The Combination Products Handbook

Combination products are a difficult niche because they combine so many different elements. However, today’s guest literally wrote the book on the topic, and she’s joining the podcast to share her insights. In today’s episode, Susan Neadle and I spoke on the topic of Combination Products, and specifically how she recently wrote the Handbook on this topic, with many co-authors from FDA.

Susan is a recognized international Combination Products and Medical Device expert with over 30 years of industry experience. Her FDA peer-reviewed book, “The Combination Products Handbook: A Practical Guide” is available for purchase through CRC Press. Listen to the episode to hear about her past experience and how she ended up in products, how the different chapters of her book came to be, and how her collaborators were involved.

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Some of the highlights of this episode include:

• Susan’s past experiences in the industry

• How Susan got into the combination products space

• Specific examples of the multilingual approach Susan had to take

• How the different chapters in Susan’s books evolved and who collaborated with her

• What it was like to work with so many different professionals on the book

• Thoughts about challenges that may be addressed in the future

• How to harmonize language differences in the glossary

• Overcoming the challenge of being a niche within a niche and juggling multiple fields

• How industry knowledge interacted with FDA knowledge

Links:

Susan Neadle on LinkedIn

20% Discount for  The Combination Products Handbook

Combination Products Consulting

Etienne Nichols LinkedIn

Greenlight Guru Academy

Greenlight Guru

Memorable quotes from Susan Neadle:

“It was really a great adventure, being there right at the ground level when it all started.”

“If people aren’t able to use the product effectively, they’re not going to take their drug, which means all sorts of other ramifications.”

“It’s important to understand what are the combination inspection product criteria.”

“It was great, although it would have been much easier if I was trying to write the book by myself, because I have control of my own timelines.”

Transcript

Announcer: Welcome to the Global Medical Device Podcast, where today's brightest minds in the medical device industry go to get their most useful and actionable insider knowledge direct from some of the world's leading medical device experts and companies.

Etienne Nichols: Hey, everyone. Welcome back to the podcast. My name is Etienne Nichols, and I am the host of today's episode. Today, we got to speak with Susan Neadle. And if you're not familiar with her, she's an expert on combination products, and specifically, she wrote the book on it. It's coming out May 9th, probably already out in your timezone, The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined Use Systems. I want to get that right because I kept calling it The Handbook for Combination Products, which is not what it's called. It's The Combination Products Handbook. When I saw that she published this, I had to reach out to her and I didn't even know the extent of her experience. I was impressed with just what I saw, but Susan Neadle is a recognized international combination products and medical device expert with over 30 years of industry experience. Her leadership, her innovation, and her best practices have been recognized with multiple awards, including the 2022 ISPE Joseph X the Phillips Professional at Achievement Award for Significant Contributions as an integrator of industry and regulators, the Johnson Medal, Johnson& Johnson's highest honor for excellence in research and development, and as a finalist in TOPRA's 2021 Award for Regulatory Affairs Excellence. She's a principal consultant now and the president of Combination Products Consulting Services. Among her contributions, she serves as chair of the ISPE Combination Products COP and lead author for both ASTM International and AAMI Combination Product Steering Committee Standards. She serves as a faculty at University of Maryland Baltimore County Campus College of Natural and Mathematical Sciences and at AAMI for Combination Products and Medical Device Quality System Curricula. She speaks frequently at public venues on wide- ranging combination product topics. Her FDA peer- reviewed book, as I mentioned, The Combination Products Handbook: A Practical Guide, is available for purchase through CRC Press. I could keep going on because her bio keeps going on. As you can see, she is well- connected and well- known in the industry. She used those contacts to write this book. You'll find out a little bit more about that in a minute, including a lot of FDA contacts. We hope you enjoy this episode from Susan Neadle on The Combination Products Handbook and a little bit more on the combination products industry. Hey, everyone. Welcome back to the Global Medical Device Podcast. My name is Etienne Nichols. I'm the host of today's episode. Today with me is Susan Neadle from the Combination Products Consulting Services. I hope I got that right, Susan. How are you doing today?

Susan Neadle: You got it. Very good. Nice to meet everybody.

