Managing Risk When Developing Combination Products

In this episode of The Combination Products Handbook: The Series, host Tom von Gunden discusses Chapter 6 on risk management from The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined Use Systems (CRC Press) with the book’s editor, Susan Neadle, and chapter co-author Edwin Bills. Susan and Ed share their perspectives on the centrality of risk management and patient safety to pre-market and post-market considerations during combination product development and commercialization.

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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, a chapter by chapter take on The Combination Products Handbook: A Practical Guide. 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 6: “Combination Products Risk Management.” For that discussion, I am joined by chapter coauthors, Edwin Bills and, of course, the handbook’s overarching editor, Susan Neadle.

Welcome, Ed. Welcome, Susan.

Susan Neadle:

Thanks for having us.

Edwin Bills:

Happy to see you.

Thanks for joining.

Susan, I'll start with you. Can you talk a little bit about the obvious choice of positioning a chapter about risk management in a handbook about combination products?

Neadle: The previous chapter, Chapter 5, is on integrated product development. Foundational to your product development and foundational to the entire product lifecycle is pre-market and post-market risk management, which is central to that. I couldn't have a conversation about product development without talking about risk management from the beginning. You need to consider it right from the beginning of the development of any products.

Great. Susan, can you lay out some of the key terminology that provides a foundation for understanding what's covered in the chapter?

Neadle: Sure. It’s important before we can even engage in this conversation to understand, what is this product development that we're doing? What is everything that we're doing across the lifecycle all about? It's about driving products that are going to be safe and effective for their intended use for their intended users in their intended use environment. The word safety is the core there. What is safety? Safety is defined as freedom from unacceptable risk. What's risk? Risk is the probability of the occurrence of harm and the severity of that harm. What's harm? Harm is injury to people, property, or the environment, including physical or mental injury, which could also be associated with lack of product availability.

A couple of other key terms that we will be using as we have this conversation are hazard and hazardous situation. A hazard is a potential source of harm, and a hazardous situation is exposure to that potential source of harm. You need to understand that vocabulary to be able to then engage in the rest of the conversation we're about to have. There are times when people get confused between those terms. I always say that there is the hazard, which is the potential source of harm, and then the hazardous situation, which is where you're exposed to that potential source of harm. That’s a helpful foundation for our discussion today.

Great, thanks for setting that context.

Ed, I'm going to turn to you now. Obviously, when we're talking about combination products, we're talking about the combination of something. One of the most common combinations has to do with a drug constituent part and a device constituent part. Using that as a common example to start into the topic of risk management, what does that basic distinction point out in terms of the considerations that come into play in the combination product world when it comes to risk?

Bills: There are a lot of similarities in the way we approach risk management between the device and the drug. In the device world, we use ISO 14971 to describe the process that we're going to use and the fact that it is a lifecycle process, which starts before the design development process and goes all the way to the end of the product lifecycle, when the last one is removed from the field. We are talking about an overarching process. It can even start in clinical trials because the regulations and standards in that area require you to have a risk analysis to conduct those activities. It’s a huge process. The device side was developed using that standard.

When ICH Q9 was being developed, the Risk Management Standards Committee for ISO was asked to participate because we had already developed a standard that had been out for several years at that point. We had some experience with it, and one of our members, who had drug and device experience for a large company, detailed over to the committee that created ICH Q9. That’s why you see a lot of terminology like Susan has just described that shows up in both documents. If you look at ICH Q9, you'll see words like risk, which has the same definition as in ISO 14971. As you go down the line, they come across because of that cooperative effort in developing that second document.

Neadle: The big thing that sticks out between the two is, when you look at risk management, that activity that is done for devices and device constituent parts. The focus there is very much on the harm associated with that product. You’re doing this assessment of a progression from hazards to hazardous situations to harms and the severities of those harms in ICH Q9 and Q9(R1), which came out about a year and a half ago. In that document, the term hazard is introduced. But there's very much a focus on understanding the risks associated with your manufacturing process such that you have controls in place that the drug that comes out the back end is what you intended it to be. You are still using it for some of the same purposes, but the focus is a bit different from that perspective.

Bills: Now, on the device side, we focus more on design development. We still focus on manufacturing, but less so. On the drug side, the focus, as Susan has said, is more on the manufacturing of a product.

Neadle: There’s also the human factors piece of it. On the device side, you start thinking about the tasks that somebody has to be able to effectively interact with a device’s user interface to be able to achieve safe and effective use. Safe, again, is freedom from unacceptable risk. You’ll see in this chapter and then again in Chapter 7, where we dig into human factors, the fact that you have to take that into account as you're thinking about risk management for combination products.

Bills: Human factors in devices is another thing that starts early and is one of the keys to design input, which is the first stage of design development. That means human factors and risk management have to start before design development.

