Preparing For Combination Product Regulatory Inspections

In this episode of The Combination Products Handbook: The Series, host Tom von Gunden discusses Chapter 9 of The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined Use Systems (CRC Press) with the book’s editor, Susan Neadle, and chapter co-author Kim Trautman. On the topic of combination product regulatory inspections, Susan and Kim outline and comment on key inspection readiness considerations including CGMPs, quality system requirements, drug and device terminology, supplier controls, and FDA guidance.

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The Combination Products Handbook: A Practical Guide for Combination Products and Other Combined Use Systems Edited by Susan W.B. Neadle, CRC Press, 2023

Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of The Combination Product Handbook: The Series, in which we go chapter-by-chapter through The Combination Products Handbook: A Practical Guide. My name is Tom von Gunden, chief editor of Drug Delivery Leader and your host for the series. Today I am joined by the book's editor and co-author for today's chapter, Susan Neadle.

Welcome, Susan.

Susan Neadle:

Hi. Great to be here.

I am also joined by chapter co-author Kim Trautman.

Welcome, Kim.

Kim Trautman:

Thank you very much.

So, the chapter we're going to discuss today is Chapter 9. And the focus there is on inspections and inspection readiness. So, Susan, as we often do, I'm going to ask you to contextualize or describe the positioning of this topic within the framework of the book ― where it fits and why. Also, a little bit about your recruiting Kim to join you in authoring the chapter.

Neadle:

Sure. Answering the first question, why it's in the book, where it's in the book. At this point in the book, we have already gone through, what is a combination product? What's the regulatory pathway for combination products? CGMP [Current Good Manufacturing Practice] expectations for combination products, new product development, lifecycle management.

So, we're at a point now on human factors. We're at a point now in the readers’ understanding of combination products. The full end-to-end lifecycle, all the way through post-market safety reporting. This is the point where somebody should be able to say, hey, you know what I've got to worry about? Am I compliant with everything I [need to] know? I've learned about it. Hopefully I've been applying it. Am I compliant? What do I do if I have an inspection? And the only health authority that currently has a specific inspection program for combination products is the U.S. FDA.

So, I thought that, at this point in the book, it would be great to focus on that USFDA inspection approach for combination products.

Now, the next part of that question was, why did I choose Kim? I had reached out to Kim to co-author this chapter with me because she was one of the people who helped write the quality system regulations and combination product regulations. And having worked with her in the past and while in industry and then even after, I just knew she'd be a great voice on this topic to be able to bring perspective to the readers. So. there you go.

Well, speaking of that voice, we'd love to hear that. So, Kim, do you want to join in and talk a little bit about how you see the significance of the inspection topic in a handbook about combination product development?

Trautman: Sure. So, I've been in the industry for over 40 years, starting off with industry and then working at FDA for 24 years. And, like Susan said, in the early ‘90s, I was in charge of writing the Quality System Regulation and its preamble. And then part of that was a lot of international harmonization work. But as that was published in 1996 and we came to about 1999, there was the 21st Century drug or pharmaceutical initiative that Dr. Woodcock at the time put together on emerging topics for the 21st century. And Combination Products was one of those important working groups.

And I was the CDRH’s, or Center for Devices [and Radiological Health], representative on that combination product workgroup. And this is where some of the initial FDA guidance documents came out of this workgroup and, eventually, led to a couple of things. Number one, as part of writing those guidances at FDA, we sat all the centers down and did an analysis of the different GMPs, [good manufacturing practices], literally, line by line. What was similar? What was different? Both ways. So, for example, for pharmaceutical [21 CFR Part] 211 GMP and [21 CFR Part] 820 quality system regulatory requirements, we sat down and looked at 211 to 820 and then also did the flip of 820 to 211. So, those of us in that work group had a very, very detailed working knowledge of that analysis, to include analysis of that med, biologics, all those different regulations.

Eventually that turned into Part 4, which is the GMP requirements for combination products. But also, part of that analysis was really getting people within FDA to even understand the GMP across the different sectors. And those initial working groups had work groups from the centers. But one of the main things that we knew we were still maybe not covering as well at the FDA at that time was that we had to educate the investigators and the inspection workforce.

