Part 2: Winning Formula to Navigate Combination Products
Highlights:
Susan Neadle recently penned the highly anticipated "Combination Products Handbook," a practical guide that collects her years of industry experience into a comprehensive resource.
Learn more about the AAMI course Susan is teaching and the Community she is building to support global regulatory standards within combination products.
Susan discusses the difference with ICH Q9 R1 and ISO 14971. ICH Q9 R1 is focused more on the process whereas ISO 14971 focuses on the risk management and hazard-harm correlation.
Memorable Quotes:
“People sometimes get the FMEAs confused with risk analysis. The FMEA is a Failure Modes Effects Analysis. It's looking for hazards.” - Susan Neadle.
“Harmonization will make things easier for both developers and manufacturers, along with the regulatory agencies.” - Stephanie Canfield
“The FDA guidance when they finally issue it, they are supposed to communicate as to their expectations on control strategies relative to EPRs. But the key message there is that it's not just the EPRs, it's all those things that lead to compromised medical care that you've gotta be paying attention to. But specifically to EPRs, selecting the right specifications, making sure that you're doing verification validation relative to those EPRs is key.” - Susan Neadle
Show Links:
Transcript:
Intro: Hi everyone, and welcome to The Factor, A global medical device podcast series powered by Agilis by Kymanox. Susan Neadle and Stephanie Canfield are back for part two. And if you haven't listened to part one, do that first and then come back to this episode. They chatted about Susan's new book, The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined Use Systems. And how it brings clarity of understanding for global Combination Products guidance and regulations. Today, they continue the conversation, diving into risk management plans, control safety in the United States, and the polarizing viewpoints of ICH Q9 vs. ISO 14971. And that's where we start this episode.
Shannon - 00:00:54: So you mentioned risk management. So in Combination Products, I'm always hearing folks kind of aligned 14971 to or ICH Q9 based on which area they came up to speed on, I guess, and kind of dismiss the other. What are your thoughts on that? Are they that different or what do you think?
Susan - 00:01:15: So it's not, but it is kind of funny. It's almost like a religious affiliation. I am absolutely you know, sworn to ICH Q9 or I'm absolutely sworn to ISO 14971. And the challenge that you have with Combination Products is you really do need to integrate both. Now for ICH Q9, which just recently was updated to ICH Q9 R1. If you fundamentally look at the steps that you go through for risk management, they're very similar between those two standards. That said though, when somebody's doing risk management on the drug side, the tendency is that the focus of ICH Q9 R1 is focused on the process, the manufacturing process. I need to understand what are my CQA's for that drug. Generally I'll get some of those through my quality by design activities and some of the clinicals. Those are going to help inform what is critical about the quality, what are the critical quality attributes of the drug itself. But then it's all about, I need a manufacturing process that's going to be able to reliably and reproducibly give me that specific drug. And then I'm going to do specific tests at the back end to ensure that I got what I said I was going to get. That tends to be the focus of ICH Q9 R1, very, very process focused. I'm not saying it's exclusively process focused, but it is very process focused. Now, when you look at ISO 14971 now this kind of goes to the comment we were just having, the focus there when we talk about risk management is very much on hazards, hazardous situations and harms. So that hazard-harm correlation in ICH Q9 is not really the focus, it is when it comes to ISO 14971. When you read AAMI TIR it states, you have the freedom to use whichever base risk management system works for your business. However, the obligation that you have when it comes to Combination Products risk management is you need to look at each of the device, each of the drug and the device constituent parts and how they interact together because it's those interactions that may introduce new hazards, hazardous situations, or changes in the severity of harm. So if I step back just for a moment in case People aren't familiar with all the definitions, risk, we mentioned it before, is the probability