Combination Product Compliance: PMOA, 21 CFR Part 4 & QMS Alignment

Updated August 4, 2026 ░░░░░░

#467 Combination Product Compliance PMOA, 21 CFR Part 4 & QMS Alignment

Navigating the regulatory landscape for combination products requires understanding how primary modes of action (PMOA) dictate oversight pathways. In this episode, host Etienne Nichols sits down with Jim Fentress, Director of Regulatory Affairs at Galero (a Santa Group company), to unpack the structural differences and hidden pitfalls when medical device and pharmaceutical worlds collide. They discuss how the FDA handles lead agency designation across CDRH and CDER using interagency agreements and official Requests for Designation (RFD).

A central theme of the discussion is managing quality management systems under 21 CFR Part 4. The pair explore the friction that occurs when pharmaceutical companies act as lead applicants for drug-led combination products, requiring them to incorporate device design controls (ISO 13485 / QMSR) and CAPA systems into their existing CGMP framework. Jim explains the practical realities of integrating Part 210/211 elements—such as calculation of yield and stability testing—into a single, operational QMS without overcomplicating procedures.

Finally, the conversation delves into critical execution details: risk management under AAMI TIR105 (ISO 14971 vs. ICH Q9), labeling classifications (single entity, co-packaged, and cross-labeled), and strict change control protocols. Jim highlights how post-market design changes to a device constituent part can impact the pharmaceutical partner's NDA or baseline regulatory filings, underscoring the necessity of transparent cross-industry communication from initial development through full commercial release.

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Key Timestamps

00:00 – Introduction to combination products and guest Jim Fentress.
00:48 – Understanding Primary Mode of Action (PMOA) and regulatory pathways (FDA vs. European authorities).
01:57 – FDA interagency agreements (CDRH and CDER) and Requests for Designation (RFD).
03:00 – 21 CFR Part 4 quality system integration (CGMP Part 210/211 and QMSR/Part 820).
05:22 – Navigating the communication gap between pharma companies and device manufacturers.
07:44 – Calculation of yield in drug manufacturing vs. medical device production.
09:05 – Risk management for combination products (AAMI TIR105: evaluating device-on-drug and drug-on-device risks).
12:15 – Bridging ISO 14971 and ICH Q9 framework structures in registration files.
13:16 – Design controls, user needs, and human factors validation (Module 5 / Section 3.2.R ECTD filings).
15:06 – Labeling pathways: Single Entity (Integral), Co-Packaged, and Cross-Labeled products.
18:18 – Change control risks: How minor device modifications affect drug application filings (NDAs, CBER/CDER supplements).
20:41 – Advice for device manufacturers partnering with pharma: Alignment on risk, documentation depth, and cleanroom requirements.

Top takeaways from this episode

Establish Cross-Disciplinary Risk Management Early: Adopt frameworks like AAMI TIR105 to integrate traditional device risk protocols (ISO 14971) with pharmaceutical risk management (ICH Q9). Ensure assessment of cross-interaction hazards (e.g., drug interactions with delivery plastics, viscous drug effects on ejection times).
Define Clear Part 4 QMS Interfaces: If operating primarily under device rules (QMSR/ISO 13485), build project-specific addenda to account for drug CGMP requirements such as stability testing, container-closure assessments, and calculation of yield limits.
Align Post-Market Change Control Protocols: Establish explicit notification procedures between the device supplier and the NDA holder. Simple component material updates or geometry changes to a constituent part may require formal NDA supplements or changes-being-effected (CBE) filings with CDER.
Scope Document Deliverables Upfront: Clarify whether the pharmaceutical partner requires high-level summary reports or the complete device master record (DMR) and design history file (DHF) to populate Section 3.2.R of their eCTD submission.
Validate Cleanroom and Sterility Assumptions: Discuss cleanroom requirements early to avoid unnecessary cost structures; verify if an ISO 8 or ISO 7 environment is scientifically required for the assembly of non-sterile device constituents before adopting conservative pharma-grade aseptic norms (ISO 5).

