Webinar: Risk Assessment and Selection of Single-Use Isolator Designs

Transcript

Introduction

[Scott Patterson] 0:00
Welcome to all of our attendees, and we appreciate you taking the time to join us for another installment of the ILC Dover webinar series. I am Scott Patterson, Vice President, Pharm Biotechnical Support, and I’m excited to have collaborated with Martyn Ryder, Business and Product Development Manager for SOLO Containment, an ILC Dover company. Martyn has a lifetime of experience in pharmaceutical isolation technology and is driving innovation for containment solutions in small molecule production.

Today’s discussion will focus on tools for risk assessment and selection of single-use isolator designs. This is a bit interactive; if you have any questions during the webinar, please use the chat function to send us your questions. We’ll follow up with you at some point very soon after the webinar to address any of those questions completely.

Global Supply Chain

[Scott Patterson] 1:04
Before we dive into the technical presentation, we would like to introduce you to the global supply chain capability of the ILC Dover engineering and manufacturing network. As you can see, we have multiple locations for the manufacturing of these single-use high containment solutions. The headquarters, located in the United States in Delaware, is followed by state-of-the-art manufacturing in Blarney, Ireland, with our engineering excellence center in Switzerland, and now with SOLO Containment as part of the ILC Dover company, our operation in Stockport, UK, near Manchester.

So, with that, I’ll turn it over to Martyn for the launch of the technical presentation.

[Martyn Ryder] 1:50
Thank you, Scott. Well, it’s a great privilege to be talking to you all today. Now, we’re going to discuss risk assessment, and you’re probably thinking, “What does ILC Dover have to do with risk assessment?” Well, I want to make one thing very clear: we’re not trying to be experts in the EHS arena; we’re not trying to be experts in toxicology. First and foremost, we’re a containment business. We manufacture isolators to make the workplace safe.

In this webinar, we’re looking at a multi-tool system that gives us guidance to get the right isolator design to maximize operator safety. We’ve developed with ILC Dover a thing we’re calling Process Score, and it’s used to evaluate the hazard and risk factors generated by a specific powder processing operation. The Process Score is then used as a guide for choosing the right kind of isolator that will give us the containment performance we need.

Containment Performance

[Martyn Ryder] 2:52
As pharmaceutical materials become ever more potent, and the sampling performance criteria become tougher, for example, if we’ve got an occupational operator exposure limit of one microgram per meter cubed and we’re testing the isolator performance against EN 689 2018 version, our pass-fail rate is only 10% of the required operator exposure limit. So, we’ve got to get things pretty right to deliver a safe containment system that works day in, day out, and continues to meet our clients’ requirements.

Critical Information

[Martyn Ryder] 3:34
So, how do we select the right containment system? There are a wide range of factors that need to be considered—of course, powder dustiness, mass of powder, and also the energy imparted. But we look to our client to provide us the critical information. Safety is a key driver, so we would look to our client to provide things like the operator exposure level or the containment performance target. We’d ask, “Do we have any MSDS data? Do we have any knowledge of the required exposure limit for these materials? Are there any sensitizers or materials with other phrase warnings? And, of course, is there any toxicology data?” I’ve come across applications in the past where, although the airborne exposure limit was a fairly easy target to retain, maybe 50 micrograms per meter cubed, the product was an acute skin sensitizer. So, here we have to slant the design of the system to take account of safe removal of the flexible film isolator at the end of the campaign.

Overall, we need some information to put together a profile of each application. The risk assessment information—without that, we’re not going to be able to steer the technology to the right level to make sure we get a safe working environment.

Visualization Systems

[Martyn Ryder] 5:18
Now, I’m sure you guys have seen many of these what I call visualization systems. Some are very good; some are very effective. Back in 1997—it seemed like a long time ago—we developed this containment performance pyramid with Extract Technology, and this looked at the hazard brought by the potency of the material, if you will, and the exposure potential, the risk factor of handling that hazardous material. And back in ’97, we were looking to set up what we called a containment strategy, because we recognized that not only do we need effective containment, but the strategy has to take account of operator training, development of SOPs. Without even the best isolator system in the world, if the operators are not working with us, we may not get reliable containment performance day in and day out.