Etienne Nichols: She is also the author of The Handbook of Combination Products, and this is somehow I guess how you got on my radar on LinkedIn. I follow several people, but several people started promoting this and I said, " What is this handbook? I've got to get my hands on it." I thought, you know what? I'm just going to jump the gun and try to talk to the author. Thank you so much for being on the podcast today.

Susan Neadle: Thank you. Well, thanks for having me. I'm excited to be here.

Etienne Nichols: One of the things that I'm curious about, I've been giving myself the advice lately, pay attention to your heroes because that may inform what you think is important. For some reason, I hold authors in high regard. It seems like an insurmountable task. Maybe I'm getting ahead of myself. Maybe we could talk a little bit about your combination of products, how you even got into that and a little bit of your past. Let's do that first. Do you want to talk a little bit about your experience?

Susan Neadle: Sure. Over my career, I worked at Johnson& Johnson for many years. Prior to that, I worked at Unilever and Organon Teknika. I've worked in a number of companies. Early in my career, I started doing work mostly in medical devices, some in vitro diagnostic, and a little peppering of consumer health products. While I was working in medical devices, I got involved in combination products in the beginning in a product that was proprietary, so I really won't talk about it. However, I started getting really intrigued the space of, hey, you know what? I've developed all of these years of experience in medical devices, and huh, it's kind of fun to see what the drug side is like. Combination products really gave me this opportunity to be playing in both worlds. As I moved along my career in medical devices, and I actually was working in vision care. I'm a fellow in the American Academy of Optometry, a fellow in the British Contact Lens Association. After I got these fellowships, I was like, okay, what else can I do to challenge myself? And I jumped over to the pharmaceutical sector. While I was working in pharma, my very first role was focused on combination products. What I started to realize is, hey, this is a really growing area. I also started to realize that people in the device world use certain vocabulary and people in the pharma world use the exact same vocabulary. The definitions are different. Oops! That became my first awakening in the combination products world, and all of a sudden, I became an interpreter because I had to live in both worlds and I had to make sure that people understood what I was articulating. I got really good at being multilingual, because even biologics world is a little bit different interpretation than the drug world, than the device world. All of a sudden, it's like I'm working with people and I had to be able to seamlessly move between interpretations as I would communicate. That was the beginnings of it. I really enjoyed working in the combination product space. I was working at Janssen Pharmaceutical at that time, right around when 21 CFR Part 4, which is in the US, the combination products regulations for CGMPs, went into effect. My job was to stand up the quality system to support that for the pharmaceutical sector of J& J, and then later to do it more broadly, supporting the different segments of J& J to enable their quality systems to be compliant. It was really a great adventure being there right at the ground level when it all started. As these regulations would evolve, it's like, wow, I have to be there real time to be able to be on top of what's happening and help shape it. That's how it started.

Etienne Nichols: That's fantastic. It's interesting because I stumbled into combination products. I didn't know a lot about them. Worked primarily in medical devices, became a project manager for a drug delivery combination product, and I experienced the same thing. I liaised between the pharma partners that we were working with multiple. I didn't catch it as well as it sounds like maybe you did, but the differences in terminology, I probably needed the handbook back then. We just had this conversation. Why are we misunderstanding each other? You could pretty much guarantee if they were primarily pharma, that was their background, they would misunderstand me on this. I started to get the pieces together, but I didn't quite get to the other side of it. But just one example I could throw out was when to do a CAPA. That seems to be a different world, whether it's pharma or... Anyway, there's lots of different little nuances about that that I'm curious if maybe you have more advice on. I wonder if you have any specific examples about the multilingual approach you had to take.

Susan Neadle: My favorite one to pick on is the word package. Such a simple word, package, right? Well, if I'm a pharma person, package is my container closure. It's the thing that focuses to ensure the integrity of the drug, to protect that drug and hold the drug. Many times that device, like a syringe, is a package in the drug world. They consider it a container closure versus in the device world. But that's the medical device, right?

Etienne Nichols: That's our thing. Yeah.