References:

21 CFR Part 4: Regulation governing current good manufacturing practice (CGMP) requirements for combination products.
AAMI TIR105: Technical Information Report providing guidance on the application of risk management to combination products.
ICH Q9: International Council for Harmonisation guidelines for Quality Risk Management in pharmaceutical manufacturing.
eCTD Section 3.2.R: Regional information section of the Electronic Common Technical Document where medical device constituent data is filed.
Host Contact: Connect with Etienne Nichols on LinkedIn.

MedTech 101 Section

Primary Mode of Action (PMOA)

The primary mode of action is the single mechanism that provides the primary therapeutic effect of a combination product.

Think of a drug-eluting stent:
- The main goal is to physically prop open a blocked artery (a mechanical action performed by the stent device).
- The drug baked into the metal coating slowly releases to prevent scar tissue from re-blocking the artery (an ancillary chemical action).
Because the physical propping open is the primary therapeutic mechanism, the FDA classifies the product as a device-led combination product under CDRH. Conversely, an epinephrine auto-injector's main therapeutic outcome comes from the epinephrine drug working in the bloodstream; the plastic casing and needle are auxiliary delivery mechanisms, making it a drug-led combination product overseen by CDER.

Memorable quotes from this episode

"There's four aspects of risk that you need to take into account: what is the risk of the drug alone, the risk of the delivery system alone, the risk of the drug on the device, and the risk of the device on the drug." — Jim Fentress

"Before you even think about making a change, you need to talk to your pharmaceutical partners because now what's represented as the co-packaged device constituent element is changing, and they need to inform the FDA." — Jim Fentress

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Transcript

Etienne Nichols: Hey, everyone. Welcome back to the Global Medical Device Podcast. My name is Etienne Nichols. I'm the host for today's episode. And today I want to talk about one of our lesser known topics that, that we've talked on a little bit in the past, but it's been a while.

It's combination products and some of the different idiosyncrasies around that today. With us to talk about this is James or you go by Jim, is that right?

James Fentress: I go by either, but Jim's fine.

Etienne Nichols: Okay, well, I might go back and forth, but I'll try to be consistent. But James Fentress, director of regulatory affairs at Gilero, a Santa Group company, and we're going to be talking about combination products, most likely from the device side and some of the CDMO problems that come along with that.

One of the biggest things that we talked about when we were first kind of planning this episode, at least that I remember about, was the language gap.

And when you have the. Just.

I'll let you kind of let the set the stage for some of the combination products. But just for those listening, when you think about a combination product, there's something called a PMOA, which is the primary mode of action.

And it, it, it's dictated, it dictates which way you go through the FDA pathways and. Yeah, go ahead, I'm gonna, I can see your chomping at the bit. Take over.

James Fentress: No problem. Yeah, exactly. The primary mode of action is for the product, whether it's primarily a drug or device, mode of action.

So, for example, if you had an antibiotic impregnated central line catheter, its primary mode of action is still to be a central line catheter.

And so the drug is an ancillary effect.

So, in such case, you'd typically be regulated, at least in the United States, as a combination product. But a device.

And then, and that, that would be contrasted with something like a drug delivery device of some sort.

Yeah, like a, like an epinephrine pen.

So the, the purpose of that product is to, is to get the epinephrine into a patient that's having an anaphylactic reaction.

And so the device is ancillary. It does provide the tube and the mode of action and, excuse me, the motive action to get the drug into the patient.

But it's the drug that's the primary mode of action there.

And what's interesting is in both the United States and Europe there's a lot of fuzzy areas between what the primary mode of action is and who's actually going to regulate it.

Like in the United States it's a little bit easier because the FDA handles both drug clearances and device clearances. So it's one organization.

So they're a little bit better about figuring out where things lie is an internal aspect of it.

Whereas in Europe you have the EMA on the drug side and then you have the notified bodies and all the.

What am I, what's the term I'm searching for competent authorities that exist independently of the ema.

So, I guess my point in that though is the, the FDA actually has, if you have trouble with your primary mode of action, a number of ways to determine whether it's going to be a drug or device or how it lies in there.

One of which is they have something called the CDRH and Interagency Agreement where CDRH and the center for Drug Evaluation and Research have decided that for all these different categories of products, this will be handled by CDRH, and this will be handled by CDER.

