Intertech Engineering Associates, Inc.

Pharma Companies Challenges with Combination Devices and Planning for Variation Part 3 of 3

Part 3 of 3: The Sources of Variation in a Combination Device Timeline and Dealing with Software

Combinational products require a teamwork from personnel that requires specialized skills to ensure a fully integrated solution that meets the user needs. Some particular high-level characteristics that are important to design variation to consider when planning and scheduling are listed in the table below:


Drug/Biologic Component Characteristics

  • pharmokinetics
  • container (materials science)
  • pharmodynamics
  • drug stability
  • process controls (particularly for biologics)
  • formulation
  • Clinical data (animal/human)

Disposable Component Characteristics

  • container closure system (CCS)
  • sterility/sterilization
  • manufacturability
  • material variability
  • disposal
  • material compatibility
  • interface
    • drug/reusable
    • user/reusable
  • usability


Reusable Component Characteristics

  • durability
  • reliability
    • for life of product
    • durability of reuse
  • industrial design
  • storage between use
  • software safety systems
  • power and charge
  • electrical safety
  • performance impact of drug  delivery
  • usability
    • human interface
    • disposable interface
  • service
  • EMC
  • Manufacturability of reusable
  • component selection (specifications)

Managing Variation When Software is Part of the Medical device:

As mentioned earlier, the design process can be iterative where inputs/goals into the design process are updated as the actual characteristics of integrated systems are tested and characterized/ measured and compensations are made to optimize.  Iterative development of software can be produced using methodologies such as agile or using scrum methodology or tools, but iterative approach need not be limited to software alone. For example prototype parts and assemblies are developed for technology proofing and feasibility; as these parts change or are molded parts they will have the impact on the overall system. These impacts can be driven by changes to material properties as well as dimensional properties. Testing evaluations are often necessary, even after mathematical analysis to characterize new and changing sources of variation and recognition of the impact of interactions with other parts of the system and the overall impact on drug and biologic delivery.


In a medical device that can be controlled by software, there is an opportunity to mitigate the impact of variability due to the hardware, by software means. The operation of the device can be designed to compensate for detected or known variability, by such means as using feedback control. Adding software control loops in a device design is an example of how additional complexity is added. Complex design requires managing a highly dynamic set of conditions. The determination of if software requirements are met or identifying the shortcomings in executable software are understood when frequent testing integrations are planned for. Testing can be used to confirm development progress as well as providing data to evaluate progress in managing variation in device performance characteristics.


In order to optimize product performance, the key device performance characteristics can be defined early enough for teams to know what problems to solve and what performance to optimize during the product development process. Applying a data-driven process cycle described above, or using quality process approaches such as DMAIC (Define, Measure, Analyze, Improve and Control) support frequent measurement of performance and lay the groundwork to optimize the product design.


Software itself is not a victim to variability; software is repeatable it will perform the instructions the same way each time, but as a part of a system, the software can be a variation solution but also if poorly designed, a significant source of error impacting the ability to meet key system objectives. But that is not to say that software does not contribute to the variability in device performance, it surely does. Errors or omissions in the software design, including algorithm design, and implementation of software code itself does impact the device performance once integrated with the hardware. Testing software upon development iterations helps the developer more easily spot these flaws during development.


Software is used to implement algorithms to manage sensors and handle data which can impact the output performance. Software frequently is used to implement control and or manage variability, either by logic to identify variability and to compensate for identified variability or by indicating to the user to react to unexpected operation occurring. Adding control loops and feedback to product software means that software failure can have unintended impacts on operation and variability. Here are some examples of failures that can impact a combination device:

  • Algorithm Design Failure: algorithms can fail to identify or incorrectly compensate for variability. If the characteristics of the signals being monitored are not correctly recognized the intended system compensations will not be applied when desired.
  • Algorithm interaction: algorithms can have indirect impacts to drug delivery, such as delivery profile does not maximize the particular half-life of the drug and desired length of time and effect the drug should persist in an individual is not optimized.
  • Software Functional Failure: errors in software design and implementation can lead to system failures when the correct combination of events occurs. These are systematic and not random in nature but can be hard to identify and can be long time latent bugs in the software that can lead to system failure at the worst times.


