Resubmitting a 510(k) is More Than a Regulatory Decision

Do changes to your device warrant a 510(k) submission? There are several elements to consider when asking this question: design controls compliance, risk analysis and postmarket surveillance data, among them.

From the initialization of the enactment of the Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act, FDA employees have endeavored to define with greater accuracy those times when a change in a medical device would trigger the requirement that a manufacturer submit a new premarket notification (510(k)) to the Agency. To offer greater clarification, FDA recently released draft guidance on this topic.

As it currently stands, the regulatory criteria state that a premarket notification must be submitted when:

  • The device could be one that your company currently has in commercial distribution or is reintroducing into commercial distribution, but which is about to be significantly changed or modified in design, components, method of manufacture or intended use
  • A change or modification in the device could significantly affect the safety or effectiveness of the device, e.g., the design, material, labeling, chemical composition, energy source or manufacturing process
  • A major change is made in the intended use of the device

With the advent of ISO 14971, risk management, the decision-making process for re-design, re-submit, re-anything can now be based upon consistent, documented choices that are commonly not qualitative, but in fact, include quantitative paths toward proper compliance.

Explicit risk-based examples of modifications that may require a 510(k) submission include at least the following, singularly or collectively:

  1. Sterilization method
  2. Structural material
  3. Manufacturing method
  4. Operating parameters or conditions for use
  5. Patient or user safety features
  6. Intended Use
  7. Sterile barrier packaging material
  8. Stability or expiration claims
  9. Design
  10. Postmarket surveillance trends that trigger any of the examples above (In other words, either FDA or the submitting company are involved with postmarket surveillance and discover information that drives the device or intended use into a higher risk category, e.g. complaints, adverse events, failures, misuse, etc.)

Bearing this in mind, let's discuss the priorities you should consider in your submission.

The Role of Good Manufacturing Practice Regulation
Enter formal design controls, 21 CFR, Part 820.30. Any guidance on 510(k)s for changes to a marketed device must consider the role that current Good Manufacturing Process (cGMP) Quality System Regulation plays in changes to device design. For some types of changes, FDA continues to find that a 510(k) is not necessary and that reliance on existing cGMP requirements may continue to reasonably assure the safety and effectiveness of the device for human use.

Your company is not expected to maintain records of all changes proposed during the very early stages of the design process. However, all design changes made after the design review that approves initial design inputs for incorporation into the design, and those changes made to correct design deficiencies once the design has been released to production, must be documented. Many companies don’t play it that close to the line.

The records of these changes create a history of the evolution of the design (the Design History File or DHF), which can be invaluable for failure investigation, resubmission of a 510(k) and for facilitating the design of future similar products. Such records can prevent the repetition of errors and development of unsafe or ineffective designs. The evaluation and documentation should be in direct proportion to the significance of the change and the risks involved. Procedures must ensure that after the design requirements are established and approved, then changes to the design (both pre-production and post-production) are also reviewed, validated (or verified where appropriate) and formally approved. Otherwise, a device may be rendered unable to properly perform, and be deemed unsafe and ineffective, i.e. adulterated.

When a change is made to a specification, method or procedure, your company should evaluate the change in accordance with an established procedure to determine whether the submission of a premarket notification (510(k)) or the submission of a supplement to a Premarket Approval is required. Records of this evaluation and its results should be maintained. The safety and effectiveness of devices cannot be proven by just conducting final inspection or testing.

Medical device development is fundamentally an evolutionary process. While change is a healthy and necessary part of product development, quality can be ensured only if change is controlled and documented in the development process, as well as the production process. Again, manufacturers are not expected to maintain records of changes made during the very early stages of product development; only those design changes made after the approval of the design inputs need be documented.

At the end of the day, your company must establish criteria for evaluating changes
to ensure that the changes are appropriate for the design.

If any one of the changes that is analyzed results in your company’s decision to submit a 510(k), then the 510(k) should incorporate all of the planned changes, as well as a comparison of the changed device to the legally-marketed device. (If a manufacturer has a cleared 510(k), reference to it will aid in the evaluation of the new 510(k).) If your company's consideration of all planned changes results in a conclusion simply to document the decision-making, it should document the application of the model along with the necessary records of the validation of all changes to the device. In addition, you may also compare your device to a competitor's legally-marketed device.

