Impact of the EU MDR on Combination Product Sale and Registration in the EU

The May 26, 2021 deadline for compliance with the European Union (EU) Medical Device Regulation (MDR) is fast approaching.  For combination products with a device component—which are covered under this regulation—it is imperative that gap assessments have been completed and action plans implemented by that date to ensure the products stay on the market in the European Union.

At the Xavier Health Combination Products Summit held virtually in October 2020, AstraZeneca Global Device Quality Associate Director Mike Barnett reviewed the quality requirements for drug/device combination products and what is needed for compliance with the EU MDR.

He presented on behalf of the European Federation of Pharmaceutical Industries and Associations (EFPIA).  EFPIA is a large trade association representing pharmaceutical manufacturers in Europe.  Its Manufacturing and Quality Expert Group has evaluated the GMP aspects of the MDR and has finalized recommendations on what industry needs to do to comply.

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EU MDR and Quality System Requirements

The EU MDR presents new quality system requirements and challenges for the pharma industry.  In his presentation, Barnett focused primarily on the quality system requirements in EU MDR Article 10—the Obligations of the Manufacturer—and what it means from the pharmaceutical manufacturer’s perspective.  The requirements are dependent on the type of drug/device combination, and whether it is a single integral product or a co-packaged product.

Looking at quality system considerations for a single integral drug/device combination, one common example would be a prefilled syringe device with a medicinal product.  The goal of the quality system is to produce evidence to demonstrate compliance with EudraLex Volume 4, Good Manufacturing Practice (GMP) guidelines, Annex 1, “Manufacture of Sterile Medicinal Products.”

Questions the manufacturer may consider are:

• Which General Safety and Performance Requirements are relevant?
• What evidence is required to demonstrate compliance?
• Does the quality system deliver that evidence?

Typically, evidence that could be leveraged can be found in a firm’s design control documentation—for example, in summary reports, material certificates, plans, protocols, and reports.  This is the sort of evidence that can be used to satisfy the General Safety and Performance Requirements in Annex I.

Also, it is important to settle on what the relevant standards are.  Compliance with harmonized standards facilitates compliance to the EU medical device regulations.

“I think there is an opportunity to use specific general safety performance requirements as a source of design and perhaps as a start of product development activity,” Barnett pointed out.  “I have to mention risk, because risk is mentioned over 70 times in the General Safety Performance Requirements annex of the EU MDR. A good lifecycle approach to risk management will be needed to support compliance.”

What are quality considerations for co-packaged drug/device combinations?  In the example presented, the syringe is the device and it is co-packaged with a vial, which contains a medicinal product.  There are two possible scenarios.  In one, the pharma company is considered the legal manufacturer of the CE-marked syringe.  In this case, the pharma company needs to follow EU MDR 2017/745, Article 10, General Obligations of the Manufacturer.  That would be the goal for the quality system.

In the other scenario, the pharma company is not considered the legal manufacturer of the CE-marked syringe, e.g., if the syringe part of the product was purchased from a supplier.  Article 10 applies to the legal manufacturer of the CE-marked device, in this case, the supplier of the syringe.  The pharma company, however, needs to identify any additional applicable requirements.

In the second scenario, while the pharma firm is not the legal manufacturer of the CE-marked device, it does co-package it.  It will need to identify the applicable EU MDR requirements beyond CE-marking that would apply to the company and how it impacts the quality system.

In the absence of guidance, assumptions must be made—for example, how does Article 14, Obligations of a Distributor, apply?  Which requirements need to be in quality agreements with the legal manufacturer to provide quality oversight?  “I think this can be challenging,” Barnett admitted. “But what I want to do is to give you resources from an industry perspective that you can use to do that.”

EFPIA Paper, BSI Provide Resources

EFPIA’s Manufacturing and Quality Expert Group and the British Standards Institution (BSI) have both published resources to help combination product manufacturers navigate the various European regulatory requirements under the MDR. While the EFPIA resource is in the public domain, the BSI paper must be purchased. Both are discussed below.

The EFPIA paper, An Industry Perspective About Quality Management System (QMS) for Drug Device Combination Products, is “a good place to start if you need a place to start or want to validate some of your thinking” regarding how to apply the EU MDR, Barnett said.

The scope of the paper is a single integral and co-packaged drug/device combination product where pharma is not the legal manufacturer of the CE-marked device. The paper was produced by the EFPIA Manufacturing and Quality Expert Group—of which Barnett is a member—and written from the pharma industry perspective, examining the relationship between the EU MDR and a pharmaceutical quality system. Note that combination products for which the device has the primary mode of action are not within scope for this document.

“It is quite a large and detailed document,” Barnett pointed out. “It has points of clarification, advocacy points you might find useful to understand, and recommendations for pharma.”

The 97-page EFPIA paper includes the following sections:

• Scope
• Challenges and considerations for Quality Management System (QMS) when implementing the MDR 2017/745 for Drug-Device Combinations (DDC)
• Definition of drug/device combination product
• QMS for drug/device combination product (Device used as a drug delivery system)
• Terms and definitions
• A Pharma industry perspective on the relationship between European Medical Device Regulations MDR 2017/745 and the Pharmaceutical Quality System (Introduction to Appendix 1)
• Summary of the Requests for Clarifications from Stakeholders (Regulators) and EFPIA Points for Advocacy
• Appendix

Barnett said the EFPIA paper can help answer questions such as: What are the quality system considerations for co-packaged drug/device combinations where pharma is not the legal manufacturer of the CE-marked device?  If your starting point is ISO 13485, what else do you need to consider?

“It is useful to understand the relationship between the EU MDR Article 10 and ISO 13485,” he maintained.  “And where compliance to ISO 13485 is demonstrated it is important to understand what additional information is required to meet EU MDR Article 10 requirements.”

A detailed technical report that maps the MDR and ISO sections to each other was published by BSI in March 2018 and is available for purchase (Figure 1).

Is Certification to ISO 13485 Required?

Barnett further explored the relationship between ISO 13485:2016 and the EU MDR requirements for device/drug combination products by examining whether it is required to have 13485 certification to meet the EU MDR requirements.

While the adoption of ISO 13485 facilitates compliance to the EU MDR, he said, additional elements are required to meet the regulation.  “Adoption of and certification to 13485 may be considered as an asset for a pharma company, but it is not an absolute regulatory requirement for EU MDR.”

Consideration of certification to ISO 13485 by a pharmaceutical company, the AstraZeneca director said, should be driven by its product portfolio and global market access.  He maintained, however, there is “definitely potential to leverage the pharmaceutical quality system to meet the EU MDR requirements for the quality system in Article 10.”

Barnett recommended asking the following questions:  Do your quality system requirements cover EU MDR Article 10 requirements?  And more importantly, do you have evidence to support that compliance?

What is Needed in Addition to a PQS?

Barnett concluded his presentation with a focus on the additional device aspects that need to be considered in addition to a pharmaceutical quality system.

He provided a slide showing some specific device elements that could be considered as enhancements to the quality system (Figure 2).  “There are some device elements that would likely require additional builds in the quality system,” he pointed out.  “And these are things like post-market surveillance, substantial changes, general safety, performance requirements, clinical evaluation, and labeling unique device identifier requirements.”

In closing, the EFPIA Manufacturing and Quality Expert Group member advised combination product manufacturers to keep an eye out for any clarification guidance from the EMA and the European Commission to support implementation of the EU MDR as updated guidance may continue to be published.

“Make sure any assumptions you make are validated as new information becomes available,” he said.