Susan Neadle: I'm like, you're talking to people. A great example then is like, what are the ramifications of that? If you get into supplier quality, the things that are the important constituent parts or components of a combination product of any drug product are things that, well, because they're critical, I'm going to audit the suppliers of those things more frequently. However, well, if it's just the package, eh, I can go a little bit longer before I re- audit them, versus I'm sitting here as a device person going, no, you've got to be looking at that frequently. It's critical. At least annually be looking at those. What you started to see was because people interpreted the word package differently, people would take actions relative to their quality system implications differently just because they interpreted the word differently. If I'm a pharma person, it's like, ah, that's just the package. I'm the device person, I'm going, that's the device. You can just see the way I'm emphasizing it. That's the attitude that you would run into within the company that the people that are pharma- based are very focused on the therapeutic effect that comes with that drug. The perception sometimes is, well, the drug is all that really matters. I'd say that the thought process has matured since then, but early on that was very much people's mindset. It's all about the drug. The device people understood it wasn't just all about the device, but the user interface. That device is critical. If people aren't able to use the product effectively, they're not going to take their drug, which means all sorts of other ramifications, right? Oh wait, they can't take it effectively, complaints go up. Oh, sales go down. User compliance goes down. Really you've got to be thinking holistically, and that's the fun for me. But the magic with combination products is teaching people to think holistically, always think about each constituent part, and then what are the interactions and considerations for the combination product as a whole.

Etienne Nichols: Yeah, that's a great example. I guess we all tend to think in our different world that the universe revolves around us to a certain degree. Maybe we can dive into a little bit more later on how you evolved that thinking, but I do want to start talking a little bit about the book. How did you decide to write this book, or when in your career did you think, okay, I'm going to do this? What was the motivation there?

Susan Neadle: Late in my career at J& J, I'd been there for over 26 years, I had been traveling a lot, a lot, a lot. Right around when the pandemic hit, it actually was irrelevant that the pandemic was there. I was like, you know what? I'm done traveling a lot. I want to be able to slow down. At that point, I decided I was going to, ha ha, I was going to retire. We figured out I don't know how to retire, so that's why I was going ha ha. But as I made the decision that I'd retire, I was like, but I've got all this knowledge stored up that I don't want it to just go to waste and retire and go do other things. I want to find a way to give back. At that point, I actually reached out to the FDA to find out if they were willing to work on it with me. I spoke to John Barr Weiner, he's the associate director for the Office of Combination Products, and he agreed to help peer review the book as it was being written. That was huge, because for me, I didn't want to just get a book out. I wanted to get a book out that I knew was going to be relevant and that the FDA would look on it and say, " Yes, this is a good resource." That was an interesting experience right there, because then as I would write each chapter, until Barr was satisfied that all the chapters met expectations. His chapter, which is the introduction to the book, was held hijacked. I could not get his chapter until everybody was satisfied with the entire book. But it was a great experience because as I and the other authors that contributed to the book were writing and then getting the feedback from the FDA, so he would reach out to others in the centers to get feedback, as we get the feedback, sometimes it was hard because it was like, wait, but that's not the thinking the industry had. Well, but this is the thinking. It's a timely resource because in the United States, the combination product regulations, even though there's still opportunities, are fairly mature, especially when compared to other jurisdictions around the world. Being able to get a document in place that people could go to as a reference that gets the majority of information in one place was helpful. Working with the FDA on that was great. And then I'm involved in several industry working groups, and I teach at University of Maryland Baltimore Campus, and that was actually one of the other triggers for the book. I've been teaching for the last few years at University of Maryland and there's like no book to refer to. It was always like, okay, there's the presentation slides each time, but there's really no reference for people to go look at other than, well, here's the guidance from this country and this country and this country. People are looking all over the place trying to get information. I was like, let's create a consolidated resource that people can go to. That was another impetus for it. I started reaching out to subject matter experts that I work with in these various industry working groups. I also chair the ISPE, International Society for Pharmaceutical Engineers Combination Products Community Practice. I reached out to some of my colleagues in that forum and really were able to pull together a group of really solid authors and co- authors to contribute to writing the book. And there you have it. That's the book.

Etienne Nichols: Yeah, that's a great story. I love the interaction with the FDA. That's got to give a lot of credibility to the book itself, to the industry. Curious, I know there's a lot of other authors or co- authors. I mean, it's a long list. Can you talk about a few of them? I know you're probably going to, well, you don't want to leave anyone out, but I didn't know if you could tell us about some of them or all of them, however you want to answer that.

