Combination products represent some of the most innovative therapies in life sciences, but they're also some of the most complex to develop, manufacture, and bring to market.
By FDA definition, a combination product is a therapeutic product composed of two or more regulated components: typically a drug, device, and/or biologic. These components are physically, chemically, or otherwise combined to function as a single product, or they’re packaged together for use in a coordinated therapy.
You’ve likely encountered examples in your own work:
Pre-filled syringes
Drug-coated stents
Transdermal patches with APIs
Autoinjectors and inhalers with drug cartridges
These hybrid therapies offer huge benefits to patients, often improving convenience, compliance, and therapeutic effectiveness. But from a regulatory and quality perspective, they introduce overlapping compliance frameworks, more intricate design controls, and greater documentation burdens.
In this post, we’ll break down how combination products are classified, why they pose unique quality and regulatory challenges, and how the right document, quality, and regulatory information management approach can simplify your path to compliance.
One of the biggest challenges with combination products is understanding how they’re regulated and by whom.
The FDA determines the regulatory pathway based on the product’s Primary Mode of Action (PMOA), essentially, the component that provides the most significant therapeutic effect. This assessment determines which FDA center will take the lead:
CDER (Center for Drug Evaluation and Research) – for drug-led products
CBER (Center for Biologics Evaluation and Research) – for biologic-led products
CDRH (Center for Devices and Radiological Health) – for device-led products
If it’s not immediately clear which center should lead, the Office of Combination Products (OCP) steps in to assign a center and provide guidance. This process is governed by 21 CFR Part 3, and companies can submit a Request for Designation (RFD) to receive an official determination.
This classification is very significant. It determines:
Which regulatory framework your product must follow (e.g., GMP vs. QSR)
Which pre-market submission type is required (IND, NDA, BLA, 510(k), PMA, etc.)
Which post-market surveillance and reporting rules apply
For companies developing combination products, early alignment with the FDA and internal clarity on the regulatory pathway is critical to avoid rework, delays, and compliance gaps.
Combination product development unfolds across several key stages, each with distinct quality, regulatory, and operational challenges. While the exact sequence may vary based on product type and regulatory jurisdiction, most combination product programs follow a predictable path from concept through commercialization.
Development begins with defining the product’s therapeutic objective and delivery mechanism. During this stage, teams evaluate potential combinations (ex. pairing a drug with a novel delivery device) and begin early risk assessments, usability evaluations, and compatibility studies. Regulatory strategy also takes shape here, especially when it comes to determining the product’s Primary Mode of Action (PMOA), which influences which FDA center will take the lead.
With feasibility confirmed, product design moves forward. Device design inputs and human factors considerations are formalized under medical device design controls, while pharmaceutical teams advance formulation development, method validation, and early stability testing. Cross-functional documentation efforts begin to take shape, including the design history file (DHF), labeling drafts, and standard operating procedures (SOPs). This stage lays the groundwork for both quality and regulatory records that will support future submissions.
This phase focuses on ensuring internal and external alignment before formal submission activities begin. Regulatory teams may submit a Request for Designation (RFD) or initiate pre-IND, pre-IDE, or Q-sub meetings to clarify expectations and confirm the regulatory pathway. Content plans for submissions are developed in parallel with validation planning, ensuring that all documentation and data will meet the standards required by FDA reviewers. This is also when regulatory information management (RIM) systems begin to play a central role in tracking timelines, correspondence, and commitments.
As the product enters pivotal trials or design validation, manufacturing operations begin scaling in parallel. Process validation, analytical method verification, and batch record documentation become essential to ensure product consistency. Meanwhile, clinical trials for drug or biologic components are executed and monitored. Teams must coordinate across quality, regulatory, and clinical functions to finalize labeling, packaging, and instructions for use, all while preparing for submission compilation.
Once development and testing are complete, teams assemble the submission, which is often a complex process involving multiple modules and cross-center coordination. Depending on the product classification, this may include an NDA, BLA, PMA, or a hybrid submission involving more than one regulatory center. Throughout this stage, version alignment between quality documentation and submission materials is critical. So is the ability to respond efficiently to FDA questions or additional information requests, which requires integrated access to both regulatory correspondence and quality system data.
After approval, the focus shifts to sustaining compliance. This includes managing complaints, adverse events, and change control across all components: drug, device, or biologic. Teams must also monitor ongoing postmarket study requirements, real-world performance data, and updates to regulatory or labeling commitments. A robust QMS and RIM infrastructure becomes critical to maintaining a clear audit trail and supporting continuous improvement throughout the product lifecycle.
Combination products merge more than the technologies behind them. They also merge expectations from both quality and regulatory functions. This intersection presents major challenges when teams rely on disconnected systems or siloed processes.