Etienne Nichols: CDER, yeah.

James Fentress: And so that's one option just as a first look, but also you can reach out directly to the office of combination products for. Through a request for designation or. Or a pre request for designation.

But anyway, yeah, primary mode of action is gauging whether or not you're thinking of your product as a drug or device.

Etienne Nichols: And one of the things that's interesting to me about that is while you may you kind of alluded to.

Well, I'm not familiar with the device, the catheter, but let's just say a drug eluting stent for simplicity's sake. So the drug eluting stent is still going to be.

It's a stent, so it's going to be regulated, or the submission will go through CDRH.

But that doesn't mean they don't still need to adhere to whatever the requirements are from the drug side of the regulation. Would you, how do you, how do you kind of navigate that?

That's one of the more confusing areas in my mind.

James Fentress: Sure. Because. So really what, what it means is that's going to be regulated as a device, but it just means CDRH is going to be the lead center.

So CDER is still going to come in and evaluate whether or not the drug aspects of it is correct in much the same way that in the opposite finding, CDRH would come into a CDER reviewed NDA package to look at the medical device component of it itself.

So if we look at it.

Sorry, I lost my train of thought there.

Etienne Nichols: No, that's okay. So, yeah, so. And there's also that Part 4 area that almost kind of helps with the, with the translation between whether it's 210 and 1340. Well, Part 20, Part 820, now 1345, I guess in my mind.

James Fentress: Sure.

With respect to that, like. Yeah. The second aspect of it is how it's handled from a regulatory perspective.

And as you, you've correctly stated that at least in the US 21 CFR Part 4 articulates how different corporations and different organizations can do that. For example, it states that if you're a pharmaceutical company operating under a Part 210, Part 211 Quality System or CGMP, that there are certain aspects if you want to produce a combination device of the QMSR that you need to adopt things like design controls, things like servicing. So, if you're having an external pump or something like that, service provisions, and for companies like ours that are primarily device companies, there's adoption of the Part 210, 211 standard. That's required as well, but not fully because both of these overlap with each other.

So, in our case, under a Part 4 system, we'll adapt elements of Part 211 like stability testing, like testing requirements for drug components and closure systems, things like that.

Etienne Nichols: So when you talk to these teams, because my understanding where you're currently working, you have a wide range of customers, whether it's Fortune 500 down to someone with a single person with just an idea on the back of a napkin.

Maybe that's an extreme, I don't know. And you can correct me, what are some of the problems that you consistently face regardless of team size, when, when you're talking about these combination products?

James Fentress: The primary issue is so for us; in most cases we're dealing with pharmaceutical companies and not other device companies.

Etienne Nichols: Okay.

James Fentress: So, and one of the reasons for that is if you're going to come up with something like a drug eluting stent, chances are you're coming from a large enough organization that you can already figure out the chemistry of how to embed drug product into your device.

So it's actually very rare. In fact, I don't think we've ever seen a device led combination product come into our business.

So from a combination perspective, then we're not dealing with other device companies, but primarily pharmaceutical companies.

Etienne Nichols: And so time out for just a second, let Me clarify what you just said there. So you're not typically dealing with device LED in the sense that the company is primary a device company, but the device itself may be a device device.

PMOA.

Is that what you're. Is that, am I, am I interpreting that accurately?

James Fentress: Sort of. I think I was just speaking on the more fundamental level.

Etienne Nichols: Right.

James Fentress: We rarely see combination products at all that are device lit.

Etienne Nichols: Right.

James Fentress: Because of the complexity of their development.

Etienne Nichols: Okay.

James Fentress: So almost all of our customers are pharmaceutical companies and generally they want to pursue a drug led pathway even when an alternative pathway could be available.

Etienne Nichols: Okay, I see.

Interesting.

So, when they do that, how.

I guess there's two questions in my mind. How well does a medical device company produce a combination product?

How well does a drug company or pharmaceutical company produce a combination product? And I would, I would guess each one would have different issues.

So it kind of depends on who we want to talk to first. Do we want to talk to the pharmaceutical company or leading a combination product or do we want to talk to medical device?

