Integrating Development Processes For Combination Products

In this episode of The Combination Products Handbook: The Series, host Tom von Gunden discusses Chapter 5 of The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined Use Systems (CRC Press) with the book’s editor and chapter author Susan Neadle. The discussion highlights key aspects of a biopharma organization’s business and operations that must be effectively integrated when developing drugs and devices in tandem. These include imperatives such as establishing common terminology, applying QbD (Quaility by Design) principles, and managing supplier controls for providers of 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. My name is Tom von Gunden. I’m your host for this series, and today we'll discuss Chapter 5, “Combination Products Integrated Development.” And for that conversation, I'm joined by the chapter's author and the book's overarching editor, Susan Neadle.

Welcome back, Susan.

Susan Neadle: Thanks, Tom. Great to be here.

Great to be here, too. So, Susan, given that the title of the chapter is “Combination Products Integrated Development,” we can assume that what we're talking about at a very high level is the idea that a combination product, by definition almost, yokes device constituent parts with drug or biologic constituent parts, and so integration is key to successful work in that area. Can you tell us a little bit about how integration applies, and what facets of the thinking and approaches to integrated development of a combination product apply?

Neadle:

I think it's important to start out with the idea that, when we say integration, it's not just the integration of the drug and the device or the biological product. It's integrating your business to be successful in this space. This integrated development chapter really starts out with framing, what are some keys to success to be able to integrate your business effectively to support your combination product deliverables as well as integrating quality by design [QbD] for the drug and design controls for the device to be able to create a robust product? This integrated development chapter goes into language considerations and differences in interpretation between the drug world and the device world. It goes into the importance of the cultural organization setup and the integration of your development processes for drug and device, and then very importantly, it goes into supplier quality considerations and supplier collaboration.

Most of the time, if I'm in a room and I ask people to raise their hands for, how many of you combination products practitioners are purchasing at least one component or constituent part for your combination product, almost everybody's hand in the room goes up. That is key when it comes to your combination product development process. If you're purchasing a component or a constituent part, that has just changed your entire design process.

Let me take a step back, and I'll talk about each one of those. If we first think about language, and I mentioned this in an earlier chapter (Chapter 2), if you start thinking about, what is considered a package? A package for a drug professional is typically something interpreted as like a container closure system that contains the drug. If I speak to a medical device person, a package is a container that the device is put into. It could be a blister package. It could be a carton. But it's the thing the device goes into.

It's kind of funny when it first starts because you don't even realize it's happening. You're having conversations between each other where device professionals are speaking to pharmaceutical professionals at the company, and you're using the exact same words, and the pharma person is saying, we need the packaging to do x, y, z functions, and the device person is going, yeah, we need that device packaging to be good. What’s funny is that they're talking about two different things, because the pharma professional doesn't recognize the device as a device. They think it's a package. This can really roll all the way down into your supplier qualification process because you can say, if it's a package, the periodicity with which I'm going to do audits on that supplier, it's just the package, it's not as important as if it was something that was critical to the CQAs [critical quality attributes] of the drug, except that it is critical; it's the medical device constituent part. Throughout the business, these little trip-ups in language where you're saying the exact same word, but your vocabulary means something completely different creates so much confusion.

The chapter goes through several different pieces of terminology that are interpreted one way on the drug side, a different way on the device side, and now with combination products, the third definition that usually tends to have more of the device flavor, but sometimes it's combining the drug flavor with the device flavor. Even the term a means something different for a drug facility versus a device facility. Now, when you're making combination products, what does that mean? It's an integration of the terminology between both. That has huge implications when it comes to, what controls do I need to put in place? What do I need to take into account for my submissions? It percolates through the entire lifecycle of the product. If you don't have everybody within the business aligned on the terminology, you're setting yourself up for some pretty significant potholes in your development process.

The second big piece is around the cultural aspects. For many companies that are focused on drugs, the drug is the priority. They've always been a pharmaceutical company or a biologics company. The only thing that matters is the drug. Their whole development program centers on making sure that this drug is going to be the best drug that it can be, and the device takes a backseat. It's like, that device is a necessary evil that we have to deal with because we need some way of getting this amazing drug into the human body. What they don't necessarily take into account is the fact that that device constituent part is the human interface. It’s the thing that the user is having to interact with to give themselves a dose of that drug. If that device is not designed effectively for the intended users, the intended uses, and the intended use environment, then when it's time for the person to actually use the product, they may say, This is too hard to use. It's too much of a pain. This hurts too much. I'm not going to use this product. Then they stop taking their doses compliantly. Maybe it’s that the device doesn't function properly and they consistently get overdoses. What's the impact of that?

