On-Demand Webinar Replay: Parker Polyisoprene Compounds for Pierceable Elastomeric Closures

Good morning. It's 11:00. I'm going to give it one more minute for all those to join and then we'll start. For those that just joined us, I'm giving it well, here it is. It's eleven one. I think we'll go ahead and get started.

Good morning. Welcome to Parker's Webinar on polyisoprene compounds for Pierceable elastomeric closures. My name is Natalie Hicks. I've been with Parker for 18 years and have held various roles of responsibility throughout that time. In 2017, I was promoted to my current position as Life Science Business Development Manager for Parker Engineered Materials Group.

Before I introduce our guest speaker, let me review a few Housekeeping items for the Webinar. First, all participants are in listen only mode to reduce background noise during presentation. Second, there are two ways to ask questions of our guest speaker and panelists. First is in a chat format. During the webinar;. Participants can ask questions during the webinar by using chat Q and a feature found in the Zoom Control Panel at the bottom of your screen. If you would like to ask a question during the presentation, please click on Q&A, type in your question and one of our panelists will answer the question. All participants can view asked and answered questions.

The second way to ask the question is live at the close of the presentation. At the close of the presentation, I will ask participants for questions. Again, use the Q&A feature found in the Zoom Control Panel to raise your hand. I will call upon the participant to ask the question and unmute you. At that point, a participant can ask a question live. So that's it for Housekeeping.

Let me introduce our guest speaker today. Dale Asby is Group Vice President, Technology and Innovation of Engineered Materials Group of Parker Hanson Corporation in Cleveland, Ohio. His responsibilities include directing technology transfer across the global footprint of the Engineered Materials Group locations, as well as serving as the key technology representative for advanced technology research. Dale joined Parker in June 1986 as an Applications engineer with the O-ring Division and had an increasing responsibility with each time frame. And in 2004, he was promoted to the Group Vice President, Technology Innovation Engineer, Materials Group. So with that, I'm going to kick it over to Dale to give his previously recorded message on Polyisoprene Compounds for Pierceable Elastomeric Closures. Dale.

Thank you very much, Natalie, and good morning, everyone. It's my pleasure on behalf of the Engineered Materials Group of Parker Hannifin to be given the opportunity to present the subject this morning of polyisoprene compounds for pierceable elastomeric closures. This is intended to be the first in a series of webinars related to the subject of pharmaceutical, bio-pharmaceutical and medical device applications.

The agenda for today will be, as you see here, to give you some background on the application, some background relative to the history of some of the regulatory standards in this area, and then go into detail on one of these regulatory standards, the kind of de facto standard in this particular application. And then at the end of the presentation, I'll go through some of the data associated with the development and commercialization of a polyisoprene recipe that we've worked very hard on to meet or exceed the requirements of this standard, which is called the USP <381> standard. And then at the very end, we will open it up for questions and answers from the audience.

So elastomeric closures are commonly used to seal containers and vials for pharmaceutical preparations where contents are transferred via hypodermic needle.

Elastomeric formulations. There are many elastomer formulations that have been developed and could be developed for this particular application. Of course, elastomer formulations are not just the polymer itself. We're going to be focusing on polyisoprene polymer this morning, but there are many more types of polymers that could, be used, elastomeric formulations, for this type of application, ranging from SBR to natural rubber to ethylene propylene, silicone even. However, the standards that we're going to be talking about today specifically exclude Silicone polymer in these types of applications.

There are other standards, US Pharmacopia standards and other regulatory bodies that do cover silicone type sealing systems, and they'll be the focus of future webinars.

We chose polyisoprene. It's widely used in the medical device area and medical device industry. We chose polyisoprene based on its inherent properties in terms of resiliency and also relative inertness in many environments, and other companies have as well. However, polyisoprene formulations, many of the formulations, including some of our prior formulations, failed to meet all the requirements for many of the pharmacopial standards that are used for elastomeric enclosures. So the primary basis and background of this work and research and commercialization effort was really to develop, in the range of polyisoprene polymers, a material or a suite of materials that meet or exceed these stringent requirements as you're going to see throughout the course of the presentation.

