Final EMA Guideline: Quality Requirements for Combination Products

Following a draft version, the EMA has now published the final guideline, which describes what documentation is required on the subject of quality for combination products in order to gain and/or maintain a marketing authorization.

The guideline consists of 22 pages with 10 chapters. The title "Guideline on quality documentation for medicinal products when used with a medical device" is striking. The terms "combination product" or "drug-device combination" (DDC), which appeared in the past, are no longer mentioned in the final version. This is different in the U.S., where FDA uses both terms.

Although the document describes the quality aspects (Module 3.2.P) for the approval of drugs with a medical device component, it is not only interesting for the "authorizers" but for the manufacturers of these combination products, as well.

Why?

They have to implement the quality requirements of the guideline for the approval documentation on site, in production, quality control or in the development of combination products.

The focus of the guideline is on product-specific quality aspects of a medical device or medical device component that could influence the quality, safety and/or efficacy of a drug. The scope of the guideline addresses so-called "integral products", where the medicinal product is firmly (integrally) connected to the medical device (e.g. pre-filled syringe) and where the main effect is the medicinal product efficacy. Co-packaged products, where the medical device is included with the medicinal product in the packaging, are also being addressed. The guideline also refers to medicinal products for which the package insert contains references to a specific medical device that is to be used in combination with the medicinal product (referred to as "reference devices" in the guideline).

Inclusion and exclusion criteria

It is explicitly mentioned that electromechanical medical devices (including active, implantable medical devices) are also covered, as well as class I medical devices. Explicitly excluded, however, are:

  • Veterinary medicinal products 
  • In-vitro diagnostics, including ancillary diagnostics
  • System and procedure packs, which fall under Article 22 of the Medical Devices Regulation 
  • General groups of medical devices where a direct reference is made in the product information (e.g., "use of a syringe")
  • Devices falling under the first sub-paragraph of Article 1(8) of the Medical Devices Regulation.

A discussion on the impact of the medical device (part) on the Quality Target Product Profile (QTPP), the Critical Quality Attributes (CQA) and on the control strategy of the drug product should also be included as part of the dossier which is to be submitted.

Further information on the individual chapters

In the following, the guideline describes the legal basis and the application of standards and guidelines. Then it continues with requirements for the approval documentation. First, general requirements are described, followed by details on integral medicinal products, on co-packed and referenced medical devices. Notes on medical devices in clinical trials, on life cycle management and on emerging technologies then conclude the actual approval section. A chapter on definitions and abbreviations concludes the guideline.

The following are some selected requirements that also apply to manufacturers:

  • The functional aspects of the medical device should be qualified according to their complexity 
  • Compatibility between materials coming into contact with the medicinal product should be investigated to provide appropriate information. This may include simulated transport studies (e.g. chemical degradation, vibration). 
  • The critical process parameters of filling steps and finishing should be specified in detail. 
  • The process validation includes the integral medicinal product.

Other important aspects are:

  • stability studies

and

  • the container closure systems (CCS).

The guideline entitled "Quality documentation for medicinal products when used with a medical device" - available on the EMA homepage - will become valid on January 1, 2022.

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