How To Apply QbD to Drug Device Combination Products

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Today, we invite Dr. Manfred Maeder of Novartis to share how Quality-by-Design is applied in the development of medical devices and drug device combination products.

Previously, Dr. Lana Shiu of FDA shared the ongoing regulatory changes in drug device combination products.

I recommend you listen to her presentation as well to get the regulatory agency’s perspective.

Since then, more FDA guidelines have been published, more combination products have been approved and more technology is available. What does this mean for us?

We will be seeing more and more of drug-device combination products. And for those who have been only focusing on just the drug side (whether small or large molecules), we need to understand the “delivery” side of the product.

This is part 1 of How To Apply QbD to Drug Device Combination Products.

This is the audio version. As you listen, you can scroll down to view the slides.

Sun: Welcome Manfred Maeder to QbDWorks interview, I’m very glad to have you today, we met at the AAPS in 2017 biologics conference talking about biosimilars, and I remember your presentation on the combination product and how you related devices or design controls to QbD and what it means to us developers in the drug space or pharma space as well as the device, who has to interface with devices. So I think this is a topic that many of us in QbD are very interested in and we’ll have a lot of impact going forward as we get more into smart products, more unexpected occurrences outside the clinical environment where a lot of the therapy is now delivered at home or outside the doctors hands and patients, so this is a topic of very much interest and new to many of us. I want to introduce you Manfred, he’s currently at Novartis, head of device development and commercialization in biologics technical development and manufacturing, and he’s been with Novartis for how many years now?

Manfred: It totally has been seven years up till now.

Sun: Seven years, and he is an expert in statistics, quality assurance and regulations, not just in FDA but also EMEA and aseptic processing and so forth and medical devices and combination products. So he’s right now very up-to-date with how he develops and he manages his organization in developing combination product, tell us about yourself, how you got into this space and what you’re currently doing right now.

Manfred: Okay, thanks a lot and you mentioned already some topics, I have some background in pharmacy and in statistics, by training I’m a pharmacist and I have been working in multiple areas, in QA/QC manufacturing, in development and in commercial operation. My first interaction with combination products was almost twenty years ago, as I was responsible of QA, responsible for insulin pen systems and we were one of the first companies putting combination products and we didn’t know it’s combination products twenty years ago, and we were one of the first ones putting disposable insulin pens on the market, that was my first interaction with this type of products and then I also, before Novartis, I work for a device company, so I have some very really in-depth device background also from quality and regulatory perspective and also the development perspective and now since seven years I’m with Novartis, but also in a quality job and now since a few years being responsible for device development and commercialization that means lifecycle management of these devices. And device means in my case at this point of time, all of them some type of injectable systems that means prefilled syringes, auto injectors, injection pumps and other delivery systems, and these could be standalone or they could be also connected devices, that means which would be able to talk via Bluetooth to an iPhone or whatever Android and so this is the range of products we are covering at this point of time.

Sun: Excellent, so I remember in 2015, before we get into your presentation, we had Dr. Shiu of FDA, he presented the guidance document 2015, well it was finalized in 2013, it was updated in 2015 and since then, what has changed in the landscape of prefilled syringes accommodation products?

Manfred: Quite a lot has changed since that time, okay well the regulation, the law, it was endorsed and in 2013 a new guideline, a guideline on top of that came out and in January of 2017, defining a little bit more the expectations of the FDA, for example and during the last three to four years for example, five additional guidelines had been made available from the FDA only on human factors for example, so that means and also on other topics that means the expectation has risen significantly looking at the combination products landscape. The basis was the CFR part four, which was made effective in 2013, but after that a lot of guidelines and rules have changed the landscape significantly there.

Sun: Excellent, so we’ll have links to those guidelines in our post. So I think your presentation last year at the AAPS conference was very comprehensive in terms of giving it a quick overview and how we want to tie it into QbD as well, because there are a lot of similarities between how devices are developed and how we develop GTPP in QbD as well as linking it to process parameters to product performance and devices. So a lot of parallel similarities that we want to explore and how, if you’re not familiar with the devices, it is important now to get into, to see what the counterpart, how your drug is delivered to the patients, it’s important to know that as a drug developer as well, so I think this information is very useful to both the device developers as well as the drug developers.