Susan Neadle: I can probably tell you about all of them because I have the... We talked. I have the table of contents kind of memorized. I've been working on this for so long. The book starts out with an introduction by John Barr Wiener, and he's from Office of Combination Products. He really gives some insights into his perspective about how the combination products regulations came about and also a bit of a comparison to some of the practices and perspectives behind those regulations and how they also apply globally. While I had FDA peer review it, I also had people internationally reviewing it because it needs to be accurate and it does reflect the thoughts going across some global jurisdictions. In his introduction, he actually refers to some of the global jurisdictions and how it plays with them. That was good. The next chapter is what is a combination product? I wrote that chapter. What's behind that is that not every country either uses the terminology combination product or even calls it that. Some of them referred to combined use applications. Actually, if you look carefully at the title of the book, it's called The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined use Systems. This chapter very much gets at that, the fact that they're not all called combination products, but the considerations that underlie these systems, regardless of what you call them, are pretty consistent going across the world. That's that chapter. Then the next chapter is around regulatory strategies. Suzette Roan, who's currently a vice president of regulatory at Sanofi, authored that. Suzette and I have been actively engaged for multiple years at Xavier Health Combination Product Summit, which is now AFDO/ RAPS, which is how we got to know each other. Suzette did a wonderful job on that regulatory chapter, which also triggered a lot of great conversation with the FDA as we were writing it. It was almost an opportunity as we wrote the book to be able to challenge some practices and make sure that we really understood some things that we thought were the approach to take. And then based on this dialogue with FDA, we refined it in the book. Again, everybody gets to learn from the lessons we learned as we were writing it. Go ahead.

Etienne Nichols: Sorry, just to interject, something someone told me a long time ago, you don't really know what you think until you write it down. It seems like that was going on here.

Susan Neadle: Oh my goodness, that is the truth.

Etienne Nichols: That's interesting. Wow! Okay, don't mean to interrupt. Go ahead.

Susan Neadle: Oh no, it's okay. The next chapter I co- wrote with a gentleman named Mike Wallenstein. Mike works at Novartis, and he and I actually became friends and colleagues through EFPIA, which is a European pharmaceutical industry association, where I sat on the combination product CGMP working group. Mike actually helped me with the chapter on what are the CGMPs for combination products, and it goes at it both from US and Europe, because the reality is both of those approaches are the main types of approaches globally. There's differences, obviously jurisdiction to jurisdiction, but generally you could use those as the two umbrella approaches for CGMPs. We go into EUMDR a bit in addition to the Part 4 streamlined approach and the expectations under that. Then the next chapter I wrote myself. It's called integrated development. Some of the challenges that people run into with combination products is, wait, I apply quality by design to develop my drug. I applied design controls to develop my medical device. Wait, it's a combination product. I need to integrate the two. That's what that chapter goes into. It's the how do you actually integrate both approaches? How can you leverage your quality by design documentation that you've already generated without having to repeat? How maybe does your design controls actually cover some of the activities that you might have even done in QBD? That's that chapter.

Etienne Nichols: I want to read that one. I want to get my hands on that chapter for sure.

