Why Early Device Integration Is Essential in Combination Product Development

Developing a combination product is more complex than simply connecting a medicine to a delivery device. It requires careful coordination between pharmaceutical, medical device, quality, regulatory, manufacturing, and clinical teams.

For example, a drug may be delivered through a prefilled syringe, autoinjector, inhaler, wearable injector, or another medical device. Although the drug remains an important part of the product, the delivery system must also meet strict safety, performance, quality, and regulatory requirements.

One of the most common problems in combination product programs is introducing the device too late. When device planning begins only after the drug has shown promising clinical results, development teams may face rushed timelines, incomplete design controls, testing delays, and expensive product changes.

Successful Combination Product Development requires the device strategy to be integrated into the broader development program as early as possible.

Why Device Integration Should Begin Early

Some organizations treat the device as a secondary component that can be selected later in the drug development process. However, the device is not simply packaging or an accessory. It is a regulated part of the final product that directly affects how the patient receives the treatment.

Early device integration allows teams to evaluate important questions such as:

• Can the device accurately deliver the required dose?
• Is the drug compatible with the device materials?
• Can the intended patient use the device safely?
• Will the device work properly in the expected use environment?
• Can the product be manufactured and packaged at scale?
• Are the quality systems ready to support design controls?
• Will the clinical version match the planned commercial product?

Addressing these questions early gives development teams more time to solve technical or regulatory issues before they affect clinical trials or product submissions.

When Should the Device Team Join the Program?

The device team should become involved once the route of administration and the target product profile are reasonably defined. This usually happens during late Phase 1 or early Phase 2 of drug development.

Device planning should also begin well before an Investigational New Drug, or IND, submission and before the planned clinical trial start.

Organizations may need approximately 14 to 18 months to complete important early activities, including:

1. Evaluating available device platforms
2. Assessing drug and device compatibility
3. Selecting the primary container
4. Reviewing supplier capabilities
5. Updating the quality management system
6. Establishing design controls
7. Planning human factors activities
8. Preparing testing and verification strategies
9. Assessing compliance with applicable combination product regulations

Without enough preparation time, several important workstreams may need to be completed at the same time. This increases pressure on the team and raises the risk of errors, missed requirements, or delayed clinical activities.

The Three Main Stages of Device Development

Although every program is different, device development can generally be divided into three major stages.

1. Feasibility and Early Planning

The feasibility stage helps determine whether a proposed device can safely and effectively deliver the drug.

Key activities may include:

• Comparing different device platforms
• Reviewing primary container options
• Evaluating dose volume and delivery time
• Assessing drug viscosity and stability
• Conducting early usability studies
• Identifying technical risks
• Reviewing intellectual property concerns
• Evaluating suppliers and manufacturing capacity
• Establishing the quality framework for design controls

The goal is to identify major risks before the organization commits to a specific delivery system.

2. Clinical Device Development

After the platform has been selected, the program moves into formal development under design controls.

This stage may include:

• Defining user needs
• Creating design inputs and product requirements
• Conducting risk management activities
• Developing prototypes
• Performing formative human factors studies
• Establishing test methods
• Preparing verification protocols
• Documenting design reviews
• Producing devices for clinical use

Clinical devices should be as close as reasonably possible to the intended commercial product. Major differences between the clinical and commercial configurations may require additional testing or bridging studies.

3. Commercialization and Validation

The final stage prepares the product for commercial manufacturing and launch.

Activities may include:

• Completing design verification
• Conducting human factors validation
• Finalizing packaging and labeling
• Transferring the design to manufacturing
• Validating assembly and manufacturing processes
• Qualifying suppliers
• Preparing commercial production controls
• Confirming product stability
• Ensuring post-market systems are ready

The organization must show that the final product can be produced consistently and performs as intended.

Major Risks of Bringing the Device In Too Late

Late device integration can create problems that affect the entire development program.

Clinical and Commercial Products May Not Match

A company may use one device during clinical trials and select a different device for commercial launch. If the products are too different, regulators may request additional testing or clinical bridging data.

This can increase costs and delay the submission.

Human Factors Activities May Be Delayed

Human factors engineering evaluates how patients, caregivers, and healthcare professionals interact with the product.

If usability work begins too late, the team may discover that users:

• Misunderstand the instructions
• Hold the device incorrectly
• Struggle to activate the product
• Fail to deliver the complete dose
• Cannot clearly confirm that the dose was delivered

These problems may require design changes, new studies, and revised instructions for use.

