Leveraging Combination Products For Biologics Delivery

In this episode of The Combination Products Handbook: The Series, host Tom von Gunden discusses Chapter 12 on biologics delivery with chapter author Manfred Maeder and the book’s editor, Susan Neadle. Manfred and Susan comment on the challenges of moving large molecule formulations into combination products while considering product stability, usability, and supply chain.

Purchase your copy today!

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 edition of The Combination Products Handbook: The Series. 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 12, which is “Considerations for Development of Biological Products.” And for that discussion, I am joined by the chapter's author, Manfred Maeder, as well as the book's editor, Susan Neadle.

Welcome, Manfred. Welcome, Susan.

So, Susan, I'm just going to start with you, as the overarching editor of the book. So, we're here at Chapter 12 and on this topic of biologic products and its relationship to combination products. What were your thoughts about the positioning of this particular topic at this point in the book, and why you reached out to Manfred to pen the chapter?

Susan Neadle, Editor:

So, the focus on biologics in the combination product space is a really growing area. Most biologics require parenteral administration. So, with that, it's really a specialty topic, like really making sure what what's unique about biologics. Why would people care? And what are the unique considerations for biological products? So that was it. That was really the driver for it.

Think about oncology products and things like that. I'm sure Manfred will talk more about that. But that was really the key driver of including that as a special topic in the book.

Okay, great. So, we'll just pick up on that. So, at a high level, the chapter overview level, Manfred, can you tell us a little bit about what are some of the key considerations that come into the thinking about combination products when large molecule biologics enter the picture?

Manfred Maeder, Chapter Author:

Yes, absolutely. Susan just mentioned, for biological products or for certain gene therapy products, the problem is to get it around the digestive tract. And for that reason, you need some type of device, typically, to inject any biologic product. And while [with] small molecules, typically, you would see with capsules, tablets in most cases. But this is not possible for biologics.

And that's a reason biologics need some kind of application tool. And typically, this application tool, of course, needs to be a device. It could be a syringe, autoinjector, or by any other means — most of them or lots of them via the subcutaneous route. So that means some type of injection.

Also, what is a little bit more difficult with biologics compared to small molecules preparations, which are mostly chemicals — they [biologics] require some cooling. They need some cold storage. There are only very few exceptions out there not requiring cold storage. And so, they have some specifics to be covered throughout the shelf life and in the hands of the patients or HCPs [healthcare providers].

Looking at biologics up to now, several years back only pure biologics companies were working on combination products. Now, more and more pharma companies are also working on a combination product. If you look at the 5 to 10 major pharma companies worldwide, typically they have 70% plus of combination products in their portfolio. This is basically what they are working on at this point in time, with an increasing percentage. So, that means the vast majority [of] what is in development in pharma is around combination products.

And speaking of that development, I was interested in a comment or thread that you wove into the chapter, which was around the fact that, when it comes to drug formulation or product development, when combination products are the wrapper, so to speak, the consideration of the device or the combination product is happening earlier and earlier in the development process, including even as early as the preclinical stage.

Can you comment on that trend? And if it continues, what are the benefits and what's the impact of that earlier consideration?

Maeder: Yes, absolutely. Okay, one of the topics in the past, especially at the major pharma companies: the formulators, they develop the product. That means they develop the formulation. And then, at the very last stage, they came up with the idea, okay, besides the vial/syringe presentation, it would be nice to have a prefilled syringe or an autoinjector. And that typically happens very late in the overall process.

Okay, now the problem is, if the formulation is not designed to be applied with an autoinjector, for example, this might not work at all. For example, if the viscosity is quite high or it has some other incompatibilities and then this will not work. For that reason, now in the pharma companies, the formulators and the device developers are working together in a collaborative manner very early in the process. Because, with a suboptimal formulation, you cannot design a great device and vice versa. And you can have a really nice device, but, again, with the suboptimal formulation, it will not work or might not work for the patient at all.

So, for that reason, collaboration moved far early in the process makes a lot of sense. Also looking at the patient needs and also what you mentioned, to have it earlier in the development process overall. In the past, the idea was to have, for example, an autoinjector as lifecycle management or at the time of the launch of the product.

Now, there's also a tendency to use it already, like a prefilled syringe [or[ autoinjector pen system — to use these types of devices already in a clinical Phase 3 simply to gather more experience and also to evaluate if the patient can handle it properly and to perform these evaluations earlier in the overall process prior to submission and/or approval of the product.

