Introduction to Drug Device Combination Products

A combination product, per the Code of Federal Regulations (CFR), encompasses medical devices, medications, and biologics, either in combination or all together. A well-known example is the drug-eluting stent (DES), designed to prevent scar tissue in arteries by combining a scaffold with a drug coating. However, today, combination products go beyond just drugs, biologics, and medical devices. They can also include items like food, nutraceuticals, and cosmetics, often referred to as cosmeceuticals. When drugs are combined with devices, they’re known as drug-device combinations.

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What is a Drug Device Combination Product?

A combination product, as defined in 21 CFR 3.2 (e), encompasses the following scenarios:

  1. A product composed of two or more regulated components, such as a combination of a drug and a device, a biological product and a device, a drug and a biological product, or a combination of all three, which are physically, chemically, or otherwise blended to form a single entity.

  2. The bundling of two or more distinct products in a single package or as a unified unit, where these products can be a combination of drug and device, device and biological products, or biological and drug products.

  3. An individual drug, device, or biological product packaged separately, which, as indicated by its investigational plan or proposed labeling, is meant to be used exclusively with an approved and specifically designated drug, device, or biological product. This is necessary when both components are required to achieve the intended use, indication, or effect. In such cases, if the proposed product is approved, the labeling of the previously approved product may need to be altered. This could involve changes in the intended use, dosage form, strength, route of administration, or a significant dose change.

  4. Any investigational drug, device, or biological product that is packaged separately and, based on its proposed labeling, is intended for use exclusively with another specifically designated investigational drug, device, or biological product. Both components are essential to achieve the intended use, indication, or effect.

What are Some Examples of Combination Products?

According to 21 CFR 3.2(e)(1), examples of single-entity combination goods (when the components are joined physically, chemically, or otherwise) include the following:

  1. Monoclonal antibody combined with a therapeutic drug 
  2. Device coated or impregnated with a drug or biologic – Drug-eluting stent, pacing lead with steroid-coated tip, a catheter with an antimicrobial coating, transdermal patch 
  3. Prefilled drug delivery systems (syringes, insulin injector pen, metered dose inhaler)

Examples of co-packaged combination products (the components are packaged together) (21 CFR 3.2(e)(2)): 

  1. Drug or vaccine vial packaged with a delivery device 
  2. Surgical tray with surgical instruments, drapes, and anesthetic or antimicrobial swabs 
  3. First-aid kits containing devices (bandages, gauze), and drugs (antibiotic ointments, pain relievers) 

Example a of product that may be cross-labeled combination products (components are separately provided but specifically labeled for use together) (21 CFR 3.2(e)(3) or (e)(4)): 

  1. Photosensitizing drug and activating laser/light source

Drug-Device Combination Product as per MDR for CE Marking(DDCP CE Marking)

A Drug-Device Combination Product seeking CE marking under the medical device regulation (MDR) and submission to the US FDA requires compliance with both Article 1(8) and Article 1(9)(62) of Regulation (EU) 2017/745, along with applicable US regulatory requirements. This classification reflects the product’s fusion of medical device and medicinal product elements, demanding adherence to stringent regulatory standards to guarantee safety and efficacy within both the European Union and US markets.

As part of the submission process for CE marking, a comprehensive risk management plan, aligned with medical device notified opinions, must be provided to address potential hazards and ensure effective risk mitigation strategies. Additionally, the submission for US FDA approval necessitates the inclusion of a design history file (DHF) for the drug-device combination product. The DHF documents the product’s design, development, and testing processes, serving as a crucial resource for regulatory review and demonstrating compliance with US regulatory requirements. Integrating both the risk management plan and DHF into the submission ensures thorough documentation of safety, efficacy, and regulatory compliance for approval in both markets.

Also Read: EU Regulations for Marketing Medical Device Combination Products

Combination Products Project Development Process & Design Control

The Pharmaceutical organization which manufacturers the combination products are expected to implement the 21 CFR Part 210 and 211 and 21 CFR Part 820 for their manufacturing sites of the combination products. At the end of the design Phases, the DHF is compiled and shall be presented during the audits. The DMR shall be extracted from the DHF for the routine use and the tech transfer. The requirements mentioned in the DMR shall be used to create the DHR to demonstrate the routine production and compliances. As per the requirements of the ISO 13485:2016, the medical device file shall be established. The complexity of the design procedure is dependent on the Product complexity and intended use. The design control is a vital part as far as the Quality Management System goes.

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CAPA Management For Combination Products

CAPA management of drugs and device combination products are as follow:

To ensure that devices meet a DDCP regulatory  requirement of Combination Products

  • Users’ needs and intended uses
  • Requirements and Specifications
  • The DDCP regulatory pathway for combination products
  • Can be reproducibly and reliably manufactured, serviced and/or installed.

Tools for Archiving the Purpose of Combination Products

  • Establish design control procedures.
  • Develop plans for Design Projects(Include interfaces between R&D and other units)
  • Identify design inputs requirements and high-level specifications for the device
  • Develop design outputs (to final specifications)
  • Design Verification through measurement, analysis, test, or inspection that all design outputs fulfill input requirements.
  • Transfer outputs to production
  • Design Validation that the device performs and functions as intended and as users need an expert.
  • Control changes during design and development and to existing devices Document design activities in the design history file Combination Product DHF.

Why Choose Operon Strategist?

Choose Operon Strategist as your medical device consultant to benefit from our extensive expertise and experience in drug-device Combination Products. Our comprehensive knowledge of regulatory requirements and GMP regulations, including Drug (21 CFR 210/211), Device (21 CFR 820), and Combination Products (21 CFR Part 4), ensures a successful path from development to market. Contact us now for expert guidance and support to navigate the complexities of your project.

FAQs

What are drug device combination products?

Combination products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products. Due to meticulous and accurate drug targeting, local administration, and tailored therapy, combination products result in safer and more successful treatments.

What are the four categories of combination products?

There are four main categories for combination products: a product composed of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity.

What are combination medical devices examples?

Examples of combination products include prefilled syringes, pen injectors, auto-injectors, inhalers, transdermal pumps and patches, and kits containing drug administration devices or components

What are the types of combination products?

combination products are classified into three main types:
1. single-entity
2. co-packaged
3. cross-labeled

What are drug-device combination products under the MDR?

Article 117 of the Medical Devices Regulation (MDR), established by the European Commission, mandates that manufacturers introducing drug-device combination products to the market as integral devices, labeled as "medicinal products," must obtain a Notified Body Opinion (NBOp) in compliance with MDR.

What is the difference between medical device and combination products?

Remember, two devices used together or packaged jointly don't constitute a combination product. True combination products involve a drug and a device, a biologic and a device, a biologic and a drug, or all three elements working together. It's about the synergy of components that sets them apart.

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