Containment Strategy

[Martyn Ryder] 6:14
One of the key factors we need to evaluate is the material hazard presented by the range of materials—both respiratory and dermal—confirmation of all the operator exposure limits, and not base it on OEBs. OEBs can be confusing because different companies have different band levels for the same product. I’ve seen one product that’s an OEB3 for one customer or OEB5 for another customer, so we like to work with a really effective OEL or a containment performance target, which gives us micrograms per meter cubed, task-specific, or nanograms per meter cubed, again, task-specific.

We want to look at the quantification of the materials being handled, the mass transfer, and the potential for that material to become airborne. Key to all of this is careful observation of the task we’re going to contain, from beginning to end. So, the operations putting powder through a core mill or a milling machine—let’s look at how the material comes in, how the operator gets the material into the product, how he cleans down the mill at the end of the time, how the product comes out. Cradle-to-grave observation is really effective in looking at all the containment issues that we have to address.

We may have to, of course, identify process requirements like inert gas or humidity control. We may, well, certainly will look at the facility if it’s a very important material—look at the facility and its ability to provide containment backup should things go wrong. And, of course, if the isolator starts to malfunction, how do we recover from upset conditions? So these are all important factors we need to look into.

Process Score

[Martyn Ryder] 8:04
Now, with our friends at ILC Dover, we’ve been developing this idea of a Process Score, and there are four factors involved in a Process Score. First of all, the containment performance target. And on our little matrix here, we can drop down from 10 micrograms down to 0.01 micrograms. We can select a dustiness from high, medium, or low dustiness, and we can select the quantity of material being handled—small, medium, large. And then, at the bottom factor, the process. We vary from very stable, very gentle operations, such as sampling, to bulk powder transfer into a reactor or a charge port, where hundreds of kilos would be tipped into the system, into the process system.

Now, the Process Score we’re using drives out a number that ranges from about 30 to 70. You say, “What do these numbers mean?” Well, they are only a guide. The idea of putting the four key factors together to spit out a Process Score number is helping us position the flexible film isolator so it does its job effectively. We’re going to look at that in a few minutes, but we always say to our customer: The Process Score system—we’ve taken the pyramid-type approach, we’ve moved it on a little bit further—but this system is only as a guide, and it’s a guide for our engineering people, so we can look at the critical factors involved in a given operation. And they all differ in density of material, dustiness of material, and, of course, the containment performance target. But this Process Score gives us a fairly effective guide to the safety levels that we’re going to build into the isolator.

Now, we always say the final decision on what we go for is put before the client and their EHS and toxicology team. So, typically with an ILC Dover project, we’d run through this. We would come up with a concept design, we’d talk through it with the client, discuss the performance criteria, what we’re confident we can attain day in and day out, and we’d move on from there pretty much as a collaborative approach. But the beauty of the Process Score is that it gives us a very effective start point.

To summarize, if you will, the beginning to end of how the Process Score assists a containment project—as we said, we’re not toxicologists and we’re not EHS specialists at ILC Dover, so we’re looking at the client to provide the OEL or the containment performance target data, also any toxicology data. The client will be telling us product mass, container sizes, how dusty the product is, and the energy applied to that product as it’s being processed in a specific application. Then, at that point, ILC Dover folks will run the Process Score, and that will give us this key number. We’ll back that up with a process observation and a very detailed operation survey. Again, we’ll want to look from cradle to grave, see if anything “goofy” goes on at the end of the shift. We’ve all seen it—you know, a guy’s putting bags of powder into a product chute, and at the end of the day, he’s wrapping up 20 empty bags, and he might jump on them to flatten them down, creating an enormous dust cloud. Sounds crazy—it isn’t.

So, with the Process Score and the observations and surveys, ILC Dover can then provide the concept of a containment design that we are confident will meet the customer’s containment requirements. We can address the cleaning validation needs, and we can address what we call full life cycle safety. Now, we’re not done there because, as we’re bringing that forward to be installed in the plant, we need to start thinking about operator training and developing SOPs. A great time to check all the standard operator procedures is during the factory acceptance test that ILC Dover will provide for you. If we get all these steps in our evaluation chain right, there’s a strong chance that, at the end of this, we’ll come up with a super-safe containment solution, a solution that will be safe on a bad day if things start to go slightly wrong, etc.