Of course, what are we talking about in terms of the application itself? It really is, as many people, probably everyone on the webinar have seen, either personally or have seen on television or what have you a septum. The rubber black dot on the top right hand picture there is the pierceable membrane that's used to allow that transfer via hypodermic needle from a sterile environment inside the vial to a non sterile environment, pharmaceutical preparations, exotic chemistry, exotic chemicals and treatments. And so the need for high functionality in a variety of ways is paramount In this particular application.

Septa are used in many different, not just this picture here, septa are used in many different applications pharmaceutica,l of course here, but also in chromatography type preparations, in medical diagnostics, research laboratories, widely used in research laboratories, and of course, in certain medical devices.

And so, as we think about the voice of the customer in terms of improving customer outcomes, ala, the need for a fit-for-purpose type solution., these closures have had challenges in the past, due in part to the challenges with the elastomeric formulation itself.

But let's first review. The first and foremost primary functions of this elastomeric enclosure, obviously is to maintain sterility and also prevent contamination or cross contamination from the outside-- the non-sterile environment-- into the sterile vial environment. And also maximum resealability is a paramount concern. As you might imagine, many different penetrations via the needle through the enclosure, the elastomeric closure, can be challenging relative to resealability if in fact, the elastomer is not highly resilient, then this idea of self sealing, and the capacity to maintain that seal after the needle is extracted is challenging. And historically, that's been where there have been some challenges.

The ideal characteristics of any solution that would be developed would be that the elastomeric formulation would have low permeability relative to air and moisture. Very high resistance to aging. One of the other things is many of these pharmaceutical preparations can sit on shelves in laboratories and hospitals and doctor's offices for extended period of time. And so the resistance to aging of the elastomeric formulation, -- maintaining its resilience, its pliability being supple, but yet still retaining that self sealing capability -- is of utmost importance. And as I mentioned a couple of times already, the key differentiator that we've seen from our engagements with our customers is this need to resist coring.

What I mean by that is, as you can imagine in your mind's eye, as the hypodermic needle penetrates the elastomer multiple times, there could be the possibility for a boring or a coring, the vernacular that is typically used, of the elastomeric closure, excuse me. And so that would obviously cause potentially weapage through that coring area and/or actually even gross leakage in extreme conditions. And so guarding against that, designing around that -- or designing to prevent that -- is of utmost concern and one of our key design principles as we went about our material science evaluation.

There are many standards around the world. I'm going to focus this morning on US Pharmacopoeia, but there are many industry voluntary standards around the world. I've highlighted some logos for the European Pharmacopoeia, Japanese Pharmacopoeia, British Pharmacopoeia, and many others actually. But the purpose and they're beyond the scope of today's presentation. But the standard that I'm going to focus on today is USP or the organization I should say, the US Pharmacopoeia. And when I go through the history, actually, we're going to talk specifically about US Pharmacopoeia Standard <381>, or Chapter 381, as it's called. And that really started some 60 years ago, actually, relative to the first standard that the US Pharmacopoeia issued in 1942 actually had to do with the glass containers themselves, nothing to do with seals, nothing to do with elastomers, solely focused on the specifics around glass containers themselves.

Fast forward a few years. The US Pharmacopoeia, which is an industry voluntary organization, as many of these are, and the US Pharmacopoeia added a water attack specification. Fast forward. And I use that term loosely because as you can see, decades are transpiring here relative to the creation and or revision of a number of these standards. But in 1965, now, there are actually some application type information which started to be introduced into the standard for the sterile glass containers. Fast forward. Actually, concurrent with that, in 1965 was the first introduction of standards for plastics and the need for biological testing for these drugs in concert or in contact with plastic substrates. And so a good bit of work was done and started when the boom of plastics actually in general, took front stage, center stage in 1965.

And if we continue in 1970, a further addition for plastic containers for physio-chemical testing was added. Also in 1970, the National Formulary, which was a separate standard, issued the first rubber closures for injections. And subsequently actually the national formulary merged with US Pharmacopoeia. So they're the same organization right now.