I'll let you pick.

Choose your adventure.

James Fentress: So either like specifically, I think most of the issues with pharmaceutical companies that are developing combination products is internally. You have large organizations that are primarily based on drug discovery and formulations work and you don't have large mature device development operations and certainly you don't have in most cases an operable device quality system.

So, if we look at what you need to adopt as a, from a device quality system perspective under Part 4 to be Part 211 compliant, I think it's actually a little less foreign and burdensome than the opposite direction.

Because as I mentioned, one of the provisions of the QMSR that a pharmaceutical company would need to adopt in order to manufacture combination product would be Design controls under 1345 7.3, and that's design inputs, design outputs, design validation.

Also they need essentially a CAPA system as well. And these are major undertaking for, for a lot of pharmaceutical firms.

Etienne Nichols: For a pharmaceutical company, I mean, is the CAPA system completely new? It's 1345 kind of changes the game slightly I guess from where we had what we were looking at with from a CFR perspective.

But okay, so I'm just going to back up for a second because in my experience having worked with combination product companies, one of the issues is a drug company or a pharmaceutical company, they may issue their version of a CAPA much more readily than a medical device company. A medical device company is a bit more reticent to say, okay, we're going to make that a CAPA, you know, that's a big deal versus just an NC.

I don't know what your thoughts are there.

James Fentress: Actually, I don't actually have any thoughts there just because I haven't. Pharmaceutical. Yeah, but I think structurally the kind of corrective and preventative action required in 1345 is different than you would find under the ICH rules for drug development.

Etienne Nichols: Okay. Okay.

James Fentress: So it's an alternative parallel system that isn't met by the current system that they have in place.

Etienne Nichols: Okay, that makes sense.

So that does seem like you're, you're really taking something a lot more.

Well, I'm not going to say robust because the drug, you know, the pharmaceutical companies, they have a very robust system in place. The regulations are strong, but it's different.

And it's different for a lot of good reasons. You know, I mean the development of pharmaceuticals is different than the developed.

And if a hardware device.

So, if you have these different systems in place, what are the things that.

Well, I guess one of my main questions is how do you live under one QMS? Or do you have multiple QMSs under the same roof dealing with different things? How do you navigate that?

And what's the, what are the pros and cons of doing it in different ways?

James Fentress: Well, under Part 4, one option that you could do is put in both a full-fledged device quality system that meets the QMSR and a full-fledged drug quality system that meets 210 and 211.

So, in this streamlined approach that offered, that's offered in Part 4, where we only adopt some elements of Part 210, 211, the integration within the quality system itself, like as a documentation structure, isn't particularly difficult. It's almost like a child offshoot.

If you're making or if you're manufacturing drug combination products, then apply the following rules. And so there's a different set of structures that come into play there.

So structurally it's not too difficult. The more difficult aspect of it is more the alignment with the pharmaceutical companies because how we would interpret in a vacuum those elements of Part 210, 211 is likely not how a particular pharmaceutical company would.

So let me, maybe I'll give at least one example of that one. So, for example, calculation of yield. It's Part 211 something calculation of yield where at each manufacturing step for a drug process, you're required to determine what your theoretical yield is, whether you missed it or not.

So in absence of knowing a particular drug product, it's difficult to arbitrarily Say I'm going to set my alarm threshold for calculation of yield at minus 1% because you might have some drug products where maybe a 20% loss during production is considered acceptable and still representative of a process that's in control.

So I can't fully refine my calculation of yield as a quality system document outside of the specific requirements of the pharmaceutical company itself.

So, to a certain extent we have these Part 211 compliant documentation structures, but they can only be fully realized in four specific projects.

Etienne Nichols: That makes sense. And I like that you bring up that specific example of the calculation of yield, you know, with mechanic. With. I'm just actually sitting here trying to think, is there something that's kind of representative of that from the medical device side?

And maybe you have an example.

But what I, I was, I was kind of thinking of something slightly different.

I'll pause and let you see if you have something.

