Surveying Analytical Tools For Combination Product Testing

In this episode of The Combination Products Handbook: The Series, host Tom von Gunden discusses Chapter 11 on analytical testing with the book’s editor, Susan Neadle, and chapter coauthor Jennifer Riter. Susan and Jennifer discuss various analytical methods for testing compatibility, performance, stability, and safety when combining drugs or biologics with delivery devices and device constituent parts.

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The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined Use Systems Edited by Susan W.B. Neadle, CRC Press, 2023

Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of The Combination Products Handbook: The Series, where we go through the book, chapter by chapter. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for the series. Today, we're going to discuss Chapter 11 [on] analytical testing for combination products. And for that discussion, I am joined by chapter [co]author Jennifer Riter, as well as the book's overarching editor, Susan Neadle.

Welcome, Jen. Welcome, Susan.

Susan, let's start by positioning the chapter within the context of the overall handbook that you put together. What was your thinking about the need for a chapter on analytical testing and why deep into the book around chapter 11?

Susan Neadle, Editor:

So, I think I've said it in previous segments that one of the strategies for the book was to do a Part 1 that was foundational and a Part 2 of the book, where it's special topics. And one of those special topics is analytical testing.

And it's challenging. Many companies — not many, all companies — have to [operate] within [a] clear understanding of specific performance requirements associated with the device constituent part and its interactions with the drug. And the analytical approaches that you take to manage through that are really important.

And with that said, I've seen Jennifer Riter present many times on different topics associated with the standards that apply for the testing and approaches to take. And without hesitation. She has also been working with me through the International Society of Pharmaceutical Engineers’ [ISPE’s] Combination Products Community of Practice. That's really where we got to know each other the most. Jen really has played an invaluable role in helping drive that clarification around analytical. And she was a natural first person to go to. And she and Daniel Bantz, who coauthored the chapter with her, really did a phenomenal job. So, thanks.

Okay, great.

So, Jen, let's start with a high-level overview of the contents of the chapter and, hopefully, encourage folks to go actually read the chapter. So, you cover — I’m just going to glance down at my list here — you cover seven different approaches to testing, and they include compendial testing of components, biocompatibility, extractables and leachables, container closure integrity, particles analysis, performance testing, and stability testing.

If you could spend a few moments on each one of those and talk at a high level about, what's the importance of each, what does each entail, and if there's any difference among them in terms of when they're looked at or applied. Talk about when you take a look at those things.

Jennifer Riter, Chapter Coauthor:

Sure. So, when we think about an approach for analytical, we want to think about combination products and how our customers are going to develop combination products, right? So, when we look at the analytical approach and the strategy with that, we want to look through the different phases of development. So, what I wanted to start with [in the handbook chapter] was more of the foundational piece of, when they're working with the constituent parts and components of the combination product, that we start from the beginning, the simplest form of what we need to think about when they are procuring those different types of parts, which actually starts out with the compendia piece of it.

So, making sure that the different materials that they're receiving and that will be used in that combination product meets those compendial requirements, and that they work with their suppliers to make sure they have the proper documentation, then testing that has been completed to comply with the appropriate compendia standards that are out there.

So, I wanted to take a walk-through of the compendia pieces of the components and the constituent parts within that combination product. For example, the elastomers, the plastics, the glass that might be part of that combination product. So, making sure that they're thinking about, holistically, the combination product as a whole and as they're bringing that product development together with the device and the drug product, what that should look like and what is that foundational information that the customer needs to have.

So from there, once they have procured those parts and looked at the compendia piece, we want to talk about the biocompatibility piece of it: the cytotoxicity, the intracutaneous testing that needs to go on, the in vivo / in vitro testing that needs to be completed, as followed within [ISO] 10993, the ISO requirements for those materials and a device, as well as the container closure piece of what is used in that combination product.

So, talking about biocompatibility, a lot of things that are done in there when we talk about it is reference to 10993. However, 10993 also marries up with USP 87 and 88 when we talk about biocompatibility. So, when you look at USP 87 and the 88 in the qualification of those elastomer components that are used in the combination product, it also references how they're married to the ISO 10993 and the different aspects of ISO 10993. So, making sure that there's a good understanding of how do we pull this information together and how do we have the data to support what we're trying to do to bring this product to market.

