How Are Combination Products Regulated?
Combination products are an integral part of healthcare as they provide innovative treatment options for complex diseases. They can be as simple as a first-aid kit with vials and syringes or as complex as antibody-drug conjugates combined with drugs. More often, the development of combination products helps enhance the function of an already approved product to maximise patient care and safety. However, the regulatory landscape associated with these products can be challenging because of the different types of combinations and the regulatory requirements applicable to their individual components. This leads to a more specialised regulatory approach.
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Explore CMC Regulatory Services →More recently, the classification of these products has become increasingly challenging due to the growing complexity of combination products. When comparing the regulatory frameworks between the US FDA and EMA, the FDA combination products framework uses the Office of Combination Products (OCP) to coordinate classification, jurisdiction and review assignment among the relevant FDA Centres. The applicable regulatory pathway is influenced by the product’s constituent parts and primary mode of action (PMOA). In the EU, the regulatory approach depends on whether the medicinal product incorporates a device, whether the device is integral or supplied separately, and which legislation applies to the individual components.
The regulatory environment continues to evolve in 2026. Recent FDA developments include a July 2026 draft guidance on biosimilar and interchangeable biosimilar products involving container closure systems and device constituent parts, as well as ongoing implementation work around UDI requirements for combination products. The FDA’s UDI document remains draft guidance and should therefore not be presented as a final new requirement.
What Are Combination Products?
Combination products are therapeutic or diagnostic products that combine two or more regulated components, such as a drug, device, biological product, or combinations of these.
Under FDA regulations, combination products can include:
- A drug and device physically, chemically or otherwise combined as a single entity
- A biological product and device combined as a single entity
- Two or more regulated products packaged together
- Separately packaged products that are intended to be used together under specified conditions
- Drug-device-biologic combinations involving more than two constituent parts
Examples include prefilled syringes, autoinjectors, drug-coated devices, drug-delivery systems, certain inhalers and other products where the drug, biological product, and device work together to achieve the intended therapeutic purpose.
The increasing use of sophisticated delivery technologies means that sponsors need to consider regulatory classification and constituent-part requirements early in product development.
FDA Combination Product Regulation: Complete Guide
The US FDA has established a dedicated regulatory structure for combination products because these products can involve drugs, devices and biological products that would otherwise fall under different regulatory frameworks.
The Office of Combination Products (OCP) plays a central role in classifying combination products, assigning them to the appropriate FDA Centre, coordinating reviews involving multiple Centres and overseeing aspects of postmarket regulation. The three principal FDA Centres involved are:
- Center for Drug Evaluation and Research (CDER)
- Center for Biologics Evaluation and Research (CBER)
- Center for Devices and Radiological Health (CDRH)
FDA’s combination product framework is primarily established through Section 503(g) of the Federal Food, Drug, and Cosmetic Act and related regulations, including 21 CFR Part 3 and 21 CFR Part 4.
For sponsors, this means that regulatory strategy should consider not only the individual constituent parts but also how the components function together, the intended use, the PMOA, manufacturing controls, clinical evidence and postmarket obligations.
How Are Combination Products Regulated by FDA?
The FDA’s approach is based in part on the primary mode of action (PMOA) and the regulatory identity of the constituent parts.
The Office of Combination Products can determine which FDA Centre has primary responsibility for reviewing a combination product. Depending on the product, the applicable premarket pathway can include:
Combination product | Potential FDA pathway |
Device-led | 510(k), De Novo or PMA, as applicable |
Drug-led | NDA or ANDA, as applicable |
Biologic-led | BLA under applicable provisions, including 351(a) or 351(k) where appropriate |
The exact pathway depends on the characteristics of the product and the applicable statutory and regulatory framework rather than simply the presence of a particular component. FDA’s 2022 Principles of Premarket Pathways for Combination Products guidance remains an important reference for sponsors determining an appropriate premarket pathway.
The FDA also allows combination products to be reviewed through a single application or, in certain circumstances, through separate applications for their constituent parts.
UDI Requirements for Combination Products
Unique Device Identification (UDI) is increasingly relevant to combination products containing device constituent parts.
In June 2025, FDA issued a draft guidance titled “Unique Device Identifier Requirements for Combination Products.” The guidance addresses how UDI requirements under 21 CFR Part 801 and Part 830 apply to combination products with device constituent parts. It also discusses UDI labelling and submission of information to the Global Unique Device Identification Database (GUDID).