Susan Neadle: And then the next chapter I can honestly say is my personal favorite and the entire book, it's Combination Products Risk Management. I wrote that chapter together with Rick Wedge, who's out of Pfizer, and Ed Bills, who's a medical device risk management subject matter expert. I think the collaborative between the three of us was really good. That one chapter could be a book by itself, because combination products risk management does trip people up. We tried to make it very practical and help people understand how do I integrate ICH Q9(R1), which is quality risk management for pharmaceuticals, with ISO 14971 for devices. AAMI came out with a standard, AAMI TIR105, which talks about combination product risk management, but people are still struggling with the how and also something called platform approaches. If I create a device platform and I want to apply it across multiple drug products, how can I do my risk management? Do I have to repeat it over and over? What can I leverage? What can't I leverage? What is my supplier responsible for versus the sponsor responsible for? We cover that in that chapter. It was a very robust chapter. The next chapter was co- authored by a number of authors, Shannon Hoste, Stephanie Canfield. They're both out of Agilis, which just got acquired by Kymanox. Me, Bjørg Hunter, who's at Novo Nordisk and Theresa Schubalada Jansen. That particular chapter is a case study chapter on human factors for combination products. People can read the guidances. The guidances are fairly well- written, even though there's complaints on all sides about the interpretation of the word critical task, which means something different for devices and drugs. But even that said, how do I practically apply what's expected for combination products risk management? And that's what we built into that chapter. I said, risk management, I meant human factors. The next chapter I wrote with the assistance of Khaudeja Bano, Khaudeja is a vice president at. Amgen. She and I go way back because we became friends and colleagues, especially best friends actually through Xavier Health and now AFDO/ RAPS and different communities of practice. We're doing presentations together a lot. Her focus area is post- market safety reporting and my focus is lifecycle management. This particular chapter goes through the lifecycle management of combination products from design transfer all the way through, what do you have to deal with post- market? You mentioned CAPA earlier. CAPA is one of those considerations, how it's interpreted differently and what do you need to do and process validation and how that's interpreted differently for drugs versus devices and for combination products. It goes through all those elements. And then post- market safety reporting 21 CFR Part 4B is something that has challenged people in industry. Although industry is getting pretty good at it, I think from the FDA, they're not having huge issues with it other than they wish there was a little bit more reporting being done on some things. But we actually give some guidance within the chapter on here's some best practices to consider and some things that will help you meet F DA expectations. The following chapter, and this whole first half that I've been talking about is the foundational part of the book. The next chapter is combination products inspection readiness. Once you've done all those things that we've talked about until now, you've got an inspection sitting in front of you. How do you deal with that? The FDA issued in June of 2020 a combination products inspection program. We talked to what that inspection program is about. There's also... I think not in this chapter. I'm jumping the gun a little bit, but I'll mention it. There's a challenge right now in that the US does do inspections on each constituent part for a combination product when they do inspections. In Europe, if you have a medicinal- led combination product, other than a paperwork exercise to review what's called the General Safety Performance Requirements, the Annex 1 requirements of the EU MDR, they don't actually do an inspection against that if you don't have a CE marked device constituent part. Because of that, the mutual recognition agreement that holds between countries for pharmaceutical inspections does not apply for combination products. It's important to understand what are the combination product inspection criteria. And then we do have working groups right now that I'm actually chairing one through ASTM International to try to drive harmonization relative to the CGMPs. Maybe that will become a stepping stone for the FDA and others to move towards harmonization for inspections. The last part of the book we call it special topics, and the special topics includes supplier quality considerations. Fren DeGrazio, who recently retired from West Pharmaceutical, co- authored that together with Mira Ragarom, who's from Lubrizol. They go through what are the supplier quality things that you've got to pay attention to when it comes to combination products, because almost all, not every, but the large majority of combination product manufacturers will purchase at least one constituent part to make up that combination product. How do you deal with that? What supplier quality agreements, what other considerations need to be taken into account? We address that in that chapter. Then Jennifer Riter and Daniel Vance. Daniel recently retired. Jennifer is still there. They're both from West Pharmaceutical. They wrote a chapter on analytical testing considerations for combination products and all the things that you have to think about, whether it's stability or container closure integrity, all the different USP criteria that you got to address when it comes to combination product testing. Manfred Maeder, who actually co- teaches with me at University of Maryland, and he is a vice president of research and development at Novartis. He wrote a chapter on biologic considerations because so many of the combination products out there now, especially in the oncology space, are biological products. That's what that chapter covers. And then Ryan McGowan, who's ex- FDA, and he's now at AstraZeneca, he wrote a chapter on connected health, which in his digital age I know a lot of people will be interested in that chapter. And then finally, I worked together with Stephanie Göbel, Viky Verna and Sherry Marty, and we authored a book on the global evolving regulatory environment for combination products, which goes through quite a number of regions and the things that you have to take into account. The whole book is capped off by an appendix and a glossary. The appendix is about 80 pages of a review, including quick links, to all the different health authorities around the world and their interpretations of combination products and things that you need to consider, and a glossary, which is your one stop, here's all the words that you need to think about for combo. That's it.

