Part 1: Winning Formula - 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 community Susan is creating to promote discussion and action around regulatory guidance for Combination Products.
Memorable Quotes:
“It's a handbook. It's intended to provide practical recommendations and case examples and examples of warning letters, things like that, to help people who are trying to get into this space. It looks at it both from the US, so I told you the FDA peer reviewed it, but it also looks at it globally. And we had a number of contributing authors from other regions in the world, whether it be Europe or Singapore, we really had people from all over the place contributing to it.” - Susan Neadle.
“ A lot of people see human factors as a checkbox at the end. It's something they need to do for design controls to get their design validation done, not realizing it's something that should be done throughout the entire lifecycle.” - Stephanie Canfield
“ Most recently there was a guidance that the FDA issued on human factors. It was medical device focused Stephanie led the charge within the Community of Practice to submit comments to the FDA in response to that guidance. .” - Susan Neadle
Show Links:
Purchase Susan Neadle’s book: HERE
Transcript:
Intro: Hi everyone, and welcome to The Factor, A global medical device podcast series powered by Agilis by Kymanox. Today's episode is hosted by Shannon Hoste, President of Agilis by Kymanox, and Assistant Professor in the Quality Education Program at Pathway for Patient Health. With Shannon today are Susan Neadle and Stephanie Canfield. Stephanie is a Senior Consultant in human factors engineering with Agilis by Kymanox. And Susan Neadle is a recognized international Combination Products expert with over years of industry experience. She recently wrote the Combination Products Handbook. a practical guide for Combination Products and other combined use systems. And that's part of what they'll be talking about today. Here's Shannon.
Shannon - 00:00:54: Together we'll be discussing the top considerations in Combination Products. So thank you for joining us. So first off, Susan, how are you today?
Susan - 00:01:01: Good, thanks for having me. I'm excited to be here.
Shannon - 00:01:04: Excellent. How are you doing Stephanie?
Stephanie - 00:01:07: I'm good. I'm excited to be here and have a chat with the three of us.
Shannon - 00:01:11:Excellent. So congratulations on your book, Susan.
Susan - 00:01:15: Thank you.
Shannon - 00:01:17: Do you want to tell us a little bit about it?
Susan - 00:01:19: Sure. Well, so you and Stephanie were both contributing authors, so you know a bit about it. I started on it about three years ago, right around just before I retired from my career at J&J. I worked for Johnson & Johnson over years. One of the roles that I had while I was at J&J was actually heading up Combination Products. We had a center of excellence in the pharmaceutical sector and then a community of practice for J&J worldwide. So I headed up both of those. And as part of that, I got experience working on Combination Products end to end, from pre-market all the way through post-market. And when I retired, I was like, you know, I've got all this knowledge stuck in my head. I want to put it someplace. And at that time I actually reached out to the FDA to see if they'd be willing to peer review a book because I really wanted it to be something that would bring value to industry. And then I've been teaching a course at University of Maryland in Combination Products for the last several years. And there was no course book that went with that curriculum either. So I was like, you know, I should take together some of this past stuff that I've been thinking about and then the coursework and consolidate it all into one handbook, Combination Products, a practical guide for Combination Products and combined use systems. So a little bit of a long name there, but the key is it's a handbook. It's intended to provide practical recommendations and case examples and examples of warning letters, things like that, to help people who are trying to get into this space. It looks at it both from the US, so I told you the FDA peer reviewed it, but it also looks at it globally. And we had a number of contributing authors from other regions in the world, whether it be Europe or Singapore, we really had people from all over the place contributing to it. to make sure that it was a well-rounded book and would really bring value to the people that read it. I don't know, if you want, I could go through the table of contents. I know it by heart. I worked on it so long.
Shannon - 00:03:15: Excellent. Yeah, let me ask a quick question first. So from the peer review from the FDA, who was involved in that with you?
Susan - 00:03:27: John Barr Weiner, who is Assistant Director at the Office of Combination Products was the main point of contact. And then he reached out through others throughout the FDA to get feedback early on. And I can honestly tell you that I learned a lot about writing going through this because when the FDA would give feedback, it was extremely constructive. It was very focused on making it writing that would not go stale. So it's very focused on considerations and practices, irrespective of what a current guidance or standard says, but rather focused on why are you doing it and what are you doing because of that why, and then giving examples that would help people understand that. Because the reality is the regulations, the guidance, they're different all around the world, but the fundamental risk-based considerations that are underneath the things that you do for effective combination product development and risk management and lifecycle management really are common regardless of the region, despite the different regulations and whatnot across jurisdictions.