So, from the compendia to the biocompatibility, then we start thinking about that next phase of development. Once our customers have chosen and procured and looked at the compatibility of those constituent parts with the drug product and with the device, what is the next thing we need to think about as we move into phase two of development?

So, we have our parts — we have our glass or our plastic or our elastomers. What are some of the things around compatibility with the drug product and with the patient that we need to think about? And that comes into thinking about your extractables and leachables piece of it — that high-level compatibility across the device.

And when we talk about it, it's a little bit different with extractables and leachables because, not only are we thinking of the containment system or the primary container components, which fall under USP 1663 and USP 1664, but we also have to think about it as the device as a whole also following under 10993 where they mention extractables and leachables on that device aspect of the combination product. So, it's thinking about, how do I approach extractables and leachables when I look at this combination product as a whole during this phase of development?

At the same time, we're also talking about container closure integrity. So, as you're bringing the parts together, especially the primary containment system or the prefilled syringe system as a combination product, as in the simplest form of a combination product, right? We have to think about container closure integrity and how everything fits together.

Ways that you look at container closure integrity is going to be different based on that primary containment system that you're utilizing, whether you're using a cartridge system, you're using a prefilled syringe system, or if you're cross-labeling a product where you're having the vial stopper and seal co-packaged or cross-labeled with a device or a delivery system. You need to think about, how do we approach container closure integrity?

And there are different aspects and different techniques that you could use based on that container closure integrity delivery system. Things like a vial stopper and seal: you may look at tracer gas analysis via helium leak, which is a very sensitive type of technique. And looking at very cold temperatures down to negative 80 degree C, where some of those biologic products may be stored on dry ice.

Or you may need to also look at, when you're talking about a prefilled syringe or cartridge system, high voltage leak detection. And looking at how you need to look at that entire aspect of the prefilled syringe or the cartridge, starting at the plunger end, which is your container closure piece or integrity and that fit that is going to maintain your integrity, down to the needle shield or tip cap that you're actually using on the other end of the prefilled syringe.

Or if you're thinking of a cartridge system, the line seal, the aluminum seal, with the liner in it and how well you're sealing that surface and you're maintaining that container closure integrity over time.

And we want to also talk about that in phase two because, at that point, that's where you're going to start to develop your analytical methodology of what you're going to look at and what you're going to utilize as you move into phase three for your stability set downs.

Part of that, of course, we need to think about particle analysis. So, we're looking at all these nice parts coming together. And then we're seeing the effect that the environment has — the manufacturing environment has — on the drug. So, not only do you need to understand the burden of the environment that you're manufacturing in, but also each of those constituent parts that are coming in that's pulling it together with the drug product. What is that particle burden for each of those parts that come in contact with the product?

So, if you think of a prefilled syringe, you think of the syringe barrel, right? Of course, that's going to have a particle burden. You think of the plunger that you put in after you filled the barrel. That's going to have a particle burden from that end.

And then you’re taking that and putting it into an environment where everything has to come together with the secondary packaging. So, you might be taking the prefilled syringe and putting it into a blister pack or a different type of carton with an overseal, with a Tyvek lid from that perspective. So, what is the particle burden that the drug product and the device may see in the end of what gets to the patient?

So, thinking about that in phase two and understanding all those components that are coming together to get that particle analysis done is critical. And then, in the end you're looking at particles in solution per USP from that perspective. So, e're really looking at it from bringing everything together as a combination product.

And then part of that, when we look at design outputs and functionality and performance of the device, of course, that's a big piece of it. Is the patient going to get the amount of drug product delivered appropriately at the end point? And that's where you've got to look at performance and functionality of that system, whether it's a prefilled syringe aspect where you're looking at the simplest break loose and extrusion and delivered dose. Or you're actually looking at an autoinjector with that prefilled syringe in it and looking at button activation, you’re looking at delivered dose.

So, taking all of those design inputs and outputs and putting an analytical strategy together as to what types of performance testing, I need to think about to really get that dose to the patient. That's part of the aspects we're actually thinking about in phase two.