Labeling Changes
Changes in device labeling often present the most difficult questions to be addressed by your company, when deciding whether a new 510(k) submission is required. What appears to be an understated change in device labeling can have a noteworthy impact on the safe and effective use of the device. For example, making a technology or materials change can make re-labelling necessary. Commonly, they work hand-in-hand.

Changes in the Indications for Use section of labeling raise more concerns than any other aspect of labeling.
In fact, most changes in this part of the labeling will require the submission of a 510(k).


Technology, Engineering and Performance Changes
The key here is that all changes must be evaluated or validated according to the current cGMP requirements before the change can be made. The results of this common evaluation/validation are then used to guide the decision-making on submission of a new 510(k).

Almost all changes in the control mechanism for a device raise questions of safety and effectiveness. Therefore, such changes will normally require the submission of a new 510(k). This is also true for changes in operating principle, as well as changes in energy type.

A typical example of a new operating principle would be to control the device by using software in lieu of a mechanical mode of operation. Changing from AC to battery power is usually part of a redesign, to provide a portable device that can be used under different environmental conditions than the original device. Such a change would normally be accompanied by significant labeling changes, including a new or expanded Indication for Use.

Design changes or engineering changes encompass everything from the routine specification changes necessary to maintain or improve device performance as a result of feedback from users, field or plant personnel, etc., up to and including significant product redesign.

The major difficulty lies in sorting out which of the design or engineering changes are significant enough to trigger the need for a 510(k). Using the risk management tools available to the industry in conjunction with FDA go/no-go logic schemes will allow your company to make decisions properly and document them as such.

These are important concepts to help make decisions:

  • Does the change affect the Indications for Use? If the answer is yes, a new 510(k) should be submitted.
  • All changes to device design will require some level of design validation or evaluation to assure that the device continues to perform as intended. The successful application of routine design validation activities will sensibly result in manufacturers documenting their efforts and proceeding with the design change, i.e., assuring that no issues of safety or effectiveness are raised.
  • Generally, changes in device packaging or changes in the expiration date for use of a device do not result in the need for a new 510(k). Such changes are properly within the scope of GMPs.
  • Changes in sterilization have the potential to affect the safety or effectiveness of the device and, thus, must be assessed. Changes that have a lower sterility assurance level would routinely need a new 510(k), as would those that ordinarily affect the integrity of device materials. 

Changes in the method of sterilization have the potential to change performance characteristics of a device. In addition, if the sterility assurance level is lowered, your company must consider whether device safety or effectiveness may have been compromised by the new level.

Material Changes
If your company is making changes to the materials from which your device is manufactured, you should consider these changes, along with labeling changes, first. 

If the device is an implant, changes in materials that contact body tissues or fluids may critically affect the device's safety or effectiveness. Your company should submit a new 510(k) for a change in implant material where the material contacts tissue (including bone tissue) or body fluid. 

Frequently, a change in material is made to purposefully alter the performance specifications of a device. Under GMPs, your company is responsible for assessing whether a change in material affects the device's ability to meet specifications.

Sometimes changes in materials can inadvertently affect the total performance of a device. If performance specifications are inadvertently affected by a materials change, a new 510(k) will likely be necessary. Under GMPs, your company is responsible for assessing this possibility. If performance specifications are inadvertently changed, it is possible that a new 510(k) is necessary. 

In Conclusion
Well-founded changes are inevitable for a product to remain marketable and, more importantly, to ensure that your company’s devices are safe and effective for human use. It’s the nature of the business and the foundation that our industry is built upon.

Making changes to a medical device is not just about continued cGMP compliance, and conversely, not just about making regulatory decisions based upon equivalence and safety and effectiveness. Before design controls, it seemed like the final decision for resubmitting a 510(k) fell to the regulatory department. On the contrary, today, decisions for resubmitting originate in places closely associated with cGMP design controls compliance, risk analysis and postmarketing surveillance data review concerned with noteworthy trends.

John Gagliardi has had success over the past 46 years in the medical device and pharmaceutical industries because of his hands-on approach to process-orientation and business perception. He has been actively involved in research and development, quality assurance, training, operations, process architecture, FDA inspections and regulatory affairs. Mr. Gagliardi specializes in building systems in a compliant and business-ready manner. Mr. Gagliardi can be reached by This email address is being protected from spambots. You need JavaScript enabled to view it..

MidWest Process Innovation, LLC