James Fentress: Trying to think, so where would it come up in medical device manufacturing? Usually there is something that I was thinking, okay, go ahead. Well, this may be kind of moving on, but maybe we'll come back around to this when I think about some of the differences. So the drug is going to be tested very heavily to determine anything that might have an effect on the drug itself.

But one of the things that I think about that tends to potentially run through the cracks.

Pharmaceutical companies, they run stability tests and studies on everything the drug touches. But what I'm curious about is are there any things that get missed with the device and how that drug might interact with the device?

Are there any suggestions or thoughts you have there or just around the interaction between the two?

Yes, absolutely.

So one of the things when we're dealing with a drug device combination is trying to make sure that our risk management processes are robust for that.

So, when you're partnering with a pharmaceutical company that maybe doesn't know a huge amount about devices, at least from a regulatory perspective, and for us as a medical device manufacturer primarily, we don't understand the day to day of what their actual drug development pathway looked like.

So bringing together risk management, how you think of this as a single unit is somewhat difficult. A few years back, AAMI issued a TIR 105, I believe it is, which is around CGMPs. Excuse me, no. Risk management for combination products.

And it suggests exactly where you were going with it in that there's four aspects of risk that you need to take into account and occasionally people forget the last two, one of which is exactly what you meant.

So one risk is what is the risk of the drug in and of itself independent of any delivery system. And then what is the risk of the delivery system independent of any drug?

And then there's two what is the risk of the drug on the device and what is the risk of the device on the drug?

So drug on device is.

It might be, if this is particularly designed just to deliver a drug with like DMSO as an excipient, something that's really tough on plastic materials, then you might have storage considerations where the drug can damage the device, I guess theoretically without damaging the drug, although I suspect that would happen too.

And so you need to take that into account. Similarly, like if you just look at a delivery device independent of the drug and you're delivering a drug that's all of a sudden, you know, a thousand set of stokes and you have an auto injector that was designed for one set of stoke, all of a sudden, you're talking about a five minute injection that needs to make its way into risk management somehow.

Etienne Nichols: Yeah, I can remember one. Yeah, go ahead.

James Fentress: The, the effect of the device and the drug.

So which is, especially if your device has any qualifies as a primary container in that it's touching the drug in any way throughout the lifecycle and storage of the device.

But even if it's only transient, are you doing something with your device that damages the critical quality attributes of your drug?

Etienne Nichols: Yeah.

James Fentress: And in most cases it's part of a risk management discussion that needs to be had very early with a pharmaceutical partner is where are we going to draw the lines for that one?

Etienne Nichols: So, so a medical device company, they would typically use ISO 14971 for their risk management, and I think it could potentially handle quite a bit of that. But I also know pharmaceutical companies have their own methodology for risk management.

Does this mean if you use that Part 4 or the TAR technical information report, for those not familiar with that, that acronym would I.

How do you handle the risk management documentation side of a combination product when it comes to all four sections?

James Fentress: Well ultimately that needs to be coordinated by whoever's doing the market authorization.

So, in the case of a pharmaceutical partner where we're, where we're producing a drug led combination product under their NDA, then that that instruction actually needs to come from our pharmaceutical partner and how they want to join it.

So, we will typically as a, as a recommendation say obviously the device risks independent of the drug is something we can handle under 1-497-12-4971. We'd also recommend that we would also handle the drug effects of the device under that same blanket.

Whereas the device effect on the drug as well as the drug risks alone you can handle under your ICH Q9 and then just this just needs to be hybridized when you do the ECTD and talk about overall risk of your product.

Etienne Nichols: Now one of the other things I'm thinking about, because that makes all total sense design controls you brought up.

And that's another area that I'm curious about because when we talk about design controls, I can see the device side and all things that the device needs to do from a user needs, the validation perspective, all those columns, user needs the inputs, outputs, verification, validation. So, but then we have the drug. The drug, they likely have their own version of that. And that's where I start to get onto the fringe of my knowledge and abilities.

How do you marry those two thinkings together so that you have something that doesn't fight against itself? So if you, if you have those separate, I can see them almost being a little bit potentially going against each other.

But what are, what are your thoughts there?

James Fentress: So forgive me, what, what specifically is going against each other potentially?

