Understanding Supplier Quality And Controls For Combination Products

In this episode of The Combination Products Handbook: The Series, host Tom von Gunden discusses Chapter 10 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 Fran DeGrazio. On the topic of supplier quality and controls, Susan and Fran discuss key considerations for using third-party suppliers of raw materials, constituent parts, and services in combination product development.

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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 Products Handbook: The Series, in which we move through chapter-by-chapter discussions of The Combination Products Handbook: A Practical Guide. Today, we're going to discuss Chapter 10, which is on considerations for Supplier Quality. And for that discussion, I am joined, as I always am, by the handbook’s overarching editor, Susan Neadle.

Welcome, Susan.

Susan Neadle, Editor:

Thanks.

And by Chapter 10 co-author Fran DeGrazio.

Welcome, Fran.

Fran DeGrazio, Chapter Co-Author:

Hi. Good morning.

All right. Well, Susan, let's start, as we often do in this book series, with having you set the context about the topic at hand. Why the topic at all — the significance not only in the book, but where it's positioned. And I did note that this topic of Supplier Quality is positioned as the lead chapter in a section called Special Topics. So, do you want to comment on that?

Neadle: Sure. So, most companies that are engaged [in] working in the combination product space in the pharmaceutical industry tend to leverage a third party to provide them the constituent part that is not in their comfort zone, i.e., the device.

And given that such a large portion of the industry does reach out to third parties to support their combination product work, the supplier purchasing controls expectations and the supplier quality considerations and the relationship management, IP management, risk management — all those things — are really critical when building a robust relationship with your supplier to make sure that, ultimately, your combination product is going to be a success in the market.

So, I really debated, does this belong in the first part of the book or the second part of the book? I put it into the second part. It might very well just fit into the first part because using third-party suppliers is such a common practice in the combination products realm. So, that's the reason for the chapter and its placement. Like I said, it could have been the first part, but I just chose the beginning of the second part because it's a very important topic.

Good. And thank you for the context setting.

So, as you looked for expertise to provide the content in Chapter 10, can you talk a little bit about the recruiting of the authors of the chapter, one of whom is joining us today?

Neadle: Yes. So, Fran DeGrazio was obviously somebody I was going to reach out to, frankly, Fran. I reached out to Fran partly because of the role that she had at the time at West Pharmaceutical. And recognizing that, just based on her career experience working in a supplier realm to many people across the industry, she would bring a great perspective into what does it mean to have to deal with the supplier quality considerations?

The other co-author of the chapter that I reached out to was Meera Raghuram. She's at Lubrizol, and Meera had presented, at the time, at the Xavier conference. A really nice presentation about device-led combination products and some of the challenges with maybe a biodegradable device or  just different delivery types of constituent parts that maybe we don't think about every day.

And she had explicit experience on some of the committees that were working on standards related to, what does it mean to be a virgin material or a medical device-grade material? So, she brought some perspective on that to the chapter, which I also thought was very important for people who are just not used to dealing with devices and not dealing with the raw materials associated with devices.

All right. Thanks.

And so, Fran, since you're joining us, I'd love to have you start off by talking about your own thoughts about the significance of supplier quality as a topic in a combination products handbook.

DeGrazio: Yes, thanks, Tom.  I absolutely, certainly agree with what Susan said about the importance of suppliers because it is such an intricate piece of the overall combination product itself. But one of the other uniquenesses, when we're talking about supplier controls and purchasing controls, is that we're not only talking about the products but even the services that quite often are utilized by companies as they're putting together combination products.

So, whether it be a contract manufacturing organization, whether it be an analytical lab that they may be leveraging, along with, of course, the fact that, in most cases, many companies are purchasing their constituent device or certainly individual components that are coming in to form the overall combination product.

So, from that standpoint, there are always critical suppliers and service providers that are interacting with the owner and the manufacturer of the combination product. So, it's just imperative that that connection work.