However, an important 2026 distinction should be maintained:
The FDA UDI combination-product document is currently draft guidance and is not a final binding requirement.
Sponsors should therefore monitor the finalisation of the guidance and assess the applicable UDI obligations for their specific product.
For regulatory teams, UDI considerations may need to be integrated into:
- Device constituent-part identification
- Labelling strategy
- Product coding
- GUDID submissions
- Packaging and presentation
- Lifecycle management
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Explore Regulatory Affairs Services →Combination Products and Biosimilars: Device Constituent Part Requirements
This area has become particularly important in 2026.
In July 2026, FDA issued a draft guidance titled “Biosimilar and Interchangeable Biosimilar Products: Considerations for Container Closure Systems and Device Constituent Parts.” The guidance provides recommendations for developing container closure systems and device constituent parts used with proposed biosimilar and interchangeable biosimilar products.
The draft guidance expands and clarifies FDA expectations relating to delivery devices and container closure systems for biosimilar products.
This is particularly relevant for products such as:
- Prefilled syringes
- Autoinjectors
- Drug-delivery devices
- Other biosimilar presentations incorporating device constituent parts
Because the document is draft guidance and not yet for implementation, sponsors should treat its recommendations as FDA’s current thinking rather than as final mandatory requirements. Comments on the draft guidance are due October 2, 2026.
For biosimilar developers, the development strategy should therefore consider the relationship between the biological product, container closure system, delivery device, user interface, and overall product presentation early in development.
EMA: Regulating Drug-Device Combination Products
In the EU, the regulatory framework for drug-device combination products differs from the FDA’s centre-based approach.
The medicinal product component is regulated under EU pharmaceutical legislation, while the device component may also need to meet applicable requirements under the Medical Devices Regulation (EU) 2017/745 (MDR).
EMA explains that where the medicinal product achieves the principal intended action, the product is regulated as a medicinal product under EU pharmaceutical legislation. The device component may nevertheless require conformity assessment depending on how it is incorporated into or supplied with the medicinal product.
This distinction is important because a product may involve both pharmaceutical and medical-device regulatory service requirements.
EU Combination Product Regulation: MDR Article 117 Explained
MDR Article 117 is one of the most important regulatory considerations for medicinal products that incorporate a medical device.
For an integral drug-device combination, such as certain prefilled syringes, pens, patches or prefilled inhalers, the medicinal product application may need to include evidence relating to the device constituent part.
EMA explains that where an integral device would require certification if it were marketed separately, the medicinal product application should include the appropriate CE certificate or, where applicable, an opinion from a notified body regarding conformity of the device. The requirement applies under Article 117 of the MDR.
EMA’s Guideline on quality documentation for medicinal products when used with a medical device further clarifies expectations for quality documentation relating to these products. The guideline was adopted in 2021 and has applied since January 1, 2022.
Therefore, sponsors developing EU drug-device combination products should assess:
- Whether the device is integral to the medicinal product
- Whether the device would require conformity assessment if marketed separately
- Whether a CE certificate is available
- Whether a notified body opinion is required
- Device safety and performance
- Compatibility between the medicinal and device components
- Quality documentation for the complete combination
The EU framework should not simply be treated as an extension of the US PMOA approach. EU combination product regulation uses a different regulatory architecture.
EMA Combination Product Guidance
EMA issued its Guideline on quality documentation for medicinal products when used with a medical device to clarify the quality documentation expected for medicines incorporating or used with medical devices.
The guidance is particularly relevant to products where:
- A device is an integral part of a medicinal product
- A device is supplied with the medicinal product
- A device is used to administer or deliver the medicine
- Device safety and performance have implications for the medicinal product
EMA’s current information also distinguishes between integral products and products where the device is co-packaged or obtained separately. For separately supplied or co-packaged devices, applicable medical-device conformity requirements continue to apply.
Combination Product Regulation: FDA vs EMA vs PMDA vs NMPA
Although the same product may be considered a combination product in several markets, the regulatory pathway is not necessarily transferable from one jurisdiction to another.