Full Life Cycle Safety

[Martyn Ryder] 8:04
So, how do the folks at ILC Dover ensure full life cycle safety? Very good question. Our stance at ILC Dover has been full life cycle safety. We’ve got to make sure that the containment isolator we provide is safe when it’s in normal use, we’ve got to make sure it’s safe if we get upset conditions, and we’ve got to make sure it’s safe during disposal. One of the key things that we recognize as containment people is, if there’s nothing much going in and out of an isolator, it works extremely well. Scott suggested to me to look at the example of a tiger in a cage. It’s a bit weird, but a tiger in a cage is great containment because nothing needs to go in or go out unless, of course, it’s food.

Typical flexible film isolators that we’ve all seen range from simple ambient pressure glove bags at one end of the spectrum to some really complex hospital pharmacy and compounding isolators at the other end of the spectrum. And obviously, we would not rely on a simple ambient pressure glove bag with no contained entry-exit method to handle cytotoxic materials. This is where ILC Dover’s policy of full life cycle safety comes in. We are putting in the right level of technology to make sure that the isolator is safe, and if we get upset conditions or the operator is careful not to follow exactly the SOPs, we’ve still got a good level of safety.

Flexibility

[Martyn Ryder] 14:33
Now, as with hard shell isolators, flexible—sorry about that—flexible film isolators can be used with negative pressure airflow cascades, multi-layer hyperfiltration, all of which lead to safer operation. However, unlike hard shell isolators, a flexible film isolator will need to be replaced at frequent intervals when the campaign changes, or maybe when the product changes, or the isolator itself becomes damaged. So, following our full life cycle safety philosophy, we need to make sure that all of these cradle-to-grave operations are easily contained with the design we’re putting forward.

With a single-use isolator that we’re going to look at further down the line, we reduce or eliminate cleaning validation, and we save time and, of course, money with the reduced cleaning times. There’s also a reduced risk of cross-contamination as well as adherence to the new HPEL requirements. We eliminate failure points of the hardware systems. So, if a hardware isolator has been in operation for a few years, it could be that they’re starting to fatigue. But one of the things with a flexible isolator is that it’s new every time. As soon as you put that flexible enclosure on the frame and test it, it’s as good as new. Also, any operator ergonomic issues that may lead to poor practices or operator injury with a hard shell, we can very easily adjust these out with a flexible film isolator. And of course, the ability to repurpose a flexible film isolator further down the line to accommodate process changes. So, we believe, as you would imagine, that there are many big advantages both financially and ergonomically and safety level-wise with flexible film isolated technology.

So, tools to beat low exposure limits explained. We’ve talked about this Process Score, and forgive me for not sharing the matrix with you, but basically, if we look at any application, it can kick out a Process Score from as low as 30 to 60 plus. And as the Process Score increases, moving from left to right in the screen you see here, we have to add more technology to the isolator to make sure that, in a bad day condition, in fault conditions, we maintain absolute safety. Also, as you’ll see with the orange arrow, as the score increases, we really need to take more care on making sure the operator training and SOP development is flawless.

One of the things that we will discuss a little bit further on is the fact that the stainless steel base panel is a common feature of many flexible film isolators. There is a point where we have to move away from that because it’s difficult to decontaminate. So, we’ll go from a stainless-based plant that needs cleaning validation to maybe a 100% disposable design once the materials get super potent.

So, let’s suppose we’ve got a really low Process Score; let’s say it’s 30. We could put on a very simple flexible film isolator suspended by bungee cords with a breather filter, and it will do the job. ILC Dover has years of history testing isolators like this; lots of test data. And when everything is working perfectly well with a bungee-supported flexible isolated ambient pressure, we’ll get a great result—no question about that. These are safe isolators.

But what can go wrong? Well, supposing we’ve got airborne dust particles inside that isolator, and somebody takes a fall, pushing it down by compressing the volume of the flexible film chamber inwards. We could get a positive pressure spike; we could force air and possibly particulate out of the continuous line. And for some damage to gloves or damage to the enclosure, it could mean that that particulate starts to escape. Also, with this style of isolator on a stainless base pan, we’ve got to put SOPs in place to make sure that the stainless steel base pan is correctly decontaminated before the flexible enclosure has been taken off.