Neadle: One of the things that is interesting with this chapter and one of the challenges that you run into in the combination product space is bringing together ICH Q9(R1), the drug risk management, and ISO 14971, the device risk management. When we bring them together, you're having to ask some key questions. It's always about the interactions, so you're still doing your drug risk management the way you did your drug risk management before. You’re still doing your device risk management the way you did your device risk management before. But now you have this other step, which is asking, are there any new hazards or new potential sources of harm that are being introduced because I'm bringing these different constituent parts together to form a combination product? Are there any new exposures to that potential source of harm? Are there any new hazardous situations that are being introduced because I’m bringing these different constituent parts together? Finally, are there any new harms or changes in the level of severity of the harm that are being introduced because I'm combining them?

Based on those interactive risks, what controls do I need to put in place for this product to ensure that it's going to remain safe and effective for its intended use and the intended use environment with the intended users? That theme carries throughout the chapter. We talk about how to merge these programs and how to make sure that you've effectively done those assessments and walked through the process in a way that allows you to carefully and holistically consider each constituent part.

Ed, do you want to talk any more about some of the unique hazards that people will run into when it comes to these combination products or devices?

Bills: I can think of a simple one right off the top of my head. If we are going to use a syringe, and for that syringe, we initially are thinking that we'll use a glass tube. Then, somebody comes along and says that's too expensive, we're going to use a plastic syringe. What kind of interactions between the drug and the plastic syringe might occur that could lead to some risk? There could be a hazard associated with the interaction between the chemistry of the drug and the chemistry of the syringe. Those are the kinds of things we have to think of. We have to remember, too, that what the user sees is not a drug and a device. What the user sees is a system that provides them with some course of treatment. They don't care about the drug and device’s interaction. That's up to us to manage so that when we provide a product to them, it is a very low-risk product that will provide the treatment that they need.

Neadle: One of the other things that occurs to me is, again, there may be some confusion in terms of what's a hazard versus what's a hazardous situation. When it comes to combination products, I can't tell you how many teams I interface with that struggle with that. One of my favorite ones to pick on is dose error: missed dose, underdosed, overdosed, inconsistent dose. I hear many people refer to that type of situation with having a dose error as the harm. One of the points that we try to make in this chapter is that the harm is the actual injury to people, property, or the environment. That is, if somebody gets hurt or something happens that's bad -- like someone's personal information getting released and them experiencing identify theft.

When you think about dose error, it's very dependent on the specific drug that you are using for that combination product. The missed dose happened because there was a hazard; there was a potential source of harm associated with that device or the delivery system. To Ed's point, it's a system. Maybe the way those constituent parts interacted led to a hazardous situation, which was that dosing error. Depending on what the medical situation is and the specific drug that you're dealing with, it will cause a different level of harm. The harm is not the missed dose or the dose error. The harm is the actual injury that occurs because somebody was exposed to that lack of ability to deliver a dose. I'm making this point because I know that a lot of people involved in risk management struggle with that difference.

I like to use this example in the chapter: it could be a goldfish, or it could be a shark. Am I getting an injection repeatedly because I hate the wrinkles on my forehead or am I getting an injection because I'm in anaphylaxis and I can't breathe? The harm that could occur because I missed the dose that's going to fix my wrinkly forehead is that my wrinkles are there and I hate that, versus the harm that occurs because I can't get that dose when I'm in anaphylaxis, which is that I could die. Very different. But the hazardous situation for both was a missed dose. That is a very important point that we try to bring home in that chapter.

Anything you want to add to that, Ed?

Bills: Susan covered that one extremely well. I was thinking along the same lines while she was explaining it. That’s an important part of the chapter, understanding how that product is being used. In emergency situations, users need to get that EpiPen in the leg right away to get the dose. Did the needle go far enough in? Did it get there in the proper amount of time? Was the drug too viscous and it couldn't get through the needle? There are all kinds of things that fit into that situation.

Neadle: It really teaches you to think in details. With the example of a plastic syringe, what kind of plastic, what excipients, what coatings? Is it sensitive to temperatures? A lot of these products are in cold chain. You have to start thinking about the design of the device, the product as a whole, the use of that product as a whole, and the production process for that product as a whole throughout the whole lifecycle through disposal of that product. All of those across the lifecycle bring different questions around safety and efficacy for that product. What this chapter tries to teach is how to methodically go about applying the thinking in that deep way proactively.

This is a difference between ICH Q9(R1) and ISO 14971: Under ISO 14971, which is usually the foundation that people will use for doing combination products risk management, there's an expectation that you have a risk management plan. It's a formal, required, documented plan that proactively tells what your acceptance criteria are. You have to lay that out upfront and then lay out what you're going to do to work your way through that thinking. That includes clinically, operationally, design, use process, and how you are thinking end-to-end to manage the risks associated with your product. That’s a very important aspect of what we're doing when it comes to the combination product risk management.

Bills: One of the things you need to understand is that risk management is a team sport. You can't get that with just one person or two. You need to have cross-functional participation when you're deciding what harms can occur. An engineer is not the person you want to ask that question. You want to go to the medical and clinical people to find out their experience from the environment that they have worked in, which is hopefully the environment where you are going to place your product. You get expertise from that environment to come in and help you.