And so, there was a lot of discussion as to when that [21 CFR] Part 4 regulation was published and, when we were on that authoring group, what type of implementation and additional guidances might be necessary going forward? And one of those was a guide to inspections. It did not come out right away. But over time, it really became obvious that it was important to have a guide to inspections to ensure that combination products were adequately covered during the inspection process ― that FDA had assignments and continued to have signs to go out and inspect combination products.

Great. Thanks.

Susan, anything you want to add to what you're hearing from Kim on that?

Neadle: Well, the one thing that came across my mind as you were saying that, is that particular guidance for the combination products inspection program was issued in June of 2020 ― June 4th of 2020 ― which, unfortunately, was right when the pandemic was kicking in.

So, it came out. Industry was really excited for it, but then everything went to remote and I think it took some of the wind out of the sails of it. And now post-pandemic, where there's emphasis again on, okay, we're moving back to in-person inspections. Yes, there's some remote still, but I think that maybe some of the energy to get people working consistently between the centers to do these inspections, leveraging that guidance … I just don't think that it really took off the way I would have loved to see it take off. Not saying I'm asking for more inspections, but I think that it's a strong guidance, and I don't think that it has been completely adopted, even within the centers, as much as I think it could be and could help industry out.

And that leads me to turn to something I wanted to ask both of you. And that is, where the practical implementation or operational picture is. There's quite a bit of advice given in the chapter, two things: being able to understand the right terminology or understanding the participants, including front room and back room functions, and you both are bringing up navigating the agency structure.

And so, let's just turn to any of the above. What are some of the practical tips that either of you would offer in terms of how to move forward?

Neadle: Well so, one of the things I'll jump in on is that whole navigating of a combination products inspection at your facility. Many times, at many facilities, if it's a drug-led combination product, you've got a lot of people really comfortable in the drug cGMPs and maybe less familiar with the device Quality System Regulation [QSR]. And if you have a device-led combination product, it's flipped. Their comfort zone is the device cGMPs or QSRs. And their area weakness might be in the 210/211.

When you get into an inspection, what you run into is this phenomenon of, sometimes you use the exact same words in the drug world as in the device world, but the interpretation of those words is different. And so, if an inspector, let's say, is coming in with a CDER [Center for Drug Evaluation and Research] background to do a combination product inspection, and they're having to ask you questions about your device cGMPs: If you don't understand the language of the documents that they're asking for and you start providing other documents, you can have a problem.

If the people taking notes in the room ― the scribes, right, you've got scribes, you've got runners, there's a whole setup when people are doing these inspection. If the scribes don't understand both the device language and the drug language, when they're putting notes to the back room of, hey, please bring forward the following documents, and there's some design control / design verification documents being requested, they might be asking for the wrong documents, which just makes your inspection more painful. I've literally sat in the front room myself where I had to take on the role of facilitator, scribe, and runner all on one fell swoop because I was faced with a group of people that all understood drug language and didn't understand device language, and it was a drug-led combination product that was being audited for the device cGMP call-outs.

So, you really want to make sure that you've got that nailed down in terms of the training for people in your facility. And I know other chapters in the book [e.g., Chapter 5] go into some great examples of those language differences and how to interpret [them]. So that's one thing. I don’t know, Kim, if there's something you want to add to it.

Trautman:

Well, historically, I could tell you that it took me ― well, it continues today  ―it amazes me how there's still a very, very big cultural divide between drug and devices, in particular ― within the agency as well as in the industry. And I can't tell you, the countless number of regulatory meetings that I sat in, especially with respect to combination products, where people were using terms and they were using terms that are on both sides of the fence with very, very different understandings and talking right past each other. Terms like the difference between verification and validation that Susan mentioned. I will tell you the acronym CAPA [Corrective and Preventive Action] gets all kinds of people into trouble. What is meant by corrective and preventive action in the device world is absolutely not what most people think of as CAPA in the pharma world. Again, part of it is driven by how the regulations were written and came up over the decades. But also, part of it is cultural.

Risk management: that is just absolutely full of places where there's terminology that's being thrown out [into the discussions], but very, very different real expectations. So as a regulatory author when I was at FDA, as well as working in the standards world, I can't overemphasize the importance of everybody in the organization understanding terms as they're defined and as they're defined on both sides of the different commodity sectors.

Why biologics doesn't have quite as much problem is because the biologics have already had to kind of split: the center for biologics [CBER] has some products, blood products that are regulated with the same rules as devices and work with CDRH. They've got pharmaceutical products, so they already work with CDER for that. So, that area actually has had to navigate this from the beginning.