Just to reiterate this, a lot of these things have been working well for years. Nobody’s saying they are risky; we’re just saying that this design isolator is perfect for the low levels of Process Score.

Negative Pressure

[Martyn Ryder] 19:42
So, what’s the next level up? Well, if we take that isolator and we fasten it back to the frame so the enclosure is super tight, we can now run it at negative pressure. Now, while running the isolator at negative pressure, of course, and we’ve tightened it back to the frame very securely, the effect of pushing on the film is not going to create any outbursts of the particles or pressure shockwards because we’re running it at negative anyway. If we get any holes in the gloves or sleeves or, let’s say, enclosure damage, we’re going to be pulling room air into that flexible enclosure rather than seeing any particulate migrate out of the enclosure into the workroom. So, that’s quite a good safety factor.

Of course, it’s worth remembering that almost all containment isolators with a hard shell operate at significant negative pressures. It’s seen as a big safety enhancement, and at SOLO Containment, on our side of the business, we’ve always seen negative pressure as a sound point for increasing operator safety.

Again, with this design, we’ve got a continuous liner, maybe for in-out like a BIBO, we’ve got a stainless steel base pan at the bottom, and as the product potency increases a little bit, we’re going to need SOPs to decontaminate the isolator before we take it off the base part. So, with negative pressure, we’re lifting the Process Score ability from below 30 to, say, between 30 and 40—a big step forward.

Low Pressure Alarm

[Martyn Ryder] 21:23
Now, how about we fix a low-pressure alarm onto the isolator? So, it’s the same negative pressure design, but we’ve got a low-pressure alarm. So, if the operator doesn’t realize that a glove’s fallen off, if he didn’t realize there was some damage to the enclosure or perhaps it’s lifted from the base pan, as soon as the alarm detects a loss in the negative pressure in the isolator, an audible visual alarm goes off. The operator knows to stop handling APIs. The negative pressure fan will normally ramp up to try and compensate for the loss of control pressure, and by just simply adding an alarm according to our Process Score applications, it’s moving us a little bit further along the line to being suitable for high potency products.

When we get to high potency products, of course, we’re using H14 HEPA filters to control the inlet air and create that pressure drop from the room into the flexible isolator. We’re using an H14 HEPA filter on the isolator boundary to filter any particulate. But as the Process Score is driven higher by more potent materials, it’s a good and very easy and cost-effective fix to put a two-stage or a dual-stage H14 HEPA at the exhaust point. So, if the first HEPA fails for whatever reason, we’ve got a backup HEPA to make sure no product enters into the fan.

So here, we’ve got negative pressure, we’ve got the low-pressure alarm, and we’ve got dual-stage hyperfiltration. So, this is giving us more control, more safety if conditions go against us—if we get truly upset working conditions.

Pressure Decay

[Martyn Ryder] 23:19
Now, this is where I get a little bit excited. When we fit the same design of isolator with automated ball valves, all of a sudden, we can set up the isolator for a campaign. We can run the fan to a fairly decent negative pressure, close those ball valves, and do an automated countdown to make sure that the flexible enclosure is leak-proof. I love this because every time we put a new enclosure on, we press the pressure decay button on the fan, and away it goes, does its test, and it tells us, yes, this flexible enclosure is safe to operate. Now, to me, this moves us a lot further on with a Process Score. We can confidently handle even higher potency materials now because we’ve got this pressure decay test. The pressure decay test reinforces that all is safe before we use it. The low-pressure alarm lets the operator know if anything does fail during the cycle. Let’s say the continuous liner is pulled off or some glove failure—whatever—the fan will automatically increase in speed, but the alarm will go off so the operators know to stop handling the API.

Again, this design is probably compromised by the fact it’s got a stainless-steel base panel. Because we’re handling high-potency, there’s a chance that some molecules or traces of powder could get hung up between where the flexible film seals onto the base pan. Can we be absolutely sure that we get all those little pieces of trapped powder material out by doing a wash down and a clean down before we take that enclosure off for disposal? We’ve had customers who have done swab testing, and they can find trace elements if things are not done correctly. So, our risk assessment is to eliminate some of these risks.

