A combination product consists, under 21 CFR 3.2(e), of at least two differently regulated constituent parts, that is, a drug, a device, or a biological product. The FDA uses the primary mode of action to determine the lead center. Human factors is covered by a dedicated FDA guidance.
Definition and legal basis
A combination product (also called a drug-device combination product where a drug and a device are combined) consists of at least two differently regulated constituent parts: a drug, a device, or a biological product. The definition is in 21 CFR 3.2(e), part of the regulation 21 CFR Part 3 (“Product Jurisdiction”, the allocation of regulatory responsibility). The statutory basis is Section 503(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act, the US federal law on food, drugs, and cosmetics), codified in the US Code as 21 U.S.C. 353(g).
The law requires the US agency FDA to determine a lead agency center (primary agency center) for such products. Where appropriate, premarket review is to take place under a single application. According to the FDA guidance on human factors, the constituent parts retain their own regulatory identity, while the combination product at the same time forms a category of its own with, where applicable, special requirements. Under 21 CFR 4.2, a device constituent part is treated as a finished device within the meaning of the Quality Management System Regulation (QMSR).
The four types under 21 CFR 3.2(e)
The regulation distinguishes four constellations:
- Single-entity (No. 1): The regulated constituent parts are physically, chemically, or otherwise combined or mixed and produced as a single entity.
- Co-packaged (No. 2): Two or more separate products are packaged together in a single package or as a unit.
- A separately packaged product that, according to its investigational plan or proposed labeling, is intended for use only with a specific approved product (No. 3). Both products are required to achieve the intended use, indication, or effect, and the labeling of the approved product would need to change.
- A separately packaged investigational product that, according to its proposed labeling, is intended for use only with another specific investigational product (No. 4).
As examples with a drug part and a device part, the FDA guidance on human factors names, among others, autoinjectors, prefilled syringes, inhalers, and body-worn infusion systems.
Primary mode of action and jurisdiction
Which FDA center takes the lead in the review depends on the primary mode of action (PMOA). The mode of action describes how a product achieves its intended therapeutic effect. According to 21 CFR 3.2(m), the primary mode of action is the single mode of action that provides the greatest contribution to the overall intended therapeutic effects. Among other cases, a constituent part has a device mode of action if it does not achieve its primary intended use through chemical action within or on the body and is not dependent on being metabolized (21 CFR 3.2(k)). Under the statute, chemical action within or on the body alone is not sufficient for a drug or biological product PMOA.
| Primary mode of action | Lead center (21 CFR 3.4(a)) |
|---|---|
| Drug (not a biological product) | Center for Drug Evaluation and Research (CDER) |
| Device | Center for Devices and Radiological Health (CDRH) |
| Biological product | Center for Biologics Evaluation and Research (CBER) |
If the PMOA cannot be determined with reasonable certainty, the FDA assigns the product to the center that regulates similar combination products, otherwise to the center with the most expertise for the most significant safety and effectiveness questions. The FDA may require separate applications.
The Office of Combination Products (OCP) is responsible for the assignment, acting as the Product Jurisdiction Officer (21 CFR 3.6). If a product is not covered by an intercenter agreement or jurisdiction is unclear, the sponsor files a Request for Designation before the application. The OCP issues a Letter of Designation within 60 days of the filing date. If it does not, the sponsor’s recommendation applies (21 CFR 3.7 and 3.8). The type of application depends on the lead center; depending on the center, the guidance names IND, NDA, BLA, IDE, PMA, De Novo request, and 510(k). For device constituent parts, the FDA device classification is also relevant.
Manufacturing and postmarket oversight under 21 CFR Part 4
21 CFR Part 4 Subpart A governs which current Good Manufacturing Practice (cGMP) requirements apply. Each constituent part brings its own set of regulations:
- Parts 210 and 211 for a drug constituent part (medical gases: Part 213),
- Part 820 for a device constituent part, as the QMSR since February 2, 2026 (see QMSR and design controls),
- Parts 600 to 680 for a biological product,
- Part 1271 for human cells, tissues, and cellular and tissue-based products (HCT/Ps).
The manufacturer demonstrates compliance through a cGMP operating system. It can either meet the requirements for each constituent part separately or choose the streamlined approach under 21 CFR 4.4(b). In that case, demonstrating compliance with either the drug requirements or the QMSR is sufficient, supplemented by specifically named requirements of the other set of regulations. On the device side, these include Section 7.3 (design and development) of ISO 13485. If constituent parts are manufactured at separate sites, the system must meet all requirements applicable to that type of constituent part at each site.
Subpart B covers postmarketing safety reporting for applicants of combination products. It supplements other regulations such as 21 CFR Part 803 but does not replace them (see also post-market surveillance).
Human factors for combination products
The key source is the FDA guidance “Application of Human Factors Engineering Principles for Combination Products: Questions and Answers” of September 2023. The guidance finalizes the 2016 draft “Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development”. It supplements the general FDA human factors guidance and does not replace it. It was published before the QMSR took effect and therefore still cites the former Part 820 in places. Among other things, abbreviated new drug applications (ANDAs) and biosimilar applications under Section 351(k) are not covered. The guidance on the content of human factors information in marketing submissions for medical devices, finalized in 2026, also expressly excludes combination products and refers to the 2023 guidance.
According to the guidance, the use-related risk analysis (URRA) should consider the combination product as a whole. In addition to risks of the device and of the drug, there are risks that arise only from their interaction. For example, a viscous formulation can lengthen the injection time and the hold time and thereby lead to underdosing. The user interface comprises all points of interaction, including controls, packaging, labels, carton labeling, instructions for use, and, where applicable, training (see labeling).
