Drug-Device Combination Products: Regulatory and Technical Challenges

Introduction: The Convergence of Two Worlds

The pharmaceutical industry is witnessing a fundamental shift from traditional dosage forms toward drug-device combination products (DDCPs), driven by the need for enhanced patient compliance, targeted drug delivery, and improved therapeutic outcomes. From prefilled syringes and auto-injectors to wearable on-body delivery systems and smart inhalers, these products integrate drugs with medical devices to offer delivery mechanisms that transcend the capabilities of conventional formulations.

Drug-device combinations have improved the landscape of healthcare through both drug effectiveness and personalized medicine. The global market for these products reflects this growing importance: it grew from USD 144.59 billion in 2024 to USD 156.46 billion in 2025, and is expected to continue growing at a CAGR of 8.14%, reaching USD 231.25 billion by 2030.

However, the convergence of pharmaceutical and device technologies brings unique challenges. Unlike traditional drug products, DDCPs must satisfy regulatory requirements for both drugs and medical devices—often across multiple jurisdictions with differing frameworks. They must demonstrate not only drug safety and efficacy but also device reliability, usability, and container closure integrity throughout the product lifecycle. For pharmaceutical packaging manufacturers like Vialab Pharmaceutical Packaging Co., Ltd. , these challenges represent both a responsibility and an opportunity to deliver integrated solutions that protect drug products and enable patient-centered care.

This article explores the regulatory and technical challenges of drug-device combination products, examining the evolving regulatory landscape, key technical considerations, and strategies for successful development and commercialization.

The Regulatory Landscape: Navigating Divergent Frameworks

FDA: A Unified but Complex System

In the United States, the Food and Drug Administration (FDA) defines a combination product as either a single entity that physically, chemically, or otherwise combines two or more regulated components—such as a drug and device—into one product, or two or more separate products packaged together as a unit that includes both drug and device components. These are known as “single-entity” and “co-packaged” combination products, respectively.

The FDA’s Office of Combination Products (OCP) develops cross-cutting guidance for product classification, jurisdiction, and combination products. When the primary mode of action of a combination product is that of a therapeutic drug or biological product, the Center for Drug Evaluation and Research (CDER) is assigned as the primary regulatory Center. These are often called “drug-led” combinations, as the drug constituent part mainly drives the product’s therapeutic effect. For example, a therapeutic drug-device in a prefilled syringe would be regulated by CDER under a new drug application.

The FDA oversees these products comprehensively, with the Center for Drug Evaluation and Research (CDER) or the Center for Devices and Radiological Health (CDRH) determining the regulatory path based on whether the product acts primarily as a drug or a device. Post-marketing surveillance, risk management, and safety signal identification are key features of the FDA’s Adverse Event Reporting System (FAERS) and Risk Evaluation and Mitigation Strategies (REMS).

EMA: A Divided Approach

In the European Union, the regulatory picture is more fragmented. Combination products are officially regulated according to their primary mode of action as per EU MDR 2017/745 and MPD 2001/83/E.C., executed by the European Medicines Agency (EMA) and National Competent Authorities (NCAs). Products are classified as integral, co-packaged, or cross-labeled.

One of the main differences between the US and EU is that in the US, a combination product is fully regulated by FDA (with the support of different centers), whereas in Europe, two different and independent entities are involved. No single regulatory authority oversees the entire lifecycle of combination products in the EU. The MDR focuses on device performance and risk management while the EMA focuses on medicinal product efficacy and safety. The drug safety reporting system EudraVigilance focuses on the medicinal component, with EUDRAMED covering device aspects.

The definition used by FDA is broader than the one presented by EMA. The EMA defines a “Drug-Device Combination Product (DDC) as a medicinal product with integral and/or non-integral medical device/device component(s) necessary for administration, correct dosing or use of the medicinal product”, whereas the FDA’s definition encompasses any product composed of two or more different types of medical products (drug, device, and/or biological product).

The Challenge of Global Harmonization

The misalignment between the EU and US frameworks creates significant issues for global harmonization, affecting access, manufacturing, and patient safety. Experts have acknowledged these differences and called for greater collaboration and use of harmonized standards by the FDA and EMA.

As one former FDA official noted, combination products have historically been “something very, very difficult from an FDA perspective”. The differences of opinion are not just between FDA and other regulatory agencies, but between centers at FDA itself. Manufacturers may need to look to international standards for guidance on combination products, as “there’s still some great ways that manufacturers can navigate combination products globally, even if everything’s not perfectly aligned from the regulator’s perspective”.