Heat Sealer

[Martyn Ryder] 26:48
With our full life cycle safety, what we’re looking at now at ILC Dover is putting a flexible film on the bottom of the isolator so the isolator is still working at negative pressure, but the HEPA filters sit below the work table. One on the one-stage HEPA inlet with a motorized ball valve, two-stage HEPA exhaust motorized ball valve. We’ve got a low-pressure alarm fitted to it, so that this, we see, is kind of almost the ultimate level. Because at the end of this operating cycle, this contaminated enclosure can be vacuumed flat by the exhaust fan, so even as we squash the flexible enclosure down, we’re not creating any positive pressure in any locations. Very safe operation, and again, we’ve got the beauty of being able to do a pressure decay test at the start of every cycle, so we know before we introduce any high-potency materials, this is going in the right direction—everything is safe. Okay, bring the materials in, let’s do the operation.

You’re probably thinking, “What can get better than this?” Well, I’ve got a little bit of a wobble when it comes to crimping. Now, again, the guys at ILC Dover, in particular, have done a lot of research looking at the effectiveness of their crimping technology, and I believe ILC Dover’s crimping technology is some of the best in the world. But if I want to go to a Process Score above 60, and it’s not a flammable environment, and I could use a heat sealer, I would want to use what we call a toxic dust heat sealer here on the continuous liner exit. Why? Right—with a heat sealer, I’ll show you some pictures in a minute. We just get the waste to the end of the pouch, we pull some clean film off, the heat sealer arm is closed, we press a button, it does two welds and a cut in the middle, and we know from extensive testing that there is no chance of any molecule escape at the heat seal point, because any traces of product that are in there will be submerged in the melted polymer as the heat sealer arm comes down. Also, it’s automated, so we’re not relying on operator procedure.

So, as we’ve seen, ILC Dover has some great crimping data to show that it does work, providing everybody’s following procedure day after day. And this is where we feel that, if we’re handling a 10 nanogram product that we need to test down with EN 689, do a one nanogram pass or fail, we’d for sure want to use a heat sealer because, you know, our success with the project depends on being able to repeat the heat sealer over a day’s worth of testing and make sure that no contamination escapes.

Process Considerations

[Martyn Ryder] 28:57
Now, there are some additional process considerations that we can bring in with flexible film isolators: humidity control, oxygen control. ILC Dover has a great system called the ACM that is a PLC-powered system. I think it’s an Allen Bradley PLC on it—would that be right, Scott?

[Scott Patterson] 29:18
Yes, Martyn, the ACM, the atmospheric control module, is a fully automated system based on an Allen Bradley PLC. So here, we get all of the bells and whistles of automation, including multiple alarms, password security, and those types of features.

[Martyn Ryder] 29:42
That’s awesome. That’s awesome because, as well as the safety considerations, there may be process considerations. As we all say, safety is king. Let me just show you this image.

So, we talked about the fully disposable six-sided enclosure and how it can be decontaminated. Here’s one that we use for ADC boxing handling, and ADC toxins are some of the most potent materials known to man. We test these usually with the surf-bridge high accuracy assay method using Prox and Sodium. We’ve got quite a lot of data now; I’m pleased to say they’ve all been below the limit of detection so far. But you can see, if this enclosure is contaminated with something as risky as an ADC toxin, it’s nice to have the fan collapse it. It all rolls up for disposal, two-stage HEPA filter housing coming out—there we go onto a table, wheel it away. So, this method of using a six-sided enclosure with all the bells and whistles we’ve discussed with the Process Score really does allow us to deliver a safe system.

Let me just talk you through some of the things here—whoops. So, on the left here, we’ve got SOLO’s equivalent of the ACM. Much like Scott’s design, it’s got the alarm beacon on front that can show a number of alarm conditions. It’s got nitrogen gassing ability. Underneath the isolator, on the extreme right-hand side, you’ll see there’s a pot-shaped device with a 90-degree bend on it. Well, that’s a fully disposable two-stage HEPA filter housing that is part of the flexible enclosure. So, no matter what gets contaminated in there—the continuous liner, the gloves or gauntlets, the HEPA filters—everything is bonded to that flexible film enclosure. So, at the time of the campaign change, we let the fan run, as you saw in the video, vacuum collapse, roll it up, take it away for incineration.