of the occurrence of harm and the severity of that harm. OK, so you have to couple the two to get what risk is. There is no such thing as freedom from risk. So safety does not mean freedom from risk. Safety means freedom from unacceptable risk. So when you're looking at the risks associated with any product, there may be low risks, there may be moderate risks, there may be high risks. The low risks are generally broadly acceptable. The moderate risks, hmm, you gotta think about them and you may need to apply controls to try to bring those risk levels down. And if there's high risks, those generally tend to be those that are unacceptable. Or you have to have a very strong argument for why the benefits of using that product outweigh the risks of using that product. Okay, so those are some key terms. And then we've got the terms hazard, hazardous situation and harm. Well, a hazard is a potential source of harm. Hazardous situation is exposure to the potential source of harm. And then the harm is the injury to People property, the environment that occurs as a result of exposure to that hazard. Okay, so hazard hazardous situation and harm, very key terminology. And in ISO 14971 that's the focus. So best practice approach when it comes to risk management for Combination Products is you apply your quality by design and your ICH Q9 R1 to identify the critical quality attributes for the drug, the critical process parameters for the drug, the critical material attributes for the drug constituent part. All of those, including the intended use of that drug, are then inputs into the device and combination product risk management process. So you basically take those inputs and now you're using ISO 14971 but your ISO 14971 is not just focused on the device constituent part, it's also focused on the interactions of the drug with the device, and then those key questions that you're asking are, because the drug and the device are interacting. Do I have any new hazards now present because they're interacting with each other? Do I have any new hazardous situations? Do I have any changes in severity of harm? And those are the three really key questions that we ask when we think about Combination Products risk management.
Shannon - 00:06:18: Excellent.
Stephanie - 00:06:19: Do you find People struggle with, you know, you just gave a really clear definition of hazard, hazardous situation harm. Do you find People struggle with that and have different interpretations? Because in my experience, I have seen that.
Susan - 00:06:37: Yeah, it's actually pretty terrible. So if you can picture it, and I'll give some examples. So if you think about harms, harms are the injury that actually happens to a person, property, or the environment. So when we think about property, oh wow, you know what, a device explodes and now there's, maybe there was a drug inside that was inoculated with a blood specimen. Well, if the whole thing explodes, I now have an environmental contamination issue. That's pretty bad, right? Okay, so that would be one example. When we talk about the environment, well, now in this day and age of cybersecurity. If patient identity or any of their private information is compromised, that could lead to an environment issue. So there's, but it's usually though, when we're thinking about the harm hazards, for the most part, not all of them, but for the most part when we're doing the harm analysis associated with Combination Products, we're usually focused on the injury to a patient. And that injury is going to be specifically associated with what's the drug? What are they being treated for? What's the issue? So now I'm going to step back before I even talk about those harms. I'm going to go back to what's the hazardous situation. And remember hazardous situation is exposure to a hazard. So, a hazard might be that I have a pump malfunction that makes it so that's a sequence of events. It's causing me to have a situation where a patient is now exposed to an under dose of that drug. Okay, so under dose is the hazardous situation. The harm that occurs is what is the injury to that patient because they did not get enough of their medication. And over and over again, when I see People do their harm hazard analysis, they list things like misdose, under dose, overdose, bolus dose, whatever, they list that as a harm and it's not.
Shannon - 00:08:46: I agree.
Susan - 00:08:47: That is a hazardous situation. Your use error, if you think about human factors, my use error is actually a hazard.
Shannon - 00:08:54: Or cause to a hazard.