Region | Main regulatory approach | Key consideration |
US FDA | Office of Combination Products coordinates classification and assignment among FDA Centres | PMOA, constituent parts and applicable premarket pathway |
EU / EMA | Medicinal product and medical-device legislation interact depending on the product configuration | MDR Article 117 and medicinal-product requirements |
Japan / PMDA | Combination products are addressed through Japan’s pharmaceutical and medical-device regulatory framework | Product configuration, constituent components and applicable category |
China / NMPA | Drug-device combination products are managed according to whether the drug or device has the primary role | Attribute determination and drug- or device-led registration |
- Japan: PMDA – Japan has its own framework for combination products involving drugs, medical devices and regenerative medical products. PMDA materials distinguish combination products from certain kit products and provide specific criteria for determining whether a product falls within the combination-product framework. This means sponsors should assess the Japanese product configuration rather than automatically applying an FDA or EU classification.
- China: NMPA – China’s NMPA framework specifically addresses drug-device combination products.Under NMPA’s 2021 notice, drug-led drug-device combination products are registered according to applicable drug requirements, while device-led products are registered according to medical-device requirements. Where the regulatory attribute cannot be determined, the applicant can apply for attribute determination before registration.
NMPA also established coordination mechanisms between the Center for Drug Evaluation (CDE) and the Center for Medical Device Evaluation (CMDE) for products requiring joint evaluation.
This demonstrates why a global combination-product strategy should be built around country-specific classification and regulatory assessment, rather than assuming one global pathway.
EMA vs FDA: Key Differences for Combination Products
The FDA and EU approaches share the goal of ensuring the safety, quality and performance of combination products, but the regulatory mechanisms differ.
Under the FDA framework, the Office of Combination Products plays a central role in classification and assignment to FDA Centres, with PMOA being an important factor in determining the lead Centre and applicable pathway.
In the EU, the regulatory framework is more closely linked to the legal status and configuration of the medicinal product and device component. For medicinal products incorporating integral devices, MDR Article 117 becomes particularly important.
For multinational sponsors, this can create additional work when preparing:
- Classification strategies
- Clinical evidence
- Device documentation
- Quality documentation
- Risk-management documentation
- Manufacturing information
- Labelling
- Postmarket surveillance strategies
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Explore Medical Device Regulatory Services →The Future of the Regulatory Landscape for Combination Products
As new tools and technologies develop and are increasingly incorporated into combination products, the regulatory approach for such products becomes more complex and requires more comprehensive support from regulatory authorities.
A systematic regulatory review approach for combination products should focus on product design rationale, PMOA, constituent-part characteristics, and evaluation across preclinical and clinical development.
However, due to differences in definitions and classification/designation of products, as well as complex PMOA, different regulations apply to the products. This is different for every country.
The regulatory landscape is also continuing to evolve. In the US, FDA’s recent guidance activity includes the 2026 draft guidance for biosimilar and interchangeable biosimilar products involving container closure systems and device constituent parts, while UDI expectations for combination products continue to develop through draft guidance.
In Europe, the regulatory environment continues to develop through updates to medical-device guidance. For example, the EU’s MDCG 2021-24 rev.1 guidance on medical-device classification was updated in April 2026, reinforcing the importance of using current classification guidance when assessing products at the drug-device boundary.
It is important to note that a more enhanced regulatory and pharmacovigilance system will be required to support novel combination products and related technologies. While on one hand, the complexities in the regulatory landscape for combination products present sponsors with many challenges, on the other hand, they also bring areas for opportunities in terms of R&D, regulatory science, developing new standards and focusing on regulatory harmonisation.
Indeed, there is potential to revolutionise combination products and healthcare.
Key Regulatory Considerations for Combination Product Development
Before selecting a regulatory pathway, sponsors should consider:
Regulatory consideration | Key question |
Product classification | Is the product a drug, biologic, device or combination product? |
Primary mode of action | Which component provides the primary therapeutic action? |
Constituent parts | What individual regulated components make up the product? |
Premarket pathway | Which regulatory submission is appropriate? |
Clinical evidence | What evidence is needed for the complete product? |
Device requirements | Does the device constituent require separate conformity assessment? |
Manufacturing | Which GMP or quality-system requirements apply? |
Labelling | How should the components and their interaction be represented? |
UDI | Are UDI requirements applicable to the device constituent? |
Postmarket surveillance | Which safety and performance obligations apply? |
Lifecycle management | How will changes to one constituent affect the overall product? |
This assessment is particularly important when a product is being developed simultaneously for the US, EU, and Asian markets.
