Devices 101

The definitions and information you need to understand the complex device side of combination products

Knowledge, itself, is power, and understanding is the path to success.

In an effort to ensure the right questions are asked and the right information guides your progress, we have created a short-list of key topics that arise when pharmaceutical companies embark on new combination product ventures. The following are defined and explained below – feel free to click and jump or scroll through at your leisure.

Definition of Combination Products

Combination Products are defined within the United States as a product comprised of two or more types of regulated medical products, such as ”drug and device,” “drug and biological product,” or all three together. Each individual product in this combination is a constituent part – a device constituent part, drug constituent part, etc.

Combination Products can be cross-labeled (constituent parts sold separately), co-packaged (constituent parts packaged and sold together), or single-entry (chemically or physically combined constituent parts).

FDA Combination Product Definition

European Medicines Agency Definition of Combination Product

Examples of Combination Products with a Device Constituent Part

Below is a list of common, and not so common, medical devices systems that can fall under the combination products category when used along with drugs or biological products. With the advancement of technology and science, it is always wise to double-check the status and classification of any medical device that will be used with a drug or biological product.
Co-Packaged Products

  • Empty syringes packaged with a drug product
  • Empty injection systems packaged with a drug product
  • Transfer sets
  • Lyophilized drug product vials packaged with reconstitution components.
  • Surgical kits containing both a drug and a device to be used with it
Single-Entity Products

  • Prefilled syringes
  • Prefilled auto-injectors
  • Metered-dose inhalers
  • Dry powder inhalers
  • Nasal-spray
  • Prefilled pumps
  • Transdermal patch systems
  • Prefilled iontophoresis system Microneedle “patch”
  • Drug pills embedded with sensors
  • Contact lens coated with a drug
  • Drug-eluting stents
  • Drug-eluting leads
  • Condoms with spermicide
  • Dental floss with fluoride
  • Antimicrobial coated catheters/sutures
  • Bone cements with antibiotics
  • Live cells seeded on/in a device scaffold
  • Extracorporeal column with column-bound protein
Separate Products With Cross-Labeling

  • Light-activated drugs/biological products labeled for use with a specific light source device

Device Requirements

The user and stakeholder needs defined in early development set the list of Device Requirements for the device constituent part of the combination product. These requirements will not only relate to ease of use and appeal to the user, intended drug delivery, and efficient manufacturing capabilities, but also to its combined use with the drug itself, and possibly with necessary software and electronic components of the drug delivery system. Some Device Requirements can be reviewed independently, but some need to be studied as an integrated unit with the drug or other related components to ensure integration and such that the system as a whole is safe and effective.

Human Factors & Usability Engineering

Human Factors is the study of how a human being interacts both physically and psychologically with, in this case, a product. A focus group’s behavior toward a product can inform design and development with respect to attributes such as ergonomics, safety, human error, and ease/enjoyment of use. Usability Engineering falls within this field, and focuses on the human-technology element, specifically to ensure user-friendliness. A device constituent part’s ultimate requirement is to ready the drug for delivery and to interact with the user by delivering the proper amount of the drug to the targeted area. A human- centered design focus will inform device design, allowing for the combination product to be easily used, for the drug to be delivered as intended, and for the reduction of human error and user risk. Human factors analysis is a regulatory requirement for the development of a medical device and combination products with a device constituent part.

Primary Mode of Action (PMOA)

The PMOA is the main therapeutic component that defines the combination product’s intended use.   For drug delivery devices, that primary intended use will be attributed to either the drug part or the device constituent part of the combination product. For example, in a drug-eluting stent for opening diseased arteries, the PMOA is the device’s ability to open the artery. The drug provides a secondary PMOA as an “aid.” This designation as “primary” vs. “aid” helps determine through what regulatory body the combination product will be submitted. In the United States, a Combination Product with a PMOA related to the drug will be submitted to the Center for Drug Evaluation and Research (CDER); one related to the device will go to the Center for Devices and Radiological Health (CDRH).

Regulatory Submission Pathway

The PMOA and resulting governing center will determine the required submissions, applications and clinical trials for your combination product. These “boxes” that need to be checked off are your submission pathway. Defining your submission pathway clearly and understanding all of the steps in this process are critical to identifying key elements, such as your clinical trial strategy, device development timeline, and documentation process.

Consultants at Suttons Creek can guide you through both the development process and the submissions pathway. Governing bodies also supply guidance for your regulatory compliance.

FDA Guidance Documents

European Commission Guidance Documents

Device Platform

A device platform, in the context of the pharmaceutical industry, is a standard device made for a particular medical use. A simple definition, but a complex topic. An important, often overlooked, concern to identify about a device platform purchased from a vendor is that, even though the vendor may have done its own testing and provided documentation to demonstrate compliance with regulations, this does not mean the pharmaceutical company’s regulatory responsibilities are met. There are numerous device constituent part deliverables that must be integrated into your drug development process for this device platform to be approved as part of your combination product. Budget, strategy and process considerations must be taken into account for this. And, a piece of advice on this topic…to go along with your device platform, it is good practice to set up standardized platforms of documentation and execution to use across any project utilizing that device platform. This platforming process creates consistency and efficiency, increases control, decreases risk, and allows for substantiated improvements through iteration.

