Let’s talk about Medical Devices but a special kind of medical device, its Drug-Device Combination Products.
We will talk specifically about article 117 of the medical device regulation MDR 2017/745.
This will be important for many manufacturers that have some medical devices which are also linked to drug and drug companies that are using some medical devices and now need to know how they can submit their dossier.
There are some changes that are happening now due to the Medical Device Regulation. You would never think about that, but the Medical Device Regulation is amending the medicinal directive 2001/83/EC.
So I hope the drug companies will really understand that and put in place the right things to be compliant.
To help you with this process I propose you also to look at this interview that I have made on the podcast with Theresa Jeary. She was working for a Notified Body.
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Table of Contents
What is article 117 ?
It is a small article within the medical device regulation with a small couple of paragraphs long that has a huge impact on drug delivery products.
There’s no specific definition of a combination product in the EU legislation so we have many possible combinations that exist.
Article 117 very much impacts those products where there is a device available to deliver a medicinal product as a single integral part type system.
The auto-injector pens for insulin or for adrenaline those types of products are impacted by it and there are many existing.
Why?
Because obviously as technology is advanced good drug delivery systems can help medicinal products for patients. And before that EU MDR article, there was no involvement of Notified Bodies:
Article 117 came about to bridge a gap in the legislation that was not clear.
Its aim was to ensure that the right stakeholders were involved in the assessment process and as technology has really advanced, it probably is appropriate that there’s additional scrutiny by experts on the medical device aspects of these types of delivery systems.
We also have Drug-Device combination products where you can co-package for example measuring spoon with a medicinal product that is outside of article 117.
However, on the EMA guideline, the quality requirements for documentation should be reviewed, but they’ve gone one step further to article 117 to provide additional guidance on the expectations for documentation in those aspects.
Is the European Medicine Agency talking about this new regulation?
There is this FAQ that the EMA (European Medicine Agency) wrote to really help the drug companies to understand the impact of article 117. There’s no definition of combination product in Europe so a product will either be regulated as a medicinal product or a medical device depending on its primary mode of action. So, the drug delivery systems is purely here to deliver the drug which will have the action on the patient. So primary intended purpose of this product is the drug action. Therefore, the product although it looks like a device, is regulated as a medicinal product and those are the products that are impacted by article 117.
There are three steps when you are going to define your products first,
- Is it a medical device or not?
- What is the classification?
- and the conformity assessment route?
but if the first answer is no it’s not a medical device then you have to look at other regulations like Medicinal Product Directive.
What will change for drug companies when MDR is applicable?
If you have a product in the drug device combination, if the medical device component is not CE marked on its own, then you are required to obtain a notified body opinion on the device aspects and their compliance to the general safety and performance requirements as detailed in annex 1 of the medical device regulation 2017/745. You’re required to get this notified body opinion from obviously a MDR designated notify body. You can provide that service and that’s for all new applications after the 26th of May 2021.
Timing is very important, a very few pharmaceutical companies in this space have never needed to engage the services of a notified body and may very well be wondering “How do I go about this?”, “How do I find these people?” and “What are they looking for?”, so these are some of the key questions at this moment. The drug companies were more engaged with the Ministry of Health or MoH, so the difference here is a bit huge to be honest it’s not the same as engaging with the Ministry of Health. Notified body are a service provider, they provide conformity assessment services and charge fees but they’re not a regulator, in the same way. They’re designated by their national competent authority and the EU Commission to provide the service.
As of today there are 17 notified bodies [Check the last numbers here] who are MDR designated and it’s not clear how many more there will be. Perhaps not all of those designated MDR notify bodies are wanting to either provide the service at this time. The notified body has specific products that they can certify or it can engage with, there is a list on the NANDO database. The NANDO contains all the list of notified bodies and which kind of products you can really deal with them.
Notified bodies may not be interested to just provide a statement or information about kind of a drug device combination product, it can be also difficult for them.
Can we say that the notified body are organized?
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The timelines do vary between notified bodies, with the medical device regulation imminent and tidying up on the MDD and completing renewals. There is stretch for resource during this time. So, it’s good to have discussion with the various notified bodies to understand what their internal procedures are, because they may differ between notify body and expected timelines. Each notified body will be different it would be case by case, some devices could be very complex requiring more than one expert involved in the assessments against the GSPR [Annex I of the EU MDR 2017/745].
For example, if you had something that was electrical or maybe have something driven by software you might need more than one expert to look at the GSPR and be able to make that opinion and assessment report for the manufacturer. So, bear that in mind it will be case by case, notified bodies who are in this space are definitely trying to do the best service possible for everyone.
Be aware in terms of project planning and timelines, notified body will have their own internal procedures that they follow to provide this service. We have to provide them some clear documentation and it’s not a technical documentation, it’s a shortened STED format technical file and it’s how you demonstrate your GSPR checklist and how do you demonstrate compliance with the applicable and appropriate GSPR for your device. They will only look at the information we provide, they will ask questions undoubtedly, it should be evident that you have met the GSPR (general safety and performance requirements) that you claim to meet through data and through evidence scientific data, they will also ask how you’ve met that GSPR and how you conform with the requirements.