Susan - 00:08:56: The hazard, yes, it starts out as a hazard that could lead to the hazardous situation of underdose, overdose, misdose, needle stick injury, whatever, it's the use error that leads to that hazardous situation. And then the harm is, and now how did that impact the patient? Exacerbation of their medical condition, or I don't know, there's so many different examples that I can give for that, but hopefully that makes it really clear. But so many People get confused on that and if you're dealing with a device compound who's just doing the risk management exercise on their device constituent part, agnostic of the drug, they usually struggle the most with it because they're trying to do that full harm hazard analysis. The reality is they can take it just so far. They can get to the point where they can say, these are the hazardous situations. And then depending on the specific drug, you may have different outcomes. There's some platform approaches that can be taken for that risk management where you have, I always use that needle stick injury as the most common example. A needle stick injury is there regardless of whether I've got a drug pre-filled into my device or not. So that one's something that they may be able to take all the way to what are the harms that could occur, right, and apply some severities and probabilities. But then sometimes, based on what the specific medical condition is of a patient, oh wow, maybe they've got an immune deficiency or like a severe severely contagious disease. So think about this during the age of COVID, somebody's got a terrible case of COVID and now the needle got contaminated from them and it accidentally needle sticks somebody else. Well, that's gonna be considered a very critical injury. It's a critical severity. So that's where there are some drug agnostic harms that you can look at and you can judge. But for the most part, a lot of them are gonna be tied to the specific drug delivery, the drug that's being delivered as to what the harm is.
Shannon - 00:11:14: Yeah. And I see that too, having worked, I came up through the medical device ISO 14971, I see that in you mentioned, quality by design. Quality by design from the pharmaceutical side and on the device side you would be doing your design FMEA's your process FMEA's to assess all of those potential failure modes. In your product design and in your process, but then that top level view of hazards to harms, that needs an intended use. So when you pull those both together and then look at, okay, here's my hazards for this delivery system, and now my potential harms, but those are gonna be based on the actual drug interactions and device interactions and the intended user population and so forth. So I kind of see a lot of similar activities happening on both sides from the pharmaceutical and the medical device. But again, it needs to be pulled together in that overarching perspective to truly understand risk. Yeah.
Susan - 00:12:23: Yeah. And like I said, like the phases that you go through, the one thing that's distinct is when it comes to ISO 14971 there is a formal requirement that you have to have a Risk Management Plan. And in that Risk Management Plan, you have to prospectively define what are your risk acceptance criteria. Remember, I told you that safety is not freedom from risk, it's freedom from unacceptable risk. So in your Risk Management Plan, you've got to define what is considered acceptable versus what is not. And for anything that is not acceptable, you've got to be putting controls in place. So the Risk Management Plan is the one thing that is unique compared to ICH Q9 R1, ISO 14971 and Combination Products risk management mandate that you have to have a risk management plan. Now if you step through it though, okay, I've got to identify what the risks are. I've got to assess those risks. I've got to be able to develop controls for those risks. And then I've got to do a residual risk evaluation. Do my benefits outweigh the risks? Yes or no. And if they don't, I've got more work to do. I can't just go forward if the benefits don't outweigh the risks. And then ultimately it ties into your post-market activities because you've got to do reviews of the risks during the life cycle of the product, you're doing your post-market surveillance and reporting. So those all tie into that risk activity that you're doing early on. And then I was going to mention one thing, because you were talking about the failure modes effects analysis, whether it's design, process, application, equipment, People do all sorts of FMEAs. People sometimes get the FMEAs confused with risk analysis. The FMEA is a Failure Modes Effects Analysis. It's looking for hazards. Okay, those failure modes. If they are a potential source of harm, hazards.
Shannon - 00:14:20: Or causes the hazards.
Susan - 00:14:22: Exactly. They could just be things that are, oh, that's a failure mode. It's annoying. It's going to interfere with maybe, you know, the efficiency of my operating equipment. But if it doesn't pose a potential source of harm, it is not a hazard. 14971 is focused on the hazard harm analysis. And remember that the harm, or sorry, the risk, is the severity of that harm times the probability of that harm. So that hazard harm analysis, It's looking, so the outcome of it is, what is my level of risk? and then the controls that you apply are to bring down the level of risk.
Shannon - 00:15:04: Absolutely. You also teach with AAMI. What courses do you teach there?
