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Strategy Considerations: Integrating drug and device components of your combination product 

Advancements in drug delivery systems continue to open new avenues for treatment with the potential to improve patient comfort and outcomes. It’s a remarkable time that also creates challenges for pharmaceutical companies seeking to assess and potentially adopt these growing options. 

Amidst all this innovation and decision making, one crucial aspect often overlooked is the strategic, cross-functional approach to integrating drug and device components.  Crafting the right strategy is foundational work that is not merely advisable; it’s imperative.  

Combination products bring new rules, new complexities, new functions and partners, and new costs into the mix. Understanding and planning for how they all impact your development lifecycle at the outset of your combination product project is critical to your success and timely launch. In this article, we delve into the multifaceted considerations that underline the importance of setting the right strategy. 

New Rules:  

Regulatory Pathway: 

Navigating the regulatory landscape is perhaps the most intricate aspect of combination product development, which becomes even more complex if you are selling on a global level. A strategic approach involves practical knowledge and experience in the particular / similar device constituent parts, plus early engagement with regulatory agencies, to gain clarity on submission requirements, streamline the approval process, and anticipate potential hurdles. While current types of combination products (e.g. pre-filled syringes, auto-injectors, inhalers, etc.) certainly continue to pose challenges, a novel product type (which could include a novel device, drug, and/or biologic modality) may include unchartered territory, warranting special attention and expertise. By proactively addressing regulatory considerations, companies can minimize delays and ensure compliance with ever-evolving standards. 

Quality Management Systems (QMS): 

Maintaining stringent quality standards is non-negotiable in pharmaceuticals; it is an actual requirement. A well-defined QMS strategy includes the establishment of robust quality management systems, adhering to regulatory requirements such as Good Manufacturing Practices (GMP). By embedding quality assurance processes from the outset and ensuring that vendor quality management systems are in coalition, companies can mitigate risks, safeguard product integrity, and uphold patient safety. For the typical drug manufacturer, the most critical ‘streamlined’ QMS elements to initiate are Design Controls, Risk Management, and Purchasing Controls, though there are other elements (and, many details) to address, ideally with expert support due to the complexities of overlap and interaction between drug/biologic and device Quality processes. 

New Complexities:  

Business/Commercial Requirements: 

In the competitive pharmaceutical landscape, aligning product development with overarching business objectives is essential. This entails evaluating market dynamics, assessing competitive landscapes, and identifying opportunities for differentiation. To do this, the Commercial and Marketing teams must align with the combination product team from both a functional understanding and development timelines integration, to ensure their business inputs (device aesthetics, launch timing, minimum viable product, target markets, etc.) are incorporated into the development process. A robust strategy surrounding business and commercial requirements ensures that the investment in combination product development yields viable commercial returns, driving sustained business growth. Additionally, the business strategy must be well-aligned with partners and suppliers, most importantly the device constituent manufacturer (for a drug-led combination product). 

User Needs: 

At the heart of any successful combination product lies the patient and the HCP. Understanding the needs, preferences, and limitations of each user group is paramount. A strategic approach involves rigorous user research (human factors / useability / market research), incorporating feedback loops throughout development to ensure the final product aligns with user expectations. This not only enhances patient compliance but also fosters better health outcomes. These needs become the foundation of all further development and should be evalutated in detail. 

Clinical Bridging: 

Transitioning from preclinical studies to clinical trials necessitates careful planning, particularly in the case of combination products. A well-crafted strategy incorporates clinical bridging studies to validate the safety and efficacy of the integrated product. By leveraging existing clinical data and designing robust bridging protocols, companies can streamline the regulatory approval process and expedite market entry. This becomes more critical (and complex) in cases where the ‘to be marketed’ combination product is not utilized in earlier phase (or even pivotal) clinical trials, whereas bridging may become a significant topic without well-established precedent. 

New Functions & Partners 

The Device Team: 

Adding a device to a drug requires the addition of new experts to your team and an integration cross-functionally to get the job done efficiently and effectively. A well-staffed device team, whether in-house or outsourced, should include: 

  • Development / Engineering – Experienced device engineer that leads combination product development 
  • Project Manager – Manager with technical experience who organizes combination product programs 
  • Device Quality – Heads quality assurance for combination product, using experience applying SOPs and regulatory guidance for necessary cGMPs 
  • Risk Management – Part of Quality Management activities, this team creates and executes the project’s risk management strategy 
  • Device Regulatory – In charge of regulatory strategy and submission coordination for combination products 
  • Human Factors / Usability Engineering – The team that tests the product for safety, adherence, and positive user experience to ensure product design meets both regulatory, market, and user needs 
  • Packaging / Labeling – Working closely with the Regulatory, Commercial and Human Factors teams, this group designs compliant and user-friendly product packaging and labels 
  • Manufacturing / Engineering – The experts that will conduct design transfer and scale up production of your combination product 