And now you also mentioned to have it earlier in the clinical studies. For some of the newly developed products like gene therapy or other topics, you need to apply or you need the device to apply in very specific regions of your body. That means, if we have a treatment for your knee joints, it might be necessary to get the medication or the modified cells exactly into this area, into your knee joint. Or, into your ear or in a specific area of your ear. Also, for example, suprachoroidal injections have been developed to get the modified cells or the gene therapy products behind the eye without being too invasive.

So that means, without a device, you cannot even have clinical Phase 1 because you cannot apply it in the right spot in your body because that device at this point in time maybe doesn't exist. And so, that means that the device development and the drug development have to go hand-in-hand to understand the needs of the drug versus the device.

Neadle: So, can I jump in with one thought that I hadn't heard you talk about? A critical part of your thinking is the protein configurations, that the biological product is a much larger molecule. And as a large molecule, it's much more sensitive to the friction and shaking and vibration. So, when you're handling it and administering it through that device, the considerations of those interactions of that biologic and the device become even that much more sensitive beyond just, okay, here's the formulation. We want to make sure it's going to work, right?

I don't know if you want to talk about that at all. I know you spoke a little bit about it in the chapter.

Maeder: Yes, there are several examples out there, looking at incompatibilities in general of the devices with biologic drug products, especially. To look at a very simple example, we have seen in our development — we have seen biologic products with a standard syringe which contains silicone to improve the gliding force, for example. With Product A, everything was perfect, also during shelf life. With Product B, Product B was a biologic product. Once again, a monoclonal antibody was binding to the silicone. In binding to the silicone, it formed fibrils, which form after maybe 18 months, 18 to 24 months. It formed particles which, for an injectable product, are completely unacceptable because it would not satisfy the USP [United States Pharmacopeia] requirements for injectable products because it contains particles of a specific size or quantity. So, that means silicone, it was in this case the standard siliconization, but it was, for Product B, simply too much.

We had another product, another example of a monoclonal antibody. There, the same amount of silicone was removed from the internal wall of the syringe by the monoclonal antibody, also after 12 to 18 months. So that means silicone was removed from the boy. For that reason, it was not possible after 18 months to inject anymore, neither in a prefilled syringe nor in an autoinjector because the gliding forces — because of the lack of silicone — the gliding forces were simply too high. So that means, even if you have the same primary packaging configuration, this might behave completely differently with different types of biological products or monoclonal antibodies, for example.

There are other examples out there. For example, interaction with tungsten. That's a nice example which happened at several companies. And also, there are other interactions with the stopper materials and so on.

So that means all that needs to be considered. And if you're looking at development or the combination of the formulation and the primary packaging material and the possibility of potential incompatibilities

As far as getting these therapies into patients, another key consideration that you give considerable attention to in the chapter is, obviously, human factors and considering things like, who's actually going to administer the device and the therapy, whether that's going to happen in clinic or in a hospital or whether that's via self-administered home care.

So, can you elaborate a little bit on what you talked about in the chapter in terms of human factors?

Maeder: Yes, human factors is a very specific area of expertise. Everybody needs developing and getting products approved. And they are very significant expectations, especially from the U.S. FDA in regard to human factors activities. There are clear expectations and guidances on that, which need to be fulfilled. And sometimes there are then some expectations beyond these guidances depending on the product you are developing.

So, that means studies are being performed with patients to find out if the patients can read the instructions for use, if they can understand it, if they can handle the devices properly. And so, for that reason, there's a huge emphasis given to usability. That means that the patients can use the devices given to them properly, especially if there are any critical handling steps.

This is typically scrutinized in detail — if patients or HCPs [healthcare providers] during the administration can handle it. And for that reason, looking at that usability, typically, for example, two-step autoinjectors are expected to be state-of-the-art. That means, you uncap and you inject, so it's exactly two steps the patients have to perform.

Now, if we are looking at any sustainability efforts, for example. So, where we want to be more sustainable, we would like to have a reusable autoinjector. But that reusable autoinjector necessitates multiple user steps. Typically, it's 10 to 12 user steps. And this might not be acceptable because then it might become too complicated for the patient to have these multiple steps. And then you have to go back to the two-step, disposable autoinjector, and you are, in the end, less sustainable, possibly.

But still, in the future, both systems will be necessary, depending also on the region. Both systems will be necessary because, typically, if you perform an injection on a weekly or daily basis, you’re learning, you get used to it. So, it makes a lot of sense to have a reusable system, which also can be more complicated because if you perform it on a daily basis, it's not an issue at all.

