Creating a supportive combination product ecosystem within your drug world 

Often when we are hired by a Pharma or Biotech company to support their drug delivery device development, even in the most sophisticated of companies that have been to the combination product rodeo before, we find that they do not have a culture that fosters combination product development success. There are a few main reasons for this: 

1. Drugs/biologics and devices are developed very differently, and drug companies tend to try to fit a device’s square peg into the drug’s round hole. 
2. Drugs/biologics and devices are regulated similarly, in some cases by the same regulatory body (the FDA), however regulatory schemes are different and the divisions responsible for the review may be different. 
3. Management does not provide sufficient resources and weight to the importance of, and unique processes of, device development. 

When embarking on a combination product development program, it’s essential to recognize that each initiative is unique. The complexity and development phase will shape your company’s strategies and understanding certain key factors will play a critical role in building a robust combination product organization. These factors can be broadly categorized into: 

• Differences in Drug and Device Development Processes: Understanding the distinct timelines, methodologies, and requirements for drug and device development is crucial to aligning these processes effectively. 
• Differences in Drug and Device Personnel and Cross-Functional Teams: Bridging the gap between professionals with drug-focused expertise and those with device-specific knowledge is vital to fostering effective collaboration. 
• Differences in Drug and Device Regulatory and Quality Schemes and Strategies: Successfully navigating the regulatory frameworks governing drugs and devices requires a tailored, integrated approach. 
• Added Complexities of Post-Market Support and Surveillance Activities: Ensuring compliance and addressing post-market requirements for combination products demand careful planning and execution. 
• The Role of Management in Driving Success: Leadership must prioritize cross-disciplinary integration, resource allocation, and strategic oversight to guide the program toward its objectives. 

Below we will discuss these areas, beginning with differences in drug and device development processes, defining key details companies must grasp to better position themselves to manage the inherent challenges of combination product development while ensuring regulatory compliance and market success. Each week, we will add on to this article to complete the blueprint for creating a supportive combination product sub-ecosystem in your drug world.

Differences in Drug and Device Development Processes 

The development processes come from two very different approaches. Drug/biologic product formulation centers around discovery; scale up and refinement of the manufacturing process, validating, testing, establishing specs, then tightening the specifications as more data is collected until a safe and effective product is realized. 

Meanwhile, device development is fundamentally different.  

The design process for medical devices is governed by a subset of regulations, ensuring a comprehensive design control framework. It all starts with identifying the intended use of the device and understanding the needs of the users. These insights are then transformed into Design Input Requirements, which are tailored to the capabilities and conditions of the intended users. 

As the development progresses, the device undergoes rigorous testing to ensure that the Design Inputs align with the expected outputs, a process known as Design Verification. Additionally, the device must be validated to confirm that it effectively meets the user needs, referred to as Design Validation. This structured approach not only enhances the safety and efficacy of medical devices but also ensures they are user-friendly and reliable. 

The first hurdle companies face is recognizing this difference and not trying to shoehorn device development into the same formulation mentality as drugs and biologics. The second hurdle is making these two different processes work together by identifying critical engagement timings and understanding the differences and similarities in methodology and terminology between drug development (quality by design) and device development (design controls). 

Developing a combination product means tackling new research tasks that extend far beyond traditional drug development. These tasks encompass all aspects of the device constituent necessary to bring the product to market. For instance, if your project involves creating a novel device, device development itself becomes a significant undertaking. This process includes engineering, design, and early characterization testing to optimize and ensure the robustness of your device, ensuring functionality and safety in your intended use environment. Even in instances where you select to use an established platform, engineering activities will still be needed to ensure the platform operates with your unique drug product. This can take on various forms of testing and analysis as outlined below. 

Usability and Human Factors play a critical role in this development journey. These efforts focus on gathering real-world evidence to confirm that patients can effectively and safely use the device, particularly in home settings.  

Design Verification is a crucial step in the product development process where you will generate the data and objective evidence to show your device meets its engineering requirements, often across a range of preconditions and stress conditions (Temperature, physical agitation, humidity, etc.). 

Labeling takes on added complexity, as it must cover not only the drug’s information but also comprehensive Instructions for Use (IFU) for the device. Additionally, compliance with laws governing disposal becomes a critical consideration, especially for used or potentially contaminated components like injectors. 