And on the right side of the picture of the slide, sorry, you’ll see a heat sealing operation. So, we use a specific toxic dust heat sealer that we import, very, very effective, very reliable. And, you know, on a test we did in 2018, we used that heat sealer for a day, passing out maybe 20 different pouches, all below the limit of detection—amazing data. Very, very confident.

Value Proposition

[Martyn Ryder] 32:19
One of the things we always talk about at ILC Dover is the value proposition of using our flexible isolators. Now, we believe there are some massive advantages. Of course, safety is the king here. But let’s just look at some of the factors: If we’ve got 100 nanogram per meter cubed product, and we’re on a rigid isolator, stainless steel isolator from one of the great vendors out there, it’s probably going to be $700,000-$800,000 for a well-made, well-designed piece of kit. The consumable costs at a campaign change—maybe the HEPAs and the gloves—may be about $2,000, could be more. Then we’ve got to decontaminate that isolator before we bring in the next product. So let’s say there’s one and a half meters squared of area in there, could be more to decontaminate—maybe it takes 16 hours for cleaning, maybe then analysis costs time, 12 hours. So we’re going to run up about $2,800 in cleaning and analytical costs for the cleaning validation. But the big thing is we’ve probably lost five days production time.

Now, flip that over to the ILC Dover-style soloADC™ that’s fully disposable. We could take that isolator off and replace it within half a day. If we wanted to do a lot of retesting and validation, let’s hit a maximum of one day. So let’s just look at the value proposition here. soloADC™ flexible isolator—about $70,000. Okay, the complete enclosure kit sounds expensive at around $10,000, but that is everything. It’s the continuous liner, it’s, if you like, the isolator shell, the spill tray, all of the HEPA filters, the gauntlets. We’re going to make that fully disposable, as you saw in a little video there. So, within a maximum of one production day, we can get you back in business.

And if you look at the cost of lost revenue for a production day, maybe losing $500,000 with the rigid isolator versus $100,000 with a one-day loss with a flexible film isolator from ILC Dover. So, five-day production loss, four-day production win. And if you multiply that up over, say, six campaigns a year, we could lose up to 30 working days using rigid stainless steel isolators where we need to do the cleaning validation.

Now, this presentation is all about risk assessment, and it’s about making sure the isolator is the right design to deliver safe working conditions day in, day out, even on a bad day, even under upset conditions. But the financial argument also makes sense. Remember, with a flexible film isolator, every time you put a new enclosure on, you’re starting from scratch—everything is brand new. Test it at the factory, put it on the frame, pressure decay test it on the frame—you know that nothing’s going to let you down. And also, the revenue you save in not losing 30 days of manufacturing time a year is massive.

Conclusions

[Martyn Ryder] 35:50
So, the conclusions that we’re coming to are that, at ILC Dover, we’re confident that this Process Score mechanism and our process observation survey methods lead to a containment system that’s better matched to the process operations and the risk hazard profile. We’re not setting ourselves up as EHS specialists—heaven forbid. We’re an engineering house that manufactures flexible film isolators. We design them, we test them, we put them on-site, we do containment testing with folks like Faithbridge and others, and we’ve got a lot of data behind us.

Scott, may I bring you in? Is there anything else you’d like to add on this conclusion?

[Scott Patterson] 36:29
Well, Martyn, that was an excellent presentation to show that the right solution can be offered for a full range of applications and meeting what we’ve deemed the full life cycle safety. So no, that was excellent to show all of the options that are available to have the right capital spend to receive the right type of containment system for the process at hand. So, thank you very much for that.

[Martyn Ryder] 36:54
Well, thank you, Scott, my pleasure. So, guys, this is the end of our webinar for today. As Scott mentioned earlier, we’ll be looking forward to fielding all the questions you’re going to raise after this, and we’re here for you. We’re interested in supporting our customers by applying these new techniques, such as the Process Score and our detailed survey we’re developing. So, if I may, thank you for your time, and we look forward to receiving your questions in due course.

Thank you and goodbye.