Integrated by Design
Strategic pathways for drug-led combination products
Venkat Reddy Sunkara, Global Head of Regulatory CMC, ICON
Broadly speaking, combination products are therapeutic and diagnostic products that combine drugs, devices and/or biological products. Amongst the countries/regions that have a defined regulatory framework for combination products, such as US, EU, Canada, and Australia, the exact definition of a combination product often differs. In Asia, while major markets like China, Malaysia, and South Korea have established clear pathways, other nations, particularly within the ASEAN bloc, may lack a dedicated framework entirely.
However, a similar governing principle is the principal mechanism of action (PMOA). The PMOA is the mechanism by which the primary effect of the combination product is achieved and is used to determine how the product is regulated, i.e., drug or device or biologic. Classifying combination products and determining the appropriate regulatory pathway are vital first steps in achieving market authorisation for combination products.
Combination products, which integrate a drug and/or biologic component with a medical device component, are increasing globally. Because they do not fit neatly into a single category, regulation of these products can be difficult to navigate.
In regions with established regulatory frameworks, including the US, EU, Canada and Australia, definitions of a combination product vary. Across Asia, major markets, such as China, Malaysia and South Korea, have established clear pathways, while others, particularly within the ASEAN bloc, may lack dedicated frameworks.
Despite these differences, regulators commonly rely on the primary mode of action (PMOA), the mechanism responsible for the combination product’s main therapeutic effect, to determine classification as a drug, medical device or biologic.
The regulatory landscape, particularly for combination products with a drug PMOA, has shifted. Regulators now expect integrated quality oversight across the drug, device constituent and their interface, rather than prioritising just the drug’s chemistry, manufacturing and control (CMC). Determining the appropriate regulatory pathway and CMC approach is a critical first step toward market authorisation.
Integrated regulatory expectations
Among countries with established frameworks, including China and Malaysia, it has become typical for regulatory review to be coordinated between the relevant medical device and medicinal product agencies.1,2 With both bodies collaborating to evaluate a product’s safety, efficacy and quality, the authorisation process becomes more integrated. An integrated mindset is also reflected in regulatory shifts in the EU and U.S. Food and Drug Administration (FDA), which have moved away from quality systems that prioritise just one component of the combination.3,4
Regardless of these global trends, international convergence remains incomplete. International Council for Harmonisation guidelines Q12 and Q14 help align lifecycle and analytical expectations for combination products.5,6 However, classification, submission structure and change thresholds remain jurisdiction specific, requiring tailored regulatory strategies across markets.
Developers therefore operate within a fragmented, but increasingly convergent regulatory environment. Within this framework, PMOA remains the central organising principle for classification and CMC strategy, shaping downstream CMC design, regulatory expectations, and control strategy development.
While PMOA determines the application type and the lead regulatory authority responsible for evaluation, regulators now also assess whether the CMC strategy is appropriately aligned with the product’s mode of action. In drug-led combination products — in which the drug component drives the primary therapeutic effect — the drug’s CMC and the medical device functionality must both play a meaningful role.
In this context, regulatory CMC expectations typically include:
- Drug quality attributes that drive clinical performance and risk control
- Device functionality that has less significant risk than previous devices, fully controlled and focused on patient safety
- Clear justification that device performance variability has no clinically relevant impact on outcomes or the benefit-risk profile
Failure to meet these expectations may result in late reclassification risk or expanded device data requests. Selecting the appropriate CMC strategy for a given combination product is therefore critical to establishing a smooth path to approval.
CMC strategy pathways for drug–device combination products
The aforementioned regulatory and CMC expectations translate into three practical CMC strategy pathways for drug-device combination products. Pathway selection is driven by how tightly the medical device is integrated with the drug, and whether the product is intended for evolution over time.
Pathway 1: Drug-centric, integrated device assurance
This pathway is preferred for most integral drug-device combination products, particularly prefilled syringes, autoinjectors, inhalers and on-body injectors in which the drug defines efficacy. It is characterised by several key CMC strategy elements:
- First, quality (CMC) information should be structured within Module 3 of the Common Technical Document around the drug component, with device functionality mapped to the drug’s critical quality attributes (CQAs).
- Second, device information must be managed within the combination product’s integrated quality system rather than as standalone supplier documentation. The quality target product profile may include device-relevant specifications such as dose accuracy, injection or delivery force. The control strategy may also include device considerations such as delivery performance, stability under use conditions and mitigation of recurring product issues.
- Third, developers entering EU markets should align early with notified bodies (NBs). This supports consideration of device conformity requirements in parallel with marketing authorisation preparation, including CE (Conformité Européenne) marking or NB opinion readiness at submission.
This integrated approach is effective because regulators expect drug-led combination products to demonstrate full control of both drug and device performance within a unified pharmaceutical quality system. Presenting device details as supplier documentation is not sufficient to demonstrate control of the final combination product.