Shannon - 00:04:37: That's a very good point. So let's see, first off, Stephanie, what chapter did you work on?
Stephanie - 00:04:45: You and I worked on the human factors, applying human factors, engineering to product development and life cycle management and how we can use HF throughout the whole lifecycle, which is something people tend to forget about. A lot of people see human factors as a checkbox at the end. It's something they need to do for design controls to get their design validation done, not realizing it's something that should be done throughout the entire lifecycle. And then you get to it and all of a sudden, your product's ready to go and you're finding out things about your usability of your device or your labeling that you wish you had known earlier. And then also how to continue to apply it through lifecycle management once the product's already on the market. And also learned a lot about writing and how to work with, you know, other groups and make a chapter that fits in with a book that you haven't really seen and hope it kind of all goes together, which I think Susan, you were key in that making sure everything flowed and didn't sound like a bunch of different people all wrote this book.
Susan - 00:06:01: Yeah, and you guys did a great job. I think your specific chapter was also, other contributors included Bjørg Hunter from Nova Nordisk and Therese Schubel from J&J. And then I like snuck in a few things there, but truly I think you and Shannon. really drove most of that chapter and there's a lot of great case study examples in it. that I think are very helpful to people who are trying to get at some of these practical challenges that you run into for the different types of Combination Products and the things that trip people up over the lifecycle.
Stephanie - 00:06:40: I think the case studies were actually fairly easy because it's things we see with our clients frequently, they don't think of or again, just think of doing HF is your checkbox for your validation, your design validation. And all of a sudden you're like, now what do I do with all of this information that needs to feed back into my risk management?
Susan - 00:07:01: Yeah.
Shannon - 00:07:02: Yep, absolutely. So, besides you mentioned the chapters in the book, besides human factors, what were the other topics covered in the book?
Susan - 00:07:11: (Outline of Book)
Chapter 1 Foundation: So, Barr Weiner wrote the introduction, John Weiner, he wrote the introductory chapter to the book. And it really introduces, it has some broad thoughts around Combination Products and where we are in the maturity of regulations around it. And... talks about harmonization a bit or opportunities for harmonization. So I thought that was very helpful.
Chapter 2 Intro to Combination Product: Then the next chapter is a really basic introductory chapter of what's a combination product. And it's actually funny when I wrote that chapter, when I first got into it, I was like, oh, it's such a straightforward thing. Here's the definition from CFR 3.2 e. But then you start to discover that going around the world, everybody has a different interpretation. And some people have a different interpretation, even when they shouldn't. It depends on what those regs say, but people like to interpret it in a way that's maybe convenient for what they're doing. And then you've got constantly evolving regulations as well, which changes that definition and the interpretation. So even in the US, as recent as last year, when it came to ophthalmic drugs that are using administration devices for delivery, all of a sudden, those went from being conventionally treated as drugs to no, those are Combination Products and part four now applies. So you've got examples like that. And then looking around the globe and how, one kind of a product that's considered drug led in the United States and it's device led in Europe and it's a pure drug in China. It's like, oh my goodness. So what is a combination product chapter was the introduction.
Chapter 3 Regulatory Strategies: The next chapter goes into regulatory strategies for Combination Products. Suzette Roan contributed on this chapter, and she did a great job of working all the way from, you know, the pre-market considerations and what you need to do, going through submissions for different regions around the globe to, you know, post-market and change management. So it's a very helpful chapter.
Chapter 4 Current Good Manufacturing Practices: The next chapter is CGMPs. I co-authored it with Mike Wallenstein. That particular chapter covers the CGMPs very closely looking at CFR Part the CGMPs in the United States. It also brings in the FDA proposed rule so that people can understand when we talk about quality management system regulations, which that concept was introduced in February of last year, when it goes into effect, how does that come into play? That's also incorporated into the chapter. And then Mike partnered up with me to do some extensive descriptions of EU MDR 2017-745, to be able to help with the interpretation execution against that for Combination Products in Europe and the complexities that come with that. So we focus there.
Chapter 5 Integrated Development: The following chapter is on integrated product development. It actually starts out, and I authored this particular chapter, it starts out with some, I'll say some keys to success for Combination Products. First and foremost being language and having people understand that the language of device and the language of drug and language of biologic, sometimes you're using the exact same vocabulary words but the interpretations just a tad different. Yeah, that's true. Enough to get people in trouble. And then it goes into how do I integrate quality by design and design controls? for combination product development. some considerations, best practices, what the clinicals look like for one versus the other. And it brings in some introductory discussion of human factors because that's such an important aspect of product development. And then it touches on risk management.