Susan - 00:15:11: So through AAMI, I teach a course in design controls. And separate from that, I'm involved in the risk management course, but Ed Bills is usually the primary person instructing on that. But then I specifically teach their curriculum for Combination Products. So it goes from end to end across the entire life cycle. And it really aligns pretty well with what's in the book, actually. So that book is also endorsed by AAMI because it does so well follow information that I teach on during that class. And there's quite a bit on Combination Products risk management in there as a result of that. And then typically for that class, we also get into the human factors and design controls and pretty in depth because a lot of the companies that are coming to it, even if they're device companies struggle with how do I bring the drug considerations and the device considerations together?
Shannon - 00:16:12: So there's lots of opportunities for people to learn more about the things that you were talking about today.
Susan - 00:16:18: Yeah, and they can always reach out to me too. I do custom training. It's, you know,I just like to teach.
Shannon - 00:16:25: We're running short on time, but I wanted to ask you about what your ongoing work. So the book is now published. And I know you're moving on and you're working on some things with ASTM. And I was wondering if you could talk about that a little bit.
Susan - 00:16:42: Sure. So one of the things that we've talked about is there's this huge opportunity for harmonization. And if you look around the globe and you start seeing, you know what, Europe has a different approach to Combination Products, U.S. has a different approach, China has a different approach. It's just like proliferating in the wrong way. And in the drug world, we talk about convergence. In the device world, we've got the IMDRF, which is springing convergence, but there's nobody really focused on combination product convergence. So when I looked at it, I was like, you know what? We've got the same products, regardless of the fact that different jurisdictions may designate something as drug primary mode of action or device primary mode of action. Some don't even call them Combination Products. They just say, oh, well, it's combined use or borderline products, right? They don't even call them Combination Products. But the safety risk-based considerations that drive the need for controls are the same for those products. It's the same product, regardless of which jurisdiction you're marketing in, it's the exact same product. So what's the control strategy? Now, in the United States, the FDA defined CFR Part 4 for CGMPs for Combination Products, current good manufacturing practices for Combination Products. Currently, if you look in other jurisdictions like Europe, even though they've now started this, the notified body gives an opinion on a single integral non-reusable combination product to the competent authority. And then the competent authority will take that opinion of the notified body that's assessing through paperwork review, is this Compound compliant to the general safety and performance requirements for that drug? There's actually no CGMP inspection being done relative to the device constituent or that combination product as a whole at the manufacturer. As a result of that, there is no mutual recognition agreement for inspections between the U.S. and Europe. And People look at MDSAP, it's the same issue. There's no mutual acceptance for these types of products because there's not harmonization on the CGMPs. So the particular working group that I'm chairing in ASTM International is a best practice considerations for CGMPs for Combination Products. And specifically it's being written through the lens of international considerations. And we have health authorities, including Health Canada, USFDA, we've got TGA Australia, we've got People from Europe, notified bodies that are participating, as well as a number of members of industry. And the focus of what we're putting into this standard, this best practices standard is, here's the why, you know, the why of all these considerations, why you need controls, and then based on all these whys, here's the what the controls look like. And what the FDA and Health Canada even said during our meetings is that this particular best practices standard could be a jumping off point for health authorities to then drive those conversations to hopefully get People to adopt some minimum CGMP inspection expectations, relative to whatever the other constituent part is for that combination product. And then hopefully that leads to more mutual recognition for inspections and takes the burden off of industry and regulators alike. So that's really the big driver for that. Separate from that standard, there's another one that is gonna be kicking off, but it hasn't quite yet, cause I'm waiting to get this one done is the risk management standard. And the focus of that one is really the fact that, you know what, we've got all these different risks that people assume company by company by company, but the reality is, especially when you think about platforms, there should be some consistency in expectation and in the risk assessment. And so if I start looking at some of these platforms, a meter dose inhaler, a pre-filled syringe, an auto injector, an on-body injector, there's some basic things that I'm always gonna have to consider. And can we publish a platform approach to that so that now companies can look to that and be harmonized? And then now it's a matter of, okay, I'm gonna differentiate based on my specific intended use.
Shannon - 00:21:21: That's exciting.