Etienne Nichols: So, if you have a user need that is in the design side or the device side, and that user need has its inputs, outputs, whether it's an auto injector, for example, for a drug, for example, it maybe not, maybe not going against it, but I'm thinking of like flow rate, for example, or what else could be fresher or something along those lines, quantity filled.

They are going to be inputs of each other, which is not that it may not be that difficult to accomplish, but one may be pulling information from the other document or vice versa.

James Fentress: All right, I, I see what you're asking.

In my mind, I have kind of a, there's kind of a bunch of things coming together at once and they're going in different directions.

Etienne Nichols: Yeah.

James Fentress: So, for example, in.

The good thing is, at least from a strict when we think about user needs as a device, the device constituent element of a drug combination product falls under those device rules, meaning that we need to make sure that we develop those user needs from our pharmaceutical partner and those are developed as requirements.

So the pharmaceutical company needs to tell us a few things what the device needs to do from their user perspective.

They needed to tell us if we are packaging and handling the drug, the critical quality attributes of the drug and the two elements which feed into it, which are the, the critical material attributes and the critical process parameters.

Okay. Those can be inputs in the, the design outputs that we're creating for the Entire system and we need to feedback a couple of other things back to them. So, once we have our user needs and everything like that, because the use of the device and the use of the drug are now inseparable, we need to feed everything back through a human factors mechanism that takes into account both.

Okay, so there's. There's two bits of information going back and forth.

Etienne Nichols: Yeah, yeah.

James Fentress: It's companies and how they share. And if we look like where does everything go, then in the final market authorization.

So, most of the device constituent parts go into section 3.2, particularly section 3.2R, 3.2R, which is technically labeled regional information for most ECTDs.

And the information content in there, it could be anything from a light PMA to an easy 510(k) as far as the information that they actually need. And then module 5 is part of the clinical module, and that's where human factors validation figures into it.

Etienne Nichols: Yeah. The only other thing that I think is. Well, the only. There may be many others, I don't know, but at least one other area is how you label the device.

And so, and not necessarily talk about UDI, but I'm talking about how you packaging and labeling. I kind of keep those together in my mind for whatever reason. So co packaging, co label or cross labeling.

And there's a third option, isn't there?

James Fentress: Single entity.

Etienne Nichols: Single entity. Okay. Are you able to break those three down or give recommendations for the three?

James Fentress: Sure, sure, absolutely. From a single entity perspective, in the United States, we've got those three classifications we just talked about. In Europe, the only true combination product is the single entity.

Okay, that's not actually strictly true, but from the EMA's perspective, that's. They call it an integral drug device combination.

Etienne Nichols: Okay.

James Fentress: So that is going to be labeled like a drug product.

So, if you pick up an asthma inhaler or something like that one, that's more or less an integral drug, integral combination product, or a epinephrine pen like we used before.

What you'll see is that's not really labeled with device information.

You just see the NDC code associated with the drug product itself.

Now with CO packaging, that becomes a little bit different. You're actually allowed some flexibility.

So it's possible to have a CO package combination product so that you have a drug packaged with a syringe that's labeled solely as a drug product and simply bears the NDC information associated with the drug.

But if you create a package where you have a, like a bottle of Lidocaine and then a separate package, needle and a separate packaged syringe in the same box.

Then you're going to have some UDI information on it as well associated with the product. So, with CO package there's some, there's, there's some more weirdness that can go on there.

Etienne Nichols: Yeah.

James Fentress: Depending on what is it, what exactly it is that you're trying to do.

And cross labeling is perhaps the easiest one because then the device is just labeled like a device. The drug is simply labeled like a drug and theoretically they both point to each other.

However, in most cases you will see a pharmaceutical product that's so called one way cross labeled, meaning the pharmaceutical product might say use only with this device.

And you go to the device labeling and the device mentions nothing about the drug.

Etienne Nichols: Yeah.

James Fentress: So predominantly like if I could summarize single entities, drug lead are going to be labeled as a drug.

CO package could kind of go both ways. Depending how you want to do it. They will have the drug information on it one way or another. But it may or may not have UDI information.

And then cross labeled is just labeled like the fundamental products themselves.