Neadle: And I think under 21 CFR 820.50 for Purchasing Controls, which is one of the called-out provisions under 21 CFR Part 4  for combination product CGMPs [Current Good Manufacturing Practices], it explicitly talks about, hey, these are unique expectations. This is what we're expecting you to do for your supplier. The FDA did come out with a guidance on contract manufacturing arrangements for service providers, contract manufacturers for drug products. And that guidance is tightly related to what we talk about in this chapter as well. As a matter of fact, it has been cited a couple of times in warning letters.

So, it's a blind spot for people. So, I felt it's really important to be able to go through that in this chapter to raise the level of awareness for people across the industry.

One of the things that I noticed, initially, was that there's some coverage [in Chapter 10] of regulatory considerations. Anything else you want to add to that obvious component of combination product development?

DeGrazio: As Susan just mentioned, 820.50 is certainly the basis for Purchasing Controls. But now with, of course, the adoption and the reference taking in ISO 13485, it steps it up even to a greater extent — what the requirements are for choosing suppliers.

And so, not to say that there are not, of course, supplier and purchasing controls in the drug, just solely the drug area. But with each additional adoption, when you’re then absorbing the device regs and taking those and now taking the updated QMSR [Quality Management System Regulation] regs in, what that's really doing is pointing to a much greater degree about the importance of suppliers in the work that's being done.

And I think specifically one of the things that I would say is maybe more notable is the assessment, to bring clarity towards why you're choosing a supplier. So, why is this supplier really appropriate for that specific device, for instance, that you may be purchasing for a combination product? So, I just think it takes everything to the next level.

All right. Well, great. Thanks for that.

I also noticed that a key section of the chapter is structured around offering best practices. And some of the topics under that umbrella are things like Design Controls, Quality Agreements, Change Management, etc. So, can we talk about what value or benefit readers of this chapter will gain from diving into your perspectives on best practices?

Neadle: So, let me just jump in for a second. One thing that strikes me, the whole point of the book is to share best practices and to try to help people as they're doing their day-to-day and not just be theoretical. But that said, there's a big blind spot in industry where many of the suppliers that are working in the combination product space, specifically because they are providing services — for example, a company that is doing fill-finish activities with the device constituent part, not just creating the device, but also doing fill-finish or sterilization or testing: If they are doing those activities on the full combination product, they are then considered a combination product manufacturer. And they are also expected to comply with 21 CFR Part 4, the combination product CGMPs.

And that's usually a big surprise. Many suppliers historically have thought of themselves as component manufacturers. Or they thought that they were just making a container closure and, because they're doing a container closure, as long as they do the drug CGMPs, they're good to go.

And that has changed with the implementation of 21 CFR Part 4. And because of that blind spot, it is really important to share these best practices because sometimes you may have to partner and help educate your supplier about what's expected of them, not just what's expected of you in a sponsor role. So, with that, I'll turn it over to Fran to add more.

DeGrazio: Great point. I think really what we're trying to do within the [handbook’s] chapters is to highlight these areas that we feel are potential gaps in people's knowledge.

So, for instance, let's talk about Design Controls a little bit. You know, quite often, as mentioned, you're purchasing a device or, certainly, individual componentry from third parties. If you're purchasing what we would consider to be a platform device, which is something that could be applied maybe to use, you're purchasing a proprietary device from a supplier, you may have intentions of eventually using it with multiple drug products: The choosing of that device is really part of the design control process. And so, although you didn't design that device per se, you need to understand, of course, what was involved in the design of that product that you're now purchasing.

And also, again, what's the criteria that you use to say we need these factors? And now this platform device is going to meet those requirements. And so, that's something, as just an example, that I think is unique, a unique blind spot that is an example of what you can find in the chapters as you read through them.

Certainly, we talk about quality agreements, change control agreements. Again, quality agreements being so important when you're talking about really identifying who's responsible for what. And you want these kinds of agreements to be separate from any business document because you want to be able to update these things easily. And if you have these things tied into business contracts, it's like pulling teeth to get these things through the lawyers and everybody else. So, it's great if you can have these in more of a standalone fashion so that you really have the right people working on them, updating them, making sure it's clear who has responsibility for what within a development program.

