Understanding CGMPs For Combination Products
In this episode of The Combination Products Handbook: The Series, host Tom von Gunden discusses Chapter 4 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 Mike Wallenstein. In the exchange, Susan and Mike share their perspectives on combination product CGMP’s (Current Good Manufacturing Practices), including such aspects as regulatory definitions and differences in the U.S. and Europe, supplier controls, design controls, and manufacturer responsibilities.
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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. I am your host, Tom von Gunden, Chief Editor at Drug Delivery Leader. Today we will have a discussion on Chapter 4 on “Combination Products Current Good Manufacturing Practices,” or CGMPs. For that discussion, I am joined by the book’s editor and coauthor for Chapter 4, Susan Neadle, as well as Chapter 4 coauthor Mike Wallenstein.
Welcome, Susan. Welcome, Mike.
Susan Neadle:
Thanks for having us again.
Mike Wallenstein:
Thanks a lot.
Let's start by providing some definitions and some categorization. Can you talk a little bit about, from both the U.S. and EU perspectives, how people should be thinking about what CGMPs are and how they apply to combination products and various component parts?
Neadle:
CGMPs are current good manufacturing practices. They're the minimum expectations that an organization needs to satisfy to ensure that the products that they produce are safe and effective for the intended users and the intended use environment. And, for the intended uses, if I step back into the U.S., there are CGMP expectations that have been defined by the U.S. FDA for medical devices, there are CGMPs that have been defined for drug products, and there are also CGMP expectations that have been defined for biological products. What's unique in the combination products area is that the FDA took the time to create a distinct category of products called combination products, which also has specifically defined CGMP expectations. Those CGMP expectations cover each constituent part of the combination product and that combination product as a whole. Mike, do you want to talk about CGMPs in Europe?
Wallenstein:
We don't really have CGMPs defined. However, since 2022, we have a new Medical Device Regulation [MDR]effective in Europe. This new Medical Device Regulation also talks about drug-device combination products. That means we now have a clear regulation on how to develop and how to ensure safety and effectiveness for drug-device combination products in Europe. It’s pretty similar, but also somehow different.
Neadle:
Going back to your original question about the differences in configurations and nomenclature, in the U.S., something that's unique are combination products, which is a distinct category of product. Within that category of products, there are different configurations of products that have been defined. Under 21 CFR 3.2(e), it describes combination products that are single entity, which means they're physically or chemically combined to create one, single product. There are also co-packaged combination products where the different constituent parts are packaged together in one package. There are cross-labelled combination products where the different constituent parts are distributed separately but are required to be used together in order to achieve the intended use of that product. Those are the three main categories. Under the cross-label category, there's also a definition under 3.2(e) around those intended for investigational use. It’s broken out into the marketed and the investigational. Even that is an interesting comparison relative to Europe so I’ll turn it over to Mike to make that.
Wallenstein:
That's pretty interesting because there are some similarities. What's described as a single entity product in the U.S. is called a single integral combination product in Europe. Bottom line, these are the same. That means they are physically or chemically combined to build a single and, very important, non-reusable combination product. That is the definition of a single integral product in Europe. It is one entity containing a product which is non-reusable on the market.
The other definition is a co-packaged drug-device combination product. That means the drug and the device are building one product, however, they are not combined, but they are delivered in one package. Here is a caveat: For the device, all medical device related requirements apply. They have different obligations for the manufacturer, for the distributor, for the importer, and these rules have to apply. This is a brand-new situation, especially for pharma companies, but also medical device companies planning to distribute drug-device co-packaged products on the European market.
Neadle:
One of the things that you didn't mention was reference products. Can you talk about that too, Mike?
Wallenstein:
There's also something called reference products. However, the requirements are not so stringent as the U.S. market. What is cross-labelled in the U.S. is called a reference product in Europe. We can then differentiate between two side reference products. That means a product which is referenced on the device label and the drug label, or a one-sided reference product which is only referenced from one side. For example, a drug which should be used with a very specific syringe but are not delivered together.
Neadle:
But the labeling says that they are intended to be used together. The other thing that's unique in Europe is that idea of single, integral, non-reusable, as distinguished as a drug-device combination product or an integral drug-device combination product. The nomenclature from the June 2024 guidance that was issued in the United States -- it doesn't have to be non-reusable. So, both reusable and non-reusable. If it's single integral, it's still a combination product. In Europe, there's that distinction of, if it's non-reusable then it's considered an integral drug-device combination. If it's reusable, it doesn't have that specific title. A lot of the regulations that apply are still pretty consistent for an integral product, but it's not treated the same way. It’s complex.