Governing Agencies

Combination Products are regulated by various governing agencies, depending on where you plan to market them. Each will have its own set of complex rules and requirements. In this global marketplace, remaining compliant in an efficient and effective manner can be a very complicated puzzle to piece together.

For the United States of America, the US Food & Drug Administration (FDA) is the governing force. To serve as a focal point for all issues related to combination products, in 2002, the FDA created the Office of Combination Products (OCP). This office maintains compliance to all combination product related regulations and enforces the regulations outlined in the Current Good Manufacturing Practices (cGMP), which ensures that they are manufactured in a quality controlled environment.

For the European Union, the European Commission (EC) is the governing agency for combination products. Like the FDA’s OCP, the EC establishes and enforces combination product regulations for the safety of their constituents.

MDR and IVDR:

The European Parliament created and enforced the new Medical Device Regulation (MDR) and In Vitro Diagnostic Regulation (IVDR) in April 2017, replacing the Medical Device Directives (MDD) and the EU’s current Directive on in vitro diagnostic medical devices, in an effort to keep pace with the tremendous advancements and innovations in science and technology, to better protect patient safety, and to enhance transparency. It provides medical device manufacturers with a three-year window to implement compliance efforts before the May 2020 date of application (DOA) of the MDR and May 2022 DOA of the IVDR. Any medical device that is to be newly placed on the EU market after this date must comply with these new regulations.

Some notable changes in regulation as we switch from the MDD to the MDR and IVDR:

  • There is a broadening of the number and types of devices that are covered by the MDR. Cosmetic devices, as well as devices that have an ancillary use (e.g. devices that sterilize medical equipment), contact lenses and equipment for liposuction are now regulated under the MDR. Specifically, the MDR now officially defines a “medical device” as any “instrument, apparatus, appliance, software, implant, reagent, material, or other article intended by the manufacturer to be used, alone or in combination, for human being for one or more of the following specific medical purposes:
    1. Diagnosis, prevention, monitoring, predication, prognosis, treatment or alleviation of disease.
    2. Diagnosis, monitoring, treatment, alleviation of, or compensation for, and injury or disability.
    3. Investigation, replacement, or modification of an anatomical, physiological, or pathological process or state.
    4. Providing information by means of in-vitro examination of specimens derived from a human body, including organ, blood and tissue donations.
  • With changes to the device classification rules, some devices are being reclassified to a higher risk class, such as surgical meshes and spinal implants, requiring more stringent and longer reviews as well as an increased need for clinical data. In fact, most software that was previously classified as a Class I medical device and self-certified will require Notified Body review under the MDR.
  • The inclusion of a Unique Device Identification (UDI) mandate is another big change under the MDR. This will help make devices identifiable throughout the supply chain and sales region. Two identifiers are required, a device identifier that indicates the manufacturer and device, and a production identifier that indicates the production series/product batch.
  • Notified Bodies must be assessed and designated to new higher standards under the Medical Device Regulation before they can conduct audits of manufacturers and reviews of medical devices. As a result, there will be fewer Notified Bodies available to review submissions and certify products, as well as more stringent oversight of their activities.
  • Regulations concerning vigilance and post-market surveillance lead to the establishment of an EU database on Medical Devices, to correlate information from manufacturer, authorized representative, and importer. Information such as device registration, accredited Notified Bodies, Safety and Clinical Performance Reports, Serious Incidents, UDI, and Clinical Investigation Data will be captured.
  • Stakeholders – suppliers, manufacturers, assemblers, subcontractors, distributors, importers, and EU Authorized Representatives – will assume larger, more defined responsibilities, as the new legislation Articles outline who is responsible for what obligations to conform to regulations. The Articles also newly require a qualified and experienced medical device expert available in the company and designated responsible for regulatory compliance.

Combination Product Case Studies

Case Study: The Knowledge Gap

Device Platforms & Small Pharma:

“The Knowledge Gap”

In this case study, we observe a small pharma company that needed to execute a combination product development program. Upper management was in full support of providing resources to get the job done right, but they didn’t have the experience and knowledge to give effective direction to their teams. The first step toward success is knowing what you don’t know and seeking out those answers, so this small pharma was on the right track.

Case Study: A Divided Culture

Device Platforms & Big Pharma:

“United We Stand”

In this case study, we observe a large pharma company with the goal of reducing process inefficiencies across multiple departments for an auto injector combination product project. However, they have encountered a divided culture between their drug, device and commercialization (CMC) departments.
Case Study: We've Got This

Device Platforms & Executives:

“We’ve Got This”

In this case study, we were brought in by a large pharma company that was initiating a new combination product project and knew they were stepping into new territory that their in-house team had yet to explore. Upon meeting with this company and discussing their intended strategies and protocols, we realized that their device-inexperienced executives did not understand the “grey area” in combination product regulations and requirements and always picked the conservative approach to testing and documentation.