Stephanie - 00:21:23: Sounds good. Hopefully we get some harmonization. And I know that'll make things easier for both developers and manufacturers as long as, along with the regulatory agencies. So that's awesome.
Shannon - 00:21:33: It's a challenge.
Susan - 00:21:35: Yeah, and I know device standalone companies struggle just as much, like if they know that they're supplying a device to Pharma Companies. and everybody has their own risk matrix. It's like, oh, you know, kill me now, kill me later. How about if we just save everybody's lives?
Stephanie - 00:21:50: I like it.
Shannon - 00:21:51: Now. Excellent. One final question, if you would like to provide any input on how do you see EPR discussion evolving? Do you think we'll actually have a guidance?
Susan - 00:22:06: I hope that we have it this year. I know that the FDA is striving to get it out this year, but what actually happens, I don't know. During our meeting through the Combination Products Coalition, the FDA said that, hey, it's in review. but it's been in review for quite some time. It's supposed to be an extremely lengthy document. So what I understand is all the questions that People have been asking about it are addressed in that guidance. But that said, Okay, exactly where is it? What, you know, where is it gonna land? I did a presentation at the Pharma Conference a week ago. And I actually sent my slides to the FDA before I presented, because it was on EPRs. I wanted them to tell me whether or not I was on the right track. And they said I was. So when it comes to essential performance requirements, there's context that you need to have, right? So number one context is the FDA, when they create a definition or a guidance or standard, they tend to use US accessible free documents to be able to create their definitions. So one of the things that I have factually heard the FDA state is that the definition for essential functions, for example, that is present in ISO is not the definition for essential performance requirements. So that's like, oh, that's a big aha moment for us. So I started looking at all the different regulations and whatnot that the FDA has. So, to try to draw together what would be an appropriate definition that I'm going to assume based on all the FDA feedback from so many different submissions that I've been involved with, what is an essential performance requirement? First, you look at the design outputs. So one of the things that the FDA states is, for your design outputs, you have to have acceptance criteria and they have to ensure that those design outputs, the results of your design process, that are essential for the proper functioning of the device are identified. Okay, so they state that, that's in the regulation, 21CFR 820 30D. And with the harmonized standard for ISO 13485 under 7.4 it talks about design and development outputs. You have to specify the characteristics of the product that are essential for its safe and proper use. Okay, well, if FDA is harmonizing to 13485 safe and proper use, essential for the proper functioning of the device, I'm gonna assume that essential performance requirements are gonna have that kind of phrasing in it. Then we talk about design verification, and you have to confirm that all of your design outputs are meeting your design requirements, so that's gonna be an element of it. Design validation, we know that we have to prove that the device conforms to the defined user needs and intended uses. and it goes on to say under actual or simulated use conditions. And then we get into human factors. And specific for Combination Products, this one's a big deal because the definition of the term critical task is different for the DeMEPA combination product critical task than it is for CDRH critical task. So DeMEPA says a critical task is one that where user tasks that if performed incorrectly or not performed at all would or could cause harm to the patient or the user where harm is considered compromised medical care. Okay. They've made a really big deal about this compromised medical care. So I'm like, okay. And then we've got risk management on top of it. All right. We know ISO 14971 it comes into play ICH Q9 R1 come into play and they always say ultimately the risks link to the patient. Right? And the benefits need to outweigh the risks. And it says something to the same effect when you look at AAMI TIR 105. Then you've got this IEC60601, which is electrical and medical equipment, which is the closest that we have that says something about essential performance, and it's tying it to a clinical function. So I'm like, okay, so if I take all of that, and then I'm gonna take you to one more place that's publicly accessible document is the IMDRF. IMDRF specifically states that risk management is not, that there are essential principles is not necessarily a Combination Products document. But if you read the IMDRF description of essential principles for safety and performance of medical devices and IBD medical devices, it's from 2018. That particular document gives some great examples. And in it, it talks about essential principles for safety and performance, so it's like functionality. So if you go through all of that, and I'm running really quickly, a conclusion in this context of everything I just said to you, I've come up with a definition of EPR, which like I said, the FDA said it's on the right track. They can't tell me until the guidance issues what's right, but it's on the right track. So essential performance requirements are essential design outputs. That assure safe, effective, reliable use of your combination product without compromised medical care. It's my snippet that says that's an EPR. And if you look at that, and then you start looking at ICH Q12, implementation considerations guidance for post-market changes, it has some key questions in it, but those link back directly to what would be an EPR? What are the usability or the critical tasks accomplished, and are they accomplished without injury or issue? So what are the safety considerations to minimize medication errors? I have to look at my design and figure out what those are. Do I have the ability to deliver the label dose? Are there any impacts of the device on the drug CQA's? are any impacts of the drug on the device functionality and is the characteristic essential based on risk management. So I can put those together and I can say, those are the things that are the pointers to the EPRs for your product. It's a mouthful, but you can tell I'm a little bit.