Fast forward another decade. USP 20 was issued in 1980. And this is really the closest to as we progress to today's standard in its current form. This was really the birth of the elastomeric closure for injections. And this became where the focus shifted quickly into the world of elastomers. As you can see on the end of the page, there's been a variety of revisions. The most recent of which is in 2018, and that will be the subject of the testing requirements that I'm going to go through in a little bit more detail next.

So USP <381> Elastomeric Closures for Injections. This becomes the basis that we use, and actually the industry uses, for characterizing the ability of a formulation to be fit for function or fit for purpose, as I mentioned earlier. The chapter itself contains three major testing areas: first being biological testing, the second being physiochemical testing, and the third being functional testing. As you can see, each of the general lenses or elements of the requirements are in greater detail, and we're going to go through each one of these in some more detail.

I do list down at the bottom of this page. Also, just for reference, as you can see, as I mentioned, there are many pharmacopoeia standards around the world, organizations and subsequent standards around the world. The European standard that is closest to the USP 381 is listed down there, as is a Japanese standard. You can see the titles are slightly different. For the most part, and certainly the spirit of these other standards are all in concert with one another. But there are nuances from country to country. But in general, the approach and the need for biological, physiochemical, and functional testing are contained therein in each one of these standards around the world.

So specific to the first subset of the testing itself in USP 381 is biological testing. Now, there are two types of USP 381 materials that are referenced in the standard. Type I materials are intended for aqueous type pharmaceutical preparations in the vials. Type II are for non-aqueous and/ or special preparations, which could be in the form of powders, could be in the form of various non-aqueous preparations. And of the two, the more stringent requirements, as you'll see in the subsequent slides, are in the area of Type I. So in terms of the design space for us to develop a formulation, our focus was to make sure that we were addressing and capable of meeting or exceeding all the requirements of the Type I USP 381 material, because that is certainly also that is the broader use in industry - Type I type closures and the requirements, as I just mentioned, are more stringent.

So specific to biological testing there's in vitro and in vivo testing. And this slide is important in that and also the distinction between Type I and Type II. And so Type I materials-- in vitro testing per US Pharmacopia standard 87, if a material meets the requirements of USP 87 in vitro type testing, you're not required to go through or undergo testing to USP 88, which is the in vivo type testing. Again, as I mentioned earlier, Type I being more rigorous. And so if a material designed to be a Type I solution for USP 381, the key standard is USP 87 for in vitro testing. If in fact it's not capable, a recipes and many recipes in the industry today actually are not capable of the more stringent requirements, there still is a Type II requirement, and typically for those non-aqueous applications, and that's where the testing would ensue to test to USP 88 for in vivo testing for biological compatibility, actually. So again, the thrust of our work was Type I and for in vitro type applications, aqueous applications.

The second subset of the second area of testing is this Physiochemical testing. And you'll see here on the left hand side of the page, there's a variety of tests that are required or subsets of the chapter on physiochemical testing. And you'll notice also, as you can see in this representation, Type I and Type II, there are some differences between again, more stringent Type I versus Type II in the area of turbidity, absorbance UV absorbance and then also resistance to reducing substances. And we'll go through in a little bit more detail the results of our material development in this area. But there are also some other standards, for example, color, an acidity or alkalinity that are common or are the same from Type I to Type II type materials. And as you can see just by the comparison between Type I and Type II, whether it's turbidity, absorbance or reducing substances, Type One being more stringent in each area consistently.

Just a quick comment on turbidity. Of course, another word for that is opalescence, and it really is an arbitrary measure, actually, of the cloudiness or haziness of a fluid. Sometimes people talk about colloidal suspensions actually in this regard. But the arbitrary units of ante use Nephelometric Turbidity units is arbitrary, but it really is a light scattering method, if you will, that gives a relative ranking of how clear the solutions are if, in fact, there is some interaction between the elastomeric closure and the pharmaceutical preparation that's in the vial. And so this is a visual representation of the -- actually the intent of-- the lack of interaction between the two substances.

So interesting, test acidity or alkalinity, similarly, whether it's sodium hydroxide or hydrochloric acid, the resistance of the elastomeric formulation to these concentrations of reagents, whether acidic or alkaline, must not have an adverse effect. And it's done via typically done via titration method.

