Medical Device Development Design Validation and Preclinical Part 2

Medical Device Development: Design Validation and Preclinical, Part 2

In Packaging & Stability, Preclinical, Regulatory, Toxicology by Jennifer Shafer, Mike Hendershot and Tina Hubbell

Packaging and sterilization. Aside from the safety and efficacy of the device itself, the packaging and final processing must also be considered. The packaging material selection should be based on a few key areas: product integrity, sterilization method, and product functionality. The objective is to design a packaging system that will allow ease of access by the user while also protecting the product from internal or external breaches in sterility.

Robust materials to contain the product under all shipping and temperature conditions are imperative. Product integrity is important because a compromised product may have unintended functionality and safety effects. The packaging and sterilization processes may even render it unusable. For example, a product that has absorptive properties may not be able to be sterilized by ethylene oxide due to the high moisture content of the sterilization process; therefore, gamma radiation with a sealed pouch design would be a better choice.

It is important to consider packaging materials and sterilization methods early in the design process. The product packaging (e.g., breathable for gaseous sterilants like ethylene oxide) must be identified prior to any validation. Validation, as described in the next stage, can take a considerable amount of time. Choosing the appropriate packaging and sterilization method in the initial conceptual design phase will help manufacturers avoid choosing materials for the device itself that are incompatible with the packaging and sterilization.

Sterilization validation. Manufacturers of devices that will be sold sterile, used sterile, or cleaned between uses, must also choose and validate a sterilization method. Just as the materials chosen to build a product can affect its safety and efficacy, so can sterilization. Whether the manufacturer performs the sterilization or provides instructions to the end-user, the chosen method must be demonstrated to be safe and effective.

There are many sterilization methods to choose from. Some of the most common are:

  • Ethylene oxide (EO or EtO)
  • Steam
  • Dry heat
  • Irradiation (gamma, x-ray, or e-beam)

Different methods of sterilization can affect materials differently. For example, EO residuals can be toxic. Gamma sterilization can increase crosslinking in polymers, with varying effects. (In fact, irradiation in general is sometimes used specifically to modify the physical properties of polymers, such as tensile strength.) High temperatures, as are used in steam and dry heat, may soften or oxidize materials. Biodegradable polymers (such as PGA and PLA) require particular care in choosing a sterilization method: they’re often susceptible to heat, moisture, and radiation; and sterilization increases their degradation rates.

A manufacturer’s choice of materials should depend partly on the sterilization method. Some materials and some intended uses are more suited for certain methods of sterilization. AMI TIR17:2008: Compatibility of materials subject to sterilization provides information on the compatibility of various materials with different sterilization methods. It also describes the effects of manufacturing processing, particularly in conjunction with sterilization, as an important tradeoff to consider during design. Finally, it includes recommendations on testing for biocompatibility and functionality to validate the chosen materials and methods. As stated in section 5.1, “Material qualification tests should challenge the effect of sterilization on the functional requirements of the product and also challenge the dominant or critical failure modes or both.”

The FDA’s Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling (2015) also includes recommendations for validation (as well as describing the three basic steps of reprocessing and six criteria for reprocessing instructions). It states that validation activities

“should include the worst-case (least rigorous) implementation of the cleaning process, medical devices that represent the worst-case (most challenging to reprocess and most contaminated), and at least two quantitative test methods that are related to the clinically relevant soil. The cleaning process validation protocols should specify predetermined cleaning test endpoints. These protocols should be designed to establish that the most inaccessible locations on your devices can be adequately cleaned during routine processing.”

This testing is not limited until after the product design is set. For example, exposure of candidate materials to the maximum anticipated production dose and evaluation in a few quick, inexpensive tests will reveal any issues that might need to be resolved before the final product is ready for market.

Planning ahead for the submission. In addition to all the interlocking parts required in a regulatory submission, attention should be given to the submission itself. Having an overall plan of attack mapped out can help avoid unexpected expenses and delays. The plan should include:

  • Where to submit. Emerging markets, such as Korea or Brazil, may have fewer requirements and scrutiny. Established markets such as the EU and USA may have more rigorous requirements, but the market base is large and wealthy.
  • When to submit to each market. Starting by meeting the requirements for Europe may help meet prerequisites for a later first-in-humans trial in South America, for example, while meeting the requirements for Japan first may leave gaps for US submission.
  • Timelines for all activities. Written evaluations of existing materials can take weeks to months to complete. Preclinical and biocompatibility studies may take several weeks at a minimum and can go up to a year or more, depending on the specific requirements for a specific device. Sterilization validation can take months. Many of these activities can be performed in parallel, but some cannot.
  • Compilation of all documentation and data, including, as applicable:
    • A written overall assessment, as described in ISO 10993-1 and 14971, for biological hazards
    • Chemical characterization
    • Biocompatibility
    • Preclinical study reports (GLP).
      • Non-GLP study reports may also be submitted as supplemental data
    • Sterilization validation
    • Any necessary mechanical or electrical compliance
    • Clinical data
    • Quality system compliance

With proper attention and planning, the many aspects of the preclinical design validation stage of medical device development will come together to provide a solid basis for the next phase.

Be sure to look out for the next post in this series, Medical Device Development: Clinical Studies, Part 1.

You can view Medical Device Development: Design Validation and Preclinical, Part 1 here.

Additional contributions from Ed Arscott, Staci DeMoss and Mike Bravo.


Jennifer Shafer is a technical adviser with NAMSA, focusing on biocompatibility regulations and requirements across the globe. She holds a master’s degree in neuroscience from Johns Hopkins University and previously worked at a firm studying expertise and decision-making. She has written for an online neurofinance site, business journals, and a site that monitors medical device manufacturing developments.

Mike Hendershot

Mike Hendershot is a senior project development adviser for in vivo and in vitro biocompatibility testing at NAMSA. He has been with the organization for 16 years, including 9 years at his current post. Mike is a member of AAMI, SOT and ACT. His areas of expertise are in test selection and sample preparation.

Tina Hubbell is a Technical Advisor with NAMSA, focusing on Analytical and Chemical testing. She holds a bachelor’s degree in chemistry from the University of Toledo. Before coming to NAMSA about 5 years ago, she worked in an analytical laboratory specializing in chemical separations for volatile organic compounds and ultra-trace mercury measurements. She is an active member of the local American Chemical Society chapter and has held Executive committee positions including a two year appointment as Chair.