Etienne Nichols: The lingo. The jargon. All of it. That's great. I actually wanted to ask you about that. First of all, thank you for going through that in such detail. You have memorized it. I mean, I know you have your notes, but I'm sure all of that just rolled off the tongue. I'm very impressed. It's so cool, but the thing that I wanted to bring out is the word handbook in the title. I was curious how much of that actually got applied. It sounds like you really thought about that word when you were... Because I think, okay, boots on the ground, I just need to flip through this. I'm not going to read through it all at once. I'm going to use it when I need it. Is that the idea?

Susan Neadle: Yeah. You go to the part that you need. God bless the person that does go through it end to end. I had to do that a number of times as part of the publishing review process. I was like, oh my gosh, not again. That was a whole learning experience in and of itself for myself, but truly, you can go to the index. If you have a soft copy of it, you can do the search by term platform technologies, things like that, and it will take you to parts of the book that will really guide you. This is what you need to pay attention to for that activity that you're trying to do.

Etienne Nichols: Yeah, that makes sense. I don't know if you could see it. I mean, when I think of it, I think of like I'm pointing at my machinery's handbook up there. It's blurred out in the background, but something like-

Susan Neadle: Oh, I do see it.

Etienne Nichols: Well, something like that for combination products. Every engineer has this. Every combination product engineer probably needs something along these lines. I think that's really cool.

Susan Neadle: I'm really hoping it brings value to the industry, and it was intended to be that kind of a resource and because it does touch on multiple jurisdictions. Yes, there is a lot in the United States just because it is so mature, but it does cover other jurisdictions too. People should be able to pull it off the shelf and go, " Hey, wait, what do I do if I'm going to India?" Well, India doesn't have combination product regulations. They're going to follow device approach. It's going to guide you in some of that.

Etienne Nichols: Okay, that's really fantastic. You mentioned a few of those people were your friends, and I don't know if it strengthened the friendship or tested the friendship. I'm curious what it was like to be a conductor of such an orchestra of professionals.

Susan Neadle: It was great, although it would've been much easier if I was trying to write the book by myself because I have control over my own timelines. It was a challenge because you're also pulling together a lot of different writing styles, and you have to make it cohesive and make sure nothing's missing. And then truly topping it off with... And then I give it to the FDA and we get feedback and we have to rewrite something. It's like, oh my gosh. It was a lot of work, but it really strengthened the relationships though. I mean, we've all become, I think, really good friends and knowing that we've done something impactful for the industry. Also, it's like a mutual. We're really proud of it. I think it's good.

Etienne Nichols: Earlier on, you mentioned that, see if I can remember exactly, that the FDA's approach to combination of product is pretty mature, and that was encouraging to hear, I mean, especially from a professional such as yourself with such experience. But you also mentioned while there may be gaps, and I'm curious if you could mention how some of the... Maybe if we look to the future, what are some areas that could potentially mature even further? Any thoughts as you look to the future?

Susan Neadle: There's a couple of areas that stand out that they're really still challenging industry. Experienced professionals are really dealing with things like bridging activities. How do you decide when to bridge, and how can you justify potentially not conducting studies? Like for PK or bioequivalence, it's not readily accepted by the FDA, what's the approach that's appropriate for that? We're expecting some final guidance from the FDA on that. Essential performance requirements seems to also be a favorite topic. I will say that as I was writing about essential performance requirements in this book, we did get helpful insights from the back and forth with the FDA to shape what was written. I understand it's going to be like a 60, 70, God knows, how many page guidance document when it finally issues. It's going to be a pretty robust guidance document that issues. But before it does, people are really struggling to understand what are the expectations. There is no formal definition for essential performance requirement. There's parallels, essential principles under the IMDRF, the essential requirements, the general safety and performance requirements from the EU MDR, but there's not clear definition for EPRs. Because the FDA is indeed pushing back on sponsors who put in their applications with explicit expectations, whether it's preconditioning or whatever, when it comes to EPRs, it's a big challenge. Getting that clarity. Human factors for combination products is also a challenge and we are expecting final guidance to issue on that as well. There was draft guidance back in 2016. But in that particular space, the challenge is that some people think, oh, I need to apply the device approach. CDRH just came out with a guidance, again, for medical device human factors. Okay, but that doesn't match up with DMEPA, the Division for Medication Error Prevention, who leads the combination product human factor space. There's terminology differences. The word critical task in particular, I mentioned it earlier, is distinctly differently interpreted. In the device space, critical task is something that is related to a severe harm. In the drug space and for combination products, the word severe is not in the vocabulary. It's about does it compromise medical care? It's a much broader scope. That really is problematic for people that are practicing human factors in this space. Like I said, there's a few areas where there's a need to tweak some things.