From a quality management perspective, combination products often require compliance with:
Pharmaceutical GMPs under 21 CFR Part 210/211
Medical Device QSRs under 21 CFR Part 820
Teams must navigate:
Design controls and DHFs for device elements
Batch records and validation documentation for drug components
Complaint handling and CAPAs that span both device and pharma
Integrated risk assessments that consider clinical, manufacturing, and post-market use
From a regulatory information management (RIM) standpoint, the challenge is just as steep:
Submission content must be assembled from diverse sources and formats
Multiple regulatory pathways must be tracked in parallel
Correspondence with FDA may span CDER, CDRH, and OCP simultaneously
Change impacts must be documented not only in quality systems, but across all current and planned submissions
When RIM and QMS systems are disconnected, it becomes harder to:
Maintain alignment between quality events and regulatory responses
Ensure submission content reflects the most current, approved documentation
Respond quickly to agency feedback or inspection findings
Combination product teams need more than just compliance checklists. They need systems that can unify quality and regulatory data, support cross-functional collaboration, and provide traceability across the product lifecycle.
To manage combination products effectively, your QMS needs to do more than just meet baseline compliance. It must support cross-regulatory workflows, connect disparate components, and give your team full traceability from development through post-market surveillance.
Here’s what that looks like in practice:
Your QMS should align with both GMP and QSR standards, allowing you to document design history, track product lots, manage validation protocols, and log manufacturing deviations all in one system.
CAPAs and change requests often affect multiple components. Your system needs to link them across drug and device elements, so a change to a syringe’s needle length doesn’t get lost before it updates the batch record or labeling for the drug it delivers.
Combination products require layered risk assessments. A strong QMS should help you map, track, and reassess risks across components, not just for initial development but throughout the product lifecycle.
Whether it’s DHFs, SOPs, specs, or batch records, all documentation needs to be version-controlled, searchable, and accessible by function without duplicating or syncing across siloed systems.
With multiple regulatory bodies potentially reviewing your records, audit prep should never rely on last-minute scrambles. The right QMS can generate export-ready reports, with clear links between requirements, evidence, and approvals.
While a strong QMS helps ensure product quality and compliance, an equally robust Regulatory Information Management (RIM) system is essential to navigate the regulatory landscape, especially for combination products.
Key capabilities to look for in a combination product-ready RIM include:
Track global submission activities across CDER, CBER, and CDRH. Align PMOA-based strategies with lead agency expectations.
Maintain a structured log of FDA communications and commitments, then connect them to internal tasks, quality events, and submission milestones.
Ensure approved core documents (e.g., labeling, IFUs, specs) are reused across submissions and assess how changes ripple through future filings.
Support launch planning by coordinating submission due dates, renewal cycles, and approval timelines with visibility across all regulatory centers.
Enable regulatory teams to audit their own work for completeness, version control, and validation status before submission.
A modern RIM solution gives regulatory teams control, clarity, coordination, and confidence in a cross-regulated environment.
Despite the growing complexity of combination products, many teams are still managing quality and regulatory documentation across siloed systems:
Design files stored in a legacy device QMS
Batch records managed in spreadsheets or standalone MES tools
Submission documents housed in local drives or SharePoint
Regulatory calendars tracked manually in Excel
This fragmentation slows down audits, increases the risk of misalignment between submissions and internal records, and makes cross-functional impact assessment nearly impossible.
Some teams rely on enterprise tools that were never built for combination product workflows, forcing them to customize excessively or create manual workarounds that drain time and increase risk. Others remain stuck in spreadsheets and disconnected tools that can’t scale with growing pipelines.
The result: duplicate work, version mismatches, and constant fire drills during audits and submissions.
Combination product teams need systems that work like they do: collaboratively, cross-functionally, and without artificial silos.
Kivo was built from the ground up to support life sciences organizations managing complex products and processes. By unifying document management, quality management, and regulatory information management in a single platform, Kivo provides a foundation that scales with your product and regulatory complexity.
With Kivo, you can:
Manage DHFs, batch records, and submission-ready documents in one system
Connect CAPAs, change controls, and risk assessments to regulatory commitments
Track global submissions and correspondence without relying on spreadsheets
Align your quality and regulatory timelines in one unified calendar
Maintain full version history, audit trails, and validation logs across all functions
Teams working on combination products have used Kivo to:
Cut submission prep time by weeks
Reduce redundant data entry across systems
Accelerate audit responses with linked documentation
Eliminate version confusion between regulatory and quality teams
Combination products are transforming patient care, but they also transform what it takes to stay compliant. With multiple regulatory frameworks, overlapping documentation, and interconnected teams, life sciences companies can’t afford to manage these products using disconnected tools.
Kivo helps you move beyond the chaos. By providing one platform for document, quality, and regulatory information management, we help combination product teams eliminate silos, reduce compliance risk, and move faster, all while meeting the highest standards.
Ready to unify your combination product workflows? Click below to speak with a Kivo specialist today and learn how we can support your team.