What This Page Covers
This page covers drug-device combination products: integral combinations (where drug and device form a single product, such as prefilled syringes, autoinjectors, or drug-eluting implants), co-packaged products (where drug and device are supplied together but as separate items), cross-labeled (referenced) products (where drug and device are sold separately but labelled for combined use), devices incorporating an ancillary medicinal substance (where the device is the primary product and a drug component supports its function), and the emerging category of connected combined products that integrate medical device software with a medicinal product.
For standalone medical devices, see Medical Devices. For standalone SaMD, see Digital Health & SaMD. For the drug components themselves, see Pharmaceuticals or Biologics, Biosimilars & ATMPs. If the fundamental classification of your product is itself uncertain (device vs. drug vs. combination product), see Borderline Products. If you are unsure which category applies, contact us and we will assess the classification.
Regulatory Pathway
The regulatory pathway depends on the product’s primary mode of action and how the drug and device components are integrated. This table provides a quick overview.
| Category | Examples | Regulatory Lead | Device-obligation |
|---|---|---|---|
| Integral DDC (iDDC) | Prefilled syringe, pen, inhaler, implant with medicinal substance | Directive 2001/83/EC (pharma MA) | GSPR compliance + NBOp (if device ≥ Class Is) |
| Co-packaged | Vial + reusable pen, cartridge + injector | Both apply in full | Device must be independently CE-marked |
| Cross-labeled (referenced) | Drug and device sold separately, labelled for combined use | Both apply in full | Device must be independently CE-marked for the specific intended use |
| Device with ancillary substance | Heparin-coated catheter, drug-eluting stent, antibiotic bone cement | MDR (device-led) | NB-led, with EMA/NCA opinion on the substance |
| Connected combined product | Drug + adherence/dosing optimisation software | Directive 2001/83/EC + MDR (MDSW) | Software classified and compliant under MDR |
Common Challenges And How We Help
“We switched our syringe supplier and now need a new NBOp.”
Device component changes on a marketed product can trigger a new Notified Body Opinion, a pharmaceutical variation, and updated compatibility data. We assess the change against MDCG significant change criteria and manage the process across both regulatory tracks.
“Our Module 3 doesn’t contain any device information.”
Legacy products often have incomplete or empty Module 3.2.R sections because device data was never integrated into the pharmaceutical dossier. Under MDR, this is a compliance gap. We conduct a full review and build the missing documentation, bridging drug and device data into one coherent dossier.
“We don’t know if our product is an iDDC or co-packaged.”
The classification determines everything downstream: whether you need an NBOp or a full CE mark, who the legal manufacturer is, and how post-market obligations are split. Misclassification is common and expensive to correct later. We assess against MDCG 2022-5 criteria and confirm the classification early.
“We’re a pharma company. We don’t have a device QMS.”
For co-packaged products and CCPs, the device component needs its own legal manufacturer with ISO 13485. Building this from scratch for a single device component is rarely efficient. We can act as legal manufacturer for the device or MDSW component, taking on the MDR obligations while the pharma company focuses on the MA.
“The Notified Body came back with questions we don’t understand.”
NB review language is device regulation language. Pharma teams unfamiliar with MDR terminology and expectations lose time on misinterpretation. We handle NB interactions directly and translate findings into actions the pharma team can execute.
Integral Drug-Device Combinations (iDDCs)
The drug and device form a single, indivisible unit: a prefilled syringe, an autoinjector, a metered-dose inhaler, an implant releasing a medicinal substance. These are regulated as medicinal products under Directive 2001/83/EC. The marketing authorisation is a pharmaceutical MA. However, the device component must comply with the General Safety and Performance Requirements (GSPRs) of MDR Annex I, as required by MDR Article 117.
If the device component would be classified as Class I (non-sterile, non-measuring) as a standalone device, the MAH can demonstrate GSPR compliance through a self-assessment statement. If it would be Class Is, Im, IIa, IIb, or III, a Notified Body must issue an NBOp on the device component’s GSPR compliance. That opinion is included in the MA dossier and assessed by the medicines competent authority as part of the MA procedure.
Per the latest EMA Q&A, the GSPR compliance conclusion must be complete. Partial compliance statements or opinions that leave relevant GSPRs unaddressed are no longer accepted. The NBOp or MAH GSPR compliance statement must be in place before MAA submission. Submitting without the device compliance documentation can result in a validation error or a deficiency letter, causing delay.
Co-Packaged Products Cross-Labeled (referenced) Products
Co-packaged products combine a medicinal product and a medical device as separate items within the same packaging (e.g., an insulin vial packaged with a reusable pen injector). Cross-labeled (referenced) products are sold separately but the labelling specifically instructs them to be used together. In both cases, dual regulation applies in full: the drug under Directive 2001/83/EC, and the device independently CE-marked under MDR.