Other essential characterization and analysis activities involve compatibility testing, preconditioning or initial stability testing. Preconditioning simulates the aging and transport conditions of the drug-device combination, while stability studies will be critical for establishing the product’s shelf life.  

These examples only provide a glimpse into the considerations a company must make. Each of these elements represents a distinct challenge, underscoring the importance of a holistic and well-coordinated approach to combination product development. 

Differences in Drug and Device Personnel and Cross-Functional Teams

Device development requires the expertise of engineers. While there are plenty of engineers at Pharma and Biotech companies, they are usually associated with manufacturing operations or research and development functions and have a more scientific or academic mindset. On the device side of things, you typically need engineers who are more heavily mechanically inclined or think in systems and system integration. What may seem like simple development on the surface often turns out to be a highly complex integration of components, systems, processes and decision making that needs to function through your product’s Life Cycle Management activities. Because of this, a development operations mentality and strong combination product experience in the selected device type is required to get the job done right the first time.

The development of a drug delivery system adds new external partners to the mix. Setting up management processes and responsibilities for these new partners, creating the right amount of transparency, and clarifying roles and communication protocols are critical to taming this new beast that just grew some more arms and legs. Below is a list of your new appendages:

• Your device constituent will be purchased and developed with an OEM (Original Equipment Manufacturer)
• You may contract a CRO (Contract Research Organization) to outsource research services for device clinical or commercial development
• Your device constituent inventory will be manufactured and the final product assembled by a CDMO (Contract Development and Manufacturing Organization)
• You will most likely outsource Human Factors and Useability Studies to a contract organization
• Various testing activities will be outsourced to vendors: sterilization, design verification / stability, biocompatibility
• Your IFU (Instructions For Use) will likely be designed by an external expert
• Your packaging/IFU will be manufactured by an external vendor

“So, you’re saying I just need to hire a few companies, and the development will take care of itself?” Absolutely not! As the Marketing Authorization Holder, you bear ultimate responsibility for managing and executing the entire process. This includes having the right team on the inside maintaining diligent oversight, fostering effective cross-collaboration, and ensuring timely reviews and summaries at key milestones. Throughout the development journey, it’s crucial to actively identify, mitigate, and control risks specific to your product’s intended use and users. This level of accountability ensures the integrity and success of your combination product.

As if adding new external partners wasn’t challenging enough, internal stakeholders will also have to take on new responsibilities across the business. One example of this will be the Commercial Team. With the introduction of a combination product, this will require the commercial team to have a newfound exposure to device constituent training and education as well as cross-functional training on new Commercial activities and the resulting interactions needed between the Commercial team, Device teams, and suppliers. For example, User Needs and Design Inputs. This is a completely new responsibility for a Combination Product development team. While drugs have a Target Product Profile (TPP) that itemizes all of the drug characteristics needed for the product, User Needs and Design Inputs are unique to medical devices and combination products. User Needs and Design Inputs are typically drafted by the product development or engineering team with advisement and input from the Commercial Team, Clinical Team and other key stakeholders. This input should include providing User and Stakeholder needs to the engineers that relate to the salability and consumer appeal of the device. 

It’s easy for a drug company to dismiss the device as simply “the container for our drug,” but it’s crucial to recognize that the device is what the end user directly interacts with. This interaction plays a significant role in shaping perceptions of the drug’s brand. For teams accustomed to focusing solely on the pharmaceutical aspects, this shift in perspective can feel like learning an entirely new language. However, it’s a critical element of development that cannot be overlooked!

Another group that can be heavily impacted by the transition from drugs to combination products is Strategic Sourcing. Pharmaceutical companies typically rely on Strategic Sourcing or Procurement teams to identify, evaluate, and approve suppliers. For combination products, this process extends beyond traditional raw materials to include highly specialized device manufacturers. Suppliers may range from providers of simple components, such as needles or plungers, to producers of complex finished devices, such as autoinjectors or inhalers. Each new supplier relationship demands rigorous vetting to ensure compliance with regulatory requirements and alignment with the product’s specifications. The Combination Product team often plays a critical role in this process, ensuring that the selected suppliers can meet the unique needs of the combination product.

An essential element in managing device suppliers is the establishment of Quality Agreements, which outline the roles, responsibilities, and quality standards required of each supplier. These agreements are particularly critical for combination products, where the failure of even a single component—such as a needle in an autoinjector—can disrupt the entire supply chain. For example, a supplier’s inability to meet demand or comply with regulatory requirements could delay not only the development and approval process but also the product’s availability in the market. Changes to components, materials or processes additionally must be carefully evaluated and traced back to the programs Design History File (DHF) and Risk Management File (RMF) to ensure it remains current at all times during the products life cycle.

