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.

[Related: Did you know that you can search for enforcement actions concerning combination products in our platform?  Try our Enforcement Analytics out for free.]

Get Started with Redica for Free

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).

Mapping EU MDR to ISO 13485
FIGURE 1 | Mapping EU MDR 2017/745 to ISO 13485:2016

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.”

Additional Device Elements to be Considered if a Pharmaceutical Quality System is in Place
FIGURE 2 | Additional Device Elements to be Considered if a Pharmaceutical System is in Place

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.

Resource Links

An Industry Perspective About Quality Management System (QMS) for Drug Device Combination Products

EU GMPs, Annex 1, Manufacture of Sterile Medicinal Products

Guidance on the relationship between EN ISO 13485:2016 and European Medical Devices Regulation and In Vitro Diagnostic Medical Devices Regulation (PD CEN/TR 17223:2018, price: £280.00)

[Related: Did you know that you can search for enforcement actions concerning combination products in our platform?  Try our Enforcement Analytics out for free.]

Get Started with Redica for Free

Download the Special Report

Quality Week report sidebar

What You Will Learn from This Report:

How a major pharmaceutical company designed a program to train future leaders in quality

An industry-led initiative to advance the state of quality in the pharma industry

A pharma GMP leader’s tips for supporting quality culture within an organization

An update on FDA’s Quality Maturity Model

Redica Systems Enforcement Analytics

Compare two companies of your choice.

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Evaluate Your CDMOs

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Compare the inspection history of your CDMO sites.

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Compare the enforcement history of your CDMOs.

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Monitor compliance at your Clinical Investigator sites.

Enter your email address and someone will contact you shortly to get you started.

Redica Systems Enforcement Analytics

Prepare for inspections of Clinical Investigator sites.

Enter your email address and someone will contact you shortly to provide more Clinical Investigator data about your sites.

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to explore enforcement trends. 

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to explore observations and trends. 

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to run your custom report.

Redica Systems Enforcement Analytics

Get help choosing the right CRO.

Enter your email address and someone will contact you shortly to customize your insights.

Download the Special Report

Download your copy of THE FDA INSPECTION LANDSCAPE IN MID-2020 AND A LOOK AT VIRTUAL INSPECTION

In this summary we identify:

  • Trend analysis of FDA inspections through mid-2020
  • Strategies for preparing and hosting virtual inspections
  • New technologies to support remote inspections
Redica Systems Enforcement Analytics

Upgrade your inspection strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need to prepare for your next inspection.

Download the Special Report

CDMO Comparison opt-in

In this summary we identify:

FY2018-FY2020 GMP data for Lonza & Catalent

Top GMP primary citations

Top FDA 483 observations

Panel Discussion – Remote Audits

Panel Discussion opt in image

Featuring Panelists:
—Barbara W. Unger, Unger Consulting, Inc.
—Jerry Chapman, Redica Systems
—Stephanie Gaulding, Pharmatech Associates

Who Will Benefit?
This session will be valuable to GMP quality, regulatory, compliance, and management personnel in FDA-regulated industries who want to have a conversation on remote audits and get to know what is going on in the industry.

Turning Failure into Success

Presented on Tuesday, April 27, 2021 by Steve Greer, Executive Coach, Genesis Assist, and former Quality Leader, Procter and Gamble

What you will learn:

  • How to use the Leadership SOS Model to transform quality culture
  • How to strengthen quality systems to eliminate human error
  • How to generate ideas on how to set your organization up for success for shareholders, FDA, and staff
Redica Systems Enforcement Analytics

Get Full Access to Redica Enforcement Analytics

Enter your email address and someone will contact you shortly to answer all of your questions and get you started.

Quality Management Systems for Small Pharma and Biotech Firms

Webinar: QMS for Small Pharma and Biotech Firms

Presented by Fenton Fong, Founder, Managing Director, & Principal at xCellarate

Get instant access to the webinar video and slides.

What you will learn:

  • Common challenges small pharma firms face when developing a QMS
    Recent enforcement trends involving the Quality Unit
    Impact of the COVID-19 pandemic

Download the Special Report

APAC ad

In this summary we identify:

GMP data from FY2017 to FY2020 for the Asia-Pacific region

Top 3 GMP primary and secondary citations

Top 3 483 observations

Download the Special Report

An Analysis Of MHRA’s Latest Annual GMP Inspection Deficiencies Report

In this summary we identify:

  • Data from 2019 UK MHRA Inspections
  • Trends from 2015, 2016, 2018, and 2019 inspections
  • Conclusions drawn from an analysis of drug inspection data

Experience the Power of Redica Systems

Redica_Vert_Periwinkle_RGB_Large

SEARCH Find the inspection records you want by inspector’s name, company name, site, city, country, etc.

WARNING LETTERS Easily search the largest database of FDA Warning Letters by date, company, FDA office, or subject

SITES Quickly assess inspection records including dates and inspectors across all of your sites

INSPECTIONS Complete list of FDA inspections by date, company, category, and country

Get Complete Access to the Redica Systems Platform

Please submit your email address and one of our team members will contact you shortly to answer all of your questions and get you started with the new Enforcement Analytics platform.