China’s Evolving Framework

China has also developed its own regulatory framework for combination products. The National Medical Products Administration (NMPA) determines product management attributes based on the “primary mode of action”. The 2021 “Announcement on Matters Related to the Registration of Drug-Device Combination Products” (No. 52) further refined the attribute determination process, clarifying that device-led products are managed as Class III medical devices, while drug-led products must meet drug registration requirements. NMPA coordinates through a joint review mechanism between drug and device review centers to ensure overall product risk is controlled.

The New QMSR: A Paradigm Shift

A significant development in the regulatory landscape is the FDA’s new Quality Management System Regulation (QMSR), which took effect on February 2, 2026. This formally aligns 21 CFR Part 820 with ISO 13485:2016. The intent is to establish a globally consistent approach to quality management for medical devices.

The QMSR’s incorporation of ISO 13485 reshapes how FDA will interpret and assess compliance—particularly for device-related areas that now carry more explicit, risk‑based expectations. These changes include an increased emphasis on complaint handling, risk management principles, and a new approach to FDA inspection.

For combination product manufacturers, this harmonization with ISO 13485 introduces changes that will affect how they approach compliance with current good manufacturing practice requirements. The FDA has made conforming edits to part 4 (21 CFR part 4) to clarify the device Quality Management System requirements for combination products. As one industry expert noted, “Today’s drug pipeline is rapidly transforming, with a continued increase in drug complexity that is driving higher use of combination products. And with these combination products also come increased regulatory requirements – driving the need for combining the right technology with the right data”.

Technical Challenges: From Concept to Commercialization

Container Closure Integrity: A Holistic Approach

Container Closure Integrity (CCI) is a critical quality attribute for combination products. For injectable combination products such as prefilled syringes, auto-injectors, pen injectors, patch pumps, and wearable on-body delivery devices, maintaining sterility throughout the product lifecycle is paramount.

CCI should be built into the entire process, not merely confirmed through final testing. A holistic approach must consider all interconnected aspects of container closure integrity, not specific parts or aspects, and encompass all elements of the control strategy. The control strategy is established throughout the product lifecycle, from product design to shelf-life stability, and must address all risks and how to prevent and control them.

As combination products have become more complex and sensitive—especially with more high concentration formulations and biologics—there is a growing recognition of the need for systematic approaches to early-stage drug container compatibility testing. Industry experts emphasize evaluating different container closure systems early to minimize the potential for failures in later stages by identifying risks as early as the feasibility stage.

Unlike conventional approaches that focus primarily on chemical compatibility (stability, extractables, leachables), a comprehensive strategy must also emphasize functional performance of the combination product under stress conditions and over time. This includes assessing functional parameters such as break-loose and glide forces, characterizing the silicone layer, viscosity, particulates, and ensuring formulation compatibility with the primary container.

Extractables and Leachables: A Non-Negotiable Requirement

Extractables and Leachables (E&L) testing has become non-negotiable for pharmaceuticals, biologics, and combination products. The ICH has released a draft Q3E guideline that offers a harmonized framework for assessing and controlling extractables and leachables in pharmaceuticals and biological products, including drug-device combination products.

Common challenges in E&L studies include a lack of supplier data or incomplete supplier data for construction materials, choice of the right solvents or extraction conditions, and interference of leachables with matrix-related substances. Studies often fail to simulate worst-case conditions like high/low pH or extended shelf life.

For combination products, the challenge is amplified because materials must be compatible with both the drug product and the device function. The container closure system must not only maintain sterility but also avoid leaching substances that could compromise drug stability or patient safety.

Human Factors Engineering: Beyond Usability

Human factors engineering (HFE), also called usability engineering, plays a critical role in the development of drug-device combination products. It is no longer a “nice-to-have” but a regulatory expectation. The FDA’s 2023 guidance on combination products makes it clear that evaluation of a combination submission consisting of device and drug/biologic does not occur individually. Integrated HFE is the most critical tool for securing regulatory approval, confirming meaningful user adoption, and achieving better health outcomes.

Drug-delivery devices must accommodate a wide range of users. Overcoming human factors engineering challenges requires a development process grounded in deep, ongoing user insight. This begins early with qualitative interviews and direct observations to understand how patients interact with devices in real-life contexts.

The FDA has issued guidance documents on the application of human factors engineering principles to combination products, clarifying how the unique aspects of a combination product influence considerations within the HFE process.

Sterilization: Balancing Efficacy and Compatibility

Sterilization presents unique challenges for combination products. Not only must the manufacturer be certain that all components within the kit reach a sterile state, but all materials must also be compatible with the sterilization process. Where the product is provided pre-combined, one or more of the components may be sensitive to particular methods of sterilization, and the challenge becomes one of developing a process that can assure sterility without compromising the fundamental properties of those components.

The growing number of sensitive combination products and biopharmaceutical products that are not easily sterilized with traditional terminal sterilization approaches adds further complexity. For teams working on injectable or combination products, delays in sterilization can disrupt submission timelines, push back production runs, and introduce additional risk during critical phases of development.