Differences in Drug and Device Regulatory and Quality Schemes and Strategies

There are very specific requirements and regulatory pathways with nuanced approaches needed for each drug/biologic and device combination. There is no cookie cutter regulatory pathway. Many of the niche situations you will find yourself dealing with are not well covered, or not covered at all, in guidance. Even with knowledgeable combination product specialists on the payroll, if they have not worked on that device type, with that particular niche situation before, or in a while, their knowledgebase may be stale. Employee turnover, which tends to be relatively high in the Pharma/Biotech world, can also contribute to a knowledge gap.

To complicate your regulatory strategy further, guidance is continually evolving and differs globally. This makes it necessary to constantly keep up with regulatory intelligence and modify regulatory strategies, having team members who are steadily focused on combination products. For example, below are some of the various permutations and combinations that your combination product could fall within.

• Single Entity Products ​
• Drug PMOA — filed as IND (investigational); and NDA (small molecule) or BLA (large molecule) ​
• Device PMOA — filed as IDE (investigational); and PMA or 510(k) depending on classification ​
• Co-Packaged Products ​
• May be one submission (e.g., same as single entity), or ​
• May be a combination of submissions, e.g., 510(k) for device constituent and BLA for drug constituent; ​
• Even with multiple submissions, the PMOA submission needs to include reference to the other licenses ​
• Determinant is typically whether the constituents included in the package are “off- the shelf” and have existing registrations ​
• Cross-Labeled Products ​
• Typically, two separate submissions, connected through labeling ​

When it comes to quality systems, drug development primarily falls under Good Manufacturing Practices (GMP), emphasizing chemical stability, sterility, and consistent pharmacokinetics. Key processes focus on raw material controls, process validation, and robust batch record documentation to ensure drug safety and efficacy.

In contrast, device development adheres to Quality System Regulations (QSR), particularly 21 CFR Part 820 in the U.S., which prioritize design controls, risk management, and traceability. Device quality systems are heavily driven by iterative testing, human factors engineering, and post-market surveillance to ensure safety and usability.

When developing a combination product, the quality system must account for both GMP and QSR, often requiring a hybrid approach that carefully integrates the two processes in a manner that is compliant yet not overly burdensome. At Suttons Creek, we often encounter clients diving into combination product development without a robust 21 CFR Part 4-compliant quality system. This is obviously not ideal and often needs careful remediation tailored to the company’s specific needs. However, overcorrecting by implementing an overly complex quality system can be just as problematic. We’ve seen companies burdened by cumbersome processes that lead to a chain reaction of non-conformances, CAPAs, and deviations, which may signal to regulators that the system isn’t functioning as intended. The key lies in striking a balance—creating a quality system that ensures compliance while remaining practical and aligned with the organization’s scale and maturity. A right-sized approach, grounded in risk management and streamlined processes, reduces inefficiencies and positions companies to navigate the complexities of combination product development effectively, avoiding delays and ensuring safety and compliance.

Collaboration across teams with expertise in drugs and device quality systems is vital. Establishing a unified quality system that draws from both GMP and QSR ensures that the final product meets all safety, efficacy, functionality and usability requirements.

Added Complexities of Post-Market Support and Surveillance Activities

Upon approval of your product the complex work continues! Below we look at a few specific examples and considerations you and your team need to keep in mind.

Scaling issues with a combination product. 

Scaling is different for a combination product from clinical studies through marketing. Clinical studies require a smaller number of devices to be produced than the volume that will be required for commercial launch. The planning for this transition often needs to take places years in advance to ensure a smooth transition to market volumes. Detailed plans need to be made for a weighty supply increase if this product is anticipated to be widely used (think about some big therapy areas, such as ulcerative colitis and Crohn’s disease). These changes might entail not just ordering larger volumes but potentially mold modifications or small design changes as you move from manual or semi-automated processes to fully automated assembly processes. All of this adds both technical and logistic complexity that needs to be managed with a high degree of finesse.

