[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.