Certainly, engineers understand failure modes and the things that can happen to a product in the manufacturing process. Manufacturing engineers understand how the other manufacturing processes can fail, but you need all of those people. If you're buying things from outside to come into for your product, now you need some purchasing expertise and quality engineering people that work in that environment. I was originally a supplier quality engineer, and we got into a lot of things like that. It's a team sport. It requires a lot of people to participate, and at different times it's different sets of people. When you get to post-market, the design people have moved on to other products, and you're dealing with people that are taking complaints and investigating failures, which is a different set of people. It’s the entire team that contributes to this.

Neadle: Absolutely.

As I was listening, something came to mind that I'd like to return to for a moment. At some point, you were expanding the concept of devices to remind us that they're also delivery systems. I wonder if any of the considerations that we've been discussing have any additional things to factor in when we apply a platform approach. Do you have anything to say about platforms?

Neadle: One of the common practices in the pharmaceutical industry is to try to use the same device type, if not the same device, for delivery or administration of different drugs. The FDA does not recognize that term platform per se as a device. But commonly, that's the terminology that we use. The challenge that you run into goes back to my original statement: Who are the intended users, what are the intended uses, and what's the intended use environment? What are the unique risks for that specific device with respect to each of those intended user insights? What potentially unique controls need to be put in place based on that intended user population?

If I use that example of giving myself Botox, I'm using a syringe that was intended for me to deliver Botox. Now, say that I'm using that exact same syringe as a platform to deliver this emergency use product. Is it going to meet the user's needs for an emergency use situation when I can't sit there and read the directions or get the angle just right? I can't go through that in an emergency. You have to start thinking about those human factors, which include considerations around the emotional state of the person, their dexterity and ergonomics to be able to interact with the product. Human factors are a core part of that risk management conversation.

When it comes to platforms, you always have to make sure that people recognize that it's not just a matter of saying, use it with your new drug. Rather, take a step back and ask, what are the unique considerations that I have to take into account? What are the new potential hazards, new potential hazardous situations, and changes or increasing severities of harm that could come from the combined use? With changes or increasing severity of harm, take a step back because sometimes that combined use of constituent parts actually lowers the severity. That's a good thing, take credit for that, but still take that into account as you're designing and developing that product.

With a platform mindset, some of the challenges that come into play are using the same needle safety device with multiple products and finding that getting a needle stick is a common hazardous situation. If a person gets exposed to a needle sharp, the harms that could come from that could be dependent on the health condition of the person or dependent on the sequence of events that leads to their exposure to that sharp. Was it exposed to somebody who was already sick, or was it the same patient that's getting stuck with their own needle? The sequence of events that surround that exposure will dramatically change the outcomes in terms of the harms. When you're thinking about a platform, you've got to be able to step back and think about what unique controls are needed because of the specific hazards and hazardous situations that could be created by using that platform device for this new intended use or user population.

Okay, great. As we move into the final stretch of the conversation, I'd like to open this up to both of you to offer words to the wise. As folks are looking to bolster or build out an effective risk management practice or approach, what would be in the category of either “must address and must do” or, alternatively, “must avoid”? What should you ask? What should you do? Either one of you can start if you have some key takeaways for folks who will become readers of Chapter 6.

Neadle: Go for it, Ed.

Bills: I'll say, “Start early.” Risk management, like human factors, needs to start at the very beginning. As soon as you know the intended use, the intended use environment, and the intended users, you can start risk management and human factors. If you do that, you're going to help reduce your overall cost of development and the time. If you find problems at the end that you have to go back and fix, that gets really expensive and time-consuming.

The best thing you can do is start early and get that cross-functional participation. The FDA has always said, if you didn't document it, you didn't do it. You’re going to need documentation. We talk about a system for documenting risk management in the chapter. At the very end, we tie it together with the idea that the risks are remaining seen by the users and how all this documentation flows together. That’s the best contribution I can make at this point.

Susan, any final “must do’s”?

Neadle: Two key things. First, if you're working with a supplier and you're purchasing that device constituent part, don't just assume that the risk files that that supplier has generated are going to satisfy your needs. If they give you access to their risk file or their risk assessment, that can be a good starting point to reference and use in your risk management plan. Be keenly aware that it is still your responsibility as a sponsor of a combination product to address the unique considerations of the combined use of the constituent parts. Typically, your suppliers are thinking about it agnostically. You have to bring it together and talk about your intended users, intended uses, and intended use environment.

The second big thing is that when you're doing combination product risk management, you’ve got to be asking whether you do it based on ICH Q9(R1) or on ISO 14971, which is more common. Always ask these questions. Are there any new potential sources of harm because I'm bringing these constituent parts together? A potential source of harm is a hazard. Are there any new possibilities of being exposed to that potential source of harm because I'm bringing these constituent parts together? That's my hazardous situation. Are there any new harms or changes in severity of harm because I'm bringing these constituent parts together? Finally, do the controls that I am implementing address the potential risks, hazards, hazardous situations, or harms associated with each constituent part and the combined use system as a whole? If I have all five things addressed, I will be in good shape doing my combination product risk management and my suppliers’, which is an underlying piece of that.

Good advice from both. I want to thank you, Susan and Ed, for joining us to discuss Chapter 6. I'd like to encourage the viewers of this episode to become readers, if they haven't already, of The Combination Products Handbook, including Chapter 6. And we'll see you next time.