Adherence to a software development process, which allows frequent build-test-optimize, allows teams to integrate software into the device and evaluate the operation and detect failures.



Planning of the lifecycle of a combination product project should be done such that the development of the drug and each of the device components development can be aligned with integration points in mind. There are periods where parts of the device need to be developed to a certain degree, to support the combination product.  Not planning these points may cost additional time to an already long development phase of the product lifecycle.


There are other processes that a pharmaceutical company may not have in place, that need some planning and prep time. Some of these processes may be centered on quality systems necessary for manufacture and during the maintenance phase of the lifecycle, such as device change controls, complaint reporting, unique device identifiers, and service of durables.  But there are important processes that need planning and implementation time that is part of the development phase, and three important ones include considerations for usability and usability studies, adoption of a preproduction configuration management process, and a design control process for medical devices, and if necessary software development which can be complicated.


Pharmaceutical companies who pursue a combination device eventually recognize that variability in the manufacture and design of a reusable and disposable medical device become an additional burden that can stretch out launch times, once major drug milestones and completed. A device development process that is done under controls and is focused on the evolution of a device concept that is clearly defined, designed, documented, tested and optimized is one more likely to succeed. The companies that can target design team activities and project milestones that adopt principles such as DMAIC (Define, Measure, Analyze, Improve and Control) or DMAIC like approaches for measuring performance and proofing design and manufacturing solutions see better development success.

Pharma Companies Challenges with Combination Devices and Planning for Variation Part 2 of 3

As discussed in the first part of this article series there are three important device development activities that are frequently overlooked or underestimated by drug manufacturers in a combination device project. From a project planning perspective, these activities should drive key project milestones, during a combination product development phase of the product lifecycle. This part of the article series covers these keys in more detail.



Key Activity 1: Manufacture of the devices for the development lifecycle:

An important integration point between the drug development timeline and device development timeline to consider is the device build milestones that are needed for each clinical trial. Multiple device builds will be intended for the assessment of safety, effectiveness and include device performance. The Phase 1 clinical requires attention to safety, but later clinical objectives require the device manufacturer to assure the devices used meet important effectiveness criteria to provide assurance in the conclusions of the clinical studies. Devices used in phase 2 and 3 clinical trials require building devices with a known configuration and a configuration management process to be in place.


A pragmatic device design process includes iterations or phases of controlled design, the evaluation and optimization of the design based on specific controlled inputs (or requirements) as well optimization of outputs to address performance as the development commences. The outputs of the design during iterations or phases should be managed and have defined configurations. If the configuration is unmanaged or unknown the design progresses and changes, and perceived improvements and optimization is not controlled or managed. Device development without configuration management would be considered an uncontrolled development. Making changes to a device in this type of an uncontrolled development is no better than ‘trial and error’ development. Confidence in the design and in the future performance of the device is more difficult to assess without some design controls. Device developers find that changes to the design based on results from an uncontrolled system result in incorrect conclusions which lead to development delays due to erroneous data or conclusions.


A configuration management process starts with identifying the items that are to be maintained under configuration control.  Configuration management includes the tracking, control, baselining, storage and providing for the controlled change of defined items.  Typical items that will require configuration management are: records/documents (i.e. requirements, design descriptions or specifications), material composition, software versions/builds, hardware versions, sub-systems, assemblies, and components, manufacturing test systems, calibration methods, as well as test units and units under test themselves.  A procedure or plan should identify how a particular configuration item is to be managed. Within a project configuration, items will be developed and updated.  These configuration items are defined by documents that are to be controlled. It should be determined which documents and items are to be controlled and when, as well as the process to keep items and documents in sync and a process for how changes are made.  Typically an effort to sync configuration documentation should be made part of each iteration or phase planned for.


Key Activity 2: The planning for usability:

Another important integration point between the drug timeline and device timeline to consider is device usability. The FDA frequently states that manufacturers don’t adequately consider use errors, and this leads to clearance issues with the FDA.  The FDA is particularly concerned with medical device developers addressing human factors in their design and testing their design in usability studies to address use errors. Planning the usability studies on the timeline is important to the overall planning of a combination device.