But I will tell you, if you do come from one of those two traditional sides ―pharma or devices ― Susan is absolutely correct: That exact same word can be used with very, very different expectations by who might be receiving ― either hearing the request or giving information during the inspection.

The other thing I have found as a consultant now, after having retired from FDA, [is] that a lot of one of the constituent parts may be contracted out [to] a contract manufacturer or contract developer. And  there is an overreliance by the base combination product manufacturer ― that I have found that ― that [the outsourced] contract manufacturer knows exactly what they're supposed to be doing and, therefore, they trust them. But when it comes time [for] inspections, as the finished product manufacturer, they are not able to articulate how that contract manufacturer really did meet some of those regulatory intents.

So, more and more, people are going to where the specialization is. Sometimes, FDA will go to the contract manufacturer, depending on a whole set of roles. But other times, they're going to try to get that information from the inspection that they're in. And if you don't have someone both in the front room and in the back room that has ready access to that documentation [and] can prove that that finished combination product manufacturer has read and reviewed and understands what that contractor is doing for them on that commodity sector, I have seen it lead into some pretty rough inspections.

Neadle: Yeah, spot on. And that bit about people outsourcing to third parties: It's a very, very, very common practice in the combination product space. So, purchasing controls, using the 820.50 interpretation, ISO 13485 clauses. It’s a very, very disciplined process required.

The FDA has issued a guidance on contract manufacturing arrangements for drug manufacturers. And when you look at that guidance, it really is telling you the same things that you're seeing out of purchasing controls under the 820s. But there's a need for that guidance, for that structured approach, for your quality agreements and for the working relationships on the drug side when you're outsourcing to a third party for the device constituent part. It's just so important getting that right. I'd say that's probably one of the #1 Warning Letter findings I see cropping up. Because people just don't understand the differences in expectations there. So that one's really important.

Trautman: And again, staying on this topic of suppliers. It really is amazing culturally. For example, I have found that there is a common expectation ―I don't know where it's driven, it’s not actually in any 211 words. But there is an expectation that you always have to have supplier audits. Now I think, over the past three or four decades, this has been driven by the fact that there are key ingredients like API and so forth ― those key suppliers that require stricter, more risk-based supplier audits. But it has evolved over those decades into a thought process on the pharma side that you pretty much always have to have supplier audits.

That is absolutely not the thought process on the device side. Device manufacturers literally have thousands and thousands and thousands of suppliers. They have to, again, just by virtue of the products ― the hardware, software, wetware ― it's just a more diverse product portfolio. And, as such, there are those requirements that Susan mentioned for purchasing controls that really do require you to use a risk=based system to categorizes different suppliers and to get assurances depending on the risk.

Now, those assurances might come from a supplier audit, or they might not. There are absolutely certain chemical sectors that absolutely want nothing to do with the medical device industry because they don't want liability lawsuits and will never allow a supplier audit of their facility. So, on the device side, historically there has always been a little bit more flexibility [on], how do you get those supplier control assurances that you need and not a complete reliance on supplier audits? Where, on the pharma side, there is just a little bit different mindset: that supplier audits are just what everyone is supposed to do.

And again, I've seen that become an issue during inspections. If someone is not able to articulate and if you have a pharmaceutical FDA inspector coming in and expecting those supplier audits to be there, you need someone that's able to articulate how you are meeting the regulatory requirements, you are getting the assurances, and you do have the controls in place. But you're doing it via this means and not necessarily a supplier audit.

So again, it's a lot of handling during the inspection of the different mindsets that historically have come up over the decades.

Neadle: Yes. And the approved supplier lists: making sure that the supplier you have on your approved supplier list ― that you're using them for the thing that they were approved for, not something else. Again, that’s another nuance, so it's a complicated area. But that said, when it comes to the inspections, people are looking for that: Oh, let me see your complaints. Oh, you had complaints associated with that particular raw material. Let's talk about the supplier. Show me your quality agreement. It's a thread that you just pull.

And if people don't understand the expectations, if there's the overreliance on the suppliers, which there often is, sometimes the suppliers thought of themselves as component suppliers and now they're considered device constituent parts suppliers. But wait, maybe they didn't do design controls. Those are the kinds of things that are blind spots for a lot of companies because they just assume, well, I've got a great relationship with the supplier. They've got a great reputation, so they must have it together. They might still not have all of these things buttoned up because they have a different interpretation and what they're doing.