Etienne Nichols: But the cool thing about that is if that draft guidance is coming maybe around EPRs, it sounds like you've already had that conversation, so what you already have written, I assume, will be already harmless.

Susan Neadle: It will reflect some of it. Obviously the FDA cannot unfairly share, oh, here's what it says. Can't do that. However, the spirit of what's behind in EPR is captured within the book.

Etienne Nichols: Yeah, that's very cool. The glossary, I had a question about that. Because of the difference in language between whether it's drug, biologic, or medical device and so on, how did you harmonize that with the glossary?

Susan Neadle: I actually listed all three. I listed. If I look up the word critical task, it states this is what it is in CDRH, this is what it is in CDER, and this is what it is when it's a combination product. Same thing for the word manufacturer, that's another good one. The word manufacturer is in interpreted one way for device manufacturers. It includes design and specification development. For drug manufacturers, it's got a different interpretation. For biological manufacturers, it's got a different interpretation. And then there's combination product manufacturers. It combines them all. That's covered as well in the book.

Etienne Nichols: That's fantastic. In my experience, and maybe this is going back to the beginning of our conversation, so apologies for circling the wagons here, but in my experience, combination products are niche within a niche. If you have experience or knowledge of combination products, it's like you're a dark unicorn or something strange in the world. I don't know. I just made that one up. But is that your experience?

Susan Neadle: You start buying a horn that I can wear.

Etienne Nichols: That's right. Black swan and a uni... I don't know. But is that your experience and do you see that changing? And if so, how do we overcome that challenge?

Susan Neadle: I do think it started that way. I think it's starting to evolve. That's part of the reason why we even have courses like the one that we teach at UMBC. I also teach combination products curriculum through AAMI, and I teach it through my own business. When you look at that combination product space, more and more manufacturers are understanding that they need to make sure that their different groups, whether it's their pharm people, their device people, all need to get trained in the language of combo because it's an increasing part of their business. Especially, like I said, oncology space. Most of these oncology drugs are combination products, and that's a huge growing area. What are you going to do if you don't understand combination products? We're educating. And then when I've been teaching, I'll pick on the AAMI classes, I can actually tell you that there's a number of health authorities from around the world who have been attending those classes too, because the health authorities are trying to up their game and shape some of the regulations they're coming out with. I think that people are recognizing it. The master's curriculum that we have at UMBC and there's other universities that are increasingly doing it, you've got to be able to bring people's competency up so that the industry is going to be able to grow more seamlessly. It can't be this, let's put it over on the side. You've got to integrate it into your CMC stage gates. These are the deliverables for the device and the combination product, not just the drug. If you're a device company, these are the deliverables for the drug constituent part, not just the device. Like I said in the beginning, you've got to be thinking each constituent part combination product as a whole in everything you do.

Etienne Nichols: Yeah, that's great. I almost feel silly asking this next question, but I'm going to ask it anyway, and that is, every combination product expert is probably going to fall into some pitfalls, and maybe it depends on which side of the fence they're on as far as the device constituent or the drug constituent. My specific question would be, what advice do you have? You wrote a book, so it's probably read the book.

Susan Neadle: Read chapter five.

Etienne Nichols: Okay. Well, chapter five. Okay, all right, I'll put that in the show notes just to make sure everybody's aware. Just the pitfalls people get into. I mean, the practical advice. I love that you had the interact between FDA. How was the industry, just the boots on the ground knowledge interacted with the FDA knowledge? I mean, I'm curious how that blended.