Chapter 6 Risk Management: The following chapter then goes into depth on risk management. And that particular chapter, I authored it with the support of Rick Wedge at Pfizer and Ed Bills (watch our podcast with Edwin Bills), who's also a consultant. And that chapter, I think, you know, there's ISO 14971 there's 24971, that people refer to frequently. And with the EU MDR, there's specific expectations around risk management and its implementation. It goes into AAMI, AAMI TIR 105, which is focused on Combination Product Risk Management, but that a lot of people aren't aware of. And it really is a very robust chapter. I think for anybody who's struggling on risk management, it's kind of like the go-to chapter for you. Every time I work on it, I come up with more things. So I'm sure there will be a follow on from it, but it's about pages roughly of Combination Products, specific focus for risk management, platform considerations, things like that.
Shannon - 00:12:13: I'm gonna have some further questions for you on that when we move forward.
Susan - 00:12:17: Chapter 7-8: Okay. So I'll whiz through these other chapters that we have. So the next chapter, of course, is the human factors chapter that we touched on. And then subsequent to that chapter, we have a chapter on human factors Lifecycle Management and Post-Market Safety Surveillance and Reporting. I co-authored that one with Khaudeja Bano.
Chapter 9: Then chapter nine is split into two parts. 9A is considerations for inspection readiness, and which you really can look at through a global lens. And then Kim Trautman wrote the second part of that chapter, which is focused specifically on US inspection readiness. And it looks at the June 4th 2020, inspection compliance program that the FDA issued.
Chapter 10 Supplier Quality: Chapter 10 goes into supplier quality considerations, which most, not all, but the large majority of Combination Products companies that are out there are purchasing at least one constituent part. So they've got whichever constituent part's their comfort zone, and then they're probably purchasing the other constituent part that's gonna be integrated into their combination product. So supplier quality and change management and things like that really are critical when it comes to Combination Products. So that's the focus of that chapter. Fran DeGrazio and Meera Raghuram authored that chapter.
Chapter 11 - 12: Then chapter 12 is covering Combination Products with biological products. That was authored by That one's authored by Manfred Maeder. And chapter 11 on Analytical considerations by Jennifer Riter and Daniel Bantz from West Pharmaceutical. And that one goes all the way through anything from Analytical and USP and Standards that you've gotta pay attention to, extractables and leachables, to stability. So it's a very helpful chapter, I think.
Chapter 13 Connected Health: Then finally, we go into a chapter by Ryan McGowan from AstraZeneca. He's ex-FDA. He wrote a chapter on connected health for Combination Products.
Chapter 14 Regulatory Landscape: And then we close with a chapter that was co-authored by Viky Verna, Cherry Marty, me, and Stephanie Göbel. And actually, Stephanie played a really driving role in bringing that chapter to fruition because, so much was going on in the European market with the changes in regulations there, that part of the chapter needed quite a lot of work. So she really made a huge contribution updating that to bring it on so that it's very current for people that are dealing with EU MDR.
Finalize: The book ends with a glossary on Combination Products and then has about a page, six zero page glossary on international regulations for Combination Products. So it goes all around the globe looking at all the different regions and what regulations are out there. It's got very helpful hyperlinks in it so that anybody who's trying to figure out what do I need to do for this country, that appendix is a very helpful guide for you. I think that's everything in the book. It's close to 600 pages.
Shannon - 00:15:30: That's a lot. That's a lot.
Susan - 00:15:32: So there's a lot.
Shannon - 00:15:33: Excellent. Was it more than when you first came up, considered the idea of capturing it all in a book?
Susan - 00:15:42: There were a number of times when I asked myself, what on earth was I thinking?
Shannon - 00:15:50: I can imagine that. So, Susan, you're involved in quite a bit. So you mentioned you retired from J&J.
Susan - 00:16:01: My version of retirement, it makes people laugh.
Shannon - 00:16:06: Excellent. So you also lead the Community of Practice.
Susan - 00:16:12: Yeah, I chair the International Society of Pharmaceutical Engineers, Combination Products Community of Practice. It officially became a community to practice, I think two years ago, but it's actually been running close to eight years because when I was working at J&J, at a Janssen Pharmaceutical specifically, and I had joined ISPE, I was like, there's this huge void. There's nobody talking about it, but everybody was struggling. So it started out with like eight people. It was very much very organically grown. Eight people who are quite passionate. Now we're up to close to 80 people. And very active. We meet once a month. We go through all sorts of hot topics on Combination Products, end to end across this whole scope of their life cycle. We also address benchmarking questions that people have. We're very careful to make sure we preserve confidentiality, but really it's become just a really robust forum. And I know you guys are involved in it too. So I think it's been very helpful for people.