And change control, of course, is imperative because you're talking about, these products don't just get launched and everybody wipes their hands. These products get launched, and then you have the whole future and the whole lifecycle management aspects. So, there's got to be continuous communication, discussion, and updating.

And certainly, as changes are made, there needs to be agreement as to, are these changes considered minor, moderate, major, between the two parties.

Neadle: One other thing in there, too, the other danger zone, is that many pharmaceutical companies that are leaning on a component supplier or device supplier to provide them with that device constituent part sometimes falsely make the assumption that that device supplier is taking care of a lot of the design control activities for them. They don't understand, they may be coming into it in many situations with strong expertise on the pharmaceutical side — on the drug side — but not necessarily understanding the device and going, well, I trust my supplier. My supplier is going to take care of what I need them to for this device constituent part: design controls, risk management, whatever. They really don't understand.

And so, when it comes time to setting specifications on the constituent part, scale-up of molds, there are so many different pivot points or potential potholes that you can fall into that, if you're not aware of those dangers, you've got to proceed with caution. And I think it was important to get that across to people in this chapter.

Good. Yeah. And you've both talked about the supplier component of a chapter that's about supplier quality. So, it’s obvious that you would mention that. Is there anything else you could add around what I noticed was a focus around ongoing supplier relationship management that you haven't already had in front of us?

DeGrazio: I think one of the things that's critical is that, in some cases — again, I'll go back to the use of a platform, of what you would call an off-the-shelf kind of system — the supplier may not know how that product is going to be used. So, there are certain obligations that supplier has once that product is used in a combination product.

For instance, there's handling of complaints and post-market safety requirements, and things of that nature, which, in turn, put requirements not only on the combination product market holder and the manufacturer, but people that are upstream from that, like the device supplier. And so, they need to really understand, how are you using our product?

Again, that's a key gap that exists, and it is really important to have that kind of communication with suppliers because, again, they have a responsibility in all of this. And so, you want to make sure that everybody is on the same page. And again, I see it all as communication and ultimately a trust issue between partners.

Okay. Thank you for that, Fran.

And as we move toward our last stretch of conversation for today, I want to invite both of you — each of you — to offer a recommendation or a word to the wise for readers who are, we hope, fully intending to go dive into this chapter that we've been talking about. So, is there anything that you would suggest people really be thinking about or looking for or contemplating as they dive in?

Neadle: Communicate, communicate, communicate.

DeGrazio: That is probably the biggest thing. And as early as possible. And so, I think Susan and I are both on the same page with that one, for sure. Because you want to get your suppliers engaged early. You want to make sure that the two-way communication exists.

I will tell you, it is much easier to really identify and understand what you need and make sure you're choosing — whether it be the right component, the right delivery system, the right filler for filling the drug product, whatever the service happens to be — than use someone, realize they don't have what it takes, and now you're going to have to try to control that process at the end. Believe me, that will take many more resources and much more frustration to do that. So. it's better to do the work upfront.

Susan, any additional parting advice you want to offer before we close it out for today?

Neadle: I guess the only thing I suggest is, there is a really great global harmonization task force document [from] IMDRF [International Medical Device Regulators Forum] that talks that purchasing controls, and the FDA guidance on the contract manufacturing arrangements for drug manufacturers.

They're both really, really helpful for people to reference because they will help you with framing out your quality agreements, and they lay out some of the attention to detail that you need to not miss. Because if you do, your communicate, communicate, communicate will turn into a hit your head on the wall, hit your head on the wall, hit your head on the wall.

Well, good advice. Susan and Fran, I want to thank you both for joining me for this discussion of Chapter 10 of The Combination Products Handbook. I want to thank our audience for joining. I want to encourage them to go out and find a copy of the book itself. And we'll see you here next time for the next discussion of a chapter from The Combination Products Handbook.

Thank you, folks.