Pathway 2: Dual-track development of drug and device systems
This pathway is best suited for products in which both the drug and medical device components require a similar depth of technical and clinical evidence. Such products include high-risk delivery systems, novel materials, connected or software-enabled devices, and products intended for paediatric or home use.
For CMC strategy, the medical device should be developmentally mature enough to approach expectations for a standalone product, including design controls, human factor validation and usability. A separate, but aligned, device technical file should be maintained, even for drug-led submissions.
The strategy should also anticipate future regulatory obstacles. For the FDA, this includes review across multiple agency centres through the inter-centre consult expansion. In the EU, this includes preparation for lifecycle reassessments triggered by substantial product changes as the device evolves.
While this pathway typically requires higher upfront CMC investment, it can reduce risk during post-approval changes and support more efficient global rollout, resulting in fewer downstream regulatory complications.
Pathway 3: Platform-first strategy for multi-drug deployment
This pathway applies when a stable medical device platform is intended to support multiple drug products over time, as for multi-asset delivery platforms or franchise devices. The device platform is fully qualified once, with new drug variants introduced through bridging of comparability data.
Device evaluation places heavy upfront emphasis on extractables and leachables, device robustness across formulations, and human factors in a broad patient population. Thorough characterisation of the medical device enables efficient post-approval drug extensions with minimal device re-review.
Although this pathway is commercially attractive, it is only viable if early scientific advice confirms regulatory acceptance of the platform logic. Without this confirmation, development typically defaults to Pathway 2, making early consultation critical.
Converging regulatory focus
Across regions and pathways, regulatory evaluation is increasingly converging in five key areas that developers should consider when developing CMC strategy:
1. Interface CQAs
Regulatory focus is increasing on interface-related CQAs, including dose accuracy, delivery force, extractables, siliconisation and container closure-device interaction.
2. Human factors as a quality attribute
Human factors are increasingly treated as part of the overall control strategy, rather than solely as an aspect of clinical usability.
3. Change management clarity
Clarity on what constitutes a “substantial device change” remains limited, particularly in the EU, where requirements are case-specific and not fully harmonised.
4. Supplier governance (EU context)
Marketing authorisation holders are expected to demonstrate active oversight of medical device suppliers, rather than relying solely on vendor certifications.
5. Lifecycle foresight
Regulators increasingly expect developers to demonstrate how the product can evolve over time without triggering re-authorisation, including clear strategies for managing post-approval changes.
Strategic recommendations
Several broad strategies can help navigate this evolving regulatory landscape for drug-device combination products.
While the regulatory classification and pathway selection should be established early, the CMC strategy should be designed with the expectation of regulatory challenge and treated as an integrated quality system, rather than a modular dossier exercise. In addition, the CMC narrative should be closely aligned with PMOA logic and the clinical risk drivers underlying the selected product classification, including drug-device interface considerations.
Moreover, developers should build change resilience into the original control strategy, as retrofitting is costly and slow. In the EU context, NB engagement timing is now a critical path item, rather than an administrative step. In countries such as Japan and other members of the ASEAN bloc, where pathways are not clearly defined, coordinating with regulatory bodies early when possible may help to navigate uncertainties.
Although approval pathways and requirements are complex, adherence to these core principles — early regulatory alignment, integrated CMC-PMOA strategy design, and lifecycle-aware control strategy development — can help position developers to support the successful approval of drug-device combination products.
References:
- Hoshi, R. et al. “China’s Regulatory Framework for Combination Products: Ongoing Challenges and Potential Opportunities.” International Society for Pharmaceutical Engineering. 4 Aug 2022. https://ispe.org/pharmaceutical-engineering/ispeak/chinas-regulatory-framework-combination-products-ongoing.
- Ministry of Health Malaysia. “Guideline for Registration of Drug-Medical Device and Medical Device-Drug Combination Products.” 20 Jun 2019. https://portal.mda.gov.my/index.php/documents/guideline-documents/1098-guideline-for-registration-of-drug-medical-device-and-medical-device-drug-combination-products-second-edition-20-june-2019/file
- European Medicines Agency. “Guideline on the quality requirements for drug-device combinations.” 29 May 2019. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-requirements-drug-device-combinations-first-version_en.pdf
- 21 CFR Part 4 -- Regulation of Combination Products. https://www.ecfr.gov/current/title-21/part-4. Accessed 7 May 2026.
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. “Technical and Regulatory Considerations for Pharmaceutical Lifecycle Management. Q12” 20 Nov 2019.
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. “Analytical Procedure Development. Q14” 1 Nov 2023.
Venkat Reddy Sunkara is global head of Regulatory CMC at ICON. He has extensive expertise in managing Chemistry, Manufacturing, and Controls (CMC) aspects of regulatory submissions and post market compliance, supporting clients in achieving and maintaining adherence to global regulatory requirements. He brings over 20 years of pharmaceutical industry experience, including more than 10 years in CMO/CRO environments specializing in Regulatory CMC.