In comparison to a stand-alone drug, a combination product contains drug plus device(es), the associated labeling and packaging, instructional material and even potentially training devices. Careful consideration needs to be paid to all aspects of the process, including drug product supply, device supply capabilities (suppliers), CMO to fill the drug into devices, and packaging and labeling CMOs. All of these finish steps may be done by one manufacturing site or multiple manufacturing sites that need to operate with a high degree of coordination. If your finished combination product requires refrigeration, then transport from one finishing site to another must be controlled. These logistics can add up to real world impact – for example, think of all the press about shortages of weight management drugs like Ozempic, Mounjaro, Zepbound and Wegovy. In many instances with these weight management drugs, the drug itself is available but other elements of the supply chain are causing a bottleneck.

Commercial and Marketing Challenges

Launching a combination product introduces unique challenges that extend beyond traditional pharmaceutical development. These challenges, present during both development and post-approval phases, require strategic planning and cross-functional collaboration. While many decisions are technical in nature, they significantly influence the commercial claims and approaches available to your business. Key considerations include:

Pricing and Reimbursement Strategy: Developing a pricing model for combination products is complex, as it must account for the value of both the drug and device components. Reimbursement pathways can vary significantly by market, requiring robust evidence to support cost-effectiveness, such as real-world data or health economics models.

Shelf Life Considerations: Unlike standalone pharmaceuticals, combination products must address the shelf life of both the drug and the device. Stability studies must evaluate how these components interact over time to ensure safety, efficacy, and usability.

Industrial Design and Branding: The industrial design, including colors, labeling, and ergonomic considerations, is critical for usability and market differentiation. These elements must be defined early in collaboration with engineering teams, as downstream design changes can lead to delays, increased costs, and regulatory hurdles.

Managing Regional Labeling and Language Variations: Global distribution necessitates localized labeling and instructions for use, often in multiple languages. Ensuring compliance with regional regulations and cultural expectations is critical to successful product adoption.

End-User Support and Training: Effective end-user support strategies can drive adoption and adherence while reducing misuse risks. These strategies may include:

• Nurse Trainers/Educators: Providing in-home training for patients, particularly for devices with complex functionality.
• Web and Phone Support: Offering accessible resources, such as instructional videos or live support, to guide patients through device use.
• Integration with Specialty Care Providers: Facilitating connections between patients and physicians or specialty pharmacies for prescriptions and product access.

Note – The FDA closely monitors training materials, websites, and videos to prevent unsupported promotional claims. Training methods may also need to be validated through Summative Human Factors studies to ensure their effectiveness and compliance.

How can management set the combination product team up for success?

It is very easy, based on the proportionate size of the needed drug/biologic development budget and timeline versus the device development budget and timeline, that the device is an ancillary side-project, or even afterthought, of the drug/biologic. Think about how much strategic focus you put into buying a home versus the brainpower you put into selecting a banana at the grocery store. The difference feels like that to Pharma/Biotech leadership. However, drug delivery systems are a very user-centric product, and the combination product’s market success will rely equally on the user’s opinion of the device as it does on the effectiveness of the drug. Inadequate attention to your device constituent can also delay launch when drug/biologic and device processes are not aligned or you run into regulatory approval delays. We have been called in by many a company that ran into problems on the device side that caused their product to not get approved. Changing this mindset is a necessity that many companies realize too late.

To complete our thoughts on setting up a combination product ecosystem within your drug world, below is a listing of the top eight pieces of advice we give our clients:

1.  When a drug/biologic company views devices in the above way, it often goes beyond process into a cultural space – making change more difficult and requiring change to start from the top down.

2.  The device team cannot be siloed nor tacked on as a sub-team of a drug team. Instead, the device team needs to become an integrated part of an overall product development team, adopting a cross-functional, collaborative approach. This product development team must expand to include all of the additional stakeholders that come with the addition of a device constituent mentioned earlier (OEM, CDMO, supply chain, testing facilities, the Commercial team), ensuring phase-appropriate cooperation and inputs. Below is a listing of internal teams that need to come together for success.

3.  The device team needs to have current hands-on experience in the type of device being brought to market. Often Pharma and Biotech companies hire device experts, but they have purely medical device experience and lack the combination product knowledge that will support alignment of development processes and a successful regulatory pathway. This is why it is highly recommended that these companies strategically outsource certain roles and responsibilities to combination product consultants who have worked across many combination products and can bring current best practices to the table.