Compatibility Problems May Appear Late

The drug formulation must work properly with the selected device.

Possible compatibility issues include:

• Injection force that is too high
• Delivery time that is too long
• Inaccurate dose delivery
• Container breakage
• Device blockage
• Material interaction with the drug
• Reduced drug stability
• Leakage during storage or use

Discovering these issues during late-stage development can lead to significant redesign and retesting.

Quality Systems May Not Be Ready

Pharmaceutical quality systems may not fully address medical device design controls, human factors requirements, device risk management, or other combination product responsibilities.

Waiting until late development to close these gaps may create incomplete documentation, unclear responsibilities, and submission readiness concerns.

Why Design Verification Often Causes Delays

Design verification confirms that the device meets its approved design requirements. It is not simply a final test performed at the end of development.

Verification depends on several activities being completed correctly beforehand, including:

• Clear product requirements
• Measurable acceptance criteria
• Approved test methods
• Representative samples
• Qualified equipment
• Defined environmental conditions
• Complete protocols
• Proper statistical methods

If the product requirements are unclear, the team may not know exactly what to test. If the test methods are unreliable, the results may not demonstrate that the device meets its requirements.

Test Method Validation Is Frequently Underestimated

A test method must consistently produce accurate and reliable results. Even when a company uses an established device platform, a method may need to be updated or validated for the specific product configuration.

Problems with test methods can add months of work, especially when the team must:

1. Investigate unexpected results
2. Modify the method
3. Repeat method development
4. Validate the revised method
5. Retest product samples

Planning verification and test method validation early can reduce these delays.

Four Factors to Consider When Selecting a Delivery System

Choosing a delivery device requires more than comparing cost, appearance, or supplier claims. The decision should include input from several functions.

1. Design Control and Regulatory Requirements

The delivery system must be developed and documented according to applicable design control requirements.

Teams should understand:

• Which organization owns each design activity
• What documentation is needed
• How supplier records will be reviewed
• Which standards apply
• How changes will be controlled
• What information must be included in the regulatory submission

A device platform may already have supporting information, but the final combination product must still be assessed for its intended use.

2. Human Factors Strategy

The organization must clearly define:

• Who will use the product
• Where the product will be used
• What training users will receive
• Which steps are critical to safe use
• What mistakes users could make
• Whether those mistakes could cause harm

Early formative studies can help identify usability problems while changes are still manageable.

3. Technical Compatibility

The selected device must be compatible with the drug’s physical and chemical characteristics.

Important factors may include:

• Dose volume
• Drug viscosity
• Required injection speed
• Container closure system
• Needle size
• Delivery accuracy
• Product shelf life
• Storage temperature
• Sensitivity to light or movement

A platform that works for one formulation may not automatically work for another.

4. Manufacturing and Supply Readiness

The organization must also determine whether the device can be produced, assembled, packaged, and supplied at the required volume.

Questions to consider include:

• Are the device components available?
• What are the supplier lead times?
• Is specialized assembly equipment required?
• Can the supplier support clinical and commercial demand?
• Have packaging and shipping requirements been evaluated?
• Are backup suppliers available?
• Who is responsible for incoming inspection and release?

Supplier limitations can quickly become critical program risks if they are discovered too late.

Common Combination Product Development Mistakes

Several mistakes appear repeatedly across combination product programs.

Treating a Platform Device as Plug-and-Play

Established device platforms may reduce development risk, but they do not remove it.

Changes in any of the following areas may create new requirements:

• Drug formulation
• Dose volume
• Patient population
• Use environment
• Storage conditions
• Container materials
• Delivery time
• User interface
• Instructions or labeling

The final product must be evaluated based on its actual intended use.

Delaying Design Controls

Design controls should guide development from the beginning. Trying to recreate design documentation after major decisions have already been made can result in missing records and weak traceability.

Skipping Early Human Factors Work

Waiting until validation to evaluate usability is risky. Validation is intended to confirm that the final user interface can be used safely, not to serve as the first opportunity to identify major design problems.

Underestimating Development Timelines

Device development includes technical studies, supplier work, documentation, risk management, human factors, verification, validation, and manufacturing preparation.

These activities often take longer than expected.

Allowing Teams to Work in Silos

Drug, device, quality, clinical, regulatory, and manufacturing teams may use different processes and terminology. Without regular communication, teams may make decisions that conflict with one another.

How Organizational Silos Affect Development

Pharmaceutical and device teams often follow different schedules and development methods.