Etienne Nichols: What about change? So just kind of to wrap that up, I think that's really interesting. One of the other things that you said about, you go to the device, it may not point back to the drug, it may not say anything at all about the drug. And that kind of makes sense to me because it could be a device that's potentially used with many different drugs.

I would assume that that may be why, I don't know if you want to touch on that as to why.

James Fentress: Sure. So, if you look like a lot of devices are like, even if we take a general syringe, and I Forget if it's ISO 7886 or 7864 that talks about syringes. But anyway, if you look at a general syringe requirements, if you're doing a 510(k) on it, it has basic fluid testing, fluid chemistry testing that's intended to show that generally it doesn't, I think it's ph titration.

So it doesn't raise or lower the ph of drugs and it doesn't let any metal ions into it.

And first. So for most short term uses that's probably considered acceptable. But let's say you were taking as a combination product, you wanted to use that as primary packaging all of a sudden, well then, it kind of doesn't matter what the regulatory clearance was because you're using it outside of, you know, a short-term use of drug and now you have to validate it as a primary container.

Etienne Nichols: Okay.

James Fentress: But there's a peripheral aspect of it which is actually probably more interesting. So. And it's how you handle change control for device constituent elements of a combination product.

Etienne Nichols: That's where I was going next. Yes, let's talk about change control.

James Fentress: So. And let me take that same syringe like you can actually. The funny thing is you can actually produce a syringe that never has a 510(k) and that when you label it as it goes out of your factory, it's registered with the NDC code of the CO package combination product it was designed for.

So let's say you had to design a syringe that had like a specialty plunger because you really needed really low dead volume and it had specialty materials in there because there was some really harsh excipient.

Traditionally a syringe would require a 510(k), but you can actually have it as a device constituent part of a CO package combination product that's only regulated as a drug product.

But in such case, the whole do I need another 510(k) evaluation for a product change to a syringe?

No longer really applies.

What applies is in that particular case, whether or not you need to do an NDA supplement or a CFE or one of the other routes associated with the change in your drug application.

And so you can't fall into the trap of oh, I just changed the end plunger on it. That doesn't touch the drug.

That's not a problem. No new 510(k).

It's. Before you even think about making that change, you need to talk to your pharmaceutical partners because now what's represented as the CO packaged device constituent element is changing and they need to run that through whether, how they need to inform the FDA of the change.

Etienne Nichols: That is really interesting. So the relationship between a medical device manufacturer and the drug manufacturer is an intricate one to me.

And I guess a lot of it goes down to how it's packaged, how it's labeled and who's responsible for what.

Any comment?

James Fentress: No, that's absolutely true because here I was giving the example of syringe which was regulated as a drug product for fundamental. Yeah, because it was only cleared as part of an NDA.

And so and that. And like I said, that's a corner case. If we're just producing syringes that are part. That in their finished package form are put along with their, with the drug product, then you know that not. That wouldn't necessarily apply.

Actually it would.

Forget I said that that's fine.

What's interesting about that is, you know, the drug, the pharmaceutical company timeline is so long typically, and it's interesting that you said you typically work with the pharmaceutical companies that are maybe producing a medical device or whatever, whatever the case may be that they're after.

So, what are some of the things if we go to the other side, a medical device manufacturer who is working with the pharmaceutical company, what is some piece of advice that you would have for them as they're navigating that relationship? Because it does seem to be a more complicated relationship that a lot of people don't necessarily speak the language of one another, whether it's 2, 11 to 8:20, whatever the case may, whatever the difficulty is, I think the most important things is to align from the first conversation on a few different things.

So one of them is how risk management is going to be handled and how those responsibilities are going to be split up like we talked about.

The other one would be expectations of level of detail for documentation.

And boy, I haven't even explained what that could mean. But in that section 3.2 R, I've had companies that give really high-level summary reports for the device constituent parts and those that actually want to put the entire risk management file for the, for the device constituent parts in the same sections.

Etienne Nichols: Wow.

James Fentress: So, and so when you're, when you're working with a potential pharmaceutical partner, I need to know if I'm planning for 60 hours of work or 1200 hours of work for that, that, that particular element because I don't want to disrupt the relationship later by saying you're asking me for more than I expected.