Packaging: Bridging Two Design Logics

Traditional pharmaceutical packaging and standard device packaging follow different design logic. Combination products bring these two systems together, which introduces several technical challenges. A combination product package may contain multiple regulated components that must be protected, organized, and presented in a way that ensures safe and effective use.

The most common compatibility issues identified in combination product packaging include particulate challenges (55.6%), sterility issues (27.8%), and leachables (16.7%). Using an original container closure system can save 12–24 months in development timeline, according to 76.2% of respondents.

Best Practices for Successful Combination Product Development

Early Engagement and Cross-Functional Collaboration

One of the most critical success factors in combination product development is early engagement across functions. A lot of the risks in combination product development come from timelines not being fully aligned or lack of cross-functional collaboration. Companies should align across drug timelines, device timelines, and regulatory timelines, ensuring that device design controls and risk management processes are fully integrated with overall drug development plans.

Early data generation and integration of device considerations set the foundation for long-term product success. Rather than treating container closure system selection as a procurement step, companies should integrate it into their entire strategy and evaluate it beforehand.

Data-Driven Decision Making

The challenge in combination products is to provide performance data at the system level and help reduce drug manufacturers’ development risk by specifying a verified system rather than individual components. Until recently, pharma companies have been burdened with the complexity and costs of designing and justifying combination products that meet both medical device and drug requirements.

A data-driven approach to evaluating container closure systems—assessing functional parameters, compatibility, and performance over time—can help avoid costly, resource-intensive fixes later in the process.

Strategic Regulatory Planning

Given the differences between FDA and EMA frameworks, strategic regulatory planning is essential. In the US, everything lies with the FDA, and one submission is needed. In the EU, two completely separated entities—a Notified Body and the EMA or a National Health Authority—review the submission.

Manufacturers should consider early pre-submission meetings with regulatory agencies to clarify pathways and expectations. The FDA has implemented pre-submission facilities quite successfully over years, and similar facilities are anticipated in the new European system.

Vialab’s Role in Combination Product Packaging

At Vialab Pharmaceutical Packaging Co., Ltd. , we understand the unique challenges of drug-device combination products. Our comprehensive portfolio of pharmaceutical packaging solutions is designed to meet the demanding requirements of both drug and device components:

Injection Pens (Disposable & Reusable) : Engineered with precision to ensure accurate dosing and reliable performance, supporting patient adherence and therapeutic outcomes. Our pens are designed to accommodate the functional performance requirements that are critical for combination product success.
Glass Vials & Tubes (Parenteral Grade, Precise Dimensions) : Manufactured to meet strict pharmaceutical standards, with both clear and amber glass options to address light sensitivity requirements. Every vial is produced with rigorous quality control to ensure container closure integrity.
Sterile Vials (Ready-To-Use, Wash & Sterilized) : Processed in cleanroom facilities to meet ISO and GMP standards, reducing time-to-market and contamination risk for combination product manufacturers.
Aluminum & Aluminum-Plastic Caps (Tamper-Evident, Various Sizes) : Designed to maintain container closure integrity throughout the product lifecycle, from filling through patient administration.
Customized Packaging Solutions (Pen Cases, Accessories, Etc.) : Tailored to meet the specific needs of combination product developers, ensuring that all components are protected and presented for safe and effective use.
Strict Quality Control (ISO/GMP Compliant) : Our quality management systems are designed to meet the rigorous expectations of both pharmaceutical and device regulations, supporting our customers’ regulatory submissions and commercial success.

Conclusion: The Future of Combination Products

Drug-device combination products represent the frontier of pharmaceutical innovation, offering the potential for improved patient outcomes, enhanced compliance, and personalized medicine. However, the path from concept to commercialization is fraught with regulatory and technical challenges that require specialized expertise, integrated approaches, and strategic partnerships.

As the market continues to grow—projected to reach USD 231.25 billion by 2030—the demand for high-quality packaging solutions that bridge drug and device requirements will only increase. Manufacturers must navigate divergent regulatory frameworks, demonstrate container closure integrity, manage extractables and leachables, incorporate human factors engineering, and ensure sterilization compatibility—all while maintaining rigorous quality standards.

Vialab Pharmaceutical Packaging Co., Ltd. stands ready to support combination product developers with comprehensive packaging solutions that meet the highest standards of quality, safety, and reliability. With our advanced production lines, cleanroom facilities, and commitment to ISO and GMP compliance, we deliver the components and expertise that combination products demand.

Whether you are developing a prefilled syringe, an auto-injector, a pen injector, or a wearable delivery device, Vialab has the capabilities to protect your drug product and enable your device function. Contact us today to learn how we can support your combination product development and commercialization.