If that user interface on the device side is not working well to the point that it isn’t satisfying its intended purpose, that combination product may not be successful, and all the energy and effort that went into creating that wonderful drug, may be for not if nobody can use the product properly. That is why it's so important that when you're constructing your business model, there's a recognition from a budget perspective, as well as your organizational infrastructure, to make sure that you have people that understand and have the expertise in the device development, the expertise in the drug development, and the expertise in integrating the two.

You always have to take into account the interactions that could happen between this device and this drug or biological product. Along with human factors, which there's a whole chapter on, those activities are absolutely essential for the success of your product when it's going to get to the marketplace. The integrated development process really focuses on looking at your CMC [chemistry, manufacturing, and controls] stage gates, looking at the device deliverables, and making sure that they're proactively integrated in so that you're not missing key steps in that device development, and so that in the end, the product that you do create meets the intended uses, intended user needs, and an intended use environment.

When I talk about the budgeting piece of that, this is a really important point. There's a lot of companies that say, you know what? We're going to use a platform approach with our device. We're just going to go purchase an off-the-shelf device, and we're going to use it for all of our combination products. That's a great thought and spirit. However, there is an expectation that you've got to consider. Who are the intended users for your specific product? What are the intended uses? Is it a pediatric patient or is an elderly person? Is it somebody who has low vision issues? When you start taking those things into consideration, those are human factors. They will come up in the human factors chapter [Chapter 7] discussion.

When you start taking them into consideration for your integrated development process, you say, I want to use that platform device, but is there anything I need to do differently for that product to make sure it's still going to satisfy the needs of those that are intended to be using that product? That starts to color your process. From that budgeting perspective, typically pharma organizations tend to make it all about the drug. There is heavy resourcing that goes into making sure that any specific molecule is getting the funding it needs to make sure that that drug is developed to the hilt. There might not be that same level of energy and effort that goes into creating a platform that you want to use from the device side that could work across multiple different drugs. So, can I pool resources from multiple molecules to help fund a robust device development program, or am I always going to say, nope, every single molecule needs to fund itself. So, whatever portion we can eke out from that molecule to support the device development project-by-project, that's what the device development team needs to work with. I don't know if you can feel it, but there's a conflict in that. It creates real stress in the organization.

You also have organizations that say, I'm going to wait until my Phase 3 clinical trial, just go get me a device. Just give me the same device you're already using. Now, you're taking all of those considerations about how to make sure that the device is going to work for those intended users, intended uses, and intended use environment, and you're setting up the device to be a potential weak link in your overall product success. That’s key.

The last point, when I talked about the three keys of success: There is language as well as organizational infrastructure and culture. Don't operate in silos; you've got to have people working together. But there's also this supplier piece. Suppliers are a really critical part of combination product lifecycles, and many people are purchasing either components or the device constituent part. You run into a lot of disconnects where the suppliers historically thought that they were only manufacturing container closures and thinking, okay, that's great, it's a container closure, it's a component, I don't have to apply CGMPs to my component. That's the mindset. The challenge that you have now is educating those suppliers to help them see that what they're producing is not just a component but a device constituent part. If you're now creating the device constituent part for that combination product, there's a bunch of CGMPs that now do apply. And the design controls activities that they need to put in place to support the robustness of that product become key. And you, as a drug-led combination product manufacturer who wants to leverage whatever information they've [the suppliers] put together – probably agnostic of the drug – you've got a job cut out for you. These companies that don't see themselves as device manufacturers haven't necessarily put the appropriate infrastructure in place. Getting past the regulatory and quality side of it, there is also the science that goes into considering, what are the specification needs, what are the windows that I need to operate in, and the tolerance build-ups?

You run into a problem because a lot of the drug companies will look to those device suppliers or component suppliers and, whatever specification that company provides, they'll say, that's probably good. We trust them because they're the experts in the device. We're just going to purchase it and use it. That's dangerous because you've got to take into account the material properties of that device, the coating material. Could it interact with the excipients in my formulation? All of those interaction questions start coming up again, and you've got to make sure that you've got effective controls in place as part of your design process to help vet those issues. I go into a lot of detail on the supplier aspect in this chapter, and then there's even more in the chapter on supplier controls [Chapter 10]. I think that's an important chapter to dig into. It’s an important facet of the integrated development process.

Broadening the coverage, as the chapter itself provides: You cover internal considerations like language and culture. You talk about external considerations, like working with suppliers, how they see themselves, and how the organization and the supplier collaborate. Staying on that latter piece, which is external to the organization, so to speak, an obvious component would be to think about the regulatory agencies and standards-setting bodies. When it comes to combination products specific to the integration component, what are some of the standards, regulations, and guidance considerations that you highlight in Chapter 5 and want to comment on here?