Wallenstein:
It’s one of the biggest challenges that the pharmaceutical industry had to get used to. Now they are. It’s new. It's a challenge. For me, working in the pharmaceutical industry, it's really my daily business to overcome this burden within the company and also with suppliers. Suppliers in European markets are not used to it. That's pretty clear. They are also not used to the different roles and responsibilities whenever we’re talking about the importer role for a device which is imported from outside of the EU to the EU to be distributed with the drug. In the past, companies were co-packaging the device to the drug, and that was it. Now, suddenly, they are really defined requirements, and that's a challenge for the pharma companies. We don't have to talk about the details of development activities at this point in time, because before we come to that, there are some legal obligations which could be showstoppers for some companies because they are not resourced to do them.
Anything else that either one of you has to say to illustrate how the coordination of efforts works amongst sponsors, suppliers, manufacturers, and contractors when it comes to making sure that everybody who's responsible for addressing CGMPs is appropriately playing their part?
Neadle:
With some of it on the U.S. FDA front, you need to manage it through purchasing controls and supplier controls. There are explicit expectations that we'll talk about when we get to Chapter 10 or 11. But for the purposes of this conversation, I would say that your supplier quality agreements are really the tool that companies are equipped with to help manage some of those expectations and who owns what responsibility to make sure that you're meeting the CGMP obligations for your combination product, both during development and, very importantly, post-market. I'm going to turn it over to Mike because it does get much more complicated on the European front. There are some complexities on the U.S. side, but I'll save them for the purchasing controls chapter. This aspect of the CGMPs is very distinct for Europe.
Wallenstein:
I can take the European ball here; however, I would also refer to a later section of the book. One of the key differences is a definition of the combination product manufacturer. There is a difference between the U.S. and European definitions. In the U.S., manufacturing could have multiple hats, whereas in the EU, it is defined as a specific obligation within the European Medical Device Regulation about the manufacturer’s role and responsibilities. The manufacturer is meant here as the device manufacturer, so the manufacturer of the device’s constituent parts.
We again have to differentiate clearly between co-packaged and single integral drug-device combination products. As we mentioned briefly earlier, for co-packaged drug-device combination products, the manufacturer has a very specific role. The distributor has a very specific role with responsibilities. The importers also have specific roles. We have something called specification developer, and then we have something called custom package producer. All of these specific roles are very important if we're talking about co-packaged combination products.
If we are talking about single integral combination products on the European markets, the rules are pretty easy. The manufacturer of a single integral drug-device combination product is the marketing authorization holder. That's it. That's an important role. You don't have to take care about importer, distributor, authorized representatives, and all the details which you can find in the book. These are really the important roles you have to consider for both sides.
Independently, if you are developing or manufacturing a drug-device combination product in the U.S. or in Europe, your internal organization is important, and you have to internally ensure that the functions are working together. Let's say you're speaking the same language. It is not so easy to mitigate between drug development functions and device development functions within the company. That is one of the key challenges we have to overcome when dealing with drug-device combination products within your organization.
Neadle:
I absolutely agree. We’re going to talk about that more in Chapter 5.
I love the implicit promotions for the rest of the episodes in this series. While we're still talking about Chapter 4, I noticed that there's a lot of emphasis given to the various aspects, stages, and components of what you might call design controls. Things such as design inputs, design outputs, design review, design verification, design validation, and design change controls. Anything you can say to help the folks tackle addressing what those various components about design mean for delivery?
Neadle:
I'll take one step back because I forgot to mention it before. When we talk about the CGMPs for combination products, what the FDA has done is they've said, there are a lot of commonalities between the CGMP expectations for drugs and for devices. With those commonalities, they recognize that if you're fulfilling a base quality system for your drug or your device, you're doing a lot of the same things. There are some distinct provisions of the CGMPs that have distinct interpretations between the two.
