Combination Product Regulation Basics

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Combination Product Regulation Basics

Authors: Helen Simons

What is a combination product and why is this important from a regulatory perspective?

The simple answer is that a combination product is a product which comprises of two or more items which are covered by different regulations, for example a pharmaceutical and a medical device. As they are covered by two different combination product regulation structures, then more care needs to be taken when determining the regulatory strategy as it will be more complex.

This blog explains how these types of products are regulated in the US and EU.

How do regulators define combination products?

Combination product regulations definitions are located in 21CFR part 31 by the FDA and part (10) of the preamble of 2017/745 Medical Device Regulations2 and Article 1(2) of 2001/83/EC3 by the European Commission.

The EU definition of a combination product is quite short stating “Products which combine a medicinal product or substance and a medical device”.

They further define Medicinal product as “(a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or (b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.”

The FDA goes in to more detail:

3.2(e) Combination product includes:

  1. A product comprised 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;
  2. Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;
  3. A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or
  4. Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

When dealing with combination products which may have different aspects and benefits, we need to be clear about what the FDA defines as the Primary Mode of Action.

3.2(m) Primary mode of action is the single mode of action of a combination product that provides the most important therapeutic action of the combination product. The most important therapeutic action is the mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.

3.2(k) Mode of action is the means by which a product achieves an intended therapeutic effect or action. For purposes of this definition, “therapeutic” action or effect includes any effect or action of the combination product intended to diagnose, cure, mitigate, treat, or prevent disease, or affect the structure or any function of the body. When making assignments of combination products under this part, the agency will consider three types of mode of action: The actions provided by a biological product, a device, and a drug. Because combination products are comprised of more than one type of regulated article (biological product, device, or drug), and each constituent part contributes a biological product, device, or drug mode of action, combination products will typically have more than one identifiable mode of action.

Examples of combination products and their primary mode of action are listed in Table 1 – Combination Product Examples.

Device TypeCombination ofPrimary Mode of ActionCommentary
InhalerDevice + Drug
(single entity)
DrugThe inhaler is there to deliver the drug and has no medical benefit of its own
Anti-microbial coated surgical implantDevice + Biologic
(single entity)
DeviceThe device would provide its medical benefit without the coating but provides additional functionality by being a combination
Vial kitDevice + Drug or Biologic
(co-packaged)
Drug or BiologicThe vial of drug or biologic is considered the primary packaging of the drug and not a device itself, however as soon as it is packaged in a kit with a syringe and needle then it becomes a combination product

How are combination devices regulated in the USA?

Within the USA, combination device or combination product regulation are under the jurisdiction of the Food and Drugs Administration (FDA). Specifically, these fall within the remit of the relevant lead centre depending on the nature of the product. This will be:

  • Centre for Devices and Radiological Health (CDRH) for device lead combination products
  • Centre for Drug Evaluation and Research (CDER) for drug lead combination products
  • Center for Biologics Evaluation and Research (CBER) for biologics lead combination products

The applicable lead centre is determined by the Office of Combination Products (OCP). An indication of where your product may be assigned can be determined by reviewing the capsular descriptions of jurisdictional determinations from the OCP4.

The primary center will be the center which the product submission goes to and determines what type of submission is needed for the product. The relevant subject matter experts will still be involved in the submission review even if they are drawn from another center within the FDA.

Combination products which have a primary mode of action which relates to the device aspect of the products are regulated as devices. Hence the applicable pathways to market are 510(k), De novo and Premarket approval application (PMA) depending on the risk profile of the product.

Combination products with primary mode of action related to a drug product will be required to submit an Investigational new drug application (IND) or new drug application (NDA) as applicable. For biologics this would be a biologics licence application (BLA).
Where a company is developing just the device component of a drug or biologics led product, this can be submitted using the Master File5 (MAF) approach with the FDA. This allows the details of the device to be referenced within other drug or biologics applications. This can be a useful route when it is known that the device is intended to be a platform used with multiple drugs or biologics (e.g. generic inhaler or injection pen) and saves repeating the work for each drug application. It is also used when a pharma company is buying the device from a subcontractor and the subcontractor wishes to protect their IP on the device.

How are combination products approved for use in the EU?

Within the EU we need to again consider the primary mode of action of the combination product. If the primary mode of action is the device then it is regulated through the Medical Device Regulations (2017/745) and the lead will be taken by the Notified Body for the product.
For drug or biologics led combination products the application needs to be made to the European Medicines Agency (EMA)6 but will require “the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer’s EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device.”7 (i.e. a Notified Body’s assessment of the product).
Similarly, Notified Bodies will contact the EMA for a regulatory opinion on any drug or biologics aspects of an MDR application8.
Notified bodies which are certified to approve combination devices can be found by searching the NANDO database9 and looking for the relevant product code(s), for example:

  • MDS 1001 Devices incorporating medicinal substances
  • MDS 1008 Devices utilising biologically active coatings and/or materials or being wholly or mainly absorbed or locally dispersed in the human body or are intended to undergo a chemical change in the body

MDCG 2019-1410 gives details on how to use MDR codes when searching for appropriate notified bodies.


The MDR lays out rules for classifying medical devices and this informs the pathways available. For combination products the applicable rules are:

  • Rule 6: All surgically invasive devices intended for transient use are classified as class IIa unless they: are intended to administer medicinal products by means of a delivery system, if such administration of a medicinal product is done in a manner that is potentially hazardous taking account of the mode of application, in which case they are classified as class IIb.
  • Rule 7: All surgically invasive devices intended for short-term use are classified as class IIa unless they: are intended to administer medicines, in which case they are classified as class IIb.
  • Rule 8: All implantable devices and long-term surgically invasive devices are classified as class IIb unless they: are intended to administer medicinal products, in which case they are classified as class III;
  • Rule 14: All devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product, as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the devices, are classified as class III.
  • Rule 20: All invasive devices with respect to body orifices, other than surgically invasive devices, which are intended to administer medicinal products by inhalation are classified as class IIa, unless their mode of action has an essential impact on the efficacy and safety of the administered medicinal product or they are intended to treat life-threatening conditions, in which case they are classified as class IIb.
  • Rule 21: Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body are classified as:
    • class III if they, or their products of metabolism, are systemically absorbed by the human body in order to achieve the intended purpose;
    • class III if they achieve their intended purpose in the stomach or lower gastrointestinal tract and they, or their products of metabolism, are systemically absorbed by the human body;
    • class IIa if they are applied to the skin or if they are applied in the nasal or oral cavity as far as the pharynx, and achieve their intended purpose on those cavities; and
    • class IIb in all other cases.

The theme you will see here is that the default for the majority of cases is IIa (IIb for implantable) and then increased to the next class (IIb or III) when there is a potential for a hazardous situation. Hence, an initial hazards assessment or risk analysis will be required to determine into which classification your combination product falls.

Helen Simons is the Director of QA/RA at StarFish Medical. Helen’s education is in Mechanical engineering, with a background of product development and QMS development across multiple industries with consumer and industrial products to medical devices, IVD and combination devices.

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