Common Regulatory Challenges for Combination Products
Combination products can create challenges across the complete product lifecycle.
- Classification and Regulatory Jurisdiction –Determining the correct regulatory classification can influence the entire development strategy.
- Primary Mode of Action – For FDA submissions, understanding the PMOA can help sponsors determine the likely lead Centre and regulatory pathway.
- Device Constituent-Part Requirements – A device constituent can introduce additional requirements relating to design, performance, usability, quality, conformity assessment and lifecycle management.
- Global Regulatory Differences – A product classified in one way in the US may require a different regulatory assessment in Europe, Japan, or China.
- Manufacturing and Quality – The interaction between drug, biologic and device manufacturing processes can introduce additional quality considerations.
- Clinical Development – Sponsors may need to demonstrate not only the safety and efficacy of the medicinal component but also the suitability and performance of the delivery system.
- Post – market Surveillance – Combination products can create additional considerations for adverse-event reporting, device complaints, product quality issues and safety monitoring.
Combination Products and Regulatory Strategy: What Sponsors Should Do Early
Sponsors developing combination products should establish the regulatory strategy before the product design is fully locked.
A practical approach includes:
- Define the product and all constituent parts.
- Determine the likely regulatory classification.
- Assess the PMOA where relevant.
- Identify the applicable regulatory authority and lead review pathway.
- Determine whether device conformity assessment is required.
- Map clinical, nonclinical and quality evidence requirements.
- Assess country-specific differences before global dossier development.
- Evaluate postmarket and pharmacovigilance requirements.
- Monitor regulatory updates throughout development.
- Build lifecycle-management considerations into the initial strategy.
Early regulatory planning can help sponsors avoid redesigning development programmes after classification or regulatory requirements have already been established.
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It combines extensive regulatory intelligence, experience, knowledge and technology-enabled solutions to deliver support across a spectrum of regulatory challenges.
DDReg can support combination-product programmes through activities including:
- Regulatory strategy development
- Product classification assessment
- Global regulatory pathway assessment
- FDA combination-product strategy
- EU combination-product regulatory assessment
- Regulatory gap assessment
- Submission strategy
- Lifecycle regulatory support
- Pharmacovigilance and postmarket regulatory support
- Cross-market regulatory coordination
For complex combination products, early regulatory planning can help align product development, regulatory strategy and market-access objectives across multiple jurisdictions.
Conclusion
Combination products are reshaping pharmaceutical and healthcare development by bringing together drugs, biologics, medical devices, and advanced delivery technologies. However, their regulatory requirements can vary significantly between markets, making a global strategy difficult to apply without local assessment.
The FDA combination products framework relies on product classification, the Office of Combination Products, and the appropriate FDA Centre. In the EU, MDR Article 117 plays an important role in regulating certain drug-device combinations. Recent developments also highlight the need for ongoing regulatory monitoring. FDA’s July 2026 draft guidance addresses biosimilar products, container closure systems, and device constituent parts, while UDI requirements for combination products continue to evolve. Japan and China follow their own regulatory approaches, reinforcing the importance of country-specific classification and planning.
DDReg supports pharmaceutical, biotechnology, and medical-device companies with combination-product classification, regulatory strategy, submission planning, lifecycle management, and global regulatory support.
Frequently Asked Questions
Combination products are products that combine two or more regulated components, such as drugs, biological products and medical devices. Under FDA regulations, they can include single-entity products, co-packaged products and certain cross-labelled products.
MDR Article 117 addresses medicinal products that incorporate certain medical-device components. For relevant integral combination products, the medicinal-product application may need to include evidence relating to the device's conformity assessment, including a CE certificate or notified-body opinion where applicable.
FDA issued draft guidance in June 2025 addressing UDI requirements for combination products with device constituent parts. The document discusses UDI labelling and GUDID submissions. It remains draft guidance and is not for implementation as a final requirement.
NMPA distinguishes drug-led and device-led drug-device combination products. Drug-led products are registered under applicable drug requirements, while device-led products follow applicable medical-device requirements. Where the regulatory attribute cannot be determined, applicants can seek attribute determination before registration.
Classification can influence the applicable regulatory pathway, evidence requirements, reviewing authority, quality documentation, clinical strategy and postmarket obligations. Early assessment can therefore help sponsors avoid regulatory and development delays.