Lots of details on each of these tests are outlined in the USB 381 standard. That's not the purpose of this webinar this morning; just to give you a general feeling of the differences between Type I and Type II and what the scope of testing is

Continuing on the physiochemical testing portion, there are also additional tests for extractables, whether they be heavy metals, zinc, resistance to ammonium, and then also volatile sulfides. Again, no difference between Type I and Type II applications in this area, common requirements in each one of these four categories for both materials.

Moving in to the third area of testing requirements and testing for USP 381 are the functionality testing requirements. And there are three areas: penetrability, fragmentation, and self sealing capacity. And I started my talk with a little bit of discussion about this challenge relative the self sealing after, or via multiple penetrations through the septum itself. The interesting thing about this, too, is this is really the heart of the voice of the customer frustration and/or need for improved material science solutions. And the testing here. We chose to certainly make sure that at a minimum, we were capable or are capable of meeting requirements of the standard, but we also thought that we would focus on -- because on this had such a high customer dissatisfaction -- focus on designing a solution, elastomeric formulation solution, that would be highly resistant and actually even much more robust than what the standard indicates. So I'll go through this in a little bit more detail.

The results actually, as you'll see in that specific area, in terms of functionality, you'll see what we did in addition to what I've just described in three areas, biological physiochemical and functionality testing, we did actually some extra testing in terms of functional use that I'll share with you in just a moment.

So the results for the Parker material in the first area, biological testing, as I mentioned, Type I material must meet requirements, meet the requirements of Cytotoxicity testing per USP 87 and the Parker polyisoprene material, -- there's a lot of details in this particular test, again subject of a future webinar --but the results obtained by the testing for USP 87 shows that our material is capable of and does meet the requirements from a biological testing perspective.

I insert this slide here in terms of physical and mechanical properties, just by way of broader application potential for this technology. I also inserted here a comparison between another standard, again beyond the scope of today's session, another US Pharmacopoeia Class VI standard, which was actually Class I through Class VI (designed for a variety of plastics but have been applied to a variety of substrates, elastomers, composites, a variety of different materials over the years). Notice the similarities between the USP 381 type material and the compliant material that we've developed in terms of mechanical properties. So physical and mechanical properties, the hardness of the material, both for 381 as well as plastics type applications are similar. The tensile strength of the material is capable for both standards, elongation, tear strength, and of course, this idea of resiliency, as one way to measure is a compression set resistance is very similar. And again, the reason I include this is because in addition to SEPTA and the focus of USP 381, this type material because of the work that we've done in mechanical properties here in addition to or on top of the USP 381 requirements, makes it also a possible candidate for use in other sealing applications in medical devices, pharma or biopharma type applications, as is evidenced by these mechanical properties.

By the way, there are no mechanical property requirements in the USP 381 standard. Interestingly, as I mentioned previously, the three areas biological, functionality and physiochemical are the areas of focus. But by way of analogy for other related applications, you can see the property development of the suite of materials that we develop.

And then the second subset back to 381. Now, in terms of the specific requirements for Type I versus Type II, as I've already previously mentioned, you can see the Turbidity testing, absorbance, reducing substances, all are slightly different and hence more stringent, as I've mentioned. And then the balance of the testing for the physiochemical portion of the 381 standard, our commercialized technology is capable of meeting all of the requirements, and again, specifically the Type I requirement.

Finally, the functionality testing, as I mentioned, those three areas penetrabilit,y fragmentation, self sealing capacity, the ability to meet those three subsets of the functionality testing with a 21 gauge needle. I'm going to talk about that in the next slide a little bit. The standard only requires this testing to be done with a 21 gauge needle. And for those of you that are not familiar with the again, an arbitrary gauging system, the OD of a 21 gauge hyperdermic needle is 32,000th point 032 inch (.032"), and so that is the diameter that is being expected or that is penetrating the elastomer on obviously a frequent basis to extract pharmaceutical preparations from the vial itself.

