology reduces utilities, minimizes cross-contamination risks, and directly protects patients. It simplifies compliance with regulations, particularly those addressing the hierarchy of controls, where PPE as a primary barrier is not permissible by law. Instead, containment at the source is the most effective approach.

The new generation of flexible dynamic isolators, equipped with the ACM, provides easy control of internal environments, including parameters like pressure, relative humidity, and inerting. This mitigates risks during events like glove failures or seal leaks at transfer ports.

Containing complex processes requires robust and reliable solutions that ensure operators return home safely—a goal that remains central to all we do. Many thanks to everyone for joining this webinar. It has been a pleasure for Stephanie, Scott, David, and me to share this information with you. Thank you and have a great day.

Goodbye.