But if you look at preparations we are considering, like monoclonal antibodies, you have an injection once a quarter or twice a year. And for that reason, the autoinjector or the application systems have to be as simple as possible. And this is being reflected and being evaluated during these human factor studies to find out if the patients are capable of handling these combination products properly,

Neadle: To add to that, you've also got the situation where many biologics, just to get them in the marketplace for speed-to-market, you might come out with a lyophilate of that biological product in a vial. And then the reconstitution steps on top of everything else, right? I've seen 17 steps in an Instructions For Use. So, it really does get complicated when it comes to these biologics.

Maeder: Yes, absolutely. That's one of the reasons why I'm saying, typically, the lyo product is being used possibly for a clinical Phase 1. And later on in the process, the expectation for our formulators is that it has to be a solution. Lyo is not acceptable anymore for end of Phase 2 or Phase 3 and, of course, not for commercial products.

But, of course, if you have an orphan product, with very limited numbers of users, of course it still might be a lyo product, which would or could be marketed possibly with more handling steps then, unfortunately. Absolutely agree.

I'm going to shift gears a little bit here to another consideration that you give attention to in the chapter, Manfred. And that is, folks that are developing a biosimilar downstream from the original therapy, and sometimes that being a decade or more later and certainly with advances in delivery technologies having happened in the meantime.

So, can you comment a little bit about what folks need to think about if they're in the realm of biosimilars, after the original therapy has been set up in some other kind of delivery —device in the past?

Maeder: Yes. That can be a little bit more complicated because, first of all, the task for a biosimilar is to have it, of course, be biosimilar. So, then we are talking about the biologic product. It has to be biosimilar. This has to be proven and demonstrated. Okay, that's the easier part. Let's put it this way. Also, quite challenging sometimes.

So that's the easier part. And then this device most likely has been developed at least 12 to 15 years before. And so, in most cases, these devices are still quite complicated with multiple handling steps. To have a biosimilar and to be able to claim interchangeability, everything —the drug as well as the device — there's the expectation it has to be identical, with the same handling steps and so on. However, this needs to be looked at, and, in lots of cases, it's also depending on reimbursement and so on. And who's administering it? In lots of cases, this doesn't make sense because, nowadays, you can have by far simpler devices as compared to 15 years ago — more convenient, simpler devices for the patients. And then you cannot claim interchangeability anymore.

But you make these new devices very convenient for the patients. For example, I don't need to set up. That means less pain, faster injections and easier handling steps. All that has to be taken into consideration, as well as if the administration is done by an HCP and in the setting of in the rooms of the physician or if it can be done in a home setting.

Gotcha. I like to open it up at the end of these chapter discussions with a pretty high level, forward-looking question, which is: What do you see on the horizon? So, this time I'll contextualize it. And, Susan, obviously if you want to weigh in on this as well.

So, looking out on the horizon in terms of innovation in the technology or advancements in the patient experience, what are some of the either the exciting opportunities or the challenges or hurdles to be overcome as we look to improve and advance the way we deliver these large molecule or biologic formulations to folks via combination products?

Maeder: One clear trend is, for example, that we are looking into platforms. That means we have a standard syringe and, if possible — I mentioned our hurdles before with siliconization but to have a standard syringe, ideally, or a standard autoinjector system and so on. To have some standards or platform devices, which we can use for multiple chemicals and biologic products, for example.

So that means there's some kind of standardization, which also makes it easier for the patient because you would see, in lots of cases, maybe the same device. And so, that means standardization is one topic.

Also, time-to-market will be cheaper and faster because not everything has to be developed from scratch once again if you have a standard device and are only putting different molecules in there and bringing it to the market.

Also, these discussions have been done with multiple authorities, including the FDA, to understand how such types of standardization could be done and could be submitted and to simplify and ease the regulatory process. Okay, that's one side of the coin for standard preparations.

The other topic, what I alluded to before, is to have some very specific devices. That means injection into a joint, for example, into your ear, or for ophthal preparations. We are also looking at multiple options for brain delivery at this point in time.

So, there are very new and interesting areas which need to be covered. And again, to bring the formulation, mostly biologic, into the right spot of your body. So, this is what is happening also in parallel. So that means, in other words, these would be, of course, very specific devices, where one device is for one preparation or one formulation, of course.

All right. Great. Well, Manford and Susan, I want to thank you for joining me for this discussion of Chapter 12 of The Combination Products Handbook. And I also want to thank our audience for joining us, and we hope to see you here again soon. That's it, folks