The European Medicines Agency (EMA) has released a question-and-answer guidance on the implementation of Regulations (EU) 2017/745 and (EU) 2017/746 concerning medical devices and in vitro diagnostic medical devices. This document offers practical insights into implementing these regulations for combination products comprising both medicinal products (or substances) and medical devices. Such products fall under either the pharmaceutical or medical device framework, depending on their primary mode of action.
The guidance document covers regulatory and procedural guidance for:
- Integral drug-device combinations (medical devices that form an integral product with a medicine, such as pre-filled syringes) and their lifecycle management.
- Medicinal products that include a medical device in their packaging (referred to as co-packaged) and how these should be labeled.
- The consultation procedure for medical devices with an ancillary medicinal substance (a substance that supports the proper functioning of the device).
- The consultation procedure for companion diagnostics, diagnostic tests that are essential for the correct use of a specific medicine.
How to Submit Minor Variations to the Device (or Device Part):
- As for any other changes, the market authorization holder (MAH) should determine whether there is a potential impact on the delivery, quality, safety, and/or efficacy of the integral Drug-Device Combination (iDDC).
- If the MAH determines that the change impacts the registered information, or if the change does not impact the registered information but the MAH concludes that there is an impact on the delivery, quality, safety, and/or efficacy of the iDDC, a variation application should be submitted.
The MAH of the integral combination has the overall responsibility to ensure that the device used in the integral combination is supported by an up-to-date notified body (NB) opinion.
Minor changes to the device (or device part) that do not impact the safety or performance of the device (part), or the intended use of the device but still require an update of the registered information in the marketing authorization application (MAA), should be submitted with the corresponding variation application according to the variation guideline. The MAH should assess and provide justification whether the change has no significant impact on the device to justify the absence of a NB opinion. Otherwise, proof of compliance with the Medical Device Regulation (MDR) should be provided. An assessment of the proposed change will be performed case by case upon submission. In cases where the need for a variation and/or the category of the change is unclear, it is recommended to consult the national competent authority for medicinal products that issued the Market Authorization.
Some Examples:
- Change in Qualitative and/or Quantitative Composition of a Device (Part)
The replacement of a material (change in qualitative and/or quantitative composition) of a device (part) by an equivalent one for a medical device (part) that is not in contact with the medicinal product but requires an update of the registered information can be submitted as type IA notification under B.II.e.6 – change in any part of the (primary) packaging material not in contact with the finished product formulation (such as the color of flip-off caps, color code rings on ampoules, change of needle shield (different plastic used)), as long as all conditions stated in the Variations guideline are met.
The replacement of a material (change in qualitative or quantitative composition) by an equivalent one for a medical device (part) in contact with the medicinal product should be submitted under the B.IV.1 category of variation classification.
If the change in composition also includes a change in manufacturer, both should be submitted in a single variation under the B.IV.1.z category of variation classification, type IB, or type II depending on the criticality.
- Change in the Sterilization Method for a Device (Part)
Changes to the sterilization method for the device part of an iDDC with no change in the sterilization site should be submitted under the B.II.b.3 category of variation classification.
If there is a change in manufacturer, the addition of a new sterilization site with the corresponding sterilization method should be submitted under the B.II.b.1 category of variation classification.
Of note, in case of several changes to the existing device resulting in the addition or replacement of a new syringe (e.g., change not limited to the supplier of some device parts of the existing syringe but other changes are introduced as well such as an alternative syringe with changes to the design and materials of the existing device parts), both the change in composition including the change in manufacturer should be submitted in a single variation under the B.IV.1.z category of variation classification, type IB, or type II depending on the criticality.
- Change in Dimensions to a Device (Part):
Changes in dimensions to a device (part) not in contact with the medicinal product (such as finger grip, plunger rod) that do not impact the functionality or performance of the device but still require an update of the registered information can be submitted as a type IA notification under B.II.e.6 category, as long as all conditions stated in the European Commission variation classification guideline are met.
Changes in dimensions to a device (part) in contact with the medicinal product (such as needle, syringe barrel, plunger) that require an update of the registered information should be submitted as a type IB or type II variation under the B.IV.1 category of variation classification, depending on the criticality of the change.
- Change in Suppliers of a Device (Part):
Suppliers of the device (part) for iDDC should be stated in section 3.2.P.7 according to the Quality Working Party (QWP) – Biological Working Party (BWP) guideline on medicinal products used with a medical device.
A variation under category B.II.e.7 of variation classification – change in supplier of packaging components or devices of the guidance for applicants for the preparation of the ‘precise scope’ section of the variation application form (EMA/220707/2017), should be submitted to add/delete a supplier of a medical device (part).
In case of addition or replacement of the supplier of the device (or device part), if the risk assessment performed by the MAH has concluded that the change is non-significant and there are no other changes to the device beyond the change in suppliers, a statement can be included in the submission to justify the absence of an NB opinion / EU certificate/ EU declaration of conformity.
If the device manufacturer is also performing sterilization and the device (part) is supplied as sterile ready-to-use, the change should be submitted under the B.II.b.1 category of variation classification in line with submitting the transfer of test methods for testing of biological medicinal products to a new or already authorized testing site.
For more information, please refer to the official guidance provided by the European Commission. You can access the document at the below link:
Questions and answers on implementation of the medical devices and in vitro diagnostic medical devices Regulations ((EU) 2017/745 and (EU) 2017/746): [https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/questions-answers-implementation-medical-devices-vitro-diagnostic-medical-devices-regulations-eu-2017-745-eu-2017-746_en.pdf]