Trautman: And a manufacturer can't depend on the fact that FDA may also be inspecting that supplier. FDA is very, very clear on the fact that companies can't use FDA’s inspection. So, if that component or constituent part supplier is also a finished manufacturer and might be audited by FDA, FDA says, no, no, no, no, no, that's not your assurances. You need to go get your own assurances.

All right. Well, thank you both for the deep dive on that.

I'm going to let you both catch a breath, clear your thoughts, and I'm going to wrap up with one final invitation to respond from both of you. And it's a broad, open-ended one:

So, as our audience become ― if they aren't already ― readers of The Combination Products Handbook and dive into Chapter 9 on inspections and inspection readiness and, more importantly, look out over their worlds and the likeliness that they'll be involved in inspections: Is there anything out on the horizon that you would suggest people really attend to as they move forward, both in terms of what they glean from reading the chapter and as they do the inspection work in their own universes?

Neadle: Do you want to go first?

Trautman: Sure. So, one of the things on the device side that has actually been going on for probably the last 30 years is the harmonization of the Quality System Regulation with a standard called ISO 13485. In February of 2024, the FDA, for the first time since 1996, has revised its quality system, or 820, requirements and is now harmonized with 13485 more completely than all the work that I did when I was at FDA that we were working on, in the fact that the Quality Management System Regulation, which is called another acronym, QMSR. It was published in February 2024 and becomes effective in February 2026. It incorporates that 13485 reference into the 820 requirements, verbatim, to include the ISO 9000 terms and definitions standard.

Now, 820 still has its linkages and certain clauses that you have to pay attention to, etc. But from a combination product perspective, at the same time, the agency did a concurrent amendment to the Part 4 GMPs and changed out, because the numbers in 820 have changed, and again, because 13485 is incorporated by reference, a lot of the direct requirements are going to come from 13485. So, the concurring amendment for combination products now talks about 13485 clause numbers to that 2016 version that’s explicit in the QMSR regulation.

So, not going to teach our audience on that topic, but from an inspection perspective, what this is going to mean is that the guide to medical device inspection will be revised. The current guide to inspection for medical devices is called the Quality System Inspection Technique, often referred to as QSIT. FDA in the QMSR final rule and preamble talks about the fact that QSIT will be one of the things that must be updated and revised. So, how that guide to inspection is going to be revised is something in the future that all of our quality and regulatory folks are going to have to pay attention to. And we don't know, those of us sitting here right now, exactly when it will come out or exactly what it's going to say. But it absolutely is something that people will have to pay attention to.

And again, just like Susan and I were already talking, you will have to understand what that guide to inspection is. And then you will also have to understand the nuances for some of those topics that we already discussed ― risk management, supplier controls, again, depending on the lingo that's used in devices ― and be able to extrapolate that further into the combination product world. So, that's definitely something on the horizon that we all want to watch out for.

Neadle: Yes, and I'll build on that. With that, the device called-out provisions for those with drug-led combination products, the callouts are the same. But the explicit interpretations ― it’s distinct. And some of it’s got a higher bar to meet than the way it's worded currently under the 21 CFR 820.30, 820.50, 820.100. It’s a little bit higher bar than 820.20, even ― the  availability of your management audits and things like that. They're not necessarily protected in a not-for-cause audit the way they have been in the past.

So, I think that there's a lot to be seen with this. Industry is going to have to come to grips on it. The FDA states, when they came out with the QMSR and they made the edits to Part 4, that it is not intended to change what you're doing for Part 4. They say that, but pay attention to the details. The devil's always in the details. And when it comes to CAPA, more explicit expectations on statistical techniques. Before, it wasn't a callout explicitly. Now, it's specifically embedded within that provision. So, there's quite a lot of detail to it. I'm not going to get into all that.

Trautman: Yes, much more explicit measuring and monitoring of processes and products that are pulled in. So, all of that will have to evolve with that science and with those new regulatory requirements. Hence, how we handle that through the inspection process. Absolutely.

All right, well, thank you both for that. And thank you for joining me, Kim and Susan, for this episode of The Combination Products Handbook series. And to our audience, thank you for joining and we'll see you next time.