So what we did in this particular area is we certainly were capable and met the requirements of the functionality portion of 381. But we also thought because this is such a pain point for our customers, we thought that we would design a test, a self sealing type capacity test, with even larger needles. You'll notice the inverse relationship in terms of gauging and 21 gauge. The lower the gauge number, the larger the diameter of the hyperdermic needle. And a 16 gauge, just by way of framing this, a 16 gauge needle is roughly twice the outer diameter point 065 inch (.065") outer diameter, versus a 21 gauge as I mentioned earlier is an .032 inch diameter, and so much more stringent. Obviously, the larger the OD, much more stringent and much more aggressive on the elastomer. And so we tested, developed a test, that would also be a repeatability test to address this, what I mentioned earlier about this coring phenomenon or resistance to coring based on multiple penetrations. We developed a stringent test both in terms of cycles as well as the size of the hypodermic needle itself.

And so we were able to survive 20 punctures, hence these green checkmarks. Twenty punctures with each of these gauge needles. You pull a vacuum, bring it back to atmospheric temperature and put it in a dye solution to see if in fact, there's any leakage. And so we were able to design this test and actually prove empirically from a functional perspective that the characteristics of the formulation that we developed really do exceed the requirements of 381, and really do excite and enable our customers to -- with assuredness -- be able to use our formulations very easily and reliably.

So, in summary, the formulations were designed certainly unique compositions, unique curing systems, et cetera, et cetera. That really is the key differentiation that enables what I've just presented to you, low compression set, the absorbance data, et cetera, et cetera. And quite honestly, the ability to exceed the Type 1 requirements, especially in functional areas, is very exciting. And we're very happy to be able to offer this technology in a variety of applications, certainly for elastomeric closure seals, but in other applications where good mechanical properties, as I mentioned, as well as these unique properties of self sealing and then of course, noncontamination of the pharmaceutical preparations in a sterile environment.

So with that, we will move to the question and answer session of the presentation. Thank you very much for your time and look forward to your questions.

Thank you, Dale. I will now open it up for questions. As a reminder to ask the question, use the Q&A feature found in the Zoom control panel to raise your hand. I will call upon the participant to ask question and you can ask a question live. Give it a few minutes for people to find that Q&A button at the bottom and ask that question. Okay, I see we have a hand. Okay, the question. We're going to answer this live, "Does this material come in colors and does it need to be tested to the USP Type 1?"

This is Saman (Saman Nanayakkara, engineering manager, Parker Hannifin Composite Sealing Systems Division). It's a natural color. However, we have the ability to make it color as needed. So once we change the color we need to test the material to USP 381 Type I.

Thank you. We do have one more question. "How does polyisoprene do with various types of sterilization?"

The experience we have so far, it stands well with different stabilization methods including steam, EB and gamma.

We have another question up there. "What are the typical applications where we can use this?"

In general, septums and any other sealing applications. As you can see during the presentation, it has very good compression set, so it's very good resilience. So anything you need sealing can use it.

All right. Thank you. And then one more question. Actually you have two questions coming in. So one from Jonathan, "Are material recipes all produce and owned by Parker?"

Yes.

Okay. And then one more, "Are there any limitations or intensity of time to exposure?"

Intensity of time of exposure? I'm not sure of the question, exposure to what?

Yeah, if I may. This is Dale. I guess the question with regard to the requirements per USP 381 and the qualification or the necessary testing, there are specific time limits, concentrations, et cetera, et cetera of course, in the standard itself. That actually-- the application with OEMs with pharmaceutical companies --that actually is the in use testing that's required by the OEMs So there is actually in many instances exhaustive testing requirements over and above requirements of USP 381 and the work that we've done and shared this morning. There's additional interaction studies that need to be performed with whatever the unique chemistry of the drugs are. So the answer is it can be and there can be limitations based on the uniqueness of the chemistry that are in contact with the materials.

Okay. Thank you. And that's all our time for today and that's all the time we have to take questions. I want to thank again Dale and the panelist, Saman, who was helping to answer some of those questions. I want to thank you, the participants, for joining the Parker webinar on Polyisoprene Compounds for Elastomeric Closures.

The link to this recording will automatically be sent to all those registered for this webinar. So if there's something you missed or someone in your organization you think you should hear this webinar worries you will have access to this webinar. So thank you again for your attendance. Please stay safe. Please stay healthy. Goodbye.