For the critical task, the guidance introduces a term of its own, the combination product critical task. This means a user task that, if performed incorrectly or not performed at all, would or could cause harm to the patient or user. Here, harm expressly includes compromised medical care, including through medication errors. For a stand-alone medical device, by contrast, the threshold is serious harm. For time-critical products such as an emergency autoinjector, the guidance states that all or most tasks are usually critical tasks.
Further statements of the guidance:
- Human factors validation testing usually takes place before the application, using the final finished combination product, that is, the product including packaging, labeling, and, where applicable, training.
- If training is part of the user interface, the training program, including the training of the trainers, must be validated. If training is optional, both trained and untrained users can be tested.
- The results go into the HFE/UE report in the application. The manufacturer submits the URRA with the critical tasks together with the protocol of the validation study.
- In the case of changes, the scope of a repeat validation depends on the result of the URRA and can be limited to the affected scenarios.
- Inquiries go to the lead center and should request the involvement of the other centers and the OCP, for device center procedures for example through a Pre-Submission.
Regulation in the EU
Regulation (EU) 2017/745 (MDR) does not define the term “combination product” and creates no separate category with its own procedure. The English text mentions it only once in passing, in Article 70(7); the German version does not use the word. Instead, Article 1 regulates the demarcation from medicinal product law:
- Paragraph 8: If a device incorporates, as an integral part, a substance which, if used separately, would be a medicinal product within the meaning of Directive 2001/83/EC, and that substance has an ancillary function, the MDR applies. If it has a principal function, medicinal product law applies to the whole product.
- Paragraph 9: A device intended to administer a medicinal product is governed by the MDR. However, if the device and the medicinal product form a single integral product that is intended exclusively for use in that combination and is not reusable, medicinal product law applies to the whole product.
In both cases, the general safety and performance requirements in Annex I of the MDR apply to the safety and performance of the device part. To this end, Article 117 amends Directive 2001/83/EC: The marketing authorization application includes, where available, the results of the conformity assessment of the device part, such as the EU declaration of conformity or the certificate of a notified body. If they are missing and the MDR would require the involvement of a notified body, the authority requires an opinion from a notified body. For further reading, see notified body, CE marking and technical documentation, clinical evaluation and PMCF, and UDI.
| Aspect | USA | EU |
|---|---|---|
| Legal term | Combination product (21 CFR 3.2(e)) | Not defined, no separate category, regulated through Art. 1(8) and (9) MDR |
| Basis for assignment | Primary mode of action | Function of the substance (ancillary or principal), inseparability of the whole product |
| Device part | Constituent part, finished device within the meaning of the QMSR | Requirements under Annex I MDR, evidence under Art. 117 for the medicinal product authorization |
A combination product unites at least two differently regulated constituent parts from drug, device, and biological product. In the US, 21 CFR 3.2(e) defines four types, and Section 503(g) of the FD&C Act requires a lead FDA center.
The FDA uses the primary mode of action to decide whether the drug, device, or biologics center takes the lead in the review. Manufacturers meet the manufacturing requirements under 21 CFR Part 4 through a shared cGMP operating system.
For human factors, the 2023 FDA guidance applies, with its own combination product critical task. In the EU the term is not defined; the demarcation runs through Art. 1(8) and (9) MDR.
Frequently asked questions (FAQ)
What does primary mode of action mean?
The primary mode of action is the single mode of action of a combination product that provides the greatest contribution to the overall intended therapeutic effects (21 CFR 3.2(m)). It determines whether the FDA’s drug, device, or biologics center takes the lead in the premarket review.
Who decides in the US which FDA center is responsible?
The Office of Combination Products is the Product Jurisdiction Officer. If there is no assignment through an intercenter agreement or jurisdiction is unclear, the sponsor files a Request for Designation. The office then issues a Letter of Designation, under 21 CFR 3.8 within 60 days of the filing date.
Does the human factors guidance for medical devices also apply to combination products?
Not on its own. The guidance on the content of human factors information in marketing submissions, finalized in 2026, expressly does not address combination products. The guidance “Application of Human Factors Engineering Principles for Combination Products: Questions and Answers” of September 2023 applies instead, to be read together with the FDA’s general human factors guidance.
Is there a combination product in the EU like in the US?
The MDR does not define the term and creates no separate category with its own procedure. Article 1(8) and (9) are decisive: What matters are the function of the medicinal substance in the product and whether the device and the medicinal product form an inseparable whole. Depending on this, the MDR or medicinal product law applies, but for the device part always Annex I of the MDR.
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More about our usability engineeringSources
- FDA Guidance: Application of Human Factors Engineering Principles for Combination Products: Questions and Answers (September 2023)
- FDA Guidance: Content of Human Factors Information in Medical Device Marketing Submissions
- FDA Guidance: Applying Human Factors and Usability Engineering to Medical Devices
- 21 CFR Part 3, Product Jurisdiction
- 21 CFR Part 4, Regulation of Combination Products
- Federal Food, Drug, and Cosmetic Act, Section 503(g) (21 U.S.C. 353(g)), Regulation of combination products
- 21 CFR Part 820, Quality Management System Regulation (QMSR)
- 21 CFR Part 803, Medical Device Reporting
- ISO 13485:2016, Medical devices, Quality management systems, Requirements for regulatory purposes
- Regulation (EU) 2017/745 on medical devices (MDR)