Shannon - 00:17:17: Excellent. Stephanie, I believe you've been involved for a little while with the ISPE.
Stephanie - 00:17:23: Yeah, I joined before I was in HF, standalone HF consulting, and was quality engineering for Combination Products. And it was incredibly helpful to get and have a space to talk with your industry colleagues who are going through the same struggles. Have you ever come across this situation? What did you do? What worked best for you? Have you gotten feedback from the agency or notified bodies? How are you dealing with notified body opinions? All of that. And it was very helpful in that space, but also from the human factor space, I found that it's helpful. Everyone's got questions and it's a space where we can talk about, oh, well, our most recent DMEPA review, we got this feedback or something along these lines. And it's, a very helpful space to have those conversations that typically you would only have around a cup of coffee at a conference. And so it's nice to be able to have that space where we can have those conversations.
Susan - 00:18:24: Yeah, we go in deep. It's not like there are surface level conversations. We can go in pretty deep, which is nice. We also, and Stephanie was directly involved in this with Shannon. One of the other things that we do through our community of practice is we comment on regulations. and guidance as they're issued by regulators around the world. So through ISPE, we actually submitted comments on Health Canada's update that they had communicated they were making relative to Combination Products or drug device combinations, as they refer to them. We commented directly on the World Health Organization regulatory framework for medical devices. And I can actually tell you of what we submitted through ISPE was adopted by WHO in that. So that was great. We commented on China as they were coming out with their regulations. And then most recently, there's been a number of different things we commented on, but most recently there was a guidance that the FDA issued on human factors. It was medical device focused, but Stephanie led the charge within the community of practice to submit comments to the FDA in response to that guidance. I don't know, Stephanie, if there's anything you want to add to that, but I thought that was very powerful and hopefully much of it gets taken into account by the FDA.
Shannon - 00:19:43: So Stephanie, to add on to Susan's question, I was curious about your engagement with the committee during that. Are you seeing engagement on the human factors activities? Were folks interested in commenting?
Stephanie - 00:19:58: Folks were interested, especially there was, you know, a lot of us come from the drug side of things. And this, again, as Susan said, it was a device-focused guidance that came from CDRH. Because in the combination product space, we have to align with both in different parts of what we're doing. It was people wanted the alignment. And so there was comments from people from several pharmaceutical companies who were engaged in providing comments so that they can figure out and we can all figure out together how best to move forward with HF and make sure that we are all submitting things the same way so that we hopefully get similar feedback throughout the industry.
Susan - 00:20:47: And I think part of it also, right, we were really trying to drive towards maybe a bit more harmonization with ISO terminology. because when you look at the human factors, guidance. It calls it risk analysis. However, a lot of the work that's being done for it isn't just pure risk analysis. And it kind of messes up the terms that are used in and knowing that that's a harmonized standard, we gave feedback trying to see if we can get the FDA to align their terminology with the terminology, because I think it will help industry as a whole with less confusion when it comes to doing things like use-related risk analysis.
Stephanie - 00:21:36: I agree because, as we pointed out, they call it risk, but they don't use occurrence. And so it's not really risk because the definition of risk involves occurrence.
Susan - 00:21:51: Yeah, they just really focus on severity.
Stephanie - 00:21:53: Yeah.
Shannon - 00:21:54: I'm gonna go on record. I think it may be a use-related hazard analysis.
Susan - 00:22:00: That really is what it is. It's a use-related hazard and harm analysis, but it's not a risk analysis.
Shannon - 00:22:06: Yeah. We'll see. We'll start the movement.
Stephanie - 00:22:10: It'll be interesting to see. It'll be interesting to see how they, what gets adopted and how things get edited. I went and looked and there were quite a few people who commented on it, so fingers crossed. Yeah.
Susan - 00:22:26: Well, and I know I was in a, so I sit in a number of different industry associations. One of them that I participate in is Combination Products Coalition. And we had a meeting with the FDA just a couple of weeks ago, and this particular guidance came up as one of the discussion points. And there's a little bit of chuckles like, oh, we clearly like that document. And it was a little bit like, okay, yes, we understand the feedback. So hopefully we'll see what goes.
Outro - 00:23:01: All right, we're gonna hit the pause button right there on this conversation with Susan Neadle and Stephanie Canfield. Next time, Shannon asks Susan about the polarizing viewpoints of ICH Q9 vs. ISO 14971 risk management plans and control strategy in the United States. You won't want to miss it. 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 or watching this episode. Please subscribe and 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 see you again soon on The Factor.
Stay tuned as we continue our conversation with Susan Neadle in our next episode.
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