Susan Neadle: It actually wasn't hard, because the intent of the book was to drive best practices as well. When the FDA communicates, the FDA is sharing with you, these are the bare minimum expectations that we have. The guidance documents are not theoretically enforceable, but they do reflect the FDA's current state- of- the- art thinking. You are expected to be performing current state- of- the- art or document justification or rationale for why what you're doing is appropriate if it's not aligned with that current state- of- the- art approach. I think having the dialogue to just state this is what industry does and or thinks and being general, because every industry, every company has their own unique take on the approach or the spin on it. But there's some general themes in how people approach it, which I can honestly say too, when I finished my main career that I had done for so many years and went into consulting, what I started to see going from company to company as I go to different clients is that, oh, look at that, they all have the same exact issues. They call it something different, or they all think that they're alone and woe is me, I'm the only one that's suffering this poor, terrible thing. But for better or for worse, it's the exact same stuff. Recognizing that actually made it easier to be able to reflect in the book, here's some common practices and here's the best practice that's probably going to help you cope with whatever this is. I think the risk management chapter is a good example of that, where over and over, I hear companies struggling to do risk management for combination products. Here's some basic practices, and here's what the definition and the interpretation of harm and hazard and hazardous situation really is. Don't get yourself into a bind because ultimately what matters is what's the overall residual risks in that product that the patient or the user is going to have to contend with? Have you addressed those? Because if you haven't, they don't care if you used ISO 14971 or ICH Q9. They care that they're dealing with those residual risks. Work on your control strategy and how to do that.

Etienne Nichols: Yeah, that's good advice. Risk management is such a controversial topic in and of itself, even if you're only in medical devices. Blending two industries, you have to finesse that, I'm sure. I'm excited to see what you have written in there. Well, thank you for all the work that you put into this. I really appreciate it. I appreciate the passion you have for it and also the motivation. It seems very pure just to help the industry. I really appreciate that.

Susan Neadle: Thank you. It really is. It's like, okay, now maybe I can retire. Yeah, right, it won't happen, but okay, I can try.

Etienne Nichols: Well, now you have the freedom to do whatever you want. That's great. Where can people find whether it's you or how to find the book? Of course, we'll put a link in the show notes, but what's the best place to find you?

Susan Neadle: Me, you can get me on LinkedIn or my email address is sitting right up above my head there, sneadle@combinationprod.com. You can reach out to me there. You can reach out to me on LinkedIn. And then the book, you can go onto the Routledge website, and I'll send you the link with a discount code too. You can go directly onto the Routledge website, or you can go through... I've actually seen it on Amazon, which I was like, oh, wow, I'm selling something on Amazon. That's so cool. I never knew I could do that.

Etienne Nichols: All right. Well, very cool. Any last words or a piece of advice for the listeners?

Susan Neadle: I truly do hope that the book brings value to you. If you have any feedback, reach out to me with that too, because second edition's always down the road. It won't happen this year. Okay? I need a break.

Etienne Nichols: Change is inevitable. No, I understand. Very much appreciate it. Okay, well, I'll let you get back to it. You're a busy person and appreciate all the work you've done already. We will see you next time.

Susan Neadle: All right, sounds good. Thanks again for having me.

Etienne Nichols: Thank you so much for listening. There were a few things we talked about after we got off the recording that I wish that we'd had continued to record. She told the story about how when the World Health Organization, the WHO, medical device regulatory built a regulatory framework around combination products, the first draft mentioned combination products was in a throw your hands up approach. The ISPE, the International Society for Pharmaceutical Engineers, told her, " You shouldn't be throwing your hands up. You should be the ones to show the standardized approach. The rest of the world is looking to you." The WHO, the World Health Organization, adopted their terminology. It's a great story. It's really interesting. If you want to hear more about it probably better told than what I can do, reach out to Susan Neadle on LinkedIn and ask her about that. I hope you enjoyed the episode. If you want to know more about our award- winning software, you can go check that out at www.greenlight.guru. Whether it's document management system, CAPA management system, design controls, or our risk management system, or our EDC, our electronic data capture for clinical investigations, this is software built by MedTech professionals for MedTech professionals. Check it out at www.greenlight.guru. Finally, please consider leaving us a review on iTunes. It helps others find us and it lets us know how we're doing. Thanks again. We'll let you get back to the rest of your day. Take care.

About the Global Medical Device Podcast:

The Global Medical Device Podcast powered by Greenlight Guru is where today's brightest minds in the medical device industry go to get their most useful and actionable insider knowledge, direct from some of the world's leading medical device experts and companies.

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