Drug teams may focus on:

• Clinical evidence
• Formulation development
• Dose selection
• Drug stability
• Clinical trial timelines

Device teams may focus on:

• User needs
• Design requirements
• Risk management
• Verification
• Human factors
• Manufacturing controls

Both areas are necessary, but problems arise when teams work separately.

For example, the clinical team may change the dose volume without recognizing that the new volume exceeds the device’s validated operating range. Similarly, the device team may propose a design change without understanding how it could affect drug stability or the clinical protocol.

Regular cross-functional meetings, shared timelines, and clearly assigned responsibilities can reduce these risks.

The Value of Cross-Functional Training

Cross-functional training helps teams understand how their decisions affect the complete product.

Pharmaceutical teams benefit from learning about:

• Design controls
• Device risk management
• Verification and validation
• Human factors engineering
• Device supplier management

Device teams benefit from learning about:

• Drug development stages
• Clinical trial requirements
• Formulation constraints
• Regulatory submission strategy
• Drug stability expectations

A shared understanding improves communication, supports faster decisions, and helps teams identify risks earlier.

Platform Devices Versus Bespoke Devices

Organizations must decide whether to use an existing device platform or develop a custom solution.

Advantages of a Platform Device

Platform devices may provide:

• Existing design history
• Established manufacturing processes
• Available usability information
• Lower technical risk
• Shorter development timelines
• More predictable costs

However, the platform must still be assessed for the specific drug, users, dose, and use environment.

When a Bespoke Device May Be Appropriate

A custom device may be considered when:

• The drug has unusual technical requirements
• No existing platform can deliver the required dose
• The target users have special usability needs
• A unique user experience is important
• The device provides a competitive advantage
• Product differentiation is a major business goal

Custom devices can offer greater flexibility, but they usually require more time, funding, testing, and regulatory planning.

The more novel the device, the greater the technical and regulatory uncertainty.

Practical Steps for Better Device Integration

Organizations can reduce development risk by following several practical steps:

1. Engage device specialists early.
   Include device expertise when the route of administration and target product profile are being developed.
2. Create an integrated development plan.
   Connect drug, device, clinical, quality, regulatory, and manufacturing milestones.
3. Evaluate platform limitations.
   Do not assume an existing platform will work outside its established conditions.
4. Establish design controls early.
   Document user needs, requirements, risks, decisions, testing, and design changes as development progresses.
5. Start human factors planning before clinical use.
   Identify users, environments, critical tasks, and possible use errors.
6. Plan test method development early.
   Ensure methods are reliable before formal verification begins.
7. Review quality system readiness.
   Identify gaps in design controls, supplier management, complaint handling, and post-market processes.
8. Assign clear responsibilities.
   Define who owns device decisions, documentation, supplier oversight, and regulatory deliverables.

Building a More Reliable Development Program

Early device integration gives organizations the time needed to make informed decisions, identify risks, and prepare strong technical and regulatory documentation.

The most successful programs do not treat the delivery device as a late addition. They manage the device as a fully integrated and regulated part of the final product.

By involving device teams early, aligning cross-functional stakeholders, establishing design controls, and planning verification and human factors activities in advance, organizations can reduce costly redesigns and improve clinical and commercial readiness.

Frequently Asked Questions

1. What is a combination product?

A combination product includes two or more regulated product types, such as a drug and a medical device. Examples include prefilled syringes, autoinjectors, drug-delivery inhalers, and wearable injectors.

2. When should device planning begin?

Device planning should usually begin once the route of administration and target product profile are defined. This often occurs during late Phase 1 or early Phase 2 and should happen well before the planned clinical trial or regulatory submission.

3. Can an existing device platform shorten development time?

Yes. An established platform may reduce technical and manufacturing risk. However, it must still be evaluated for the specific drug formulation, dose, users, storage conditions, and intended use.

4. Why are human factors studies important?

Human factors studies evaluate whether intended users can operate the product safely and correctly. They can identify confusing instructions, difficult handling steps, and possible use errors before the product reaches the market.

5. What happens when the clinical and commercial devices are different?

Major differences may require additional testing or bridging studies to show that the commercial product remains safe and effective. This can add cost and delay regulatory approval.

6. What is one of the biggest causes of device development delays?

Poor planning for design verification and test method validation is a frequent cause of delays. Verification cannot proceed efficiently unless product requirements, acceptance criteria, and reliable test methods are already established.