EMA adopts guideline on quality documentation for medicinal products when used with a medical device

The European Medicines Agency (EMA) has adopted a guideline on quality documentation for medicinal products when used with a medical device.

The guideline was adopted on 22 July 2021 and will come into effect on 1 January 2022.

What is the guideline about?

The guideline:

describes the information that should be presented in the Quality part (CTD Module 2) of a marketing authorisation dossier for a medicinal product when it is used with a medical device, or device part, and submitted in accordance with Directive 2001/83/EC and/or Regulation (EC) 726/2004.
considers the requirements, as laid down in Directive 2001/83/EC and/or Regulation (EC) 726/2004, where the action of the medicinal product is principal
provides clarification regarding documentation for medicinal products in respect of a marketing authorisation application (MAA) or post-authorisation applications
focuses on product-specific quality aspects of a medical device, or device part, that may have an impact on the quality, safety and/or efficacy (and hence overall benefit/risk determination) of a medicinal product
considers three different, yet common, configurations of medicinal products used with medical devices, and describes the information that should be submitted to a Competent Authority (CA) for each of these configurations (see the section below entitled ‘When does the guideline apply?). Depending on the configuration and the potential impact on the benefit-risk assessment of the medicinal product, the information that should be submitted will differ
reflects current quality assessment practices and defines the additional documents/information for the three configurations described in this
also takes into consideration the amendment to Annex I, Directive 2001/83/EC (concerning supportive information to be submitted to CAs) introduced by the Medical Devices Regulation ((EU)2017/745, MDR) by way of Article 117 (see Section 5.4 of the guideline). Here you can view the Q&A document referred to in section 5.4.

The core precept of this guideline is that the Competent Authority responsible for the regulation of medicines will evaluate the device (part) specific aspects relevant to the quality safety and efficacy (and hence overall benefit/risk determination) of the medicinal product, and that, as applicable, the Notified Body will assess the relevant General Safety and Performance Requirements (GSPRs) for the device (part).

Which medicinal product types are in scope of the guideline?

The guideline applies to chemical, biological or radiopharmaceutical medicinal product.

Also in scope are medicinal products:

utilising electromechanical devices (including active implantable devices), electronic add-ons and digital elements of devices where they are expected to impact, even potentially, the benefit-risk assessment of the medicinal product from a quality perspective; however, in this regard, it is acknowledged that more detailed guidance may be required in future
intended to be used with a Class I medical device

Which products are out of the scope of this guideline?

The following products are out of scope of this guideline:

In-vitro diagnostic devices, including companion diagnosticc) System and procedure packs regulated under Article 22 of the MDR.
General groups of devices where reference is directly made, or inferred, in the product information, (e.g. “using a syringe or “an infusion line”, etc…).
Products falling under the first sub-paragraph of MDR Article 1(8).

Does this guideline apply to Advanced Therapy Medicinal Products (ATMPs)?

Article 117 of the MDR does not apply in the case of combined ATMPs as defined under Article 2(1)(d) of Regulation (EC) No 1394/2007.
The information related to the medical device part(s) of combined ATMPs are detailed in ATMP specific guidelines.
Where ATMP specific guidelines do not indicate the location of the relevant information in the dossier, the principles in this guideline should be followed.

The content of this guideline should be taken into consideration in the following cases because of their potential impact on the quality, safety and/or efficacy of the ATMP:

Medical devices that are co-packaged with ATMPs.
Separately obtained devices which are referenced in the medicinal product’s product information

Further information on ATMPs is provided in section 2, Scope of the guideline.

When does the guideline apply?

The guideline applies in the following three cases:

Configurations where a medicinal product and a medical device are placed on the market as a single integral unit.
Title	Definition	Applicable legislation	Examples
Integral (Drug-Device Combinations)	Devices that when placed on the market incorporate, as an integral part, a substance that, if used separately, would be considered as a medicinal product and has an action that is principal and not ancillary to the action of the device (second sub-paragraph of Article 1(8) of the MDR).	If the principal mode of action of the products is pharmacologic, metabolic or immunologic, they are regulated under the medicinal products framework (i.e. Directive 2001/83/EC or Regulation (EC) No 726/2004, as applicable). They are referred to as Drug-Device Combinations (DDCs) The relevant general safety and performance requirements (GSPRs) of Annex I of the MDR apply with respect to the safety and performance of the device (part). Article 117 of the MDR applies (see further information provided below on what this means).	Medicinal products with an embedded sensor where the sensor is a medical device and its action is ancillary to the medicinal product.
Integral -Administration devices (Drug-Device Combinations)	Devices intended to administer a medicinal product, where the device and the medicinal product are placed on the market in such a way that they form a single integral product intended exclusively for use in the given combination and which is not reusable (second sub-paragraph of Article 1(9) of the MDR. Typically, these devices have measuring or delivery functions	If the principal mode of action of the products is pharmacologic, metabolic or immunologic, they are regulated under the medicinal products framework (i.e. Directive 2001/83/EC or Regulation (EC) No 726/2004, as applicable). They are referred to as Drug-Device Combinations (DDCs) The relevant general safety and performance requirements (GSPRs) of Annex I of the MDR apply with respect to the safety and performance of the device (part). Article 117 of the MDR applies (see further information provided below on what this means).	Examples include 1. Single use: -prefilled syringes -pre-filled pens -pre-filled injectors (including autoinjectors None of the above are intended to be re-used or refilled once the initial doses provided are exhausted. 2. Drug-releasing intra-uterine devices and pre-assembled, non-reusable applicators for vaginal tablets. 3. Dry powder inhalers and pressurised metered dose inhalers that are preassembled with the medicinal product and ready for use with single or multiple doses but cannot be refilled when all doses are exhausted. 4. Implants containing medicinal products whose primary purpose is to release the medicinal product.
Configurations where a medicinal product and a medical device are not placed on the market as a single integral unit, but the medicinal product is intended for use with a device.	–		–
Title	Definition	Applicable legislation	Examples
Co-packaged (not considered a drug-device combination)	A medicinal product and a medical device are packed together into a single pack (e.g. carton), which is placed on the market by the Marketing Authorisation Holder.	This product is not considered a drug-device combination as the medical device falls under the first subparagraph of Article 1(9) of the MDR. Where the medical device is co-packaged with the medicinal product the administration device is governed by the medical device framework. These administration devices must meet the requirements of the MDR and will need to be CE marked.	-Oral administration devices (e.g. spoons, syringes) -Injection needles
Referenced (not considered a drug-device combination)	The product information (SmPC and/or package leaflet) of the medicinal product refers to a specific medical device to be used (e.g. identified by its brand name and/or specific description), and the specified medical device is obtained separately by the user of the medicinal product.	Devices referenced in the medicinal product information, or medicinal products referenced in the information supplied with the device, are not considered drug device combinations. In these cases, the administration device is governed by the medical device framework. These administration devices must meet the requirements of the MDR and will need to be CE marked.	-Nebulisers and vaporisers -Refillable/reusable dry powder inhalers and metered dose inhalers; spacers for inhalation sprays

How does the MDR and in particular Article 117 impact marketing authorisation applications?

Article 117 applies to DDCs referred to under the second subparagraphs of MDR Articles 1(8) and 1(9).
Article 117 does not apply in the case of combined advanced therapy medicinal products as defined under Article 2(1)(d) of Regulation (EC) No 1394/2007.

Marketing authorisation applications for a DDC submitted as of 26 May 2021, must demonstrate that the device part meets the relevant requirements of Annex I of Regulation (EU) 2017/745 as follows:

If the device part has a CE marking, then the applicant has to provide a Declaration of Conformity or, where applicable, an EU certificate issued by a notified body designated for the type of device part in question, allowing the manufacturer to affix CE marking to the device
If the device part does not hold a CE marking and the dossier does not include a declaration of conformity or where applicable, an EU certificate issued by a notified body designated for the type of device part which has a risk classification of sterile class I, measuring class I, class IIa, class IIb or class III medical device, then the applicant must provide an opinion from a notified body on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to Regulation (EU) 2017/745.
Additional information may be requested during the review of the benefit/risk assessment of the medicinal product in order to ensure a safe and effective use of the DDC.

Should this guidance be read in conjunction with any other documents?

Yes it should, as detailed in section 3, ‘Legal references, Application of Standards and Guidelines’ of the guideline.

In addition, you will also find the document, Questions & Answers for applicants, marketing authorisation holders of medicinal products and notified bodies with respect to the implementation of the Medical Devices and In Vitro Diagnostic Medical Devices Regulations ((EU) 2017/745 and (EU) 2017/746) helpful to improve your understanding.

Source: European Medicines Agency