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.

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