Building off of what Mike said about some of the terminology, this actually comes alive when you think about the CGMPs. If you have a drug-led combination product, presumptively you have a drug-based CGMP operating system. If 21 CFR 211 or maybe ICH Q9 or Q10 is what you're used to working under, in that situation, the FDA has some specific called-out provisions. There are management controls, design controls, purchasing controls, and corrective and preventive actions depending on your product installation and servicing.
These called-out provisions sometimes sound very similar, like say, purchasing controls. On the device side, we do purchasing controls, corrective and preventive action, and management controls in the drug world. So, of course, we're not worried about those. We're just focused on design controls. Before I go into design controls, I just want to make this point. I've spent a lot of time in this chapter going through the design controls. Design controls give people a lot of problems, so there is a lot of practical hands-on advice for best practices to be successful for design controls. That said, do not ignore those other called-out provisions. The reason they are called out is that they are interpreted differently than they would be for the drug’s CGMPs alone. If a drug-device combination product has a drug-based CGMP operating system, you are going to have to ensure that you are interpreting and applying those specific, called-out provisions in your organization using the device interpretation, not the drug interpretation. That is a total blindside for a lot of people.
There’s a hefty portion of this chapter spent on design controls because so many people struggle with, How do I do this? I'm used to quality by design [QbD]. The FDA says that you can leverage information that you may have generated using QbD if it's appropriate and you can justify it. However, when you think about project management practices, that includes [the following considerations for project managers]: I need to have a project plan. I need to have clear requirements and understanding around my user needs. I need to take those user needs and translate them into specific technical design requirements. Now I'm going to design the thing based on those design requirements, and I'm going to come out with something which is an output. Now I'm going to verify that that output actually meets those requirements. Does it meet the user needs? I'm going to validate it.
What I just walked through is basic project management. The difference is that, when it comes to combination products and medical devices, the expectation is that project management is a mandate. Design controls is a mandatory process that you're working your way through that starts with making sure you understand your user needs and translate them into design inputs. Those design inputs will incorporate inputs based on risk management and human factors. You're going to take all that and create specific technical design requirements through an iterative design process to come out with your design outputs. Of those design outputs, you need to identify which ones are essential for that product to function the way it's intended to function safely, effectively, and usably.
With that, you've got to verify that that product is working as it should. You're doing design reviews as you go through each stage to make sure that you've done what you said you were going to do in your plan that you put together in the beginning. Once you've gone all the way through that and you're like, yes, this thing meets all the specifications that I intended for it. I've got test methods defined for it, and I know that they're working. It's reliable, it's got all these characteristics. That is what I asked for the product to be. Now, does it actually suit the user's needs? I have to do that design validation, which could be clinical or in the form of my human factors studies. There's a lot more to that. Risk management is the foundation for the entire thing. Every step of the way you're doing risk management.
Wallenstein:
That’s an excellent explanation, Susan. Let me also try to explain why we need design controls within the device world. Don’t forget that the design control requirements are coming from the device side of the regulation. There is a fundamental difference between devices and drug products. This fundamental difference is that, usually, when we talk about standard devices, I can test the functionality of my devices. I can test if it works. That means I have two built-in design control measures to define what I can test on my device product. That's the reason we are talking about designing in.
For drug products, I cannot test my drug products. One of my standard questions if I'm giving trainings is always, what do you think is the amount of test drugs on the market? I'm getting very colorful answers, but the reality is zero. You cannot test the drug efficiency. You cannot test if the drug is [already] on the market. You have to build tests into your manufacturing process. That's why we are talking about process validations in the drug world and design validations in the device world. You can test the device without destroying the device, but you cannot test the drug without destroying the drug. That is a philosophical difference, and the reason the regulations were developed differently.
Neadle:
If you look at those regulations, there's process validation on the device side too, but when it comes to the combination product, if you think about the drug constituent part, it's about in-process controls. What are my established conditions? Think about ICH Q12. There are all these things that you need to consider to make sure that the process is repeatable and reproducible so that if I'm taking the active pharmaceutical ingredient [API] and sticking it into this process, I know that coming out the back end of this process my drug is what it should be. On the device side, I'm designing all of that in. There's a huge emphasis on that design part. And then, I have to validate the process to make sure that when I assemble this product that I've designed, it is going to be repeatable and reproducible in its production.