4.  All stakeholders need to understand the basic considerations and critical challenges of drug delivery system development, what their role is within the overall process, and how other functions can affect the work they are doing to bring it to market. When a team is created for a new combination product, trainings should be held to ensure all team members have a basic understanding of the combination product arena and get updated on current best practices and regulatory changes (there are always changes, thanks to the newness of this industry and its constant innovation). This education will support the development of SOPs that create alignment between the various functions within the overall product development team, including external partners, that gives everyone protocols to follow. A solid knowledgebase allows understanding of the work to be done, so these SOPs are written to guide the work without being over prescriptive.

5.  Alignment is utterly dependent on cross-functional/stakeholder collaboration and communication systems. For a combination product to get developed successfully, you will be bringing multiple internal departments together, along with external partners. Furthermore, you will be communicating with regulatory bodies that will be guiding deliverables contributed to through collaborative efforts by multiple stakeholders. Since all of these people will not be sitting in the same room together, knowing when to engage is a key element of alignment. Having a communication strategy and agreed upon communication platforms throughout the lifecycle of the product, from strategy creation through postmarket surveillance is critical to getting your combination product on the market…and keeping it there.

6.  A full lifecycle approach in which your product team is taking upstream and downstream effects of decision-making into account from strategy through postmarket surveillance is necessary in combination product development. Decisions made about device design can affect how it interacts with the drug, while drug formulation decisions affect the design inputs for device development and combination product regulatory strategy. Market research and marketing decisions made by the Commercial team can affect device design, along with Human Factors and Useability studies and the resulting design change and packaging/IFU decisions made. Device design decisions and Human Factors/Useability studies will affect the user training and support initiatives designed by the Commercial team. And the list goes on…

7.  Cultural change management needs to take place to educate and prepare the organization, from the executive suite down to those executing project tasks, to prepare and support the individuals involved for this new mindset.

8.  Leadership influence/support of the above. Messaging from the top down is important to ensure the entire product team

• • Acknowledges that a combination product is more than the sum of its parts from a regulatory and development perspective and that the device is not just some “off the shelf” shell that goes around the drug product at the end (for the record, there is really no such thing as an off the shelf drug delivery device).
  • Recognizes when the company doesn’t have the needed experience and filling those gaps in strategic minds and execution specialists (knowing there are issues are half the battle).
  • Buys into a collaborative, cross-functional approach to align stakeholders and drug/device processes.
  • Supports continual education and cultural change management within the combination product teams (turnover and time away from combination product projects can contribute to a shift away from your desired culture and a constant need for reeducation).

AUTHOR

Bryan Bobo, Principal Consultant, Suttons Creek – With over 9 years of experience in the pharmaceutical industry, Bryan has extensive knowledge of combination product development and what it takes to launch products on the market. He has practical and hands-on experience in various types of drug delivery systems from his years as both a Device Development Engineer as well as project and program management positions. In addition to his direct product development experience, Bryan engages with the global combination product community through his participation on various international standards committees as well as other various industry forums.  

Jonathan Amaya-Hodges, Director, Technical Services, Suttons Creek – Jonathan has over 16 years of multidisciplinary experience in regulated medical products (drugs, biologics, medical devices, and combination products) at multiple global companies. He has practical experience in Development/Engineering, Quality Assurance, and Regulatory Affairs for various types of combination products with a focus on drug delivery. Additional background includes digital health (including smart packaging/connected devices and software as a medical device, or SaMD) and in vitro diagnostics, along with clinical development (bridging) and lifecycle management for combination products. Jonathan engages with the global combination product community by speaking at conferences, lecturing in courses, serving key roles within prominent industry organizations, and interfacing with regulators on a variety of topics.

Carolyn Dorgan, Director, Technical Services, Suttons Creek – Carolyn Dorgan has 10+ years of experience in the Medical Device and Combination Product industries, including 6 years at the FDA leading the Infusion Devices team. Carolyn is active in the international regulatory community through speaking engagements and has participated in over a dozen international standards ranging from infusion devices, to needle-based injection systems, on-body delivery systems, and infant incubators. In addition, her unique approach to product development and risk management has been instrumental in working with products for which there are no established performance or regulatory standards which include pediatric medical devices, novel on-body drug delivery systems, and rare disease combination products. Carolyn has a demonstrated ability for working through complex problems at a system level to implement practical solutions using her multi-disciplinary background which includes engineering, software, cybersecurity, human factors, and business.