Many drug industries may not know what is GSPR, it is a check list with around 23 requirements, to go through one by one and prove that you are complying to each of those requirements and also provide some evidence that you are complying to that, there may be some requirements that are not applicable for your product, in that case just fill not applicable and provide the reason why is it not applicable. You must also provide which standard you are following, which documents you’re having, which tests you have done to comply to that.
If you have doubt regarding the GSPR checklist or how to execute, don’t worry feel free to contact me. I’ will be happy to help. I also have templates for GSPR checklist, you can purchase from the below link.
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Will the notified body provide any record after their review?
Notified bodies do not provide consultancy services, we can’t approach them at preliminary stages to get their opinion or suggestion, you must consult the notified bodies once you have completed every documentation with evidence that your device has meet GSPR requirements.
The notified bodies will check if the product has met the requirements as stated and if there is enough evidence to meet the requirements or not.
The notified body will issue then a report giving their opinion, like a summary report in this process the competent authority, the medicines agency makes the decision on the product.
So, that report needs to be detailed enough to tell the competent authority what the notified body has assessed and if they accept that the GSPR is good. After all this, it will provide a nice summary statement to show the assessment conducted by the notified body on the technical documentation if everything is satisfactory or if there are any issues.
The points are raised within the report, identifying any issues they’ve seen within the data or anything that they don’t feel is appropriate.
Is the report from Notified Body submitted with their Marketing Authorization Application?
If your device is not CE marked or if it’s a high-risk classification, then you will get an opinion from the notified body and submit that as part of your marketing authorization application to your health authority.
If you have a CE mark, then you can submit your declaration of Conformity from the device manufacturer saying you meet requirements and a copy of the CE certificate from the EU notified body for the device.
These are the options given in article 117 to manufacturers in terms of what they have to submit.
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Will the Notified Body timelines be impacted if the assessment is not done correctly?
Yes, there are more questions asked by competent authorities on currently marketed medicinal products with device components, and asking manufactures if they have met the essential requirements of Annex I of MDD (Medical device directive).
Even though MDD is updated to medical device regulation, the manufactures should be aware that the device part need also to be compliant as per medical device directive Annex I.
if you’re a very traditional drug company you may not have the awareness of the different regulations or directives for your product, some drug companies may not look at the medical device regulation and move forward on their project.
So, it is about talking to the right people and engaging with the right stakeholders to make sure your project works as smoothly as possible.
To engage with consultants that are knowledgeable on combination products or medical devices so that they can really help you.
Are Drug companies with IVDR products aware of this new regulation and its impact?
There are huge changes in the IVD regulations (IVDR 2017/746) in comparison to the IVD Directive (IVDD 98/79/EC), there are many IVD manufacturers who don’t fully appreciate the impacts of the regulation on them at this time.
Certainly, for the companion diagnostic products, there is also a consultation that needs to happen with the notified body who will certify the IVD, along with the drug competent authority who has knowledge of the disease that the drug is treating.
The regulations are encouraging more discussion and sharing of knowledge between key stakeholders which is appropriate.
We need to be more practical at this minute in time, as EMA issues its guidance. It will be a learning phase, as everyone should learn about this new process of getting notified body opinions.
The National Competent Authorities, the Drug Competent Authorities, the European Medicines Agency will allow this time to settle in for everyone. We know that there are still questions that need to be answered but we should give time to the authorities to define their policy.
The Medtech Europe and EFPIA issued a white paper on Companion Diagnostics under the IVDR. This is providing some clear questions that these 2 entities are asking the Commission and the EMA. Check the link here to have a copy of this document.
Should the manufactures stay connected with Notified Bodies even after their product approval?
As all QA RA people will tell, “It depends”.
It’s not required to maintain the contact unless it is necessary. If the manufacturers are making any significant changes to the device, that can have an impact on those GSPR or if they have to gather new evidence to support the GSPR because of a change, the notified body opinion will be required again.
The design change will require a continuous review process and a new opinion from Notified Body which has issued the original opinion to support the changes.
Here is a Position Paper issued by Team NB related to article 117 of the EU MDR 2017/745. You will see inside the flowchart that can be used to define if your product need a new opinion from a Notified Body.
The notified body will not turn up to do audits every year like for medical devices. Article 117 is very much about just ensuring an opinion of the technical information for a Drug-Device combination provided by a notified body and that’s appropriate only for this.
A pharmaceutical company should make sure whoever is providing their device, that they do have an appropriate level of quality management system in place. ISO 13485 would be a guarantee that this company understands the requirements to manufacture medical devices.
Conclusion
I have seen lot of medical device manufacturer struggle to find a notified body, so it would be a bigger struggle for drug companies as it will not be a long-term engagement and it can be something interesting for notified bodies.
If you need to have some opinion or discussion to clarify your situation, you can contact a consultant instead of notified body. I’m a consultant and I can help you to be compliant with these requirements.
Feel free to contact me.
Medical Device expert. Monir founded Easy Medical Device to help Medical Device companies to place compliant products on the market. He proposes his consulting services so don’t hesitate to contact him at info@easymedicaldevice.com or +41799036836
My objective is to share my knowledge and experience with the community of people working in the Medical Device field.