Formative usability testing can be aligned with the timing for some the phase 1 and phase 2 clinical studies done with potential patients and users. Formative testing is used to drive the determination of the design as well as help to capture requirements for the user interface, etc.. Test and evaluations with users and potential patients should be focused around device tasks were anticipated safety is involved and areas where the interaction with the user may be particularly complicated. The evaluation or testing really allows the developer to explore and understand the design options to better suit use conditions and better meet user and or potential patient needs. Drug and biologic design lifecycle is longer, but not planning for formative usability of the device will result in delays much closer to the end of the drug development.


Usability analysis does not just focus on device failure hazards; it also includes identifying and applying measures to eliminate or reduce use-related hazards. These hazards might result from aspects of the user interface design that cause the user to fail to adequately or correctly perceive, read, interpret, understand or act on information from the device.

Screens used for the human interface can be presented and prototyped, in a rapid fashion using high language tools and graphics development kits. When necessary a graphical user interface (GUI) can be generated and quickly evaluated before device function is needed in the development lifecycle for the device. These rapidly developed screens can then be integrated into the device design at a later step of the development process.

The final usability study/test is referred to as the summative usability study. Summative testing are tests with users to validate the final configuration meets the user need and provide for safe and effective use.

Key Activity 3: The coordination and application of design controls to address sources of variability:

Another important set of key activities is applying device development controls and practices to address product variability and performance. The FDA regulatory design controls are defined per the regulation part 21 CFR 820.30. When the device is defined, designed, built, analyzed for risks, verified and validated can all be plotted along the device development timeline. The device design part of the lifecycle can take many different forms, such as more of a serial set of phases or more iterative set of design builds and these can be represented in the project timeline as corresponding milestones as a device design is developed.

Much of the challenge of scheduling of the design of the device is the uncertainty associated with proofing design output solutions, identifying tasks to target project risks, factoring time to solve problems and driving out variability. Optimizing the design comes down to determining the best technical solutions to meet the needs of the users and the requirements. A good design control process provides managers and designers with clear visibility of the design process and the objectives targeting a short cadence of accomplishments. Having a short manageable time frame of tasks and good visibility of the goals for that time frame allows the team to react and effectively manage the design process. Within a timeframe, a team can specify the need/activities to be addressed, identify the problems to solve and the associated project risks than in the timeframe formulate solutions or make corrections to the current design and then evaluate or verify the intended objectives are met and characterize the performance of the solutions.


The project manager for a combinational device should look over the horizon and plan activities and milestones in a schedule to target the effort in a controlled process. To address the most significant risks in a device a controlled process should be put in place to target the sources of variability.

One approach to targeting sources a variability in the combination product

Based on experience the development lifecycle the management of project milestones and its integration points help to ensure the development team stays on target. As the project progresses and objective driven milestones are reached, project risks associated with milestones are being reduced. Similarly, setting device performance milestones can also positively impact variability in the design outputs. What is difficult is planning for what is unknown as the design evolves and iterations are measured.

In a nimble development model applying iterative cadence to define the goals, measure the outputs, analyze the resulting data, and optimize the design has the best results. Successfully driving this controlled cadence is effectively achieving a design control. One approach to driving this cadence in the development lifecycle should be the adoption of scheduling a set of milestones to address the variables that contribute to uncertainty and variability in the important product characteristics and primary mode of action.

At these milestones the evolution of the device/system should include meeting the functionality goals, characterizing and measuring operational outputs as well as optimizing them to meet the performance needed or expected by the end users. The project schedule can be developed indicating the milestones across the list of tasks used for resource management as in the case of the simplified figure below.



(milestones schedule figure)


The simplified Gantt presents a project schedule that is driven by achieving target milestones. These milestones are not going to be the same for each project. They should be determined by considering the overall timeline, the major phases of the drug and device clearance process, and identifying key activities and setting goals and quantifiable objectives to resolve these. Frequently key milestones come from a project risk evaluation that is part of the initial planning process and is consistently evolved through the project, much like the schedule is.

The next section of this article series will dive deeper into sources of variation and how software in a medical device is part of the variation challenge and solution. We would be interested in your own experiences with milestone planning and on tackling key activities in a combination medical project. Please add your comments or questions to keep a dialog going.