Shannon - 00:28:34: No, I. and pulling all of the inputs together, right? This is. These are the drivers. Interesting.
Susan - 00:28:44: Yeah, and then the FDA in the guidance when they finally issue it, they are supposed to communicate as to their expectations on control strategies relative to EPRs. But the key message there is that it's not just the EPRs, it's all those things that lead to compromised medical care that you've gotta be paying attention to. But specifically to EPRs, selecting the right specifications, making sure that you're doing verification validation relative to those EPRs is key.
Shannon - 00:29:13: I think this will be another area that'll be important to that what you talked about earlier on some of the harmonizations because it could be interpreted very broadly and then we can end up with a bunch of interpretations right?
Susan - 00:29:24: Yeah like the GSPRs in Europe are different right? So we talk about general safety performance requirements we're like but that's not the same as essential performance requirements like oh my god here we go.
Shannon - 00:29:34: Yeah.
Stephanie - 00:29:35: Yep agree I've had that conversation many times.
Shannon - 00:29:40: So working out a common approach and even common interpretation, be that through examples, through standards. Excellent. Well, I for one am very thankful for all of the work that you lead and participate in in making these things happen both through the ISPE and AAMI and this book that is now available for folks to review. And I appreciate how you pull in other experts as well to contribute in those. and inform those. So I think it moves us all along, right? Keep moving.
Susan - 00:30:16: Well, thank you for partnering with me on the journey. We're all on a journey together.
Shannon - 00:30:20: Absolutely.
Susan - 00:30:21: Thank you.
Shannon - 00:30:22: So before we wrap up, question, how can the listeners get access to your book and learn more?
Susan - 00:30:30: Sure, so you can access the book on the, you can get it on Amazon, but the better way to get it right now, cause I have a discount code, is on the routledge.com website is www. HYPERLINK "http://www.routledge.com/"routledge.com. and you can look up the Combinations Products Handbook, a practical guide on that website. And the discount code is S253. Gives you like 25% off or something. Um, and you can reach me through LinkedIn or you can contact me on my email. It's sneadle@combinationprod.com.
Shannon - 00:31:17: Excellent, and we'll put those in the links in the notes as well. So Stephanie, I think I'm probably speaking for you. I feel the same this way about whenever I have a chance to talk to Susan, I always learn something in that conversation.
Stephanie - 00:31:30: Yes.
Shannon - 00:31:31: So I'm very appreciative to have you both here today. Thank you again. It's been a great deep dive into considerations for Combination Products. And thanks to our listeners.
Outro - 00:31:48: That was Susan Neadle and Stephanie Canfield. By the way, Susan's book, The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined Use Systems, is available wherever books are sold. Click the link in the show notes to get your copy. Thank you so much for listening to or watching this episode. Please subscribe or follow this podcast on whatever app you're using right now. Or follow Agilis by Kymanox on LinkedIn for all updates. This Episode is edited and produced by Earfluence. We'll talk with you again soon on The Factor.
Stay tuned next week as we meet with Richard Houilhan and discuss EUDAMED.
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