Manfred: Absolutely and this is maybe, to comment on that, and this is also what is driving us, myself and also my team, this is really driving us because we want to make it as convenient as possible for the patient, that means once you have an auto injector available and not the vial syringe system which is the classic system, vial syringe you have to go to your doctor maybe twice a week, maybe weekly, maybe once a month, you have to go to your doctor to receive the injection and with an auto injector that enables the patients to inject themselves and this is a huge benefit and convenience for the patients to make sure, which would enable them and to have a regular treatment and so this is, I think really is one of the topics which is driving us, to make it as convenient as possible for the patient.

Sun: Absolutely, so the landscape is changing on how we deliver drugs and therapy to the patients. So we’ll talk about that in the presentation, so without further ado, let’s go into the presentation.

Manfred: Okay, first I try to briefly summarize and we will go through that presentation, linking drug device critical to quality product attributes and the process parameters to product performance that means in the end, what does it mean for the patient? First slide, first of all, I would like to give a little bit of background, I intend to talk a little bit about the regulatory landscape, which is really changing and also it changed since last year quite a bit, then we have a quick look at the development process, and then I also have some examples of quality relevance for the patient and also some technical points to consider, and this will be one example, and also maybe one of the important points is the increasing number of drug need medical devices and there I would like to provide some background to you. First of all, last year in 2017, this was the first year that more biologics products had been submitted to the FDA for approval than small molecules, and 2017 was the first year that happened within the US, that means more and more biologics products are requesting approval and the only way to get the biologics, typically the only way to get biologics into the body is through an injection and there are also some other means out there or some other technologies, but they are not approved yet at this point of time, so an injection or infusion that’s the only way, so for that reason, we need more and more devices and also medical innovation is really moving fast and also patients are more empowered, they’ve find out that there are more convenient ways, that means especially if you look at biosimilar, the device really can make a difference, if you imagine one application has a vial syringe, a filtration needle and an injection needle with 15 handling steps for the patient and similar presentation has an auto injector, a two-step, that means you remove the cap and inject yourself and so this can make a big difference especially for biosimilars for example.

Sun: Correct, if I may interject, I know the patient adherence is one of the main topics because the topics of drug delivery as well.

Manfred: Yes, absolutely, this is absolutely true and this is the reason we try to develop our systems to make them convenient as possible for the patient, that means also we’re going to more and more, very thin needles to thin wall needles, and also to have sizes of needles which typically you would not notice even in some cases, so that means to improve the patient experience, this is very important for us absolutely. I am also there and you mentioned patient compliance, there are also advances in digital technology that means, basically there are opportunities available in the near future where you can track if the injection has been performed, when it has been performed, has it been injected completely, all this type of feedback information can be collected maybe by smartphones and also can be provided to the doctor if this information, if there’s a wish this information should be shared and so there are lots of opportunities available or will become available these days and also to track compliance, which can be a huge cost savings absolutely. Also it is important to see what we observe recently, we are also known and traditional companies are collecting this data, evaluating this data like Apple IPM, a lot of people have a Fitbit, so you could combine this information of your Fitbit looking at heart rate and then other parameters, you can collect this information and can link that with your medication and you can see if it has an effect on the heart rate, glucose level and whatsoever depending on the medication you are taking.

Sun: Right, with artificial intelligence, this has become more powerful.

Manfred: Exactly, that’s the path we are going down and to see also maybe in some case to be able to predict any worsening of health condition. Okay now, if you move on and the presentation, the regulatory landscape is quite diverse, first of all, if you look at an auto-injector for example or prefilled syringe, this is defined by CFR part four in the US, in the US it’s a combination product and in Europe, following the medical device directive or since a few months, the medical device regulation which is being endorsed right now and which will become active within the next two years and are mandatory within the next two years and there it’s defined as either a medical device or a medicinal product. The term combination product does not exist in Europe and not in the most countries worldwide and combination product is a US terminology and there was the draft guideline in Europe last year by the EMA, talking about DDCs that means drug device combinations, but still the regulatory pathway is either a medical device or a medicinal product, if it’s a prefilled syringe, primary mode of action typically is the medicine or the product, though it’s of course a medicinal product in in that case. Also moving on in the presentation, looking at the combination product, following the US definition, a combination product can be either a single entity, that means the fixed combination which is for example prefilled syringe or an auto injector, it could be co-packaged, that means you pack a file together with a syringe and a needle for example that’s co-pack or it could be cross labeled, that means in other words, a device is distributed to the patient or to the customer and separately, a cartridge is distributed and the cartridge says use with that device XYZ and the device says you have to use it with that cartridge from company XYZ, and so that means it’s distributed separately but there is a cross reference to use one in combination with the other.  Also, this is a unique in the US FDA, Canada for example, we only have single entity or co-pack and most other countries only use the single entity combination product as the definition, so that means it’s only one subsection of the US definition, which makes the overall regulatory process worldwide quite complicated.