Etienne Nichols: Yeah.

James Fentress: And then the third thing is aligning with what, what kind of manufacturing environment that you actually need for your final product.

So, in a case like ours, we're, we, we would generally take in a pharmaceutical product that's being manufactured by the pharmaceutical company that would be integrated at our site with device constituent parts in one way or another to fit one of the, the three different classifications of combination products, and then it would leave under our final quality control release.

Etienne Nichols: Hmm.

James Fentress: So, what we find is in, in pharmaceutical companies that have only worked in a sterile aseptic fill environment, even ISO 8 environments are not particularly common. You see ISO 5 inside of ISO 7, we will get requests for a syringe that is or another device which is produced in an ISO 7 environment.

And we have to work with the pharmaceutical company to understand is that just what they expected? Is that what they think or is that what they need?

Because in many cases that's actually going to be far more conservative than what they actually need.

Etienne Nichols: Yeah.

James Fentress: So, align on hazard and risks, align on the expected level of details for different documentation package and make sure that you understand and have coalesced on what kind of manufacturing environment is necessary.

Etienne Nichols: I really like that last point you said because a lot of times people will default to the most conservative thing, which is on the surface level sounds like a very smart thing to do or safe thing to do.

But as an engineer, I was told very early on what's the best tolerance for every part that you make?

And you might think, well, how do I answer that? Well, the answer was the, the loosest tolerance possible that still meets the spec and still the, you know, doesn't cause any quality issue.

And just because for manufacturability, for profit, for whatever, you know, if, if, if it, you know, you can't be tight on everything, you have to have a certain tolerance level for manufacturability. So that, and that, that seems to apply in this case as well.

Really enjoyed the conversation. Any last piece of advice that you might have for anyone working in combination products, either side, just places to point them, places to find you any, any piece of advice in general.

James Fentress: Oh, two things.

One, and you already spoke with her back in 2003 is Susan Needle.

She wrote the Combination Products Handbook and it's truly an excellent resource for whether you're coming from the pharmaceutical side or the medical device side to just bring you up to speed as type of regulations that you might deal with and the type of problems that you might want to think about.

Etienne Nichols: It's been a long time since that, that episode. Maybe we need, I need to have her on again, but we'll put a link to that show note, link to that episode in the show notes so that if you're interested listening, you can check that out as well.

But yeah, thank you for bringing that up as well.

Where can people find you and what you're up to so people can find me? Our current website is gilero.com however, we are a Sonar group company and we're going to be rebranding here in the next couple of months.

So when we have our Sonar USA website up and running, you should be able to find me there.

I'm also on LinkedIn, although not particularly active there.

Etienne Nichols: Sure.

James Fentress: And, and those are my primary ways to contact me.

Etienne Nichols: All right, great. And if anybody has any questions or thoughts on this episode or anything you'd like to hear in the future, definitely reach out to me.

I try to answer every message on LinkedIn. I am active there. I've recently found out that a lot of my messages are going to this other there's and I I never navigate over to that.

So I realize I've missed some of your messages out there. So apologies for that.

But keep sending them. Don't, you know, keep your persistence. Let me know if there's anything in particular you'd like to hear from us in the future.

And as always, thank you so much for listening. We will see you all next time. Take care.

Etienne Nichols: Thanks for tuning in to the Global Medical Device Podcast. If you found value in today's conversation, please take a moment to rate, review and subscribe on your favorite podcast platform. If you've got thoughts or questions, we'd love to hear from you.

Email us at podcast@greenlight.guru.

Stay connected. For more insights into the future of MedTech innovation. And if you're ready to take your product development to the next level. Visit us at www.greenlight guru. Until next time, keep innovating and improving the quality of life.

About the Global Medical Device Podcast:

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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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Etienne Nichols

Etienne Nichols is the Head of Industry Insights & Education at Greenlight Guru. As a Mechanical Engineer and Medical Device Guru, he specializes in simplifying complex ideas, teaching system integration, and connecting industry leaders. While hosting the Global Medical Device Podcast, Etienne has led over 200...