When it comes to the combination product, I need that validated drug process where that drug is basically treated almost as a design input into my combination product design controls process. I now need to make sure I'm preserving the characteristics of that drug when it's interacting with my medical device. The drug process still stands, I still have to do my QbD, I still have to go through my clinical phases for the drug, but underlying that is the fact that there is this device that could interact with that drug. Is there some reason that, because of the device drug interactions, it could modify the way that drug functions? If it's a biological product, it could modify its configuration, in which case, it no longer even has the biological benefit that you're expecting when you're delivering it. That's why there's this interplay. It's the integration of QbD and design controls that is so critical.
For people on the drug side, when you're doing QbD, it's a best practice. You're doing the science. You have to identify the established conditions and the in-process controls. But the specific process of doing QbD and how you come up with your design space, that's not necessarily prescriptive. There’s not a mandate that you do it a certain way. Design controls are an absolute mandate. It's like project management and best practices except that you have to have everything signed off. It has to be done in a certain order. You have to have a plan that says you proactively established acceptance criteria. When you get through the whole thing, you have a design history file similar to your drug dossier, but not quite the same. In this design history file, it is the history of all the decisions you made in coming up with that product to ensure it's going to be safe, effective, reliable, and usable -- all based on risk management. It ties into your risk management process.
I don't want to put either of you on the spot if there's no other takeaway statement to make, but I'm sure there will be. For those folks who have jumped into the book and read Chapter 4 or are, hopefully, encouraged by this discussion to do so: As they move through what is actually quite an exhaustive chapter, what would you advise folks to really attend to and focus on as they move through the material covered there?
Wallenstein:
Take care about the human factors evaluation if you are designing a drug-device combination product. Consider the differences and commonalities between the U.S. and Europe. Take care about the additional provisions like the CAPAs [Corrective and Preventive Actions], which are opened on your behalf by your manufacturing suppliers. Don't forget to integrate your suppliers into your systems. That's really important. Usually, you are developing a drug-device combination product together. Ensure that you have, as a marketing authorization holder, appropriate access to supplier documentation in case you need it for submissions. And again, take care about your human factors because your design validation depends on the user needs and that you fulfill the user needs with your drug-device combination products.
Neadle:
In Europe, your general safety and performance requirements include that you have to demonstrate the human factors. Do you want to say more about general safety and performance requirements, Mike, before we go on?
Wallenstein:
That's a book of its own. It’s general safety and performance requirements. Let's translate them to the Essential Performance Requirements [EPRs]. These are the essential requirements to demonstrate safe and effective drug delivery. These are the general safety and performance requirements, and several of them are predefined within the European Medical Device Regulation, and some of them are fully applicable for drug-device combination. Take care to consider them.
Good advice. Susan, any other final words to the wise reader from you as they dive into the chapter?
Neadle:
Make sure that you're very keenly aware of that definition of a combination product manufacturer, and partner with your suppliers, partner being the key word. Historically, many of these drug companies or drug CDMOs that have been taking components that they've been purchasing and doing fill-finish activities for you, they're doing the assembly process for you. In the U.S. interpretation, they have become combination product manufacturers. That component that historically was a container closure is potentially, now interpreted to be a medical device. Because it's a medical device, for those companies that had always said, we’re just component manufacturers, none of those CGMPs apply to us, that's no longer the case. If you are making a component that is a device constitute part, you are now a medical device manufacturer.
If you're also taking that medical device and doing fill-finish activities on that medical device, now you're a combination product manufacturer, which means that these combination product CGMPs apply to you. Many suppliers do not understand that they are on the hot seat of part 4 for their products. It is absolutely critical that sponsors are partnering with them because, ultimately, your combination product for which you are the market authorization holder could be made or broken by the fact that your supplier is not compliant with the CGMP call-outs. You want to make sure that you're working with them, educating them, and helping them become compliant if they're not already, because your product hinges on their product, but you, as the sponsor, hold the overall responsibility for the whole thing. Even if you're a device manufacturer and you're making a combination product, you're responsible for the drug. If you're a drug manufacturer and you're purchasing the device, it doesn't matter that you purchased it; you're responsible for each constituent part and the combination product as a whole and all of its CGMPs.
Good advice from both of you. Great coverage of Chapter 4. I encourage our audience to check out the book and Chapter 4. Stay with us for the upcoming episodes of The Combination Products Handbook: The Series. Thank you, Mike. Thank you, Susan. Thank you to our audience for joining us. See you next time.