Neadle:

One of the keys here is to talk about what it takes to have a solid foundation to work on. Now you want to come out with your specific product. What do I have to do to build on that foundation? One of the things the FDA and other health authorities have done is built product-specific guidance documents that are intended to leverage all the learnings the FDA has gotten over the years with different products on the market and challenges that have been encountered with the performance of those products.

With that, they make suggestions through these guidance documents about what they would consider to be current, state-of-the-art best practices on things to measure. What are critical deliverables associated with a metered-dose inhaler or a dry powder inhaler? There is product-specific guidance that I can turn to. For injection devices, there's product specific guidance. Whatever the product is that you are planning to come out with, take the time to go through the FDA database of guidance documents, ISO standards, and ICH standards. Look at each of these to get hints to help you meet the bare minimum expectations, which are the CGMPs [current good manufacturing practices] for your product in your development process.

Ultimately, when that product is ready for market, you've already taken into account the things that could be big risk factors and the things that could drive negative interactions that might impede the performance of the product. That’s one of the big recommendations that I give. The chapter goes through a review of a number of the guidances that are out there for pre- and post-market consideration. But there's a larger focus on pre-market throughout this chapter.

Okay, great. What we've discussed so far takes us up to about the halfway point of Chapter 5. The back end of the chapter takes deeper dives into drug constituent part considerations and device constituent part considerations. You talk about things like whether you're leveraging an already existing constituent part versus something new. You talk about approaching generics. You conclude the chapter with some comments and reminders about manufacturing. Susan, I'll leave this up to you. Hopefully, you have something you want to talk about here. What else would you illustrate for folks? Call it what you will: keys to success, pitfalls to avoid, risks to avoid or mitigate. What might you point to for folks to focus on as they read Chapter 5?

Neadle:

Let's take a giant step back. Every single one of us that works in the health care industry, what's our purpose? Our purpose in life is to create products that are going to improve patients’ lives. As we're doing that, we want to make sure that the products that we develop are safe and effective for use. Why do we do integrated development? Why do we do risk management? Why do we do human factors? It's all around driving that safe and effective product performance so that when it's in the hands of those who need to use the product, they can get the benefits that were intended. Now, if you take any of that for granted, all of a sudden, you’ve got a problem.

There's a case study in the chapter that talks about red cell aplasia with epoetin alpha. This case study predates the regulations for combination product CGMPs and combination part regulations in general.

I think it might have been a trigger for them; that's my hypothesis. In this case study, there is an example of pharmaceutical companies that were operating in the traditional fashion where the device takes a back seat and the only thing that matters is the drug formulation. They had a drug formulation that had been delivered in a hospital through an IV bag, and they were trying to make it more convenient for users. What’s the answer to that? Let's go to a prefilled syringe or an autoinjector.

In this case, it was a prefilled syringe that they wanted to move to. To put it into the prefilled syringe, they said, we're probably going to need to do something to adjust the viscosity of the drug to make it more accommodating for this prefilled syringe. Let’s go ahead and add a surfactant to the formulation. We checked: It doesn't impact the stability of the drug. The drug works great even with the excipients in the formulation. We're good to go. They started making these prefilled syringes with this drug, only to discover that the surfactant  ̶  that excipient in the formulation, which is considered not even something to worry about, interacts with the silicone coating that was in the syringe. All of a sudden, there are particulates being created and injected into people. There were 13 deaths associated with this case study. It stemmed from people not giving the device constituent part enough thought. It was all about the drug formulation.

That case study speaks to why we are doing all the work that we're doing. It’s to make sure that the device doesn't take a backseat anymore. People need to consider, yes, that drug is critical. We need to make sure that that molecule is all it can be, but we need to make sure that whichever device we choose to use with that molecule isn't going to mess with the molecule. The molecule that's delivered to the patient needs to be the molecule we intended it to be so that the patient can reap the benefits and not have to suffer the consequences.

That case study really resonated with me. I could look through that entire product development chapter and note that they missed the point about asking the right questions. They tried to leverage preexisting data, but they weren't taking into account something new about the device. With all of those things, it was like a perfect storm, and it led to 13 deaths, which was very sad. That’s why I think the entire combination products topic is so important for the industry.

This particular chapter is a foundation for making sure that you've got the appropriate building blocks and you're taking the right things into account. There's a lot of different types of devices out there to deliver drugs and, intentionally, this chapter does not go into every single type of device and what is critical for every device type. The reality is that technology is evolving. It's continually changing. The chapter focuses on the common considerations that you must always take into account as you're doing that integrated development process so that, ultimately, whatever device-drug configuration you've got at the back end is going to work.

Great coverage of the chapter. I, like you, found that case study example to be particularly illuminating in terms of illustrating the key considerations from an integration perspective. Thank you again, Susan, for joining me. We hope to see our audience again for our next discussion, which will be about Chapter 6 in The Combination Products Handbook. So long, folks.