So, when you look at that, we're looking at extractables and leachables. We're looking at particles. We're looking at performance and functionality. We're looking at container closure integrity. All of this is something that needs to be taken into consideration and put in as part of your strategy for developing that combination product. And you actually have to break it down to really understand what you're going to do, at what point in time, as you are further developing that drug product with the device and delivery system.

And then lastly, we talk about stability testing in the end. And that puts us into phase three, before commercialization. So, we're bringing all that testing together. At that point, you already have your foundational piece of information of all the component constituent parts that are coming together for the combination product with the compendium outcome of biocompatibility.

Then you're taking your extractables and leachables analysis. You've already determined what leachables you're going to look for in the drug product overstability. So, you have the leachables test methods available to look at those targeted leachables when you hit phase three and you do your stability set down in your testing at each time point.

Then you're doing the same thing with container closure integrity. You've narrowed down the type of testing technique you want to do. You have your methods ready to go to meet USP 1207 requirements as deterministic methods. And you're actually testing that overstability, as well as particle and performance. At that point, when you're looking at performance testing, you will [have] already identified and determined your essential design or delivery outputs from that perspective. So, you're making sure that that performance, you're looking at those key types of performance measurements that you're going to look at throughout stability and then upon release of the product.

So, by the time we get around to stability testing, we want to make sure all of that foundational stuff that we set ourselves up for success when we get to stability testing is there. So, that's why it's key to really start from the beginning of what are the things we need to think about in phase one when choosing our materials and our systems to look at the compatibility of the drug product all throughout the performance, the chemical compatibility, into the point that we get to stability testing, and we're ready to test that throughout the shelf life of the product.

So, that gives you an overview of why we've put it in that fashion in the book.

Great. Yes, thanks for that thorough walkthrough. And I'm going to follow up, Jen, with you in a moment about how to organize around some of these approaches and practices. But before I do, I want to turn to you, Susan, and see if any thoughts or comments come to your mind as we hear from Jen on the overview of the chapter.

Neadle: Well, the one thing that struck me as we were working on this chapter was, we had peer review feedback: John ‘Barr’ Weiner and the FDA had gone through to give their perspective on the contents in the chapter. And at one point, one of the challenges we had was, what about device-led combination products? And how do we make sure we're addressing that appropriately within the chapter?

I don’t know, Jen, if there's anything you want to add to that, but I know that that was something that we had to go back and really look at because the original version of that chapter really was only on drug-led. And we definitely had to add some aspects into that.

Riter: Actually, it was nice because it got you thinking a little bit more about the transdermal side and also the implantable side of these types of combination products. So, when we went back and we looked at some of the requirements around those, especially for extractables and leachables, around performance and compatibility and things like that, it's funny how it actually was very similar to device-led, versus drug-led.

So, you are using the same set of, I would say, requirements when you're looking at extractables and leachables. You're looking at the guidance around USP 1663 and 1664 when you're looking at the adhesives and things that are utilized with the combination drug product, for example, with the transdermal.

So, with the transdermal, you're thinking about a patch that's going to be put onto the body. And you're mixing the drug with a solvent, with an adhesive to really put that on the skin. And how do you properly look at extractables and leachables of that particular combination product, and how do you approach it? And really, it was relatively similar to what we would do with the drug device-end; the principles of it were the same.

Same thing when you're talking about, let's say, a stent that you're putting into the body. And the approach that you use for a stent to look at that material and that compatibility of that material from an extractables and leachables [perspective] was similarly the same, not only that but from a biocompatibility perspective as well. The testing regimen of what you needed to look at was very similar.

There might be some nuances here and there just based on placement and implantability in the body. Of course, length of time it's going to be in contact with the patient or in the patient from that end. But the principles and the guiding approach were the same.

Neadle: Yes, and I think that that was part of what was important in our learning in putting this chapter together. Many of the examples and case studies that we give throughout the book are on drug-led combination products. But as we worked our way through it, the reason that we just stuck with that is that, for the large part on the device-led combination product side, it's the same questions, right? You're having to ask the same questions and challenges. It's about the interaction effects between the device and the drug.

So, whether you're a drug-led product, biologic-led product, or a device-led product, where the harms, hazards, and hazardous situations that could be presented, and how do these things all interplay with the analytical testing that you're doing, the device design that you're doing … So, I thought that that was really helpful that this specific chapter, I think, really kind of drew that out from us in putting that chapter together.