Sun: As usual yes.

Manfred: As usual, yes. And if we move on to the next slide, and this is a description that was a snapshot of last year and looking at who has a formal definition in the regulation like US has a formal definition and also Canada, China and so on, they have a formal definition what is a combination product, I mentioned already EU, does not have a formal definition of a combination product, informally right now talking about EDC’s proactiv device combination but there is no regulation out there yet, and then it’s their mechanism that’s also listed on the slide, several countries have a termination mechanism and then if we look at the other parameters on that slide, looking at evaluation process, manufacturing controls, labeling, postmark reporting and so on, if you look at that pretty much each country has a different regulation and different expectations how to deal with that, so dealing with combination products these days is somewhat complex, even more complex than broad products.

Sun: Absolutely, so in this case, do you first target the USA markets since it is the most complex? Or do you start with the lower requirements of…?

Manfred: We typically would target, for US and Europe, that’s the first target is US and Europe, because US is one of the most complex but comparing US and Europe, Europe has also some additional expectations, for example the essential requirements to not have, that means this is the clear description what the device is capable to do and how it plan to achieve that, this does not have to be submitted in the US but this is part of the submission package in Europe for example and this is changing in the US, at this point of time, in the near future they might become necessary in the US or to be submitted, so that means in US, we have to have it, in Europe we have to submit it. So that’s the reason we are targeting specifically through US and Europe and also Japan because Japan also has some very specific requirements, for example if you look at siliconization of cartridges or prefilled syringes, Japan has very specific requirements for the silicon which are not present in US and Europe.

Sun: Very interesting.

Manfred: And then the additional ones, Canada and Brazil and then couple of other examples where there’s one or two additional specific requirements, but then we look into that and typically we fulfill that, but again US, Europe are the two most important ones first and then Japan because it’s not possible to develop a product without taking these requirements into consideration.

Sun: For combination products, is there such an organization such as the ICH that promotes harmonization across different region?

Manfred: Yes and no, there’s two organizations which I’m also a member of and contributing, there’s the CPC which is called combination product coalition, which is US based and there we are in constant exchange with the FTA, that means, we are discussing with the FTA on a regular basis upcoming and maybe also options for upcoming new regulation and what makes sense, what doesn’t make sense, from an industry perspective, and so there is a constant exchange, and this also we started in Europe, this is ongoing also since very few years right now, it’s called EPE, this is the biologics organization in Europe, and since the biologics organization is dealing quite a lot with combination products what I explained before, also there we started to have more and more interactions with authorities, we had a meeting earlier this week with MHIE and EMA representatives on that topic for example, but an overarching organization that you questioned, overarching organization doesn’t exist yet at this point of time.

Sun: So it’s still growing and a lot of changes to be expected in the future?

Manfred: Yes, absolutely, this is absolutely true. Okay, now if we look at ICH what we just mentioned, ICH Q10 the objectives and there we are describing quality attributes which are appropriate to meet the needs of the patient, and also we try to make sure, we are making sure we are compliant with the approved regulatory filing and also it’s important following ICH Q10 it’s very important to develop and use effective monitoring and control systems and to look at the suitability and capability of the process, and this is all written at the original text for the ICH Q10 written for track products, for substance and track products of course. At this point of time, it is a few years old and not considering combination product, but we come to that a little bit later, these thoughts are quite inherent to the development process of a device in general.

Sun: Correct.

We mainly covered the regulatory landscape of drug device combination products in part 1.

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