Experience the Power of Redica Systems

Complete the form and one of our experts will reach out to you to schedule a demo and answer questions about our subscription options.

INDEX INFORMATION  Redica consolidates regulatory data in real-time on the single largest database for quality, safety, and compliance intelligence.

STRENGTHEN DATASETS Redica machine intelligence algorithms identify and triage risk signals to derive meaning from vast amounts of private and public data.

ANALYZE & INTERPRET PATTERNS Redica instantly models the customer-specific regulatory risks, trends, and opportunities that stand to fundamentally change compliance operations.

Redica Systems Enforcement Analytics

Upgrade your inspection strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need.

Impact of the Global Pandemic on Recent Data Integrity and Regulatory Non-compliance Trends

Webinar: Impact of the Global Pandemic on Recent Data Integrity and Regulatory Non-compliance Trends

Presented by Paul Smith, Agilent Technologies on Aug. 26, 2020

What you will learn:

  • Examples of essential laboratory actions to remain compliant during the pandemic
  • Recent data integrity non-compliance findings and trends
  • Essential strategies to find, understand, and leverage regulatory non-compliance data

Get the scoop on recent data integrity 483 observations!

  • FY 2020 Data Integrity 483 Observations
  • Data Integrity Observations for Human Drugs
  • Observations Falling Under GMP
  •  

Past, Present, and Future of Quality Culture

Presented by Regulatory Compliance Associates Distinguished Fellow Susan Schniepp

What you will learn:

  • How the 2014 FDA quality metrics initiative led to greater focus on quality culture
  • New quality culture tools and standards under development by PDA and other organizations
  • Best practices for quality culture, including case studies with lessons learned

Changing Medical Device Regulations

Presented by Redica Systems 

What you will learn:

  • The latest developments regarding the EU MDR
  • Quality Systems requirements for medical devices
  • Regulatory updates affecting medical devices

Download the Special Report

Combination Product Report

What You Will Learn from This Report:

The latest U.S. and European regulatory developments

The impact of smart combination products

How the EU MDR impacts drug-device combination products

Download the Special Report

5 GMP Case Studies Report

What You Will Learn from This Report:

In-depth analysis of the findings

Lessons learned

How companies can avoid similar shortcomings.

Experience the Power of Redica Systems

Redica Systems Expert Jerry Chapman to Present at SQA Annual Meeting

Index Information Redica consolidates regulatory data in real-time on the single largest database for quality, safety, and compliance intelligence.

Strengthen Datasets Redica machine intelligence algorithms identify and triage risk signals to derive meaning from vast amounts of private and public data.

Analyze & Interpret Patterns Redica instantly models the customer-specific regulatory risks, trends, and opportunities that stand to fundamentally change compliance operations.

Download the 510(k) Sample

What You Will Learn from This Sample:

See how a 510(k) submission is structured

Find out what information to include

Review correspondence between sponsor and FDA

Redica Systems Enforcement Analytics

Unlimited Access to Reports and Data

Enter your email address and someone will contact you shortly.

Download the Special Report

5 GMP Case Studies Report

What You Will Learn from This Report:

The first countrywide import alert issued by FDA

An inadequate deviation investigation

An inadequate product specifications and a product recall

Process validation issues at a CMO

A different perspective on process validation and the culpability of the quality unit

 

A.I. for Quality and Compliance Teams

August 3 webinar

Presented by Redica Systems Senior GMP Quality Expert Jerry Chapman

What you will learn:

  • A basic understanding of data sources, machine learning, NLP, and A.I. tools
  • Building and applying Expert Models
  • Two case studies, one on sterile manufacturing/503B and one on data integrity

Human Factors – Compliance and Applications

June webinar

Presented by Alison Sathe, Founder, Regulatory Mark & Valerie Fenster, Director of Insights and  Human Factors, Kaleidoscope Innovation 

What you will learn:

  • Human factors strategies from simple drug products to complex surgical devices
  • Primary and secondary labeling development and evaluation for usability
  • Human factors activities from product development to post-market
  • International strategies: expectations for human factors in regulatory submissions in international markets

Experience the Power of Redica Systems

Redica Systems Enforcement Analytics

Sign up for your FREE account today and get instant access to Enforcement Analytics.

Experience the Power of Redica Systems

Redica Systems Enforcement Analytics

Let us know who you are and we’ll be in touch to answer all of your questions and get you started.

Redica Systems Enforcement Analytics

Keep up with the latest Regulatory Developments on Clinical Trials

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Save your team valuable time when using External Monitoring.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Save time and Resources when using External Monitoring.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Get immediate access to the news that matters to your sites.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

See how we can help you eliminate yet another spreadsheet.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Stay ahead of changing regulations.

Enter your email address and someone will contact you shortly to get the data and analysis you need.

Redica Systems Enforcement Analytics

Upgrade your CDMO monitoring strategy.

Enter your email address and someone will contact you shortly to get the data and analysis you need.

Redica Systems Enforcement Analytics

Upgrade your CDMO management strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need.

Discover the power of the most comprehensive database of 483s in existence.

Our database of over 20,000 483s is retyped and tagged, making it easy to create an Observation Report in seconds.

Eliminate days of work and get your FREE personalized 483 Observation Report.