Riter: Yes, absolutely.

So, I'm going start with you on this final question that I have, Jen. And then Susan, if you want to weigh on this as well, obviously feel free.

So, Jen, you laid out in detail some of the components, the various types of tests that need to be considered in the various stages in the process where those need to be applied. So, a lot to think about for organizations.

So, whether this organizing around these practices is done internally or via outsourcing or some combination of the two, do you have any words to the wise or advice about how people should think about how to set up a strategy and a practice around applying the right analytical testing along the way of a product development pathway?

Riter: Sure. So, from that perspective, working closely with your suppliers and the knowledge of your suppliers is critical, right? They have a lot of information that already may be available for you from that perspective — making sure that those really are the experts in looking at that initial compatibility with your drug product and your delivery system.

So, pulling on the experts and the subject matter experts within your suppliers is key. And working closely with them in a partnership, right? Because these are critical materials and critical components to the system. And they [the suppliers] want to be successful with you. It's very important that you pull them in from the beginning and make sure you're getting recommendations from them and getting the appropriate information on the parts or systems that they're supplying to you.

So, that's the first and from that end, you may need to pull them into your approach with developing that strategy because there might be some subject matter expertise where you're going to pull from and pull them into those conversations. Because, as we recommend and as you see throughout the book, you need to in parallel develop the drug product with the delivery system.

That parallel, starting from phase one — that all has to be done together for a combination product right from the beginning. The same with your analytical strategy, right? You need to sit down and plan, okay, how are we going to define the design delivery outputs and everything? Now so, how are we going to test those? When are we going to test those?

So, that all has to be with the development plans and making sure that you're including your analytical department, your toxicology department from the beginning. So, everyone is aware of what that strategy is. There are also third parties that can assist you with pulling this together from an analytical perspective.

So, lean on some of those consultants, those third parties, those contract manufacturers,  CDMOs, CROs, in order for bringing that together. For someone that maybe is an emerging company and trying to bring a combination product to market, it’s not easy, as we know. And we know it's ever evolving and ever changing. So, lean on those industry experts and those industry partners to help bring you through that process.

But it's important to lay this out in the beginning because you don't want to get to phase three of development and figure out that you haven’t done what you need to do around properly qualifying the analytical techniques that go into testing at phase three.

And I have been part of many of these conversations. And so, it's really thinking about it from the beginning and really developing that delivery system with the drug product together, pulling in those external partners and the industry experts to make sure that you're on track. And maybe things weren't thought about in your initial discussions as you started to plan it. And that's where the help really comes in.

So, that's ‘my words to the wise’: lean on the SMEs in the industry and your partners.

Great. Good advice. Susan, anything you want to add to that before we close for today?

Neadle: Maybe just one bit of context is the platform devices. People try to use off-the-shelf devices or products that — I'm just going to use quotes around the word platform because the FDA does not recognize device constituents as platforms. But there is the ability to leverage some preexisting data.

Even when you're leveraging the preexisting data, though, you have to take into account the unique drug/device interactions for the specific combination that you're working on. And when you're leaning on the suppliers and CDMOs and what not, as Jen said, the one “watch out for” is, remember, they're thinking agnostically of your drug. Your responsibility is to think of the combination product as a whole. So, don't over-rely on them. You want to rely on them to make sure you're getting their insights, but you still have a key role for your combination product as you bring it to market. And I think that we bring that point home towards the latter part of that chapter.

Riter: Yes, and it's a good point because nothing is “off the shelf,” right? There is always development that needs to go into the most sophisticated off-the-shelf type of delivery system. So, there's always development. There's always that compatibility with the drug product, the delivery of that product, how it gets to the patient. So, I would always say there's — we call them “platforms” even though they're not recognized, and we call them “off-the-shelf,” but they're really not off-the-shelf, right? There's still more development that needs to go into that to get it to the point where you're going to have the data and the information to really submit that for approval. So, a very great point, Susan.

Okay. Well, Jennifer and Susan, I want to thank you both for joining me for a conversation of Chapter 11 of The Combination Products Handbook.

I want to thank our audience for joining us for this discussion. And we hope that you will dive into the book, and we hope you'll return here for our next episode of The Combination Products Handbook: The Series. See you next time.