The device needs its own conformity assessment, technical documentation, and Notified Body certificate (for Class IIa and above). It also needs its own legal manufacturer under MDR with an ISO 13485 QMS. Pharma companies that do not have device QMS infrastructure can work with a third party as legal manufacturer for the device component: the pharma company holds the MA for the drug, the device LM holds the CE mark and MDR obligations for the device.
Devices Incorporating an Ancillary Medicinal Substance
The reverse scenario: a medical device where a medicinal substance is integral to the device’s function (e.g., a heparin-coated catheter, a drug-eluting stent, an antibiotic bone cement). These are regulated as medical devices under MDR. The Notified Body leads the conformity assessment, but the medicines competent authority (EMA or a national authority) must provide a scientific opinion on the quality and safety of the medicinal substance.
Borderline Cases
Classification is not always obvious. MDCG 2022-5 provides guidance for distinguishing integral DDCs from co-packaged products, using criteria around physical integration, exclusive use with a specific drug, and reusability. When the classification is genuinely uncertain, getting it confirmed early through competent authority consultation or regulatory advice prevents costly rework later.
A separate and prior question is whether the product is a combination product at all. Substance-based products, nasal sprays with mixed mechanisms, and products at the boundary between pharmacological and physical modes of action may be purely medicinal products, purely medical devices, or combination products depending on the mode-of-action assessment. For products where this fundamental classification is uncertain, see Borderline Products.
Connected Combined Products and Digital-Enabled Therapeutics
A newer and increasingly important category: medicinal products combined with medical device software to create an integrated therapeutic offering. These Connected Combined Products (CCPs), sometimes called Digital-Enabled Therapeutics (DETs), add software-driven functionality such as adherence monitoring, dosing optimisation, or behavioural interventions that complement the pharmacological treatment.
In the EU, CCPs fall under the same drug-device combination framework: the drug under Directive 2001/83/EC, the software under MDR as MDSW. There is no unified EU framework equivalent to the FDA’s PDURS guidance. Development requires simultaneous expertise in pharmaceutical regulation, MDR compliance for MDSW, IEC 62304 software lifecycle, and clinical validation of the combined therapeutic effect. For pharma companies that prefer not to take on MDR legal manufacturer obligations for the software, we can act as legal manufacturer for the MDSW through our ISO 13485-certified platform.
There is growing strategic interest in CCPs as a lifecycle management tool. The drug-software combination creates a new product with its own regulatory and IP identity, which can extend commercial life beyond the original molecule’s exclusivity period.
What is Needed Across the Development Journey
Discovery & Concept
Product classification: integral DDC, co-packaged, device with ancillary substance, or CCP. For legacy products, gap analysis of existing documentation against current MDR requirements. Determine primary mode of action and applicable regulatory framework. Device classification under MDR Annex VIII. Regulatory pathway mapping including NB involvement. For CCPs: software qualification under MDCG 2019-11.
Preclinical
Biocompatibility evaluation of device component (ISO 10993). Container closure integrity and extractables/leachables studies. Drug-device compatibility assessment. Sterilisation validation where applicable. For CCPs: initial software architecture and risk assessment.
Design & Development
Parallel drug and device development tracks with integrated project management. GSPR compliance planning for the device component. Container closure integrity, extractables/leachables, compatibility studies. Human factors engineering and usability studies (IEC 62366). For CCPs: IEC 62304 software lifecycle, cybersecurity assessment. QMS covering both pharmaceutical and device requirements.
Clinical
Clinical programme designed to generate evidence for both the drug MA and the device GSPR compliance. Human factors validation studies. For CCPs: clinical validation of the combined drug-software therapeutic effect.
Regulatory Submission & Approval
NBOp submission and assessment for the device component (where required). Integration of device data into the CTD for the pharmaceutical MA. GSPR checklist and supporting technical documentation. For co-packaged products: parallel CE marking process for the device. For CCPs: integrated regulatory submission addressing both drug and MDSW.
Launch & Market Access
Labelling covering both drug and device requirements. EUDAMED registration for device components where applicable. For CCPs: potential for differentiated market access positioning and value-based pricing models.
Post-Market & Lifecycle Management
Dual PMS: pharmacovigilance under pharmaceutical framework plus device-specific surveillance under MDR. Change management assessed against both pharmaceutical variation rules (EC 1234/2008, C/2025/5045) and MDCG significant change criteria. New NBOp where device changes are significant. For CCPs: software version management.
Example Projects
8-Month NBOp for Legacy Combination Product
Legacy combination product (approved 10+ years) had outdated Module 3 GSPR evidence. Device documentation existed but sat siloed outside the pharma dossier. We delivered document sorting, Annex II Technical Documentation creation, Module 3 updates, and a bridging strategy using existing data only. Result: positive NB Opinion in 8 months with zero new testing required. Subsequently engaged for a new product development where we realigned the programme with regulatory requirements mid-project, breaking down internal RA/CMC/device silos.