Additional / Collaborative Functional Areas:  

  • Regulatory CMC 
  • DP/Formulation Development 
  • Manufacturing / CMO / Supply Chain 
  • Device Suppliers 
  • Program Management 
  • Commercial / Marketing 
  • Regulatory (Clinical) 
  • Clinical Development 
  • Medical Affairs 
  • Business Development 
  • Drug Safety / PV 

Device Selection: 

Selecting the appropriate delivery device is a critical decision with far-reaching implications. This process must include meticulous evaluation of multiple factors such as: 

Competitive Influence: Are you looking to innovation as your competitive advantage, or does competitive advantage rely in getting into the market first or fast? The answer to that question will lead you in the direction of selecting an “off the shelf” product (note: no “off the shelf” product is actually “ready to go”) or selecting a vendor who can customize or originate a novel device. 

Drug Compatibility: Technical considerations should be mapped out to ensure factors like fill volume, injection depth, injection time variability, etc. align with the specifications/capabilities of the device considered. 

User Experience: Everything from the packaging, instructions for use (IFU) and the actual product needs to be assessed through the lens of Human Factors and Usability to ensure a safe, effective and desirable user experience. 

Quality / Regulatory: Regulatory approval history of both the device and the vendor is a strong indicator when it comes to your own success utilizing them for your device constituent part. 

Manufacturing / Supply Chain: It is important to think about your entire product lifecycle when making choices about your device and vendors. Does the vendor meet both your small volume and scale up needs? Do they have existing fixtures and assembly capabilities to produce the required device? 

Postmarket Activities: Your product lifecycle does not end when it gets on the market. Postmarket surveillance and iterative improvements through new generations are necessary to continue regulatory compliance, ensure patient safety, and maintain or grow market share. It is important to select a vendor who can support your postmarket needs as well. 

Business: All of the above needs to be weighed against the cost per unit and whether that cost allows you to sell your combination product at a competitive market price. Other business considerations may include sustainability and environmental concerns, like whether the product is disposable or reusable. 

Vendor Management:

Once you have your device vendor selected, the real work begins. Having a dedicated manager in charge of vendor relationship and deliverables management is important, and it begins at the initial contract level to ensure that both parties are clear on roles, responsibilities, communication systems, and requirements for quality management. Regulatory and quality systems vary vendor to vendor, along with support resources and capabilities, so setting mutual expectations up front and maintaining oversight to keep all parties on track is necessary with each contracted vendor. A common misconception is the expectation that “off the shelf” devices – even those already commercially available – are “ready to go” and “regulatory submission ready.” Part of vendor management is identifying the expected gaps in a device’s approval-readiness and clarifying activities and roles for filling those gaps.  

New Costs: 

It is obvious to all that adding a drug delivery device to your drug/biologic will come with additional costs, but the extent of these costs is widely underestimated. Underbudgeting at the outset of a combination product generally results in less efficiencies, more delays, lost revenue, unhappy investors, and patients losing out on life-changing healthcare options. Exact costs will vary based on variables like the type of drug and device, whether it is “off the shelf” or novel, and your overall commercial strategy, but in any case, it is critical to accurately forecast: 

  • Device Costs (such as sub-assemblies, primary container, device development costs, CMC container testing, customization)  
  • Assembly Costs (such as assembly, labeling/packaging raw materials, labeling / packaging labor, QA/QC, fill finish / drug-related QC, validation and manufacturing scale up for Commercial, potential need for new equipment) 
  • Design History File Development Costs (such as project management, clinical deliverables, commercial deliverables, formative human factors, summative human factors, design verification testing) 
  • “Other” Costs (such as drug cGMP’s, device quality management system (QMS), expert outside support in areas like strategic planning, device selection, vendor management, and regulatory support) 

In conclusion…

The importance of setting the right strategy for drug delivery combination product development cannot be overstated. By aligning goals and processes and considering new factors and personnel unique to drug delivery device integration, companies can maximize the likelihood of success in this dynamic and highly competitive landscape. Embracing a strategic mindset not only enhances product performance but also fosters innovation and efficiency, ultimately driving positive outcomes for patients and stakeholders alike. 

AUTHOR

Jonathan Amaya-Hodges, Director, Technical Services, Suttons Creek, Inc. – 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.