10-Product DDC Portfolio Review
Comprehensive DDC portfolio assessment across 10 products. Identified misclassifications across multiple products (iDDC vs. co-packaged), generated concrete action items including PIL updates for incorrect device information, and navigated internal sensitivity around classification changes. Key strategic outcome: identified data bridging opportunities between two products with identical devices that had previously been treated as separate regulatory files. Result: portfolio-wide efficiency gains through data reuse and corrected regulatory pathways.
Co-Packaged Legacy Product: From Empty Module 3.2.R to MDR Readiness
Client discovered that a co-packaged legacy product (licensed-in) was not MDR compliant. Module 3.2.R was effectively empty and no MDR certificate existed for the device component. Full compliance check revealed data gaps including reuse cycle and compatibility issues. Updated Module 3.2.R with new certificate data and missing device evidence. Identified concrete action items for co-pack system qualification. Result: MDR-ready dossier with complete Module 3.2.R, product rescued from non-compliance status.
Working on a Combination Product?
Tell us about your product, its components, and your target markets. We will assess the regulatory pathway and outline how we can support.
Speak with an ExpertFrequently Asked Questions (FAQ)
How do I know if my product is an integral DDC or a co-packaged product?
MDCG 2022-5 sets out the criteria: physical integration, exclusive use with a specific drug, and non-reusability. If the drug and device form a single unit that cannot be separated and reused (e.g., a prefilled syringe), it is integral. If they are supplied together but function as separate items (e.g., a vial plus a reusable pen), it is co-packaged. Borderline cases exist, and getting the classification confirmed early is worth the effort.
When is a Notified Body Opinion required?
For integral DDCs where the device component would be classified as Class Is, Im, IIa, IIb, or III as a standalone device. Non-sterile, non-measuring Class I device components do not require an NBOp; the MAH provides a GSPR compliance statement instead. For co-packaged products, the device must be independently CE-marked, which involves Notified Body assessment for Class IIa and above.
How long does a Notified Body Opinion take?
It varies, but typically several months. The timeline depends on NB workload, the completeness of the submission, and the complexity of the device component. Submitting a well-structured package following the MDR Annex II documentation format, with a complete GSPR checklist and all supporting data, is the most effective way to reduce the timeline.
What documentation does the pharmaceutical dossier need to include about the device?
The CTD must address the impact of the device component on the Quality Target Product Profile, Critical Quality Attributes, and overall quality strategy of the medicinal product. This includes container closure integrity, extractables and leachables, drug-device compatibility, human factors data, and the NBOp or MAH GSPR compliance statement. The EMA guideline on quality documentation for medicinal products used with a medical device provides the framework.
How do we handle post-market surveillance for a combination product?
PMS must cover both the drug and device dimensions. Pharmacovigilance applies under the pharmaceutical framework. Device-specific PMS (trend reporting, vigilance for device-related incidents) applies under MDR. The two tracks need to be coordinated, particularly for safety signals that could involve both the drug and the device component.
What happens when we change the device component of a marketed product?
Changes must be assessed against both the pharmaceutical variation framework (EC 1234/2008 and the variation categorisation guideline C/2025/5045) and the MDCG significant change criteria for the device. A change that is significant under MDR may require a new NBOp or supplementary NB assessment, and may also trigger a variation on the pharmaceutical side. The two assessments need to be coordinated.
What is a Connected Combined Product?
A CCP combines a medicinal product with medical device software to create an integrated therapeutic offering. Examples include adherence monitoring apps paired with a specific drug, dosing optimisation tools, or software that manages aspects of a disease alongside pharmacotherapy. In the EU, the drug is regulated under Directive 2001/83/EC, the software under MDR as MDSW. There is growing strategic interest in CCPs as a lifecycle management tool for products facing patent expiry, since the drug-software combination creates a new product with its own regulatory and IP identity.
How does the US approach differ?
The FDA classifies combination products based on primary mode of action and assigns them to a lead centre (CDER, CBER, or CDRH) under 21 CFR Part 3. The Office of Combination Products coordinates review. For software combined with drugs, the FDA's PDURS (Prescription Drug Use-Related Software) guidance provides a clearer framework than currently exists in the EU. We coordinate parallel EU and US strategies to manage the differences.
What if we don't have a device QMS?
For co-packaged products and CCPs, the device or software component needs its own legal manufacturer under MDR with an ISO 13485-certified QMS. Pharma companies often don't have this, and building one from scratch for a single device component is rarely efficient. We can act as legal manufacturer for the device or MDSW component, taking on the MDR obligations (CE marking, technical documentation, Notified Body relationship, post-market surveillance) while the pharma company focuses on the MA for the drug. This model keeps the two regulatory tracks cleanly separated. For integral DDCs, the situation is different: there is no separate device LM role, and the pharma company must address device requirements within their pharmaceutical QMS.
My product does not seem to fit any standard category. What do I do?
Some products genuinely fall outside the standard iDDC, co-packaged, and ancillary substance categories, or sit on the boundary between combination product and pure device or pure drug. A detailed regulatory assessment is required. We can assess the mode of action, consult with competent authorities where needed, and recommend the classification and pathway that best fits.